Evolution in heterogeneous populations: from migration models to fixation probabilities.

Although dispersal is recognized as a key issue in several fields of population biology (such as behavioral ecology, population genetics, metapopulation dynamics or evolutionary modeling), these disciplines focus on different aspects of the concept and often make different implicit assumptions regarding migration models. Using simulations, we investigate how such assumptions translate into effective gene flow and fixation probability of selected alleles. Assumptions regarding migration type (e.g. source-sink, resident pre-emption, or balanced dispersal) and patterns (e.g. stepping-stone versus island dispersal) have large impacts when demes differ in sizes or selective pressures. The effects of fragmentation, as well as the spatial localization of newly arising mutations, also strongly depend on migration type and patterns. Migration rate also matters: depending on the migration type, fixation probabilities at an intermediate migration rate may lie outside the range defined by the low- and high-migration limits when demes differ in sizes. Given the extreme sensitivity of fixation probability to characteristics of dispersal, we underline the importance of making explicit (and documenting empirically) the crucial ecological/ behavioral assumptions underlying migration models.

Obesity-related phenotypes are associated to parental longevity in a Swiss population-based study

PURPOSE. Longevity has been attributed to decreased cardiovascular mortality. Subjects with long-lived parents may represent a valuable group to study cardiovascular risk factors (CVRF) associated with longevity, possibly leading to new ways of preventing cardiovascular disease. Purpose: Longevity has been attributed to decreased cardiovascular mortality. Subjects with long-lived parents may represent a valuable group to study cardiovascular risk factors (CVRF) associated with longevity, possibly leading to new ways of preventing cardiovascular disease. Methods: We analyzed data from a population-based sample of 2561 participants (1163 men and 1398 women) aged 55--75 years from the city of Lausanne, Switzerland (CoLaus study). Participants were stratified by the number of parents (0, 1, 2) who survived to 85 years or more. Trend across these strata was assessed using a non-parametric kmean test. The associations of parental age (independent covariate used as a proxy for longevity) with fasting blood glucose, blood pressures, blood lipids, body mass index (BMI), weight, height or liver enzymes (continuous dependent variables) were analyzed using multiple linear regressions. Models were adjusted for age, sex, alcohol consumption, smoking and educational level, and BMI for liver enzymes. Results: For subjects with 0 (N=1298), 1 (N=991) and 2 (N=272) long-lived parents, median BMI (interquartile range) was 25.4 (6.5), 24.9 (6.1) and 23.7 (4.8) kg/m2 in women (P<0.001), and 27.3 (4.8), 27.0 (4.5) and 25.9 (4.9) kg/m2 in men (P=0.04), respectively; median weight was 66.5 (16.1), 65.0 (16.4) and 63.4 (13.7) kg in women (P=0.003), and 81.5 (17.0), 81.4 (16.4) and 80.3 (17.1) kg in men (P=0.36). Median height was 161 (8), 162 (9) and 163 (8) cm in women (P=0.005), and 173 (9), 174 (9) and 174 (11) cm in men (P=0.09). The corresponding medians for AST (Aspartate Aminotransferase) were 31 (13), 29 (11) and 28 (10) U/L (P=0.002), and 28 (17), 27 (14) and 26 (19) U/L for ALT (Alanin Aminotransferase, P=0.053) in men. In multivariable analyses, greater parental longevity was associated with lower BMI, lower weight and taller stature in women (P<0.01) and lower AST in men (P=0.011). No significant associations were observed for the other variables analyzed. Sensitivity analyses restricted to subjects whose parents were dead (N=1844) led to similar results, with even stronger associations of parental longevity with liver enzymes in men. Conclusion: In women, increased parental longevity was associated with smaller BMI, attributable to lower weight and taller stature. In men, the association of increased parental longevity with lower liver enzymes, independently of BMI, suggests that parental longevity may be associated with decreased nonalcoholic fatty liver disease.

Parametric imaging for characterizing focal liver lesions in contrast-enhanced ultrasound.

The differentiation between benign and malignant focal liver lesions plays an important role in diagnosis of liver disease and therapeutic planning of local or general disease. This differentiation, based on characterization, relies on the observation of the dynamic vascular patterns (DVP) of lesions with respect to adjacent parenchyma, and may be assessed during contrast-enhanced ultrasound imaging after a bolus injection. For instance, hemangiomas (i.e., benign lesions) exhibit hyper-enhanced signatures over time, whereas metastases (i.e., malignant lesions) frequently present hyperenhanced foci during the arterial phase and always become hypo-enhanced afterwards. The objective of this work was to develop a new parametric imaging technique, aimed at mapping the DVP signatures into a single image called a DVP parametric image, conceived as a diagnostic aid tool for characterizing lesion types. The methodology consisted in processing a time sequence of images (DICOM video data) using four consecutive steps: (1) pre-processing combining image motion correction and linearization to derive an echo-power signal, in each pixel, proportional to local contrast agent concentration over time; (2) signal modeling, by means of a curve-fitting optimization, to compute a difference signal in each pixel, as the subtraction of adjacent parenchyma kinetic from the echopower signal; (3) classification of difference signals; and (4) parametric image rendering to represent classified pixels as a support for diagnosis. DVP parametric imaging was the object of a clinical assessment on a total of 146 lesions, imaged using different medical ultrasound systems. The resulting sensitivity and specificity were 97% and 91%, respectively, which compare favorably with scores of 81 to 95% and 80 to 95% reported in medical literature for sensitivity and specificity, respectively.

Predicting species distribution: offering more than simple habitat models

n the last two decades, interest in species distribution models (SDMs) of plants and animals has grown dramatically. Recent advances in SDMs allow us to potentially forecast anthropogenic effects on patterns of biodiversity at different spatial scales. However, some limitations still preclude the use of SDMs in many theoretical and practical applications. Here, we provide an overview of recent advances in this field, discuss the ecological principles and assumptions underpinning SDMs, and highlight critical limitations and decisions inherent in the construction and evaluation of SDMs. Particular emphasis is given to the use of SDMs for the assessment of climate change impacts and conservation management issues. We suggest new avenues for incorporating species migration, population dynamics, biotic interactions and community ecology into SDMs at multiple spatial scales. Addressing all these issues requires a better integration of SDMs with ecological theory.

Unfolding nature "in silico" : overcoming practical and metodological limitations of species distribution models

Abstract : The existence of a causal relationship between the spatial distribution of living organisms and their environment, in particular climate, has been long recognized and is the central principle of biogeography. In turn, this recognition has led scientists to the idea of using the climatic, topographic, edaphic and biotic characteristics of the environment to predict its potential suitability for a given species or biological community. In this thesis, my objective is to contribute to the development of methodological improvements in the field of species distribution modeling. More precisely, the objectives are to propose solutions to overcome limitations of species distribution models when applied to conservation biology issues, or when .used as an assessment tool of the potential impacts of global change. The first objective of my thesis is to contribute to evidence the potential of species distribution models for conservation-related applications. I present a methodology to generate pseudo-absences in order to overcome the frequent lack of reliable absence data. I also demonstrate, both theoretically (simulation-based) and practically (field-based), how species distribution models can be successfully used to model and sample rare species. Overall, the results of this first part of the thesis demonstrate the strong potential of species distribution models as a tool for practical applications in conservation biology. The second objective this thesis is to contribute to improve .projections of potential climate change impacts on species distributions, and in particular for mountain flora. I develop and a dynamic model, MIGCLIM, that allows the implementation of dispersal limitations into classic species distribution models and present an application of this model to two virtual species. Given that accounting for dispersal limitations requires information on seed dispersal, distances, a general methodology to classify species into broad dispersal types is also developed. Finally, the M~GCLIM model is applied to a large number of species in a study area of the western Swiss Alps. Overall, the results indicate that while dispersal limitations can have an important impact on the outcome of future projections of species distributions under climate change scenarios, estimating species threat levels (e.g. species extinction rates) for a mountainous areas of limited size (i.e. regional scale) can also be successfully achieved when considering dispersal as unlimited (i.e. ignoring dispersal limitations, which is easier from a practical point of view). Finally, I present the largest fine scale assessment of potential climate change impacts on mountain vegetation that has been carried-out to date. This assessment involves vegetation from 12 study areas distributed across all major western and central European mountain ranges. The results highlight that some mountain ranges (the Pyrenees and the Austrian Alps) are expected to be more affected by climate change than others (Norway and the Scottish Highlands). The results I obtain in this study also indicate that the threat levels projected by fine scale models are less severe than those derived from coarse scale models. This result suggests that some species could persist in small refugias that are not detected by coarse scale models. Résumé : L'existence d'une relation causale entre la répartition des espèces animales et végétales et leur environnement, en particulier le climat, a été mis en évidence depuis longtemps et est un des principes centraux en biogéographie. Ce lien a naturellement conduit à l'idée d'utiliser les caractéristiques climatiques, topographiques, édaphiques et biotiques de l'environnement afin d'en prédire la qualité pour une espèce ou une communauté. Dans ce travail de thèse, mon objectif est de contribuer au développement d'améliorations méthodologiques dans le domaine de la modélisation de la distribution d'espèces dans le paysage. Plus précisément, les objectifs sont de proposer des solutions afin de surmonter certaines limitations des modèles de distribution d'espèces dans des applications pratiques de biologie de la conservation ou dans leur utilisation pour évaluer l'impact potentiel des changements climatiques sur l'environnement. Le premier objectif majeur de mon travail est de contribuer à démontrer le potentiel des modèles de distribution d'espèces pour des applications pratiques en biologie de la conservation. Je propose une méthode pour générer des pseudo-absences qui permet de surmonter le problème récurent du manque de données d'absences fiables. Je démontre aussi, de manière théorique (par simulation) et pratique (par échantillonnage de terrain), comment les modèles de distribution d'espèces peuvent être utilisés pour modéliser et améliorer l'échantillonnage des espèces rares. Ces résultats démontrent le potentiel des modèles de distribution d'espèces comme outils pour des applications de biologie de la conservation. Le deuxième objectif majeur de ce travail est de contribuer à améliorer les projections d'impacts potentiels des changements climatiques sur la flore, en particulier dans les zones de montagnes. Je développe un modèle dynamique de distribution appelé MigClim qui permet de tenir compte des limitations de dispersion dans les projections futures de distribution potentielle d'espèces, et teste son application sur deux espèces virtuelles. Vu que le fait de prendre en compte les limitations dues à la dispersion demande des données supplémentaires importantes (p.ex. la distance de dispersion des graines), ce travail propose aussi une méthode de classification simplifiée des espèces végétales dans de grands "types de disperseurs", ce qui permet ainsi de d'obtenir de bonnes approximations de distances de dispersions pour un grand nombre d'espèces. Finalement, j'applique aussi le modèle MIGCLIM à un grand nombre d'espèces de plantes dans une zone d'études des pré-Alpes vaudoises. Les résultats montrent que les limitations de dispersion peuvent avoir un impact considérable sur la distribution potentielle d'espèces prédites sous des scénarios de changements climatiques. Cependant, quand les modèles sont utilisés pour évaluer les taux d'extinction d'espèces dans des zones de montages de taille limitée (évaluation régionale), il est aussi possible d'obtenir de bonnes approximations en considérant la dispersion des espèces comme illimitée, ce qui est nettement plus simple d'un point dé vue pratique. Pour terminer je présente la plus grande évaluation à fine échelle d'impact potentiel des changements climatiques sur la flore des montagnes conduite à ce jour. Cette évaluation englobe 12 zones d'études réparties sur toutes les chaines de montages principales d'Europe occidentale et centrale. Les résultats montrent que certaines chaines de montagnes (les Pyrénées et les Alpes Autrichiennes) sont projetées comme plus sensibles aux changements climatiques que d'autres (les Alpes Scandinaves et les Highlands d'Ecosse). Les résultats obtenus montrent aussi que les modèles à échelle fine projettent des impacts de changement climatiques (p. ex. taux d'extinction d'espèces) moins sévères que les modèles à échelle large. Cela laisse supposer que les modèles a échelle fine sont capables de modéliser des micro-niches climatiques non-détectées par les modèles à échelle large.

Establishment of models to study mouse and human retinogenesis "in vitro" : isolation and characterization of retinal stem cells

SUMMARY IN FRENCH Les cellules souches sont des cellules indifférenciées capables a) de proliférer, b) de s'auto¬renouveller, c) de produire des cellules différenciées, postmitotiques et fonctionnelles (multipotencialité), et d) de régénérer le tissu après des lésions. Par exemple, les cellules de souches hematopoiétiques, situées dans la moelle osseuse, peuvent s'amplifier, se diviser et produire diverses cellules différenciées au cours de la vie, les cellules souches restant dans la moelle osseuse et consentant leur propriété. Les cellules souches intestinales, situées dans la crypte des microvillosités peuvent également régénérer tout l'intestin au cours de la vie. La rétine se compose de six classes de neurones et d'un type de cellule gliale. Tous ces types de cellules sont produits par un progéniteur rétinien. Le pic de production des photorécepteurs se situe autour des premiers jours postnatals chez la souris. A cette période la rétine contient les cellules hautement prolifératives. Dans cette étude, nous avons voulu analyser le phénotype de ces cellules et leur potentiel en tant que cellules souches ou progénitrices. Nous nous sommes également concentrés sur l'effet de certains facteurs épigéniques sur leur destin cellulaire. Nous avons observé que toutes les cellules prolifératives isolées à partir de neurorétines postnatales de souris expriment le marqueur de glie radiaire RC2, ainsi que des facteurs de transcription habituellement trouvés dans la glie radiaire (Mash1, Pax6), et répondent aux critères des cellules souches : une capacité élevée d'expansion, un état indifférencié, la multipotencialité (démontrée par analyse clonale). Nous avons étudié la différentiation des cellules dans différents milieux de culture. En l'absence de sérum, l'EGF induit l'expression de la β-tubulin-III, un marqueur neuronal, et l'acquisition d'une morphologie neuronale, ceci dans 15% des cellules présentes. Nous avons également analysé la prolifération de cellules. Seulement 20% des cellules incorporent le bromodéoxyuridine (BrdU) qui est un marqueur de division cellulaire. Ceci démontre que l'EGF induit la formation des neurones sans une progression massive du cycle cellulaire. Par ailleurs, une stimulation de 2h d'EGF est suffisante pour induire la différentiation neuronale. Certains des neurones formés sont des cellules ganglionnaires rétiniennes (GR), comme l'indique l'expression de marqueurs de cellules ganglionnaires (Ath5, Brn3b et mélanopsine), et dans de rare cas d'autres neurones rétiniens ont été observés (photorécepteurs (PR) et cellules bipolaires). Nous avons confirmé que les cellules souches rétiniennes tardives n'étaient pas restreintes au cours du temps et qu'elles conservent leur multipotencialité en étant capables de générer des neurones dits précoces (GR) ou tardifs (PR). Nos résultats prouvent que l'EGF est non seulement un facteur contrôlant le développement glial, comme précédemment démontré, mais également un facteur efficace de différentiation pour les neurones rétiniens, du moins in vitro. D'autre part, nous avons voulu établir si l'oeil adulte humain contient des cellules souches rétiniennes (CSRs). L'oeil de certains poissons ou amphibiens continue de croître pendant l'âge adulte du fait de l'activité persistante des cellules souches rétiniennes. Chez les poissons, le CSRs se situe dans la marge ciliaire (CM) à la périphérie de la rétine. Bien que l'oeil des mammifères ne se développe plus pendant la vie d'adulte, plusieurs groupes ont prouvé que l'oeil de mammifères adultes contient des cellules souches rétiniennes également dans la marge ciliaire plus précisément dans l'épithélium pigmenté et non dans la neurorétine. Ces CSRs répondent à certains critères des cellules souches. Nous avons identifié et caractérisé les cellules souches rétiniennes résidant dans l'oeil adulte humain. Nous avons prouvé qu'elles partagent les mêmes propriétés que leurs homologues chez les rongeurs c.-à-d. auto-renouvellement, amplification, et différenciation en neurones rétiniens in vitro et in vivo (démontré par immunocoloration et microarray). D'autre part, ces cellules peuvent être considérablement amplifiées, tout en conservant leur potentiel de cellules souches, comme indiqué par l'analyse de leur profil d'expression génique (microarray). Elles expriment également des gènes communs à diverses cellules souches: nucleostemin, nestin, Brni1, Notch2, ABCG2, c-kit et son ligand, aussi bien que cyclin D3 qui agit en aval de c-kit. Nous avons pu montré que Bmi1et Oct4 sont nécessaires pour la prolifération des CSRs confortant leur propriété de cellules souches. Nos données indiquent que la neurorétine postnatale chez la souris et l'épithélium pigmenté de la marge ciliaire chez l'humain adulte contiennent les cellules souches rétiniennes. En outre, nous avons développé un système qui permet d'amplifier et de cultiver facilement les CSRs. Ce modèle permet de disséquer les mécanismes impliqués lors de la retinogenèse. Par exemple, ce système peut être employé pour l'étude des substances ou des facteurs impliqués, par exemple, dans la survie ou dans la génération des cellules rétiniennes. Il peut également aider à disséquer la fonction de gènes ou les facteurs impliqués dans la restriction ou la spécification du destin cellulaire. En outre, dans les pays occidentaux, la rétinite pigmentaire (RP) touche 1 individu sur 3500 et la dégénérescence maculaire liée à l'âge (DMLA) affecte 1 % à 3% de la population âgée de plus de 60 ans. La génération in vitro de cellules rétiniennes est aussi un outil prometteur pour fournir une source illimitée de cellules pour l'étude de transplantation cellulaire pour la rétine. SUMMARY IN ENGLISH Stem cells are defined as undifferentiated cells capable of a) proliferation, b) self maintenance (self-renewability), c) production of many differentiated functional postmitotic cells (multipotency), and d) regenerating tissue after injury. For instance, hematopoietic stem cells, located in bone marrow, can expand, divide and generate differentiated cells into the diverse lineages throughout life, the stem cells conserving their status. In the villi crypt, the intestinal stem cells are also able to regenerate the intestine during their life time. The retina is composed of six classes of neurons and one glial cell. All these cell types are produced by the retinal progenitor cell. The peak of photoreceptor production is reached around the first postnatal days in rodents. Thus, at this stage the retina contains highly proliferative cells. In our research, we analyzed the phenotype of these cells and their potential as possible progenitor or stem cells. We also focused on the effect of epigenic factor(s) and cell fate determination. All the proliferating cells isolated from mice postnatal neuroretina harbored the radial glia marker RC2, expressed transcription factors usually found in radial glia (Mash 1, Pax6), and met the criteria of stem cells: high capacity of expansion, maintenance of an undifferentiated state, and multipotency demonstrated by clonal analysis. We analyzed the differentiation seven days after the transfer of the cells in different culture media. In the absence of serum, EGF led to the expression of the neuronal marker β-tubulin-III, and the acquisition of neuronal morphology in 15% of the cells. Analysis of cell proliferation by bromodeoxyuridine incorporation revealed that EGF mainly induced the formation of neurons without stimulating massively cell cycle progression. Moreover, a pulse of 2h EGF stimulation was sufficient to induce neuronal differentiation. Some neurons were committed to the retinal ganglion cell (RGC) phenotype, as revealed by the expression of retinal ganglion markers (Ath5, Brn3b and melanopsin), and in few cases to other retinal phenotypes (photoreceptors (PRs) and bipolar cells). We confirmed that the late RSCs were not restricted over-time and conserved multipotentcy characteristics by generating retinal phenotypes that usually appear at early (RGC) or late (PRs) developmental stages. Our results show that EGF is not only a factor controlling glial development, as previously shown, but also a potent differentiation factor for retinal neurons, at least in vitro. On the other hand, we wanted to find out if the adult human eye contains retina stem cells. The eye of some fishes and amphibians continues to grow during adulthood due to the persistent activity of retinal stem cells (RSCs). In fish, the RSCs are located in the ciliary margin zone (CMZ) at the periphery of the retina. Although, the adult mammalian eye does not grow during adult life, several groups have shown that the adult mouse eye contains retinal stem cells in the homologous zone (i.e. the ciliary margin), in the pigmented epithelium and not in the neuroretina. These RSCs meet some criteria of stem cells. We identified and characterized the human retinal stem cells. We showed that they posses the same features as their rodent counterpart i.e. they self-renew, expand and differentiate into retinal neurons in vitro and in vivo (indicated by immunostaining and microarray analysis). Moreover, they can be greatly expanded while conserving their sternness potential as revealed by the gene expression profile analysis (microarray approach). They also expressed genes common to various stem cells: nucleostemin, nestin, Bmil , Notch2, ABCG2, c-kit and its ligand, as well as cyclin D3 which acts downstream of c-kit. Furthermore, Bmil and Oct-4 were required for RSC proliferation reinforcing their stem cell identity. Our data indicate that the mice postnatal neuroretina and the adult pigmented epithelium of adult human ciliary margin contain retinal stem cells. We developed a system to easily expand and culture RSCs that can be used to investigate the retinogenesis. For example, it can help to screen drugs or factors involved, for instance, in the survival or generation of retinal cells. This could help to dissect genes or factors involved in the restriction or specification of retinal cell fate. In Western countries, retinitis pigmentosa (RP) affects 1 out of 3'500 individuals and age-related macula degeneration (AMD) strikes 1 % to 3% of the population over 60. In vitro generation of retinal cells is thus a promising tool to provide an unlimited cell source for cellular transplantation studies in the retina.

Impact of biological and environmental variabilities on biological monitoring: an approach using toxicokinetic models

Biological monitoring of occupational exposure is characterized by important variability, due both to variability in the environment and to biological differences between workers. A quantitative description and understanding of this variability is important for a dependable application of biological monitoring. This work describes this variability,using a toxicokinetic model, for a large range of chemicals for which reference biological reference values exist. A toxicokinetic compartmental model describing both the parent compound and its metabolites was used. For each chemical, compartments were given physiological meaning. Models were elaborated based on physiological, physicochemical, and biochemical data when available, and on half-lives and central compartment concentrations when not available. Fourteen chemicals were studied (arsenic, cadmium, carbon monoxide, chromium, cobalt, ethylbenzene, ethyleneglycol monomethylether, fluorides, lead, mercury, methyl isobutyl ketone, penthachlorophenol, phenol, and toluene), representing 20 biological indicators. Occupational exposures were simulated using Monte Carlo techniques with realistic distributions of both individual physiological parameters and exposure conditions. Resulting biological indicator levels were then analyzed to identify the contribution of environmental and biological variability to total variability. Comparison of predicted biological indicator levels with biological exposure limits showed a high correlation with the model for 19 out of 20 indicators. Variability associated with changes in exposure levels (GSD of 1.5 and 2.0) is shown to be mainly influenced by the kinetics of the biological indicator. Thus, with regard to variability, we can conclude that, for the 14 chemicals modeled, biological monitoring would be preferable to air monitoring. For short half-lives (less than 7 hr), this is very similar to the environmental variability. However, for longer half-lives, estimated variability decreased. [Supplementary materials are available for this article. Go to the publisher's online edition of Journal of Occupational and Environmental Hygiene for the following free supplemental resource: tables detailing the CBTK models for all 14 chemicals and the symbol nomenclature that was used.] [Authors]

Integrating detection probabilities in species distribution models of amphibians breeding in Mediterranean temporary ponds

Aim  The imperfect detection of species may lead to erroneous conclusions about species-environment relationships. Accuracy in species detection usually requires temporal replication at sampling sites, a time-consuming and costly monitoring scheme. Here, we applied a lower-cost alternative based on a double-sampling approach to incorporate the reliability of species detection into regression-based species distribution modelling.Location  Doñana National Park (south-western Spain).Methods  Using species-specific monthly detection probabilities, we estimated the detection reliability as the probability of having detected the species given the species-specific survey time. Such reliability estimates were used to account explicitly for data uncertainty by weighting each absence. We illustrated how this novel framework can be used to evaluate four competing hypotheses as to what constitutes primary environmental control of amphibian distribution: breeding habitat, aestivating habitat, spatial distribution of surrounding habitats and/or major ecosystems zonation. The study was conducted on six pond-breeding amphibian species during a 4-year period.Results  Non-detections should not be considered equivalent to real absences, as their reliability varied considerably. The occurrence of Hyla meridionalis and Triturus pygmaeus was related to a particular major ecosystem of the study area, where suitable habitat for these species seemed to be widely available. Characteristics of the breeding habitat (area and hydroperiod) were of high importance for the occurrence of Pelobates cultripes and Pleurodeles waltl. Terrestrial characteristics were the most important predictors of the occurrence of Discoglossus galganoi and Lissotriton boscai, along with spatial distribution of breeding habitats for the last species.Main conclusions  We did not find a single best supported hypothesis valid for all species, which stresses the importance of multiscale and multifactor approaches. More importantly, this study shows that estimating the reliability of non-detection records, an exercise that had been previously seen as a naïve goal in species distribution modelling, is feasible and could be promoted in future studies, at least in comparable systems.

Lipid metabolism in myelinating glial cells: lessons from human inherited disorders and mouse models.

The integrity of central and peripheral nervous system myelin is affected in numerous lipid metabolism disorders. This vulnerability was so far mostly attributed to the extraordinarily high level of lipid synthesis that is required for the formation of myelin, and to the relative autonomy in lipid synthesis of myelinating glial cells because of blood barriers shielding the nervous system from circulating lipids. Recent insights from analysis of inherited lipid disorders, especially those with prevailing lipid depletion and from mouse models with glia-specific disruption of lipid metabolism, shed new light on this issue. The particular lipid composition of myelin, the transport of lipid-associated myelin proteins, and the necessity for timely assembly of the myelin sheath all contribute to the observed vulnerability of myelin to perturbed lipid metabolism. Furthermore, the uptake of external lipids may also play a role in the formation of myelin membranes. In addition to an improved understanding of basic myelin biology, these data provide a foundation for future therapeutic interventions aiming at preserving glial cell integrity in metabolic disorders.

Uncertainty Quantification with Support Vector Regression Prediction Models

Uncertainty quantification of petroleum reservoir models is one of the present challenges, which is usually approached with a wide range of geostatistical tools linked with statistical optimisation or/and inference algorithms. The paper considers a data driven approach in modelling uncertainty in spatial predictions. Proposed semi-supervised Support Vector Regression (SVR) model has demonstrated its capability to represent realistic features and describe stochastic variability and non-uniqueness of spatial properties. It is able to capture and preserve key spatial dependencies such as connectivity, which is often difficult to achieve with two-point geostatistical models. Semi-supervised SVR is designed to integrate various kinds of conditioning data and learn dependences from them. A stochastic semi-supervised SVR model is integrated into a Bayesian framework to quantify uncertainty with multiple models fitted to dynamic observations. The developed approach is illustrated with a reservoir case study. The resulting probabilistic production forecasts are described by uncertainty envelopes.

The effects of physiologically plausible connectivity structure on local and global dynamics in large scale brain models.

Functionally relevant large scale brain dynamics operates within the framework imposed by anatomical connectivity and time delays due to finite transmission speeds. To gain insight on the reliability and comparability of large scale brain network simulations, we investigate the effects of variations in the anatomical connectivity. Two different sets of detailed global connectivity structures are explored, the first extracted from the CoCoMac database and rescaled to the spatial extent of the human brain, the second derived from white-matter tractography applied to diffusion spectrum imaging (DSI) for a human subject. We use the combination of graph theoretical measures of the connection matrices and numerical simulations to explicate the importance of both connectivity strength and delays in shaping dynamic behaviour. Our results demonstrate that the brain dynamics derived from the CoCoMac database are more complex and biologically more realistic than the one based on the DSI database. We propose that the reason for this difference is the absence of directed weights in the DSI connectivity matrix.

Native homing endonucleases can target conserved genes in humans and in animal models.

In recent years, both homing endonucleases (HEases) and zinc-finger nucleases (ZFNs) have been engineered and selected for the targeting of desired human loci for gene therapy. However, enzyme engineering is lengthy and expensive and the off-target effect of the manufactured endonucleases is difficult to predict. Moreover, enzymes selected to cleave a human DNA locus may not cleave the homologous locus in the genome of animal models because of sequence divergence, thus hampering attempts to assess the in vivo efficacy and safety of any engineered enzyme prior to its application in human trials. Here, we show that naturally occurring HEases can be found, that cleave desirable human targets. Some of these enzymes are also shown to cleave the homologous sequence in the genome of animal models. In addition, the distribution of off-target effects may be more predictable for native HEases. Based on our experimental observations, we present the HomeBase algorithm, database and web server that allow a high-throughput computational search and assignment of HEases for the targeting of specific loci in the human and other genomes. We validate experimentally the predicted target specificity of candidate fungal, bacterial and archaeal HEases using cell free, yeast and archaeal assays.