Functional analysis and structural modeling of human APOBEC3G reveal the role of evolutionarily conserved elements in the inhibition of human immunodeficiency virus type 1 infection and Alu transposition.

Retroelements are important evolutionary forces but can be deleterious if left uncontrolled. Members of the human APOBEC3 family of cytidine deaminases can inhibit a wide range of endogenous, as well as exogenous, retroelements. These enzymes are structurally organized in one or two domains comprising a zinc-coordinating motif. APOBEC3G contains two such domains, only the C terminal of which is endowed with editing activity, while its N-terminal counterpart binds RNA, promotes homo-oligomerization, and is necessary for packaging into human immunodeficiency virus type 1 (HIV-1) virions. Here, we performed a large-scale mutagenesis-based analysis of the APOBEC3G N terminus, testing mutants for (i) inhibition of vif-defective HIV-1 infection and Alu retrotransposition, (ii) RNA binding, and (iii) oligomerization. Furthermore, in the absence of structural information on this domain, we used homology modeling to examine the positions of functionally important residues and of residues found to be under positive selection by phylogenetic analyses of primate APOBEC3G genes. Our results reveal the importance of a predicted RNA binding dimerization interface both for packaging into HIV-1 virions and inhibition of both HIV-1 infection and Alu transposition. We further found that the HIV-1-blocking activity of APOBEC3G N-terminal mutants defective for packaging can be almost entirely rescued if their virion incorporation is forced by fusion with Vpr, indicating that the corresponding region of APOBEC3G plays little role in other aspects of its action against this pathogen. Interestingly, residues forming the APOBEC3G dimer interface are highly conserved, contrasting with the rapid evolution of two neighboring surface-exposed amino acid patches, one targeted by the Vif protein of primate lentiviruses and the other of yet-undefined function.

Performance on a Virtual Reality Angled Laparoscope Task Correlates with Spatial Ability of Trainees

The aim of the present study was to investigate whether trainees' performance on a virtual reality angled laparoscope navigation task correlates with scores obtained on a validated conventional test of spatial ability. 56 participants of a surgery workshop performed an angled laparoscope navigation task on the Xitact LS 500 virtual reality Simulator. Performance parameters were correlated with the score of a validated paper-and-pencil test of spatial ability. Performance at the conventional spatial ability test significantly correlated with performance at the virtual reality task for overall task score (p < 0.001), task completion time (p < 0.001) and economy of movement (p = 0.035), not for endoscope travel speed (p = 0.947). In conclusion, trainees' performance in a standardized virtual reality camera navigation task correlates with their innate spatial ability. This VR session holds potential to serve as an assessment tool for trainees.

Treeline and climate change : analyzing and modeling patterns and shifts in the Swiss Alps

Summary: Global warming has led to an average earth surface temperature increase of about 0.7 °C in the 20th century, according to the 2007 IPCC report. In Switzerland, the temperature increase in the same period was even higher: 1.3 °C in the Northern Alps anal 1.7 °C in the Southern Alps. The impacts of this warming on ecosystems aspecially on climatically sensitive systems like the treeline ecotone -are already visible today. Alpine treeline species show increased growth rates, more establishment of young trees in forest gaps is observed in many locations and treelines are migrating upwards. With the forecasted warming, this globally visible phenomenon is expected to continue. This PhD thesis aimed to develop a set of methods and models to investigate current and future climatic treeline positions and treeline shifts in the Swiss Alps in a spatial context. The focus was therefore on: 1) the quantification of current treeline dynamics and its potential causes, 2) the evaluation and improvement of temperaturebased treeline indicators and 3) the spatial analysis and projection of past, current and future climatic treeline positions and their respective elevational shifts. The methods used involved a combination of field temperature measurements, statistical modeling and spatial modeling in a geographical information system. To determine treeline shifts and assign the respective drivers, neighborhood relationships between forest patches were analyzed using moving window algorithms. Time series regression modeling was used in the development of an air-to-soil temperature transfer model to calculate thermal treeline indicators. The indicators were then applied spatially to delineate the climatic treeline, based on interpolated temperature data. Observation of recent forest dynamics in the Swiss treeline ecotone showed that changes were mainly due to forest in-growth, but also partly to upward attitudinal shifts. The recent reduction in agricultural land-use was found to be the dominant driver of these changes. Climate-driven changes were identified only at the uppermost limits of the treeline ecotone. Seasonal mean temperature indicators were found to be the best for predicting climatic treelines. Applying dynamic seasonal delimitations and the air-to-soil temperature transfer model improved the indicators' applicability for spatial modeling. Reproducing the climatic treelines of the past 45 years revealed regionally different attitudinal shifts, the largest being located near the highest mountain mass. Modeling climatic treelines based on two IPCC climate warming scenarios predicted major shifts in treeline altitude. However, the currently-observed treeline is not expected to reach this limit easily, due to lagged reaction, possible climate feedback effects and other limiting factors. Résumé: Selon le rapport 2007 de l'IPCC, le réchauffement global a induit une augmentation de la température terrestre de 0.7 °C en moyenne au cours du 20e siècle. En Suisse, l'augmentation durant la même période a été plus importante: 1.3 °C dans les Alpes du nord et 1.7 °C dans les Alpes du sud. Les impacts de ce réchauffement sur les écosystèmes - en particuliers les systèmes sensibles comme l'écotone de la limite des arbres - sont déjà visibles aujourd'hui. Les espèces de la limite alpine des forêts ont des taux de croissance plus forts, on observe en de nombreux endroits un accroissement du nombre de jeunes arbres s'établissant dans les trouées et la limite des arbres migre vers le haut. Compte tenu du réchauffement prévu, on s'attend à ce que ce phénomène, visible globalement, persiste. Cette thèse de doctorat visait à développer un jeu de méthodes et de modèles pour étudier dans un contexte spatial la position présente et future de la limite climatique des arbres, ainsi que ses déplacements, au sein des Alpes suisses. L'étude s'est donc focalisée sur: 1) la quantification de la dynamique actuelle de la limite des arbres et ses causes potentielles, 2) l'évaluation et l'amélioration des indicateurs, basés sur la température, pour la limite des arbres et 3) l'analyse spatiale et la projection de la position climatique passée, présente et future de la limite des arbres et des déplacements altitudinaux de cette position. Les méthodes utilisées sont une combinaison de mesures de température sur le terrain, de modélisation statistique et de la modélisation spatiale à l'aide d'un système d'information géographique. Les relations de voisinage entre parcelles de forêt ont été analysées à l'aide d'algorithmes utilisant des fenêtres mobiles, afin de mesurer les déplacements de la limite des arbres et déterminer leurs causes. Un modèle de transfert de température air-sol, basé sur les modèles de régression sur séries temporelles, a été développé pour calculer des indicateurs thermiques de la limite des arbres. Les indicateurs ont ensuite été appliqués spatialement pour délimiter la limite climatique des arbres, sur la base de données de températures interpolées. L'observation de la dynamique forestière récente dans l'écotone de la limite des arbres en Suisse a montré que les changements étaient principalement dus à la fermeture des trouées, mais aussi en partie à des déplacements vers des altitudes plus élevées. Il a été montré que la récente déprise agricole était la cause principale de ces changements. Des changements dus au climat n'ont été identifiés qu'aux limites supérieures de l'écotone de la limite des arbres. Les indicateurs de température moyenne saisonnière se sont avérés le mieux convenir pour prédire la limite climatique des arbres. L'application de limites dynamiques saisonnières et du modèle de transfert de température air-sol a amélioré l'applicabilité des indicateurs pour la modélisation spatiale. La reproduction des limites climatiques des arbres durant ces 45 dernières années a mis en évidence des changements d'altitude différents selon les régions, les plus importants étant situés près du plus haut massif montagneux. La modélisation des limites climatiques des arbres d'après deux scénarios de réchauffement climatique de l'IPCC a prédit des changements majeurs de l'altitude de la limite des arbres. Toutefois, l'on ne s'attend pas à ce que la limite des arbres actuellement observée atteigne cette limite facilement, en raison du délai de réaction, d'effets rétroactifs du climat et d'autres facteurs limitants.

Activity in inferior parietal and medial prefrontal cortex signals the accumulation of evidence in a probability learning task.

In an uncertain environment, probabilities are key to predicting future events and making adaptive choices. However, little is known about how humans learn such probabilities and where and how they are encoded in the brain, especially when they concern more than two outcomes. During functional magnetic resonance imaging (fMRI), young adults learned the probabilities of uncertain stimuli through repetitive sampling. Stimuli represented payoffs and participants had to predict their occurrence to maximize their earnings. Choices indicated loss and risk aversion but unbiased estimation of probabilities. BOLD response in medial prefrontal cortex and angular gyri increased linearly with the probability of the currently observed stimulus, untainted by its value. Connectivity analyses during rest and task revealed that these regions belonged to the default mode network. The activation of past outcomes in memory is evoked as a possible mechanism to explain the engagement of the default mode network in probability learning. A BOLD response relating to value was detected only at decision time, mainly in striatum. It is concluded that activity in inferior parietal and medial prefrontal cortex reflects the amount of evidence accumulated in favor of competing and uncertain outcomes.

Development of spatial integration depends on top-down and interhemispheric connections that can be perturbed in migraine: a DCM analysis.

In humans, spatial integration develops slowly, continuing through childhood into adolescence. On the assumption that this protracted course depends on the formation of networks with slowly developing top-down connections, we compared effective connectivity in the visual cortex between 13 children (age 7-13) and 14 adults (age 21-42) using a passive perceptual task. The subjects were scanned while viewing bilateral gratings, which either obeyed Gestalt grouping rules [colinear gratings (CG)] or violated them [non-colinear gratings (NG)]. The regions of interest for dynamic causal modeling were determined from activations in functional MRI contrasts stimuli > background and CG > NG. They were symmetrically located in V1 and V3v areas of both hemispheres. We studied a common model, which contained reciprocal intrinsic and modulatory connections between these regions. An analysis of effective connectivity showed that top-down modulatory effects generated at an extrastriate level and interhemispheric modulatory effects between primary visual areas (all inhibitory) are significantly weaker in children than in adults, suggesting that the formation of feedback and interhemispheric effective connections continues into adolescence. These results are consistent with a model in which spatial integration at an extrastriate level results in top-down messages to the primary visual areas, where they are supplemented by lateral (interhemispheric) messages, making perceptual encoding more efficient and less redundant. Abnormal formation of top-down inhibitory connections can lead to the reduction of habituation observed in migraine patients.

Application de la modélisation moléculaire à de nouvelles approches thérapeutiques du cancer [Application of molecular modeling to new therapeutic cancer approaches].

Recent progress in the experimental determination of protein structures allow to understand, at a very detailed level, the molecular recognition mechanisms that are at the basis of the living matter. This level of understanding makes it possible to design rational therapeutic approaches, in which effectors molecules are adapted or created de novo to perform a given function. An example of such an approach is drug design, were small inhibitory molecules are designed using in silico simulations and tested in vitro. In this article, we present a similar approach to rationally optimize the sequence of killer T lymphocytes receptors to make them more efficient against melanoma cells. The architecture of this translational research project is presented together with its implications both at the level of basic research as well as in the clinics.

Age differences in the EEG N2 and P3 components during an interference task

The age-related increase in interference susceptibility has been well documented and largely attributed to a deficit in inhibition. In the present study, event-related potentials were used to investigate EEG correlates of inhibitory processing in an interference "Arrow" task. A specific interest was addressed to theN2 and P3 components that respectively refers to conflict monitoring and to efficiency of inhibition processes (Anguera et al,. 2011). Younger (N=10, Mage=24.6) and older (N=10, Mage=65.5) participants were invited to perform a task consisting in deciding, as fast and accurately as possible, whether an arrow presented on a computer screen points to the left or the right, irrespective of its position on the screen (left, middle or right). Responses were provided by key-presses using the left and right indexes. Three conditions were considered: congruent (arrow pointing to the same direction as that of the side of the screen on which it appears), incongruent (arrow pointing to the opposite direction), and neutral (arrow presented at the center of the screen). A total of 56 trials per conditions were performed. Behaviorally, the results showed that in the incongruent condition the percent of correct responses significantly decreased in both groups. After adjustment with simple RT (additional control task), the increased RTs obtained in the old group were significantly more pronounced in the incongruent condition. With respect to electrophysiological data, results showed that frontal site (Fz), the N2 amplitude was significantly larger for the younger as compared to the older (- 2.55 μV vs. -0.62 μV respectively) whatever the condition. At central site (Cz), the P3 amplitude significantly decreased in the older compared to the younger in the incongruent condition only. Our findings suggest that the increased RTs observed in older participants during the incongruent condition is more specifically linked to late cognitive resources involved in inhibiting prepotent response tendencies rather than associated with earlier stages of treatment dedicated to conflict monitoring.

MAMOT: hidden Markov modeling tool.

Hidden Markov models (HMMs) are probabilistic models that are well adapted to many tasks in bioinformatics, for example, for predicting the occurrence of specific motifs in biological sequences. MAMOT is a command-line program for Unix-like operating systems, including MacOS X, that we developed to allow scientists to apply HMMs more easily in their research. One can define the architecture and initial parameters of the model in a text file and then use MAMOT for parameter optimization on example data, decoding (like predicting motif occurrence in sequences) and the production of stochastic sequences generated according to the probabilistic model. Two examples for which models are provided are coiled-coil domains in protein sequences and protein binding sites in DNA. A wealth of useful features include the use of pseudocounts, state tying and fixing of selected parameters in learning, and the inclusion of prior probabilities in decoding. AVAILABILITY: MAMOT is implemented in C++, and is distributed under the GNU General Public Licence (GPL). The software, documentation, and example model files can be found at http://bcf.isb-sib.ch/mamot

Analyzing complex rock slope deformation at Stampa, western Norway, by integrating geomorphology, kinematics and numerical modeling

The unstable rock slope, Stampa, above the village of Flåm, Norway, shows signs of both active and postglacial gravitational deformation over an area of 11 km2. Detailed structural field mapping, annual differential Global Navigation Satellite System (GNSS) surveys, as well as geomorphic analysis of high-resolution digital elevation models based on airborne and terrestrial laser scanning indicate that slope deformation is complex and spatially variable. Numerical modeling was used to investigate the influence of former rockslide activity and to better understand the failure mechanism. Field observations, kinematic analysis and numerical modeling indicate a strong structural control of the unstable area. Based on the integration of the above analyses, we propose that the failure mechanism is dominated by (1) a toppling component, (2) subsiding bilinear wedge failure and (3) planar sliding along the foliation at the toe of the unstable slope. Using differential GNSS, 18 points were measured annually over a period of up to 6 years. Two of these points have an average yearly movement of around 10 mm/year. They are located at the frontal cliff on almost completely detached blocks with volumes smaller than 300,000 m3. Large fractures indicate deep-seated gravitational deformation of volumes reaching several 100 million m3, but the movement rates in these areas are below 2 mm/year. Two different lobes of prehistoric rock slope failures were dated with terrestrial cosmogenic nuclides. While the northern lobe gave an average age of 4,300 years BP, the southern one resulted in two different ages (2,400 and 12,000 years BP), which represent most likely multiple rockfall events. This reflects the currently observable deformation style with unstable blocks in the northern part in between Joasete and Furekamben and no distinct blocks but a high rockfall activity around Ramnanosi in the south. With a relative susceptibility analysis it is concluded that small collapses of blocks along the frontal cliff will be more frequent. Larger collapses of free-standing blocks along the cliff with volumes > 100,000 m3, thus large enough to reach the fjord, cannot be ruled out. A larger collapse involving several million m3 is presently considered of very low likelihood.

SwissDock, a protein-small molecule docking web service based on EADock DSS.

Most life science processes involve, at the atomic scale, recognition between two molecules. The prediction of such interactions at the molecular level, by so-called docking software, is a non-trivial task. Docking programs have a wide range of applications ranging from protein engineering to drug design. This article presents SwissDock, a web server dedicated to the docking of small molecules on target proteins. It is based on the EADock DSS engine, combined with setup scripts for curating common problems and for preparing both the target protein and the ligand input files. An efficient Ajax/HTML interface was designed and implemented so that scientists can easily submit dockings and retrieve the predicted complexes. For automated docking tasks, a programmatic SOAP interface has been set up and template programs can be downloaded in Perl, Python and PHP. The web site also provides an access to a database of manually curated complexes, based on the Ligand Protein Database. A wiki and a forum are available to the community to promote interactions between users. The SwissDock web site is available online at http://www.swissdock.ch. We believe it constitutes a step toward generalizing the use of docking tools beyond the traditional molecular modeling community.