The role of interleukin-2 in memory CD8 cell differentiation.

The current literature on the role of interleukin (IL)-2 in memory CD8+ T-cell differentiation indicates a significant contribution of IL-2 during primary and also secondary expansion of CD8+ T cells. IL-2 seems to be responsible for optimal expansion and generation of effector functions following primary antigenic challenge. As the magnitude of T-cell expansion determines the numbers of memory CD8+ T cells surviving after pathogen elimination, these event influence memory cell generation. Moreover, during the contraction phase of an immune respons where most antigen-specific CD8+ T cells disappear by apoptosis, IL-2 signals are able to rescu CD8+ T cells from cell death and provide a durable increase in memory CD8+ T-cell counts. At the memory stage, CD8+ T-cell frequencies can be boosted by administration of exogenous IL-2 Significantly, only CD8+ T cells that have received IL-2 signals during initial priming are able t mediate efficient secondary expansion following renewed antigenic challenge. Thus, IL-2 signals during different phases of an immune response are key in optimizing CD8+ T-cell functions, thereby affecting both primary and secondary responses of these T cells.

GeoKernels: Modeling of Spatial Data on GeoManifolds

This paper presents a review of methodology for semi-supervised modeling with kernel methods, when the manifold assumption is guaranteed to be satisfied. It concerns environmental data modeling on natural manifolds, such as complex topographies of the mountainous regions, where environmental processes are highly influenced by the relief. These relations, possibly regionalized and nonlinear, can be modeled from data with machine learning using the digital elevation models in semi-supervised kernel methods. The range of the tools and methodological issues discussed in the study includes feature selection and semisupervised Support Vector algorithms. The real case study devoted to data-driven modeling of meteorological fields illustrates the discussed approach.

Electrical neuroimaging of memory discrimination based on single-trial multisensory learning.

Multisensory experiences influence subsequent memory performance and brain responses. Studies have thus far concentrated on semantically congruent pairings, leaving unresolved the influence of stimulus pairing and memory sub-types. Here, we paired images with unique, meaningless sounds during a continuous recognition task to determine if purely episodic, single-trial multisensory experiences can incidentally impact subsequent visual object discrimination. Psychophysics and electrical neuroimaging analyses of visual evoked potentials (VEPs) compared responses to repeated images either paired or not with a meaningless sound during initial encounters. Recognition accuracy was significantly impaired for images initially presented as multisensory pairs and could not be explained in terms of differential attention or transfer of effects from encoding to retrieval. VEP modulations occurred at 100-130ms and 270-310ms and stemmed from topographic differences indicative of network configuration changes within the brain. Distributed source estimations localized the earlier effect to regions of the right posterior temporal gyrus (STG) and the later effect to regions of the middle temporal gyrus (MTG). Responses in these regions were stronger for images previously encountered as multisensory pairs. Only the later effect correlated with performance such that greater MTG activity in response to repeated visual stimuli was linked with greater performance decrements. The present findings suggest that brain networks involved in this discrimination may critically depend on whether multisensory events facilitate or impair later visual memory performance. More generally, the data support models whereby effects of multisensory interactions persist to incidentally affect subsequent behavior as well as visual processing during its initial stages.

Effects of pro-cholinergic treatment in patients suffering from spatial neglect.

Spatial neglect is a neurological condition characterized by a breakdown of spatial cognition contralateral to hemispheric damage. Deficits in spatial attention toward the contralesional side are considered to be central to this syndrome. Brain lesions typically involve right fronto-parietal cortices mediating attentional functions and subcortical connections in underlying white matter. Convergent findings from neuroimaging and behavioral studies in both animals and humans suggest that the cholinergic system might also be critically implicated in selective attention by modulating cortical function via widespread projections from the basal forebrain. Here we asked whether deficits in spatial attention associated with neglect could partly result from a cholinergic deafferentation of cortical areas subserving attentional functions, and whether such disturbances could be alleviated by pro-cholinergic therapy. We examined the effect of a single-dose transdermal nicotine treatment on spatial neglect in 10 stroke patients in a double-blind placebo-controlled protocol, using a standardized battery of neglect tests. Nicotine-induced systematic improvement on cancellation tasks and facilitated orienting to single visual targets, but had no significant effect on other tests. These results support a global effect of nicotine on attention and arousal, but no effect on other spatial mechanisms impaired in neglect.

Sex differences: From mental rotation to object location memory, an ERP study

Sex differences in cognition have been largely investigated. The most consistent sex differences favoring females are observed in object location memory involving the left hemisphere whereas the most consistent sex differences favoring males are observed in tasks that require mental rotation involving the right hemisphere. Here we used a task involving these two abilities to see the impact of mental rotation on object location memory. To that end we used a combination of behavioral and event-related potential (ERP) electroencephalography (EEG) measures.A computer screen displayed a square frame of 4 pairs of images (a "teddy" bear, a shoe, an umbrella and a lamp) randomly arranged around a central fixation cross. After a 10-second interval for memorization, images disappeared and were replaced by a test frame with no image but a random pair of two locations marked in black. In addition, this test frame was randomly displayed either in the original orientation (0° rotation) or in the rotated one (90° clockwise - CW - or 90° counterclockwise - CCW). Preceding the test frame, an arrow indicating the presence or the absence of rotation of the frame was displayed on the screen. The task of the participants (15 females and 15 males) was to determine if two marked locations corresponded or not to a pair of identical images. Each response was followed by feedback.Findings showed no significant sex differences in the performance of the original orientation. In comparison with this position, the rotation of the frame produced an equal decrease of male and female performance. In addition, this decrease was significantly higher when the rotation of the frame was in a CCW direction. We further assessed the ERP when the arrow indicated the direction of rotation as stimulus-onset, during four time windows representing major components C1, P1, N1 and N2. Although no sex differences were observed in performance, brain activities differed according to sex. Enhanced amplitudes were found for the CCW compared to CW rotation over the right posterior areas for the P1, N1 and N2 components for men as well as for women. Major topographical differences related to sex were measured for the CW rotation condition as marked lateralized amplitude: left-hemisphere amplitude larger than right one was measured during P1 time range for men. These similar patterns prolonged from P1 to N1 for women. Early distinctions were found in interaction with sex between CCW and CW waveform amplitudes, expressing over anterior electrode sites during C1 time range (0-50 ms post-stimulus).In conclusion (i) women do not outperform men in object location memory in this study (absence of rotation condition); (ii) mental rotation, in particular the direction of rotation, influences performance on object location memory; (iii) CCW rotation is associated with activity in the right parietal hemisphere whereas the CW rotation involves the left parietal hemisphere; (iv) this last effect is less pronounced in males, which could explain why greater involvement of right parietal areas in men and of bilateral posterior areas in women is generally reported in mental rotation tasks; and (v) the early distinctions between both directions of rotation located over anterior sites could be related to sex differences in their respective involvement of control mechanisms.

c-Cbl expression levels regulate the functional responses of human central and effector memory CD4 T cells.

The biochemical mechanisms controlling the diverse functional outcomes of human central memory (CM) and effector memory (EM) T-cell responses triggered through the T-cell receptor (TCR) remain poorly understood. We implemented reverse phase protein arrays to profile TCR signaling components in human CD8 and CD4 memory T-cell subsets isolated ex vivo. As compared with CD4 CM cells, EM cells express statistically significant increased amounts of SLP-76 and reduced levels of c-Cbl, Syk, Fyn, and LAT. Moreover, in EM cells reduced expression of negative regulator c-Cbl correlates with expression of c-Cbl kinases (Syk and Fyn), PI3K, and LAT. Importantly, consistent with reduced expression of c-Cbl, EM cells display a lower functional threshold than CM cells. Increasing c-Cbl content of EM cells to the same level as that of CM cells using cytosolic transduction, we impaired their proliferation and cytokine production. This regulatory mechanism depends primarily on c-Cbl E3 ubiquitin ligase activity as evidenced by the weaker impact of enzymatically deficient c-Cbl C381A mutant on EM cell functions. Our study reports c-Cbl as a critical regulator of the functional responses of memory T cell subsets and identifies for the first time in humans a mechanism controlling the functional heterogeneity of memory CD4 cells.

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

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

Behavioral phenotyping of glutathione-deficient mice: Relevance to schizophrenia and bipolar disorder.

Redox-dysregulation represents a common pathogenic mechanism in schizophrenia (SZ) and bipolar disorder (BP). It may in part arise from a genetically compromised synthesis of glutathione (GSH), the major cellular antioxidant and redox-regulator. Allelic variants of the genes coding for the rate-limiting GSH synthesizing enzyme glutamate-cysteine-ligase modifier (GCLM) and/or catalytic (GCLC) subunit have been associated with SZ and BP. Using mice knockout (KO) for GCLM we have previously shown that impaired GSH synthesis is associated with morphological, functional and neurochemical anomalies similar to those in patients. Here we asked whether GSH deficit is also associated with SZ- and BP-relevant behavioral and cognitive anomalies. Accordingly, we subjected young adult GCLM-wildtype (WT), heterozygous and KO males to a battery of standard tests. Compared to WT, GCLM-KO mice displayed hyperlocomotion in the open field and forced swim test but normal activity in the home cage, suggesting that hyperlocomotion was selective to environmental novelty and mildly stressful situations. While spatial working memory and latent inhibition remained unaffected, KO mice showed a potentiated hyperlocomotor response to an acute amphetamine injection, impaired sensorymotor gating in the form of prepulse inhibition and altered social behavior compared to WT. These anomalies resemble important aspects of both SZ and the manic component of BP. As such our data support the notion that redox-dysregulation due to GSH deficit is implicated in both disorders. Moreover, our data propose the GCLM-KO mouse as a valuable model to study the behavioral and cognitive consequences of redox dysregulation in the context of psychiatric disease.

A la recherche de symptômes de désorientation dépendant d'un déficit d'intégration multisensorielle chez l'animal : un éclairage sur les mécanismes fondamentaux de la schizophrénie

Abstract Fundamental research in psychiatric neurosciences assumes that psychiatric disorders are associated with neurobiological factors. Identification of these factors would provide therapeutic targets as well as a better understanding of the relationship between- brain and behaviour in pathological processes. We conducted experiments in an animal model of schizophrenia. Several behavioural tasks were used to evaluate spatial and working memory in these animals. The model is based on glutathione deficit during cerebral development. Indeed, a 50% decrease of glutathione has been reported in prefrontal cortex of patients with schizophrenia. Glutathione is a major antioxidant in the brain and its deficit could lead to abnormal brain connectivity. The glutathione deficit was induced in rats by perinatal (PS-P16) subcutaneous injections with Lbuthionine-(S,R)-sullfoximine (BSO), an inhibitor of glutathione synthesis. This treatment leads to a transitory 50% glutathione levels during brain development. In parallel, we conducted behavioural testing in rats with a medial prefrontal cortex lesion. This allowed us to compare early damage induced by BSO treatment with a focal lesion in adults of a brain area known to present anomalies in schizophrenia. Finally, we conducted a series of experiments in senescent rats to evaluate if cognitive deficits could be related to neurobiological changes. Our results show that an early glutathione deficit provokes cognitive deficits in adulthood. These spatial and working memory deficits resemble the cognitive deficits observed in schizophrenia. The comparison with prefrontal rats revealed that the early brain glutathione deficit provoked more severe cognitive deficits than the prefrontal lesion in adult rats. Moreover, in both cases, we observed a dissociation in memory deficits depending on the type of locomotion that was used in behavioural experiments. Indeed, BSO treated rats as well as prefrontal rats showed place learning or working memory deficits in tasks conducted on dry surfaces where they had to walk. In contrast, they showed no deficit when the same cognitive functions were tested in the water maze. This dissociation might be sustained by a difference in requirement of sensory integration between walking and swimming tasks. Résumé La recherche fondamentale en neurosciences psychiatriques repose sur le présupposé selon lequel les symptômes manifestés dans les troubles psychiatriques auraient des concomitants neurobiologiques. Ceux-ci, une fois identifiés, offriraient des cibles pour une démarche thérapeutique ainsi que des modèles permettant de mieux comprendre les soubassements biologiques du comportement et des activités mentales. Nos expériences s'articulent autour de la question de la modélisation de la schizophrénie chez l'animal. Nous avons recherché chez ces animaux des troubles cognitifs et sensoriels associés à la schizophrénie. En effet, chez l'homme comme chez l'animal, la mémoire spatiale et la mémoire de travail dépendent fortement de la capacité d'intégration et d'organisation des informations sensorielles. Les premières expériences ont été menées suite à une perturbation périnatale du développement cérébral. Celle-ci visait à reproduire une diminution du taux de glutathion dans le cerveau, des recherches précédentes ayant observé une diminution de 50% du taux de glutathion dans le cortex préfrontal de patients schizophrènes. Le glutathion étant un antioxydant majeur dans le cerveau, son déficit pourrait conduire à des perturbations de la circuiterie cérébrale. Nous avons reproduit ce déficit chez le rat, par injection de Lbuthionine-(S,R)-sullfoximine (BSO), un inhibiteur de la synthèse du glutathion... Ce traitement a été administré pendant la période périnatale (du jour postnatal 5 au jour 16) provoquant une diminution de 50% du taux de glutathion. Nous avons ensuite évalué lës répercussions de cette atteinte précoce sur le comportement des rats à l'âge adulte. Ce modèle s'inscrit donc dans l'hypothèse neurodéveloppementale qui associe la schizophrénie à une atteinte du développement cérébral normal. Nous avons ensuite conduit des expériences similaires chez des rats ayant subi une lésion du cortex préfrontal pour comparer les répercussions du traitement périnatal avec une lésion, à l'âge adulte, d'une aire cérébrale connue pour présenter des anomalies chez les patients. Finalement, nous avons évalué si les processus sensoriels et cognitifs précédemment étudiés pouvaient également être affectés lors du vieillissement normal en recherchant des corrélats biologiques des déficits de mémoire liés à l'âge avancé. Nos résultats montrent que ce déficit précoce en glutathion peut avoir des répercussions surale comportement à l'âge adulte. On a relevé une similarité avec les déficits cognitifs associés.à la schizophrénie, incluant des déficits de mémoire de travail ainsi que des déficits de mémoire spatiale. Ces déficits étaient fortement liés au type de locomotion utilisée et n'ont été observés que dans les tâches où les animaux devaient rejoindre un but en marchant mais pas dans lés tests dans lesquels ils devaient localiser une cible en nageant. Les déficits induits par la lésion préfrontale chez l'adulte étaient beaucoup plus légers que ceux découlant de l'atteinte périnatale mais présentaient une dissociation analogue en fonction du type de locomotion. De plus, des tests similaires menés au cours du vieillissement confirment que la mémoire de travail peut être affectée sélectivement par le vieillissement dans une tâche où les animaux doivent marcher, tout en restant intacte dans le bassin de Morris. Les déficits cognitifs liés au vieillissement étaient significativement corrélés à des différences de niveaux des protéines post-synaptiques PSD95 (postsynaptic density 95). L'ensemble des résultats montre que les tests qui sont fréquemment utilisés pour évaluer la mémoire chez l'animal pourraient faire appel à des processus différents. Cette différence pourrait notamment tenir au niveau d'intégration sensorielle requis pour résoudre la tâche, qui est particulièrement sollicitée au cours d'une locomotion intermittente.

Spatial pattern of floral morphology: a possible insight into the effects of pollinators on plant distribution

Pollination syndromes involve convergent evolution towards phenotypes composed of specific scents, colours or floral morphologies that attract or restrict pollinator access to reward. How these traits might influence the distributions of plant species in interaction with pollinators has rarely been investigated. We sampled 870 vegetation plots in the western Swiss Alps and classified the plant species into seven blossom types according to their floral morphology (wind, disk, funnel, tube, bilabiate, head or brush). We investigated the environmental features of plots with functional diversity (FD) lower than expected by chance alone to detect potential pollination filtering and related the proportions of the seven blossom types to a combination of environmental descriptors. From these results, we inferred the potential effect of the pollinator on the spatial distribution of plant species. The vegetation plots with significantly lower FD of blossom types than expected by chance were found at higher altitudes, and the proportions of blossom types were strongly patterned along the same gradient. These results support a biotic filtering effect on plant species assemblages through pollination: disk blossoms became dominant at higher altitudes, resulting in a lower FD. In harsh conditions at high altitudes, pollinators usually decrease in activity, and the openness of the disk blossom grants access to any available pollinator. Inversely, bilabiate blossoms, which are mostly pollinated by bees, were more abundant at lower elevations, which are characterised by greater abundance and diversity of bees. Generalisation through openness of the blossom could be advantageous at high elevations, while specialisation could be a successful alternative strategy at lower elevations. The approach used in this study is purely correlative, and further investigations should be conducted to infer the nature of the causal relationship between plant and pollinator distributions.

Testing Spatial Autocorrelation in Weighted Networks : the Modes Permutation Test

In a weighted spatial network, as specified by an exchange matrix, the variances of the spatial values are inversely proportional to the size of the regions. Spatial values are no more exchangeable under independence, thus weakening the rationale for ordinary permutation and bootstrap tests of spatial autocorrelation. We propose an alternative permutation test for spatial autocorrelation, based upon exchangeable spatial modes, constructed as linear orthogonal combinations of spatial values. The coefficients obtain as eigenvectors of the standardised exchange matrix appearing in spectral clustering, and generalise to the weighted case the concept of spatial filtering for connectivity matrices. Also, two proposals aimed at transforming an acessibility matrix into a exchange matrix with with a priori fixed margins are presented. Two examples (inter-regional migratory flows and binary adjacency networks) illustrate the formalism, rooted in the theory of spectral decomposition for reversible Markov chains.

Combined analysis of grey matter voxel-based morphometry and white matter tract-based spatial statistics in late-life bipolar disorder.

Background: Previous magnetic resonance imaging (MRI) studies in young patients with bipolar disorder indicated the presence of grey matter concentration changes as well as microstructural alterations in white matter in various neocortical areas and the corpus callosum. Whether these structural changes are also present in elderly patients with bipolar disorder with long-lasting clinical evolution remains unclear. Methods: We performed a prospective MRI study of consecutive elderly, euthymic patients with bipolar disorder and healthy, elderly controls. We conducted a voxel-based morphometry (VBM) analysis and a tract-based spatial statistics (TBSS) analysis to assess fractional anisotropy and longitudinal, radial and mean diffusivity derived by diffusion tensor imaging (DTI). Results: We included 19 patients with bipolar disorder and 47 controls in our study. Fractional anisotropy was the most sensitive DTI marker and decreased significantly in the ventral part of the corpus callosum in patients with bipolar disorder. Longitudinal, radial and mean diffusivity showed no significant between-group differences. Grey matter concentration was reduced in patients with bipolar disorder in the right anterior insula, head of the caudate nucleus, nucleus accumbens, ventral putamen and frontal orbital cortex. Conversely, there was no grey matter concentration or fractional anisotropy increase in any brain region in patients with bipolar disorder compared with controls. Limitations: The major limitation of our study is the small number of patients with bipolar disorder. Conclusion: Our data document the concomitant presence of grey matter concentration decreases in the anterior limbic areas and the reduced fibre tract coherence in the corpus callosum of elderly patients with long-lasting bipolar disorder.

Technology diffusion and the spatial distribution of wages in the US

What explains the spatial distribution of wages across US counties? I find that two of the most important factors are spatial technology diffusion and externalities due to the aggregate scale of production. One empirical finding supporting the importance of spatial technology diffusion is that average wages in a county decrease with the average level of schooling in neighboring counties when employment in the county and average wages in neighboring counties are held constant. All empirical results are obtained using anovel instrument for (endogenous) employment at the county-leveland take into account other factors (e.g. productivity-differencesacross states, climate) that may determine wages.

Improving generalized regression analysis for the spatial prediction of forest communities

Aim This study used data from temperate forest communities to assess: (1) five different stepwise selection methods with generalized additive models, (2) the effect of weighting absences to ensure a prevalence of 0.5, (3) the effect of limiting absences beyond the environmental envelope defined by presences, (4) four different methods for incorporating spatial autocorrelation, and (5) the effect of integrating an interaction factor defined by a regression tree on the residuals of an initial environmental model. Location State of Vaud, western Switzerland. Methods Generalized additive models (GAMs) were fitted using the grasp package (generalized regression analysis and spatial predictions, http://www.cscf.ch/grasp). Results Model selection based on cross-validation appeared to be the best compromise between model stability and performance (parsimony) among the five methods tested. Weighting absences returned models that perform better than models fitted with the original sample prevalence. This appeared to be mainly due to the impact of very low prevalence values on evaluation statistics. Removing zeroes beyond the range of presences on main environmental gradients changed the set of selected predictors, and potentially their response curve shape. Moreover, removing zeroes slightly improved model performance and stability when compared with the baseline model on the same data set. Incorporating a spatial trend predictor improved model performance and stability significantly. Even better models were obtained when including local spatial autocorrelation. A novel approach to include interactions proved to be an efficient way to account for interactions between all predictors at once. Main conclusions Models and spatial predictions of 18 forest communities were significantly improved by using either: (1) cross-validation as a model selection method, (2) weighted absences, (3) limited absences, (4) predictors accounting for spatial autocorrelation, or (5) a factor variable accounting for interactions between all predictors. The final choice of model strategy should depend on the nature of the available data and the specific study aims. Statistical evaluation is useful in searching for the best modelling practice. However, one should not neglect to consider the shapes and interpretability of response curves, as well as the resulting spatial predictions in the final assessment.