Modulation of Higher-Order Olfaction Components on Executive Functions in Humans.

The prefrontal (PFC) and orbitofrontal cortex (OFC) appear to be associated with both executive functions and olfaction. However, there is little data relating olfactory processing and executive functions in humans. The present study aimed at exploring the role of olfaction on executive functioning, making a distinction between primary and more cognitive aspects of olfaction. Three executive tasks of similar difficulty were used. One was used to assess hot executive functions (Iowa Gambling Task-IGT), and two as a measure of cold executive functioning (Stroop Colour and Word Test-SCWT and Wisconsin Card Sorting Test-WCST). Sixty two healthy participants were included: 31 with normosmia and 31 with hyposmia. Olfactory abilities were assessed using the ''Sniffin' Sticks'' test and the olfactory threshold, odour discrimination and odour identification measures were obtained. All participants were female, aged between 18 and 60. Results showed that participants with hyposmia displayed worse performance in decision making (IGT; Cohen's-d = 0.91) and cognitive flexibility (WCST; Cohen's-d between 0.54 and 0.68) compared to those with normosmia. Multiple regression adjusted by the covariates participants' age and education level showed a positive association between odour identification and the cognitive inhibition response (SCWT-interference; Beta = 0.29; p = .034). The odour discrimination capacity was not a predictor of the cognitive executive performance. Our results suggest that both hot and cold executive functions seem to be associated with higher-order olfactory functioning in humans. These results robustly support the hypothesis that olfaction and executive measures have a common neural substrate in PFC and OFC, and suggest that olfaction might be a reliable cognitive marker in psychiatric and neurologic disorders.

CREB-2, a cellular CRE-dependent transcription repressor, functions in association with Tax as an activator of the human T-cell leukemia virus type 1 promoter.

The Tax protein of the human T-cell leukemia virus type 1 (HTLV-1) has been implicated in human T-cell immortalization. The primary function of Tax is to transcriptionally activate the HTLV-1 promoter, but Tax is also known to stimulate expression of cellular genes. It has been reported to associate with several transcription factors, as well as proteins not involved in transcription. To better characterize potential cellular targets of Tax present in infected cells, a Saccharomyces cerevisiae two-hybrid screening was performed with a cDNA library constructed from the HTLV-1-infected MT2 cell line. From this study, we found 158 positive clones representing seven different cDNAs. We focused our attention on the cDNA encoding the transcription factor CREB-2. CREB-2 is an unconventional member of the ATF/CREB family in that it lacks a protein kinase A (PKA) phosphorylation site and has been reported to negatively regulate transcription from the cyclic AMP response element of the human enkephalin promoter. In this study, we demonstrate that CREB-2 cooperates with Tax to enhance viral transcription and that its basic-leucine zipper C-terminal domain is required for both in vitro and in vivo interactions with Tax. Our results confirm that the activation of the HTLV-1 promoter through Tax and factors of the ATF/CREB family is PKA independent.

Oxytocin response to an experimental psychosocial challenge in adults exposed to traumatic experiences during childhood or adolescence.

Long-term implications of the exposure to traumatizing experiences during childhood or adolescence, such as sexual abuse, or cancer, have been documented, namely the subjects' response to an acute stress in adulthood. Several indicators of the stress response have been considered (e.g. cortisol, heart rate). Oxytocin (OT) response to an acute stress of individuals exposed to trauma has not been documented. Eighty subjects (n=26 women who had experienced episodes of child abuse, n=25 men and women healthy survivors of cancer in childhood or adolescence, and 29 controls) have been submitted to a laboratory session involving an experimental stress challenge, the Trier social stress test. Overall, there was a clear OT response to the psychosocial challenge. Subjects having experienced a childhood/adolescence life-threatening illness had higher mean levels of OT than both abused and control subjects. There was a moderate negative relationship between OT and salivary cortisol. It is suggested that an acute stress stimulates OT secretion, and that the exposure to enduring life-threatening experiences in childhood/adolescence has long-lasting consequences regarding the stress system and connected functions, namely the activation of OT secretion. Better knowledge of such long-term implications is important so that to prevent dysregulations of the stress responses, which have been shown to be associated to the individual's mental health.

Critical thoughts on computing atom condensed Fukui functions

Different procedures to obtain atom condensed Fukui functions are described. It is shown how the resulting values may differ depending on the exact approach to atom condensed Fukui functions. The condensed Fukui function can be computed using either the fragment of molecular response approach or the response of molecular fragment approach. The two approaches are nonequivalent; only the latter approach corresponds in general with a population difference expression. The Mulliken approach does not depend on the approach taken but has some computational drawbacks. The different resulting expressions are tested for a wide set of molecules. In practice one must make seemingly arbitrary choices about how to compute condensed Fukui functions, which suggests questioning the role of these indicators in conceptual density-functional theory

Review article: Intestinal epithelia and barrier functions.

The mucosal epithelia of the digestive tract acts as a selective barrier, permeable to ions, small molecules and macromolecules. These epithelial cells aid the digestion of food and absorption of nutrients. They contribute to the protection against pathogens and undergo continuous cell renewal which facilitates the elimination of damaged cells. Both innate and adaptive defence mechanisms protect the gastrointestinal-mucosal surfaces against pathogens. Interaction of microorganisms with epithelial cells triggers a host response by activating specific transcription factors which control the expression of chemokines and cytokines. This host response is characterized by the recruitment of macrophages and neutrophils at the site of infection. Disruption of epithelial signalling pathways that recruit migratory immune cells results in a chronic inflammatory response. The adaptive defence mechanism relies on the collaboration of epithelial cells (resident sampling system) with antigen-presenting and lymphoid cells (migratory sampling system); in order to obtain samples of foreign antigen, these samples must be transported across the barriers without affecting the integrity of the barrier. These sampling systems are regulated by both environmental and host factors. Fates of the antigen may differ depending on the way in which they cross the epithelial barrier, i.e. via interaction with motile dendritic cells or epithelial M cells in the follicle-associated epithelium.

Bioreporters: gfp versus lux revisited and single-cell response.

Genetically engineered organisms expressing spectroscopically active reporter molecules in response to chemical effectors display great potential as living transducers in sensing applications. Green fluorescent protein (gfp gene) bioreporters have distinct advantages over luminescent couterparts (lux gene), including applicability at the single-cell level, but are typically less sensitive. Here we describe a gfp-bearing bioreporter that is sensitive to naphthalene (a poorly water soluble pollutant behaving like a large class of hydrophobic compounds), is suitable for use in chemical assays and bioavailability studies, and has detection limits comparable to lux-bearing bioreporters for higher efficiency detection strategies. Simultaneously, we find that the exploitation of population response data from single-cell analysis is not an algorithmic conduit to enhanced signal detection and hence lower effector detection limits, as normally assumed. The assay reported functions to equal effect with or without biocide.

Visual functions in the healthy and schizophrenic brain : from stimulus control to illusory perceptions using electrical neuroimaging

ABSTRACT (FRENCH)Ce travail de thèse basé sur le système visuel chez les sujets sains et chez les patients schizophrènes, s'articule autour de trois articles scientifiques publiés ou en cours de publication. Ces articles traitent des sujets suivants : le premier article présente une nouvelle méthode de traitement des composantes physiques des stimuli (luminance et fréquence spatiale). Le second article montre, à l'aide d'analyses de données EEG, un déficit de la voie magnocellulaire dans le traitement visuel des illusions chez les patients schizophrènes. Ceci est démontré par l'absence de modulation de la composante PI chez les patients schizophrènes contrairement aux sujets sains. Cette absence est induite par des stimuli de type illusion Kanizsa de différentes excentricités. Finalement, le troisième article, également à l'aide de méthodes de neuroimagerie électrique (EEG), montre que le traitement des contours illusoires se trouve dans le complexe latéro-occipital (LOC), à l'aide d'illusion « misaligned gratings ». De plus il révèle que les activités démontrées précédemment dans les aires visuelles primaires sont dues à des inférences « top- down ».Afin de permettre la compréhension de ces trois articles, l'introduction de ce manuscrit présente les concepts essentiels. De plus des méthodes d'analyses de temps-fréquence sont présentées. L'introduction est divisée en quatre parties : la première présente le système visuel depuis les cellules retino-corticales aux deux voix du traitement de l'information en passant par les régions composant le système visuel. La deuxième partie présente la schizophrénie par son diagnostic, ces déficits de bas niveau de traitement des stimuli visuel et ces déficits cognitifs. La troisième partie présente le traitement des contours illusoires et les trois modèles utilisés dans le dernier article. Finalement, les méthodes de traitement des données EEG seront explicitées, y compris les méthodes de temps-fréquences.Les résultats des trois articles sont présentés dans le chapitre éponyme (du même nom). De plus ce chapitre comprendra les résultats obtenus à l'aide des méthodes de temps-fréquenceFinalement, la discussion sera orientée selon trois axes : les méthodes de temps-fréquence ainsi qu'une proposition de traitement de ces données par une méthode statistique indépendante de la référence. La discussion du premier article en montrera la qualité du traitement de ces stimuli. La discussion des deux articles neurophysiologiques, proposera de nouvelles d'expériences afin d'affiner les résultats actuels sur les déficits des schizophrènes. Ceci pourrait permettre d'établir un marqueur biologique fiable de la schizophrénie.ABSTRACT (ENGLISH)This thesis focuses on the visual system in healthy subjects and schizophrenic patients. To address this research, advanced methods of analysis of electroencephalographic (EEG) data were used and developed. This manuscript is comprised of three scientific articles. The first article showed a novel method to control the physical features of visual stimuli (luminance and spatial frequencies). The second article showed, using electrical neuroimaging of EEG, a deficit in spatial processing associated with the dorsal pathway in chronic schizophrenic patients. This deficit was elicited by an absent modulation of the PI component in terms of response strength and topography as well as source estimations. This deficit was orthogonal to the preserved ability to process Kanizsa-type illusory contours. Finally, the third article resolved ongoing debates concerning the neural mechanism mediating illusory contour sensitivity by using electrical neuroimaging to show that the first differentiation of illusory contour presence vs. absence is localized within the lateral occipital complex. This effect was subsequent to modulations due to the orientation of misaligned grating stimuli. Collectively, these results support a model where effects in V1/V2 are mediated by "top-down" modulation from the LOC.To understand these three articles, the Introduction of this thesis presents the major concepts used in these articles. Additionally, a section is devoted to time-frequency analysis methods not presented in the articles themselves. The introduction is divided in four parts. The first part presents three aspects of the visual system: cellular, regional, and its functional interactions. The second part presents an overview of schizophrenia and its sensoiy-cognitive deficits. The third part presents an overview of illusory contour processing and the three models examined in the third article. Finally, advanced analysis methods for EEG are presented, including time- frequency methodology.The Introduction is followed by a synopsis of the main results in the articles as well as those obtained from the time-frequency analyses.Finally, the Discussion chapter is divided along three axes. The first axis discusses the time frequency analysis and proposes a novel statistical approach that is independent of the reference. The second axis contextualizes the first article and discusses the quality of the stimulus control and direction for further improvements. Finally, both neurophysiologic articles are contextualized by proposing future experiments and hypotheses that may serve to improve our understanding of schizophrenia on the one hand and visual functions more generally.

Survival response in the skin

Apoptosis is defined as a programmed cell death process operating in multicellular organisms in order to maintain proper homeostasis of tissues. Caspases are among the best characterized proteases to execute apoptosis although lately many studies have associated them with non-apoptotic functions. In the laboratory an antiapoptotic pathway relying on caspase-3 activation and RasGAP has been described in vitro. RasGAP bears two conserved caspase-3 cleavage sites. Under low stress conditions, RasGAP is first cleaved by low caspase-3 activity generating an N terminal fragment (fragment N) that induces a potent anti-apoptotic response mediated by the Ras/PI3K/Akt pathway. High levels of active caspase-3, associated with increased stress conditions, induce further cleavage of fragment N abrogating this anti-apoptotic response. In the present work I studied the functionality of fragment N-mediated protection in physiological conditions as well as the mechanism by which fragment N induces an anti-apoptotic response, with a focus on survivin, an inhibitor of apoptosis. During my work in the laboratory I found that mice lacking caspase-3 or unable to cleave RasGAP (KI mice) are deficient in Akt activation and more sensitive to apoptosis than wild-type mice in response to stress. This higher sensitivity to stress led to augmented tissue damage, highlighting the importance of this pathway in protection against low stress. In parallel I focused on the study of survivin expression in the skin in response to UV-B light and I found that survivin is induced in the cytoplasm of keratinocytes in response to stress where it may fulfill a cyto-protective role. However fragment N had no effect on survivin expression. In addition, cytoplasmic survivin was increased in keratinocytes exposed to UV-B light, whether RasGAP is cleaved (WT mice) or not (KI mice), indicating that survivin is not involved in fragment N mediated protection. Altogether these data indicate that fragment N is pivotal for cell protection against pathophysiologic damage and can encourage the development of therapies aimed to strengthen the resistance of cells against aggressive treatments. Importantly, this finding contributes to the characterization of how caspase-3 can be activated without inducing cell death, although further studies need to be conducted in order to completely characterize this pro-survival molecular mechanism.

Dual functions of DP1 promote biphasic Wnt-on and Wnt-off states during anteroposterior neural patterning.

DP1, a dimerization partner protein of the transcription factor E2F, is known to inhibit Wnt/β-catenin signalling along with E2F, although the function of DP1 itself was not well characterized. Here, we present a novel dual regulatory mechanism of Wnt/β-catenin signalling by DP1 independent from E2F. DP1 negatively regulates Wnt/β-catenin signalling by inhibiting Dvl-Axin interaction and by enhancing poly-ubiquitination of β-catenin. In contrast, DP1 positively modulates the signalling upon Wnt stimulation, via increasing cytosolic β-catenin and antagonizing the kinase activity of NLK. In Xenopus embryos, DP1 exerts both positive and negative roles in Wnt/β-catenin signalling during anteroposterior neural patterning. From subcellular localization analyses, we suggest that the dual roles of DP1 in Wnt/β-catenin signalling are endowed by differential nucleocytoplasmic localizations. We propose that these dual functions of DP1 can promote and stabilize biphasic Wnt-on and Wnt-off states in response to a gradual gradient of Wnt/β-catenin signalling to determine differential cell fates.

Regulation of the immune response by macrophage migration inhibitory factor: biological and structural features.

The classical T cell cytokine macrophage migration inhibitory factor (MIF) has reemerged recently as a critical mediator of the host immune and stress response. MIF has been found to be a mediator of several diseases including gram-negative septic shock and delayed-type hypersensitivity reactions. Its immunological functions include the modulation of the host macrophage and T and B cell response. In contrast to other known cytokines, MIF production is induced rather than suppressed by glucocorticoids, and MIF has been found to override the immunosuppressive effects of glucocorticoids. Recently, elucidation of the three-dimensional structure of MIF revealed that MIF has a novel, unique cytokine structure. Here the biological role of MIF is reviewed in view of its distinct immunological and structural properties.

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.

The variability of money velocity in a generalized cash-in-advance model

This paper presents a general equilibrium model of money demand wherethe velocity of money changes in response to endogenous fluctuations in the interest rate. The parameter space can be divided into two subsets: one where velocity is constant and equal to one as in cash-in-advance models, and another one where velocity fluctuates as in Baumol (1952). Despite its simplicity, in terms of paramaters to calibrate, the model performs surprisingly well. In particular, it approximates the variability of money velocity observed in the U.S. for the post-war period. The model is then used to analyze the welfare costs of inflation under uncertainty. This application calculates the errors derived from computing the costs of inflation with deterministic models. It turns out that the size of this difference is small, at least for the levels of uncertainty estimated for the U.S. economy.

MACROPHAGES FROM CROHN'S DISEASE PATIENTS EXHIBIT DEFICIENT REPAIR FUNCTIONS

AbstractBackground: Mucosal healing is becoming a major goal in the treatment of Crohn's disease. It has been previously reported that myeloid cells induce mucosal healing in a mouse model of acute colitis. The aim in this study is to investigate the pro-repair function of myeloid cells in healthy donors (HD) and Crohn's disease patients (CD).Methods: Peripheral blood mononuclear cells (PBMC) from HD and CD patients were isolated from blood samples and tested either directly or after differentiation ex-vivo into macrophages (Μφ). Intestinal macrophages (IMACs) were isolated from the bowel mucosa of patients undergoing intestinal surgical resections. Through an in vitro wound healing assay the repairing ability of these various human myeloid cells and the mechanisms responsible of wound healing were evaluated.Results: PBMC and myeloid CD14+ cells from HD and CD were not able to repair at any tested cell concentration. Μφ from HD and ulcerative colitis (UC) patients were able to induce wound healing and this capacity was partially mediated by Hepatocyte Growth Factor (HGF). Remarkably, CD Μφ were unable to promote wound healing and produced lower levels of HGF as compared to Μφ from HD or UC patients. In particular, Μφ from CD in active phase (ACD) exhibited the weakest repair function, but this defect was rescued if rh- GM-CSF was added during the differentiation of PBMCs. Interestingly, IMACs from HD promoted wound healing and produced HGF.Conclusion: We demonstrated that CD Μφ, unlike HD or UC Μφ, were defective in promoting wound healing, in particular if coming from an ACD. This deficient pro-repair function was related to a lower production of HGF. IMACs from HD colonic mucosa induced wound healing, confirming the results obtained with Μφ. Our results are in keeping with the current theory of CD as an innate immunodeficiency. In this context, Μφ may be responsible for the mucosal repair defects observed in CD patients and for the subsequent chronic activation of the adaptive immune response.

Transgenic expression of Ly49A on T cells impairs a specific antitumor response.

Inhibitory MHC receptors determine the reactivity and specificity of NK cells. These receptors can also regulate T cells by modulating TCR-induced effector functions such as cytotoxicity, cytokine production, and proliferation. Here we have assessed the capacity of mouse T cells expressing the inhibitory MHC class I receptor Ly49A to respond to a well-defined tumor Ag in vivo using Ly49A transgenic mice. We find that the presence of Ly49A on the vast majority of lymphocytes prevents the development of a significant Ag-specific CD8+ T cell response and, consequently, the rejection of the tumor. Despite minor alterations in the TCR repertoire of CD8+ T cells in the transgenic lines, precursors of functional tumor-specific CD8+ T cells exist but could not be activated most likely due to a lack of appropriate CD4+ T cell help. Surprisingly, all of these effects are observed in the absence of a known ligand for the Ly49A receptor as defined by its ability to regulate NK cell function. Indeed, we found that the above effects on T cells may be based on a weak interaction of Ly49A with Kb or Db class I molecules. Thus, our data demonstrate that enforced expression of a Ly49A receptor on conventional T cells prevents a specific immune response in vivo and suggest that the functions of T and NK cells are differentially sensitive to the presence of inhibitory MHC class I receptors.

p53-induced protein with a death domain (PIDD) isoforms differentially activate nuclear factor-kappaB and caspase-2 in response to genotoxic stress

Cells respond to DNA damage in a complex way and the fate of damaged cells depends on the balance between pro- and antiapoptotic signals. This is of crucial importance in cancer as genotoxic stress is implied both in oncogenesis and in classical tumor therapies. p53-induced protein with a death domain (PIDD), initially described as a p53-inducible gene, is one of the molecular switches able to activate a survival or apoptotic program. Two isoforms of PIDD, PIDD (isoform 1) and LRDD (isoform 2), have already been reported and we describe here a third isoform. These three isoforms are differentially expressed in tissues and cell lines. Genotoxic stress only affects PIDD isoform 3 mRNA levels, whereas isoforms 1 and 2 mRNA levels remain unchanged. All isoforms are capable of activating nuclear factor-kappaB in response to genotoxic stress, but only isoform 1 interacts with RIP-associated ICH-1/CED-3 homologous protein with a death domain and activates caspase-2. Isoform 2 counteracts the pro-apoptotic function of isoform 1, whereas isoform 3 enhances it. Thus, the differential splicing of PIDD mRNA leads to the formation of at least three proteins with antagonizing/agonizing functions, thereby regulating cell fate in response to DNA damage