Triatominae as a model of morphological plasticity under ecological pressure

The use of biochemical and genetic characters to explore species or population relationships has been applied to taxonomic questions since the 60s. In responding to the central question of the evolutionary history of Triatominae, i.e. their monophyletic or polyphyletic origin, two important questions arise (i) to what extent is the morphologically-based classification valid for assessing phylogenetic relationships? and (ii) what are the main mechanisms underlying speciation in Triatominae? Phenetic and genetic studies so far developed suggest that speciation in Triatominae may be a rapid process mainly driven by ecological factors.

Biometal muscle to restore atrial transport function in a permanent atrial fibrillation animal model: a potential tool in the treatment of end-stage heart failure.

BACKGROUND: Half of the patients with end-stage heart failure suffer from persistent atrial fibrillation (AF). Atrial kick (AK) accounts for 10-15% of the ejection fraction. A device restoring AK should significantly improve cardiac output (CO) and possibly delay ventricular assist device (VAD) implantation. This study has been designed to assess the mechanical effects of a motorless pump on the right chambers of the heart in an animal model. METHODS: Atripump is a dome-shaped biometal actuator electrically driven by a pacemaker-like control unit. In eight sheep, the device was sutured onto the right atrium (RA). AF was simulated with rapid atrial pacing. RA ejection fraction (EF) was assessed with intracardiac ultrasound (ICUS) in baseline, AF and assisted-AF status. In two animals, the pump was left in place for 4 weeks and then explanted. Histology examination was carried out. The mean values for single measurement per animal with +/-SD were analysed. RESULTS: The contraction rate of the device was 60 per min. RA EF was 41% in baseline, 7% in AF and 21% in assisted-AF conditions. CO was 7+/-0.5 l min(-1) in baseline, 6.2+/-0.5 l min(-1) in AF and 6.7+/-0.5 l min(-1) in assisted-AF status (p<0.01). Histology of the atrium in the chronic group showed chronic tissue inflammation and no sign of tissue necrosis. CONCLUSIONS: The artificial muscle restores the AK and improves CO. In patients with end-stage cardiac failure and permanent AF, if implanted on both sides, it would improve CO and possibly delay or even avoid complex surgical treatment such as VAD implantation.

Rasharkin Health Initiative

This project will build on previous work carried out over the last 3 years. There are 4 main aspects: - intergenerational work focusing on the development of a vegetable garden with pharmacy input on health advice - develop and promote the lunch club which has been very successful to date and has targeted people previously not accessing support or community services in the village - annual health fair - local carer’s advice centre to provide practice information and signposting services. This last aspect is the result of ongoing identification of the need to support carers over the last 2 years of the BCPP project. This project will be driven forward by a lay health worker working closely with the pharmacist Outcome: The project built on previous work. Some of the work included: health fayre, intergenerational garden, and luncheon club. Results from questionnaires showed that the project increased people's awareness of the causes of ill-health and how they might deal with them. People now see the pharmacist as a local and not just as someone dispensing medicine.

Task-dependent influence of genetic architecture and mating frequency on division of labour in social insect societies.

Division of labour is one of the most prominent features of social insects. The efficient allocation of individuals to different tasks requires dynamic adjustment in response to environmental perturbations. Theoretical models suggest that the colony-level flexibility in responding to external changes and internal perturbation may depend on the within-colony genetic diversity, which is affected by the number of breeding individuals. However, these models have not considered the genetic architecture underlying the propensity of workers to perform the various tasks. Here, we investigated how both within-colony genetic variability (stemming from variation in the number of matings by queens) and the number of genes influencing the stimulus (threshold) for a given task at which workers begin to perform that task jointly influence task allocation efficiency. We used a numerical agent-based model to investigate the situation where workers had to perform either a regulatory task or a foraging task. One hundred generations of artificial selection in populations consisting of 500 colonies revealed that an increased number of matings always improved colony performance, whatever the number of loci encoding the thresholds of the regulatory and foraging tasks. However, the beneficial effect of additional matings was particularly important when the genetic architecture of queens comprised one or a few genes for the foraging task's threshold. By contrast, a higher number of genes encoding the foraging task reduced colony performance with the detrimental effect being stronger when queens had mated with several males. Finally, the number of genes encoding the threshold for the regulatory task only had a minor effect on colony performance. Overall, our numerical experiments support the importance of mating frequency on efficiency of division of labour and also reveal complex interactions between the number of matings and genetic architecture.

Theoretical study of the electrostatically driven step of receptor-G protein recognition.

This study proposes a theoretical model describing the electrostatically driven step of the alpha 1 b-adrenergic receptor (AR)-G protein recognition. The comparative analysis of the structural-dynamics features of functionally different receptor forms, i.e., the wild type (ground state) and its constitutively active mutants D142A and A293E, was instrumental to gain insight on the receptor-G protein electrostatic and steric complementarity. Rigid body docking simulations between the different forms of the alpha 1 b-AR and the heterotrimeric G alpha q, G alpha s, G alpha i1, and G alpha t suggest that the cytosolic crevice shared by the active receptor and including the second and the third intracellular loops as well as the cytosolic extension of helices 5 and 6, represents the receptor surface with docking complementarity with the G protein. On the other hand, the G protein solvent-exposed portions that recognize the intracellular loops of the activated receptors are the N-terminal portion of alpha 3, alpha G, the alpha G/alpha 4 loop, alpha 4, the alpha 4/beta 6 loop, alpha 5, and the C-terminus. Docking simulations suggest that the two constitutively active mutants D142A and A293E recognize different G proteins with similar selectivity orders, i.e., G alpha q approximately equal to G alpha s > G alpha i > G alpha t. The theoretical models herein proposed might provide useful suggestions for new experiments aiming at exploring the receptor-G protein interface.

Cannabinoids reduce ErbB2-driven breast cancer progression through Akt inhibition.

BACKGROUND ErbB2-positive breast cancer is characterized by highly aggressive phenotypes and reduced responsiveness to standard therapies. Although specific ErbB2-targeted therapies have been designed, only a small percentage of patients respond to these treatments and most of them eventually relapse. The existence of this population of particularly aggressive and non-responding or relapsing patients urges the search for novel therapies. The purpose of this study was to determine whether cannabinoids might constitute a new therapeutic tool for the treatment of ErbB2-positive breast tumors. We analyzed their antitumor potential in a well established and clinically relevant model of ErbB2-driven metastatic breast cancer: the MMTV-neu mouse. We also analyzed the expression of cannabinoid targets in a series of 87 human breast tumors. RESULTS Our results show that both Delta9-tetrahydrocannabinol, the most abundant and potent cannabinoid in marijuana, and JWH-133, a non-psychotropic CB2 receptor-selective agonist, reduce tumor growth, tumor number, and the amount/severity of lung metastases in MMTV-neu mice. Histological analyses of the tumors revealed that cannabinoids inhibit cancer cell proliferation, induce cancer cell apoptosis, and impair tumor angiogenesis. Cannabinoid antitumoral action relies, at least partially, on the inhibition of the pro-tumorigenic Akt pathway. We also found that 91% of ErbB2-positive tumors express the non-psychotropic cannabinoid receptor CB2. CONCLUSIONS Taken together, these results provide a strong preclinical evidence for the use of cannabinoid-based therapies for the management of ErbB2-positive breast cancer.

Uncertainty Quantification Of A Semi-Supervised Support Vector Regression Reservoir Model

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. Recent advances in machine learning offer a novel approach to model spatial distribution of petrophysical properties in complex reservoirs alternative to geostatistics. The approach is based of semisupervised learning, which handles both ?labelled? observed data and ?unlabelled? data, which have no measured value but describe prior knowledge and other relevant data in forms of manifolds in the input space where the modelled property is continuous. Proposed semi-supervised Support Vector Regression (SVR) model has demonstrated its capability to represent realistic geological features and describe stochastic variability and non-uniqueness of spatial properties. On the other hand, it is able to capture and preserve key spatial dependencies such as connectivity of high permeability geo-bodies, which is often difficult in contemporary petroleum reservoir studies. Semi-supervised SVR as a data driven algorithm is designed to integrate various kind of conditioning information and learn dependences from it. The semi-supervised SVR model is able to balance signal/noise levels and control the prior belief in available data. In this work, stochastic semi-supervised SVR geomodel is integrated into Bayesian framework to quantify uncertainty of reservoir production with multiple models fitted to past dynamic observations (production history). Multiple history matched models are obtained using stochastic sampling and/or MCMC-based inference algorithms, which evaluate posterior probability distribution. Uncertainty of the model is described by posterior probability of the model parameters that represent key geological properties: spatial correlation size, continuity strength, smoothness/variability of spatial property distribution. The developed approach is illustrated with a fluvial reservoir case. The resulting probabilistic production forecasts are described by uncertainty envelopes. The paper compares the performance of the models with different combinations of unknown parameters and discusses sensitivity issues.

Mapping complex tissue architecture with diffusion spectrum magnetic resonance imaging.

Methods are presented to map complex fiber architectures in tissues by imaging the 3D spectra of tissue water diffusion with MR. First, theoretical considerations show why and under what conditions diffusion contrast is positive. Using this result, spin displacement spectra that are conventionally phase-encoded can be accurately reconstructed by a Fourier transform of the measured signal's modulus. Second, studies of in vitro and in vivo samples demonstrate correspondence between the orientational maxima of the diffusion spectrum and those of the fiber orientation density at each location. In specimens with complex muscular tissue, such as the tongue, diffusion spectrum images show characteristic local heterogeneities of fiber architectures, including angular dispersion and intersection. Cerebral diffusion spectra acquired in normal human subjects resolve known white matter tracts and tract intersections. Finally, the relation between the presented model-free imaging technique and other available diffusion MRI schemes is discussed.

Genetic and phenotypic architecture of metabolic syndrome-associated components in dyslipidemic and normolipidemic subjects: the GEMS Study.

Atherogenic dyslipidemia, manifest by low HDL-cholesterol and high TG levels, is an important component of ATP-III defined metabolic syndrome. Here, we dissected the phenotypic and genetic architecture of these traits by assessing their relationships with other metabolically relevant measures, including plasma adipo-cytokines, highly sensitive C-reactive protein (hsCRP) and LDL particle size, in a large family data set (n=2800) and in an independent set of dyslipidemic cases (n=716) and normolipidemic controls (n=1073). We explored the relationships among these phenotypes using variable clustering and then estimated their genetic heritabilities and cross-trait correlations. In families, four clusters explained 61% of the total variance, with one adiposity-related cluster (including hsCRP), one BP-related cluster, and two lipid-related clusters (HDL-C, TG, adiponectin and LDL particle size; apoB and non-HDL-C). A similar structure was observed in dyslipidemic cases and normolipidemic controls. The genetic correlations in the families largely paralleled the phenotype clustering results, suggesting that common genes having pleiotropic effects contributed to the correlations observed. In summary, our analyses support a model of metabolic syndrome with two major components, body fat and lipids, each with two subcomponents, and quantifies their degree of overlap with each other and with metabolic-syndrome related measures (adipokines, LDL particle size and hsCRP).

Driven fragmentation of granular gases

The dynamics of homogeneously heated granular gases which fragment due to particle collisions is analyzed. We introduce a kinetic model which accounts for correlations induced at the grain collisions and analyze both the kinetics and relevant distribution functions these systems develop. The work combines analytical and numerical studies based on direct simulation Monte Carlo calculations. A broad family of fragmentation probabilities is considered, and its implications for the system kinetics are discussed. We show that generically these driven materials evolve asymptotically into a dynamical scaling regime. If the fragmentation probability tends to a constant, the grain number diverges at a finite time, leading to a shattering singularity. If the fragmentation probability vanishes, then the number of grains grows monotonously as a power law. We consider different homogeneous thermostats and show that the kinetics of these systems depends weakly on both the grain inelasticity and driving. We observe that fragmentation plays a relevant role in the shape of the velocity distribution of the particles. When the fragmentation is driven by local stochastic events, the longvelocity tail is essentially exponential independently of the heating frequency and the breaking rule. However, for a Lowe-Andersen thermostat, numerical evidence strongly supports the conjecture that the scaled velocity distribution follows a generalized exponential behavior f (c)~exp (−cⁿ), with n ≈1.2, regarding less the fragmentation mechanisms

The role of Toll-like Receptor (TLR) 9 in the development of a T-helper (Th)1/Th2 response in the murine model of infection with " Leishmania major "

1.1 SUMMARY The role of the non-specific innate immune system is as important as the elaboration of the adaptive immune system in the initiation of an immune response to pathogens. The role of the Toll-like receptors (TLRs) in the innate immune response to virus and bacterial pathogens is widely recognised, however, little is known about the role of TLRs in host defence against eukaryotic pathogens. Immunologic investigations on the marine model of infection with Leishmania major (L. major) have correlated the outcome of the disease with expansion of different subsets of CD4+ cells, designated Th1 and Th2. The resistance of C57BL/6, CBA and C3H/He mice is linked with an IL-12 driven Th1 response. In BALB/c mice the susceptibility correlates with an IL-4 driven Th2 response. The initial event promoting the development of a Th1 or Th2 response still remains elusive. Recently, the contribution of the TLR signalling pathway in the innate and acquired immune response to infection with the intracellular protozoan parasite L. major has been demonstrated. Thus, the purpose of this study is to determine whether TLRs may play a role in influencing the outcome of the infection by directing the development of a Th1 or a Th2 response during infection with L, major parasites, in resistant C57BL/6 and susceptible BALB/c mice, respectively. We demonstrated that MyD88, the major TLR adaptor molecule is necessary for C57BL/6 to develop a resistant Th1 response following L. major infection. Our data show the essential role of MyD88 in the establishment of a protective Th1 response. We subsequently aimed to determine which TLRs may be involved in the protective response. Since TLR2 and TLR4 have shown to have a potential role for Leishmania recognition, we analysed the course of infection in TLR2 and TLR4 deficient mice on a C57BL/6 resistant background following L. major infection. Our results clearly demonstrate that TLR2 or TLR4 aze dispensable to control the outcome of the disease as the TLR2 and TLR4 knockout mice developed a protective Th1 response. With the aim of determining a potential TLR candidate important in the initiation of the Thl response, we assessed the mRNA expression of different TLRs (TLR1 to TLR9) using quantitative real-time RT-PCR at different time points during the first week of infection. The results clearly showed an upregulation of TLR7 and TLR9 mRNA expression during the early phase of infection in resistant C57BL/6 mice but not in susceptible BALB/c mice. To provide in vivo evidence for the role for, these TLRs in the outcome of cutaneous leishmaniasis, studies using TLR7 and TLR9 deficient mice on a resistant C57BL/6 background were performed. The TLR7 deficient mice developed a resistance phenotype that was comparable with C57BL/6 wild type mice. Thus, the presence of TLR7 is not indispensable for the development of a Th1 response and resistance to infection. On the contrary, TLR9 deficient mice on the C57BL/6 resistant background showed high variability in the outcome of the disease. Although some mice behave as resistant C57BL/6 mice, half of them developed high lesion following infection and showed a decrease in IFN-γ production and an increase in IL-4 as compared to wild type mice. These results suggest that TLR9 may be involved in the control of infection. To test the hypothesis that regulatory T cells (Treg) are playing a role in the high variability in the disease outcome in TLR9 deficient mice, depletion of CD4+CD25+ T cells with a specific antibody three days before infection with L. major were performed Interestingly, these treated mice developed large lesions, low IL-4 and decreased IFN-γ producion when compared to untreated mice. A better understanding of the mechanism by which Treg cells influence the outcome of the disease in TLR9 deficient mice following L. major infection is currently under investigation. Altogether, this study demonstrates the importance of TLR9 in the induction of a protective T'h1 response, a process that is involved in the resolution of the lesion induced by L. major infection. 1.2 RÉSUMÉ Le rôle de la réponse immunitaire innée a longtemps été négligé quant à l'impact qu'elle pourrait avoir dans l'initiation d'une réponse immune adaptative efficace dirigée contre un pathogène. Si l'importance des récepteurs Toll-like (TLR) du système inné dans la reconnaissance des virus et bactéries a été démontrée, son rôle dans la défense contre les pathogènes eucaryotes reste encore très élusif. Récemment, il a été montré que les voies de signalisation provenant de l'activation des TLRs pouvaient initier la réponse immunitaire innée et adaptative après une infection avec le parasite protozoaire Leishmania major (L. major). Dans un modèle marin d'infection avec L. major alors que la plupart des souches de souris telles que C57BL/6 sont résistantes à l'infection et développent une réponse immunitaire de type T helper 1 (Th1) induite par IL-12, peu de souches dont les BALB/c sont sensibles et développent une réponse Th2 induite par IL-4. La différentiation Th1/Th2 est un événement qui prend place de manière définitive lors de la première semaine après infection. Les événements précoces promouvant le développement d'une réponse Th1 ou Th2 n'étant pas connus, l'objectif de ce travail a été de démontrer un rôle des TLRs dans l'initiation d'une réponse immune innée et adaptative suite à l'infection par L. major. Nous avons démontré que MyD88, une molécule importante dans le processus de signalisation des TLRs, est nécessaire pour que les souris résistantes C57BL/6 développent une réponse Th1 protectrice. L'importance du rôle de TLR2 et TLR4 dans la reconnaissance du parasite Leishmania ayant été démontrée, nous avons privilégié l'analyse de la réponse immunitaire suite à une infection in vivo de souris déficiente en TLR2 ou TLR4 sur un fond génétique résistant. Les résultats obtenus montrent que la présence de ces récepteurs n'est pas indispensable pour le contrôle de l'infection et la polarisation d'une réponse Th1 caractéristique de la résistance à L. major. Cependant d'autres TLRs peuvent aussi activer la voie de signalisation MyD88 dépendante. L'expression de l'ARNm des différents TLRs dans les ganglions drainant de souris sensibles et résistantes pendant la première semaine d'infection a été déterminée par PCR quantitative en temps réel. Les résultats obtenus montrent que l'ARNm de TLR7 et TLR9 était régulé positivement suite à l'infection par L. major chez les souris résistantes C57BL/6 alors qu'aucune modulation n'était détectable chez les souris sensibles BALB/c. Le rôle des récepteurs TLR7 et TLR9 a donc été évalué par l'infection par L. major des souris déficientes en TLR7 et TLR9 sur fond génétique C57BL/6. Nos résultats ont clairement démontré que les souris déficientes en TLR7 montrent une réponse immunitaire identique à celle des souris résistantes C57BL/6, signifiant que TLR7 n'est pas indispensable au développement d'une Th1 ainsi qu'au contrôle de la parasitémie. Paz contre, les souris déficientes en TLR9 sur un fond génétique résistant ont montré une grande variabilité dans la réponse à l'infection. En effet, la moitié des souris deviennent sensibles à l'infection, ceci étant associé à une diminution dans la production d'IFN-γ et à une augmentation de la production d'IL-4. Ces résultats suggèrent que TLR9 est impliqué dans le contrôle de la lésion et de la réponse immunitaire suite à l'infection avec L. major. Cependant les résultats avec les souris déficientes en TLR9 montrant une grande hétérogénéité et une balance Th1/Th2 instable, nous avons émis l'hypothèse que les cellules T régulatrices pouvaient être impliquées dans ce phénomène. Nous avons effectivement constaté qu'après déplétion des cellules CD4+CD25+, les souris déficientes en TLR9 développent des lésions aussi grandes que les souris BALB/c après infection par L. major. Cependant le nombre de parasites reste le même que chez les souris C57BL/6. De plus la production d'IL-4 ainsi que celle d'IFN-γ reste extrêment bas. Les mécanismes régulateurs impliqués dans ce processus sont en cours d'analyse. Ce travail met en évidence l'importance du TLR9 dans le développement d'une réponse Th1 lors d'une infection avec L. major, un processus nécessaire pour la résistance à l'infection. 1.3 RESUME POUR UN LARGE PUBLIC La leishmaniose est une maladie parasitaire répandue dans le monde entier et touchant plus de 88 pays. L'incidence mondiale de la leishmaniose cutanée et de 1 à 1,5 million de nouveaux cas par année. Plus de 12 millions de personnes sont affectées par la maladie et 350 millions de personnes sont une population à risque. Un modèle marin d'infection avec Leishmania major (L. major) a été établi qui reproduit plusieurs tableaux cliniques observés dans le cas de la leishmaniose cutanée chez l'homme. L'analyse de la réponse immunitaire dans les souris infectées par L. major a permis de distinguer deux groupes : les souris de la plupart des souches telles que C57BL/6 sont résistantes à l'infection et développent une réponse immunitaire de type T helper 1 (Th1), alors que quelques souches dont les BALB/c sont sensibles et développent une réponse de type Th2. La réponse immune adaptative dans le modèle d'infection avec L. major à été largement étudiée. Cependant, les événements précoces déterminants pour le développement d'une réponse Th1 ou Th2 restent encore très flous. Récemment, plusieurs publications ont montré que les récepteurs Toll-like (TLR) peuvent contribuer à l'initiation de la réponse immunitaire lors d'une infection avec le parasite intracellulaire L. major. Dans ce travail de thèse, nous avons étudié le rôle de MyD88, une molécule importante dans le processus de signalisation des TLRs, dans la réponse immune suite à une infection avec L. major. En l'absence de MyD88, les souris normalement résistantes à l'infection avec L. major deviennent sensibles et développent des lésions importantes. Ces souris ne sont plus capables de développer une réponse Thl, normalement caractéristique de leur phénotype résistant. Nous avons ensuite tenté de comprendre quels TLRs, plus précisément, pouvait être impliqué dans ce processus. Malgré quelques évidences démontrant que TLR2 et TLR4 pouvaient avoir un rôle important dans l'initiation d'une réponse immunitaire adaptative à Leishmania, nous avons montré que, in vivo après infection avec L. major, la déficience d'un de ces récepteurs n'était pas suffisante à faire basculer la réponse immunitaire. Les souris C57BL/6 déficient en TLR2 ou TLR4 peuvent parfaitement contrôler l'évolution de la maladie. De plus, ces souris, malgré l'absence de TLR2 ou TLR4, sont capables de monter une parfaite réponse Thl. Etant donné que TLR2 et TLR4 n'étaient pas essentiels pour la résistance à la maladie, nous avons analysé les TLRs, parmi les 12 décrits qui pouvaient être indispensables au développement d'une réponse de type Th1 associée à la résistance à l'infection par Leishmania. Nos expériences ont montré que l'expression de l'ARN messager (ARNm) de TLR7 et TLR9 était modulée suite à l'infection par L. major chez la souris résistante C57BL/6 alors qu'aucune modulation n'était visible chez les souris sensible BALB/c. Pensant que ces TLRs pourraient jouer un rôle dans la réponse immunitaire au parasite, nous avons étudié l'évolution de l'infection dans les souris déficientes en TLR7 et TLR9. Nos résultats ont clairement démontré que TLR7 n'était pas indispensable à la résistance au parasite alors que l'absence de TLR9 avait des conséquences radicales sur le contrôle de la lésion et de la réponse immunitaire suite à l'infection avec L. major. Ce travail révèle ainsi l'importance du TLR9 dans le développement d'une réponse Th1 lors d'une infection avec L. major, un processus nécessaire pour la résistance à l'infection. Il est a noté que nos résultats sont en accord avec le fait que les motifs CpG, qui sont des immunostimulateurs interagissant avec le TLR9, ont une activité adjuvante importante dans la préparation de vaccins contre la leishmaniose. Une meilleure compréhension des mécanismes immunologiques impliquant le TLR9 dans la reconnaissance du parasite est alors indispensable pour le développement de vaccins thérapeutiques efficaces.

Natural genetic variation of root system architecture from Arabidopsis to Brachypodium: towards adaptive value.

Root system architecture is a trait that displays considerable plasticity because of its sensitivity to environmental stimuli. Nevertheless, to a significant degree it is genetically constrained as suggested by surveys of its natural genetic variation. A few regulators of root system architecture have been isolated as quantitative trait loci through the natural variation approach in the dicotyledon model, Arabidopsis. This provides proof of principle that allelic variation for root system architecture traits exists, is genetically tractable, and might be exploited for crop breeding. Beyond Arabidopsis, Brachypodium could serve as both a credible and experimentally accessible model for root system architecture variation in monocotyledons, as suggested by first glimpses of the different root morphologies of Brachypodium accessions. Whether a direct knowledge transfer gained from molecular model system studies will work in practice remains unclear however, because of a lack of comprehensive understanding of root system physiology in the native context. For instance, apart from a few notable exceptions, the adaptive value of genetic variation in root system modulators is unknown. Future studies should thus aim at comprehensive characterization of the role of genetic players in root system architecture variation by taking into account the native environmental conditions, in particular soil characteristics.

T-Cell Receptors Binding Orientation over Peptide/MHC Class I Is Driven by Long-Range Interactions.

Crystallographic data about T-Cell Receptor - peptide - major histocompatibility complex class I (TCRpMHC) interaction have revealed extremely diverse TCR binding modes triggering antigen recognition. Understanding the molecular basis that governs TCR orientation over pMHC is still a considerable challenge. We present a simplified rigid approach applied on all non-redundant TCRpMHC crystal structures available. The CHARMM force field in combination with the FACTS implicit solvation model is used to study the role of long-distance interactions between the TCR and pMHC. We demonstrate that the sum of the coulomb interactions and the electrostatic solvation energies is sufficient to identify two orientations corresponding to energetic minima at 0° and 180° from the native orientation. Interestingly, these results are shown to be robust upon small structural variations of the TCR such as changes induced by Molecular Dynamics simulations, suggesting that shape complementarity is not required to obtain a reliable signal. Accurate energy minima are also identified by confronting unbound TCR crystal structures to pMHC. Furthermore, we decompose the electrostatic energy into residue contributions to estimate their role in the overall orientation. Results show that most of the driving force leading to the formation of the complex is defined by CDR1,2/MHC interactions. This long-distance contribution appears to be independent from the binding process itself, since it is reliably identified without considering neither short-range energy terms nor CDR induced fit upon binding. Ultimately, we present an attempt to predict the TCR/pMHC binding mode for a TCR structure obtained by homology modeling. The simplicity of the approach and the absence of any fitted parameters make it also easily applicable to other types of macromolecular protein complexes.

Functional architecture of olfactory ionotropic glutamate receptors.

Ionotropic glutamate receptors (iGluRs) are ligand-gated ion channels that mediate chemical communication between neurons at synapses. A variant iGluR subfamily, the Ionotropic Receptors (IRs), was recently proposed to detect environmental volatile chemicals in olfactory cilia. Here, we elucidate how these peripheral chemosensors have evolved mechanistically from their iGluR ancestors. Using a Drosophila model, we demonstrate that IRs act in combinations of up to three subunits, comprising individual odor-specific receptors and one or two broadly expressed coreceptors. Heteromeric IR complex formation is necessary and sufficient for trafficking to cilia and mediating odor-evoked electrophysiological responses in vivo and in vitro. IRs display heterogeneous ion conduction specificities related to their variable pore sequences, and divergent ligand-binding domains function in odor recognition and cilia localization. Our results provide insights into the conserved and distinct architecture of these olfactory and synaptic ion channels and offer perspectives into the use of IRs as genetically encoded chemical sensors. VIDEO ABSTRACT:

Essays on the principles and adoption of entreprise-wide architecture

Enterprise-wide architecture has become a necessity for organizations to (re)align information technology (IT) to changing business requirements. Since a city planning metaphor inspired enterprise-wide architecture, this dissertation's research axes can be outlined by similarities between cities and enterprises. Both are characterized as dynamic super-systems that need to address the evolving interest of various architecture stakeholders. Further, both should simultaneously adhere to a set of principles to guide the evolution of architecture towards the expected benefits. The extant literature on enterprise-wide architecture not only disregards architecture adoption's complexities but also remains vague about how principles guide architecture evolution. To bridge this gap, this dissertation contains three interrelated research streams examining the principles and adoption of enterprise-wide architecture. The first research stream investigates organizational intricacies inherent in architecture adoption. It characterizes architecture adoption as an ongoing organizational adaptation process. By analyzing organizational response behaviors in this adaptation process, it also identifies four archetypes that represent very diverse architecture approaches. The second research stream ontologically clarifies the nature of architecture principles along with outlining new avenues for theoretical contributions. This research stream also provides an empirically validated set of principles and proposes a research model illustrating how principles can be applied to generate expected architecture benefits. The third research stream examines architecture adoption in multinational corporations (MNCs). MNCs are Specified by unique organizational characteristics that constantly strive for balancing global integration and local responsiveness. This research stream characterizes MNCs' architecture adoption as a continuous endeavor. This endeavor tries to constantly synchron ize architecture with stakeholders' beliefs about how to balance global integration and local responsiveness. To conclude, this dissertation provides a thorough explanation of a long-term journey in Which organizations learn over time to adopt an effective architecture approach. It also clarifies the role of principles to purposefully guide the aforementioned learning process. - L'Architecture d'Entreprise (AE) est devenue une nécessité pour permettre aux organisations de (ré)aligner les technologies de l'information (TI) avec les changements en termes de besoins métiers. En se basant sur la métaphore de la planification urbaine dont l'AE s'est inspirée, cette dissertation peut être présentée comme une comparaison entre les villes et les entreprises; les deux sont des super-systèmes dynamiques ayant besoin de répondre aux intérêts d'acteurs divers et variés en constants évolution. De plus, les deux devraient souscrire simultanément à un ensemble de principes afin de faire converger l'évolution de l'architecture vers les bénéfices attendus. La littérature sur l'AE, non seulement ne prend pas en considération les complexités de l'adoption d'architecture, mais aussi reste vague sur la manière dont les principes guident l'évolution de l'architecture. Pour pallier ce manque, cette dissertation est composée de trois volets de recherche étroitement liés examinant les principes et l'adoption de l'AE. Le premier volet examine la complexité organisationnelle inhérente à l'adoption de l'architecture. Il caractérise l'adoption de l'architecture en tant que processus d'adaptation continu. En analysant le comportement organisationnel en réponse à ce processus d'adaptation, ce volet distingue quatre archétypes représentant la diversité des approches de l'architecture. Le deuxième volet de recherche clarifie de manière ontologique la nature des principes d'architecture et envisage les contributions théoriques futures possibles. Cet axe de recherche fournit aussi un ensemble de principes, validés de manière empirique, et propose un modèle de recherche illustrant la manière dont ces principes peuvent être appliqués afin de générer les bénéfices attendus de l'architecture. Le troisième volet examine l'adoption de l'architecture dans les entreprises multinationales. Ces dernières possèdent des caractéristiques organisationnelles uniques et sont constamment à la recherche d'un équilibre entre une intégration globale et une flexibilité locale tout en prenant en compte les convictions des divers acteurs sur la manière d'atteindre cet équilibre. Pour conclure, cette dissertation fournit une explication sur le long voyage au cours duquel les entreprises apprennent à adopter une approche d'architecture efficace. Elle clarifie aussi le rôle des principes dans l'accompagnement de ce processus d'apprentissage.