Indirect likelihood inference

Given a sample from a fully specified parametric model, let Zn be a given finite-dimensional statistic - for example, an initial estimator or a set of sample moments. We propose to (re-)estimate the parameters of the model by maximizing the likelihood of Zn. We call this the maximum indirect likelihood (MIL) estimator. We also propose a computationally tractable Bayesian version of the estimator which we refer to as a Bayesian Indirect Likelihood (BIL) estimator. In most cases, the density of the statistic will be of unknown form, and we develop simulated versions of the MIL and BIL estimators. We show that the indirect likelihood estimators are consistent and asymptotically normally distributed, with the same asymptotic variance as that of the corresponding efficient two-step GMM estimator based on the same statistic. However, our likelihood-based estimators, by taking into account the full finite-sample distribution of the statistic, are higher order efficient relative to GMM-type estimators. Furthermore, in many cases they enjoy a bias reduction property similar to that of the indirect inference estimator. Monte Carlo results for a number of applications including dynamic and nonlinear panel data models, a structural auction model and two DSGE models show that the proposed estimators indeed have attractive finite sample properties.

The stabilizing effects of the acquired immunity on the schistosomiasis transmission modeling - the sensitivity Analysis

A mathematical model is proposed to analyze the effects of acquired immunity on the transmission of schistosomiasis in the human host. From this model the prevalence curve dependent on four parameters can be obtained. These parameters were estimated fitting the data by the maximum likelihood method. The model showed a good retrieving capacity of real data from two endemic areas of schistosomiasis: Touros, Brazil (Schistosoma mansoni) and Misungwi, Tanzania (S. haematobium). Also, the average worm burden per person and the dispersion of parasite per person in the community can be obtained from the model. In this paper, the stabilizing effects of the acquired immunity assumption in the model are assessed in terms of the epidemiological variables as follows. Regarded to the prevalence curve, we calculate the confidence interval, and related to the average worm burden and the worm dispersion in the community, the sensitivity analysis (the range of the variation) of both variables with respect to their parameters is performed.

Predictors of HIV-protection behaviour in HIV-positive men who have sex with casual male partners: a test of the explanatory power of an extended Information-Motivation-Behavioural Skills model.

This prospective study applies an extended Information-Motivation-Behavioural Skills (IMB) model to establish predictors of HIV-protection behaviour among HIV-positive men who have sex with men (MSM) during sex with casual partners. Data have been collected from anonymous, self-administered questionnaires and analysed by using descriptive and backward elimination regression analyses. In a sample of 165 HIV-positive MSM, 82 participants between the ages of 23 and 78 (M=46.4, SD=9.0) had sex with casual partners during the three-month period under investigation. About 62% (n=51) have always used a condom when having sex with casual partners. From the original IMB model, only subjective norm predicted condom use. More important predictors that increased condom use were low consumption of psychotropics, high satisfaction with sexuality, numerous changes in sexual behaviour after diagnosis, low social support from friends, alcohol use before sex and habitualised condom use with casual partner(s). The explanatory power of the calculated regression model was 49% (p<0.001). The study reveals the importance of personal and social resources and of routines for condom use, and provides information for the research-based conceptualisation of prevention offers addressing especially people living with HIV ("positive prevention").

Universitat i discapacitat: construint un model d’aula inclusiva en el marc universitari

La present investigació es centre en crear un programa de formació i assessorament docent per atendre la diversitat d’estudiants en el marc universitari mitjançant els principis del disseny universal de la instrucció (DUI). D’aquesta manera es pretén donar resposta: a) a la necessitat d’implementar un model pedagògic en el marc universitari que doni resposta a la diversitat d’estudiants, b) de formar i canviar actituds docents vers la discapacitat i c) d’adaptar el nou marc legislatiu espanyol en matèria de discapacitat a les aules de les nostres universitats. A través d’un procés d’investigació-acció es detecten quins són les necessitats i dificulats pedagògiques, dels docents de les diferents universitats catalanes, per construir espais educatius que garanteixin la igultat d’oportunitats als estudiants amb discapacitat. Les dades obtingudes ens permeten crear una proposta de formació pels docents universitaris, basada en el paradigma educatiu del disseny universal de la instrucció.

Sexual protection behavior in HIV-positive gay men: testing a modified information-motivation-behavioral skills model.

This study on determinants of sexual protection behavior among HIV-positive gay men used the empirically tested information-motivation-behavioral skills (IMB) model. HIV-specific variables were added to the model to determine factors decisive for condom use with steady and casual partners. Data were collected using an anonymous, standardized self-administered questionnaire. Study participants were recruited at HIV outpatient clinics associated with the Eurosupport Study Group and the Swiss HIV Cohort Study. To identify factors associated with condom use, backward elimination regression analyses were performed. Overall, 838 HIV-infected gay men from 14 European countries were included in this analysis. About 53% of them reported at least one sexual contact with a steady partner; 62.5% had sex with a casual partner during the last 6 months. Forty-three percent always used condoms with steady partners and 44% with casual partners. High self-efficacy and subjective norms in favor of condom-use were associated with increased condom use with casual and steady partners, whereas feeling depressed was associated with decreased condom use with casual partners. Condoms were used less often with HIV-positive partners. Self-efficacy as an important behavioral skill to perform protection behavior was influenced by lower perceived vulnerability, higher subjective norms, and more positive safer sex attitudes. The IMB-model constructs appeared to be valid; however, not all the model predictors could be determined as hypothesized. Besides the original IMB constructs, HIV-specific variables, including sexual partners' serostatus and mental health, explained condom use. Such factors should be considered in clinical interventions to promote "positive prevention."

Fourth order pseudo maximum likelihood methods

We extend PML theory to account for information on the conditional moments up to order four, but without assuming a parametric model, to avoid a risk of misspecification of the conditional distribution. The key statistical tool is the quartic exponential family, which allows us to generalize the PML2 and QGPML1 methods proposed in Gourieroux et al. (1984) to PML4 and QGPML2 methods, respectively. An asymptotic theory is developed. The key numerical tool that we use is the Gauss-Freud integration scheme that solves a computational problem that has previously been raised in several fields. Simulation exercises demonstrate the feasibility and robustness of the methods [Authors]

ASIST suicide prevention training - all-island evaluation report

The findings of a Public Health Agency evaluation report on a suicide prevention training programme were today presented at the North South Ministerial Council Health Sector meeting.ASIST, The Applied Suicide Intervention Skills Training programme, has to date been delivered to more than 20,000 people in the Republic of Ireland and more than 11,000 people in Northern Ireland. This two day course, delivered by a wide range of organisations including those from the voluntary/community sector, for professionals and the public helps individuals provide emergency help to people at risk of suicidal behaviour. It also develops a cooperative network among participants, since often many people have to work together to prevent suicide.Talking about the findings of this work, Dr Eddie Rooney, Chief Executive, PHA, said: "Both the PHA and the National Office for Suicide Prevention (NOSP), based in the Republic of Ireland, are concerned for any loss of life through suicide and we send our condolences to all families who have been bereaved. We know ASIST training brings a positive element to suicide prevention. Those who have been trained said that the two biggest advantages are that they know when, how and have the confidence to help people who are under pressure and that it helps to build positive links between community and voluntary organisations and the health service. I am pleased that this has been borne out in the evaluation and we hope ASIST will continue to be of enormous benefit and will contribute to a reduction in suicidal behaviour and the tragedy that this brings to our community".This evaluation found that within organisations where staff had participated in ASIST training, there were improvements in service development; staff attitudes, confidence and skills in relation to suicide and suicide intervention and in policies and procedures. At a community level, ASIST was found to have contributed to a sense of empowerment through an increased confidence in being able to deal with suicide and suicidal behaviour.The report also shows that the ASIST model offers a common language, helping communication between the community or voluntary organisations and those from a health background. In fact this training helped to cancel out any differences between those with mental health qualifications and those without, in terms of knowledge, skills, attitude and willingness to intervene. The study also confirmed that ASIST training was most relevant to those who were likely to be in contact with a person 'at risk'.In welcoming the publication of the report Geoff Day, Director of the NOSP, said: "This report is an independent evaluation of the ASIST programme, it has allowed us to demonstrate the effectiveness of the programme in increasing community participants confidence and ability to respond to individuals in suicidal crisis.He added: "The fact the evaluation was completed on an all-island basis allows the NOSP and the PHA to avoid duplication of resources, improve coordination of suicide prevention training programmes across both jurisdictions and allows us to learn from different approaches used in suicide prevention across the island of Ireland."He reiterated the Health Service Executive commitment to the continued implementation of quality assured training programmes as part of Reach out: the National Strategy for Action on Suicide Prevention.ASIST training is being rolled out in Northern Ireland as part of the implementation of the 'Protect Life' suicide prevention strategy, which was published by the Department of Health, Social Services and Public Safety in 2006.A copy of the evaluation report can be found below and in the publications section of this website, by clicking here

A Study to Examine the Attitudes of General Practitioners Towards Drug Users in the North East Region of Ireland

The research examines general practitioners attitudes and how these effect the management of drug misusers within their practice. The methodology is quantitative in approach. The instrument used is a structured postal questionnaire. Participants include all general practitioners within the North East region of Ireland. Anonymity and confidentiality of all respondents are guaranteed. Data was collected over a six week period, under the following headings - attitudes and beliefs, factors influencing treatment, treatment options, training and demographics. Attitudes and beliefs towards drug users were measured using a five point Likert scale ranging from strongly agrees to strongly disagree. The data was analysed with the aid of a computer package, SPSS allowing descriptive statistics to be presented. Results indicate that the majority of respondents are male. There appears to be sympathy towards drug users and that treatment approaches should be holistic. However, there appears to be a major lack of confidence in treating and managing drug misusers. Patient, social and practice factors all influence the decision to the drug misuser. Treatment options are varied, ranging from methadone maintenance to referral for residential treatment. However, a number of respondents offer no treatment for drug misusers. General practitioners do not feel adequately trained in treating and/or managing this client group. Results indicate that improved communication, ongoing education and more research is needed in this area.This resource was contributed by The National Documentation Centre on Drug Use.

Dementia 2013: The hidden voice of loneliness

Dementia 2013: The hidden voice of loneliness is Alzheimer's Society's annual report examining the quality of life for people with dementia.The report found that over half of the general public (54 per cent) believe that people with dementia have a bad quality of life. This was echoed in the feedback from people with dementia with 70 per cent saying they had stopped doing things they used to due because of lack of confidence. The majority of people with dementia also felt anxious or depressed (63 per cent) and a third of people (35 per cent) said they’d lost friends after a diagnosis.��Other key statistics in Dementia 2013 include:38 per cent of all people with dementia said they felt lonelyPeople with dementia said they relied on relatives and friends for social contact and yet almost a quarter (21 per cent) speak to friends or family on the telephone less than once a month. ��Only 23 per cent of the general public thought it was possible for a person with dementia to live alone ��16 per cent answered that they would not be comfortable talking to someone with dementia, 19 per cent were unsure.The findings from Dementia 2013 are based on a survey of 510 people with dementia or carers on their behalf and a YouGov poll of 2,287 UK adults.Download the full report here.������

Assessment of Severe Apnoea through Voice Analysis, Automatic Speech, and Speaker Recognition Techniques

This study is part of an ongoing collaborative effort between the medical and the signal processing communities to promote research on applying standard Automatic Speech Recognition (ASR) techniques for the automatic diagnosis of patients with severe obstructive sleep apnoea (OSA). Early detection of severe apnoea cases is important so that patients can receive early treatment. Effective ASR-based detection could dramatically cut medical testing time. Working with a carefully designed speech database of healthy and apnoea subjects, we describe an acoustic search for distinctive apnoea voice characteristics. We also study abnormal nasalization in OSA patients by modelling vowels in nasal and nonnasal phonetic contexts using Gaussian Mixture Model (GMM) pattern recognition on speech spectra. Finally, we present experimental findings regarding the discriminative power of GMMs applied to severe apnoea detection. We have achieved an 81% correct classification rate, which is very promising and underpins the interest in this line of inquiry.

Expectations, experiences and attitudes of patients and primary care health professionals regarding online psychotherapeutic interventions for depression: protocol for a qualitative study.

BACKGROUND In the year 2020, depression will cause the second highest amount of disability worldwide. One quarter of the population will suffer from depression symptoms at some point in their lives. Mental health services in Western countries are overburdened. Therefore, cost-effective interventions that do not involve mental health services, such as online psychotherapy programs, have been proposed. These programs demonstrate satisfactory outcomes, but the completion rate for patients is low. Health professionals' attitudes towards this type of psychotherapy are more negative than the attitudes of depressed patients themselves. The aim of this study is to describe the profile of depressed patients who would benefit most from online psychotherapy and to identify expectations, experiences, and attitudes about online psychotherapy among both patients and health professionals that can facilitate or hinder its effects. METHODS A parallel qualitative design will be used in a randomised controlled trial on the efficiency of online psychotherapeutic treatment for depression. Through interviews and focus groups, the experiences of treated patients, their reasons for abandoning the program, the expectations of untreated patients, and the attitudes of health professionals will be examined. Questions will be asked about training in new technologies, opinions of online psychotherapy, adjustment to therapy within the daily routine, the virtual and anonymous relationship with the therapist, the process of online communication, information necessary to make progress in therapy, process of working with the program, motivations and attitudes about treatment, expected consequences, normalisation of this type of therapy in primary care, changes in the physician-patient relationship, and resources and risks. A thematic content analysis from the grounded theory for interviews and an analysis of the discursive positions of participants based on the sociological model for focus groups will be performed. DISCUSSION Knowledge of the expectations, experiences, and attitudes of both patients and medical personnel regarding online interventions for depression can facilitate the implementation of this new psychotherapeutic tool. This qualitative investigation will provide thorough knowledge of the perceptions, beliefs, and values of patients and clinicians, which will be very useful for understanding how to implement this intervention method for depression.

Adaptively weighted maximum likelihood estimation of discrete distributions

SummaryDiscrete data arise in various research fields, typically when the observations are count data.I propose a robust and efficient parametric procedure for estimation of discrete distributions. The estimation is done in two phases. First, a very robust, but possibly inefficient, estimate of the model parameters is computed and used to indentify outliers. Then the outliers are either removed from the sample or given low weights, and a weighted maximum likelihood estimate (WML) is computed.The weights are determined via an adaptive process such that if the data follow the model, then asymptotically no observation is downweighted.I prove that the final estimator inherits the breakdown point of the initial one, and that its influence function at the model is the same as the influence function of the maximum likelihood estimator, which strongly suggests that it is asymptotically fully efficient.The initial estimator is a minimum disparity estimator (MDE). MDEs can be shown to have full asymptotic efficiency, and some MDEs have very high breakdown points and very low bias under contamination. Several initial estimators are considered, and the performances of the WMLs based on each of them are studied.It results that in a great variety of situations the WML substantially improves the initial estimator, both in terms of finite sample mean square error and in terms of bias under contamination. Besides, the performances of the WML are rather stable under a change of the MDE even if the MDEs have very different behaviors.Two examples of application of the WML to real data are considered. In both of them, the necessity for a robust estimator is clear: the maximum likelihood estimator is badly corrupted by the presence of a few outliers.This procedure is particularly natural in the discrete distribution setting, but could be extended to the continuous case, for which a possible procedure is sketched.RésuméLes données discrètes sont présentes dans différents domaines de recherche, en particulier lorsque les observations sont des comptages.Je propose une méthode paramétrique robuste et efficace pour l'estimation de distributions discrètes. L'estimation est faite en deux phases. Tout d'abord, un estimateur très robuste des paramètres du modèle est calculé, et utilisé pour la détection des données aberrantes (outliers). Cet estimateur n'est pas nécessairement efficace. Ensuite, soit les outliers sont retirés de l'échantillon, soit des faibles poids leur sont attribués, et un estimateur du maximum de vraisemblance pondéré (WML) est calculé.Les poids sont déterminés via un processus adaptif, tel qu'asymptotiquement, si les données suivent le modèle, aucune observation n'est dépondérée.Je prouve que le point de rupture de l'estimateur final est au moins aussi élevé que celui de l'estimateur initial, et que sa fonction d'influence au modèle est la même que celle du maximum de vraisemblance, ce qui suggère que cet estimateur est pleinement efficace asymptotiquement.L'estimateur initial est un estimateur de disparité minimale (MDE). Les MDE sont asymptotiquement pleinement efficaces, et certains d'entre eux ont un point de rupture très élevé et un très faible biais sous contamination. J'étudie les performances du WML basé sur différents MDEs.Le résultat est que dans une grande variété de situations le WML améliore largement les performances de l'estimateur initial, autant en terme du carré moyen de l'erreur que du biais sous contamination. De plus, les performances du WML restent assez stables lorsqu'on change l'estimateur initial, même si les différents MDEs ont des comportements très différents.Je considère deux exemples d'application du WML à des données réelles, où la nécessité d'un estimateur robuste est manifeste : l'estimateur du maximum de vraisemblance est fortement corrompu par la présence de quelques outliers.La méthode proposée est particulièrement naturelle dans le cadre des distributions discrètes, mais pourrait être étendue au cas continu.

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.

A generalized mechanistic codon model.

Models of codon evolution have attracted particular interest because of their unique capabilities to detect selection forces and their high fit when applied to sequence evolution. We described here a novel approach for modeling codon evolution, which is based on Kronecker product of matrices. The 61 × 61 codon substitution rate matrix is created using Kronecker product of three 4 × 4 nucleotide substitution matrices, the equilibrium frequency of codons, and the selection rate parameter. The entities of the nucleotide substitution matrices and selection rate are considered as parameters of the model, which are optimized by maximum likelihood. Our fully mechanistic model allows the instantaneous substitution matrix between codons to be fully estimated with only 19 parameters instead of 3,721, by using the biological interdependence existing between positions within codons. We illustrate the properties of our models using computer simulations and assessed its relevance by comparing the AICc measures of our model and other models of codon evolution on simulations and a large range of empirical data sets. We show that our model fits most biological data better compared with the current codon models. Furthermore, the parameters in our model can be interpreted in a similar way as the exchangeability rates found in empirical codon models.

SlimCodeML: An Optimized Version of CodeML for the Branch-Site Model

CodeML (part of the PAML package) im- plements a maximum likelihood-based approach to de- tect positive selection on a specific branch of a given phylogenetic tree. While CodeML is widely used, it is very compute-intensive. We present SlimCodeML, an optimized version of CodeML for the branch-site model. Our performance analysis shows that SlimCodeML substantially outperforms CodeML (up to 9.38 times faster), especially for large-scale genomic analyses.