Emotional and effortful control abilities in 42-month-old very preterm and full-term children.

BACKGROUND: Very preterm (VP) infants are at greater risk for cognitive difficulties that may persist during school-age, adolescence and adulthood. Behavioral assessments report either effortful control (part of executive functions) or emotional reactivity/regulation impairments. AIMS: The aim of this study is to examine whether emotional recognition, reactivity, and regulation, as well as effortful control abilities are impaired in very preterm children at 42 months of age, compared with their full-term peers, and to what extent emotional and effortful control difficulties are linked. STUDY DESIGN: Children born very preterm (VP; < 29 weeks gestational age, n=41) and full-term (FT) aged-matched children (n=47) participated in a series of specific neuropsychological tests assessing their level of emotional understanding, reactivity and regulation, as well as their attentional and effortful control abilities. RESULTS: VP children exhibited higher scores of frustration and fear, and were less accurate in naming facial expressions of emotions than their aged-matched peers. However, VP children and FT children equally performed when asked to choose emotional facial expression in social context, and when we assessed their selective attention skills. VP performed significantly lower than full terms on two tasks of inhibition when correcting for verbal skills. Moreover, significant correlations between cognitive capacities (effortful control) and emotional abilities were evidenced. CONCLUSIONS: Compared to their FT peers, 42 month-olds who were born very preterm are at higher risk of exhibiting specific emotional and effortful control difficulties. The results suggest that these difficulties are linked. Ongoing behavioral and emotional impairments starting at an early age in preterms highlight the need for early interventions based on a better understanding of the relationship between emotional and cognitive difficulties.

Molecular mechanisms of follicular associated epithelium differentiation

Les muqueuses respiratoires, genitales et digestives sont continuellement exposées aux antigènes de l?alimentation, à la flore intestinale et aux pathogènes. Cela implique une activité immunologique intense et finement régulée dans ces tissus. On admet que la modulation de ces réponses immunitaires muqueuses s?effectue dans des organes sentinels spécifiques appelés o-MALT (organized mucosal associated lymphoid tissues). Ces processus de modulation et la biologie de ces sites immuno-inducteurs sont peu connus. Ceci est pourtant d?une grande relevance si l?on veut faire un design rationnel de drogues et de vaccins muqueux. Dans l?intestin grèle, ces organes sont composés de follicules multiples et sont appelés plaques de Peyer. Ils sont constitués de follicules enrichis en cellules B comprenant ou non un centre germinatif, de regions interfolliculaires comprenant des cellules T, et d?une région en d ome riche en cellules dendritiques, cellules B naives et cellules T CD4+, surmontée par un epithelium specialisé, le FAE (epithelium associé aux follicules). Le FAE contient des cellules M spécialisées dans le transport de macromolécules et micro-organismes de la lumière intestinale au tissu lymphoide sous-jacent. Ce transport des antigènes est une condition obligatoire pour induire une réponse immunitaire. Les cellules du FAE, outre les cellules M, expriment un programme de différenciation distinct de celui des cellules associées aux villosités. Ceci est characterisé par une baisse des fonctions digestives et de défenses, et l?expression constitutive des chimiokines: CCL20 et CCL25. Le but de l?étude présentée ici est de rechercher les facteurs cellulaires et/ou moléculaire responsables de cette différenciation. Certaines études ont démontré l?importance du contact entre le compartiment mésenchymateux et l?épithelium pour la morphogenèse de ce dernier. En particulier, les molécules de la matrice extracellulaire peuvent activer des gènes clefs qui, à leur tour, vont controler l?adhésion et la differenciation cellulaire. Dans l?intestin, les cellules mésenchymateuses différencient en myofibroblastes qui participent à l?élaboration de la matrice extracellulaire. Dans cette étude, nous avons décrit les différences d?expression de molécules de la matrices sous le FAE et les villosités. Nous avons également montré une absence de myofibroblastes sous le FAE. Suite à plusieurs évidences expérimentales, certains ont proposé une influence des composés présents dans la lumière sur la différenciation et/ou la maturation des plaques de Peyer. La chimiokine CCL20, capable de recruter des cellules initiatrices de la réponse immunitaire, constitue notre seul marqueur positif de FAE. Nous avons pu montrer que la flagelline, un composé du flagelle bactérien, était capable d?induire l?expression de CCL20 in vitro et in vivo. Cet effet n?est pas limité aux cellules du FAE mais est observé sur l?ensemble de l?épithelium intestinal. Molecular mechanisms of FAE differenciation. La signalement induit par la lymphotoxine ß est critique pour l?organogenèse des plaques de Peyer, car des souris déficientes pour cette molécules ou son récepteur n?ont ni plaque de Peyer, ni la plupart des ganglions lymphatiques. Nous avons obtenus plusieurs évidences que la lymphotoxine ß était impliquée dans la régulation du gène CCL20 in vitro et in vivo.<br/><br/>Mucosal surfaces of the respiratory, genital and digestive systems are exposed to food antigens, normal bacterial flora and oral pathogens. This justifies an intense and tuned immunological activity in mucosal tissues. The modulation of immune responses in the mucosa is thought to occur in specific sentinel sites, the organized mucosa associated lymphoid tissues (o-MALT). This immune modulation and the biology of these immune-inductive sites are poorly understood but highly important and relevant in the case of drugs and vaccines design. In the small intestine, these organs (gut associated lymphoid tissue : GALT) consists of single or multiple lymphoid follicles, the so-called Peyer?s patches (PP), with typical B cell-enriched follicles and germinal centers, inter-follicular T cell areas, and a dome region enriched in dendritic cells, naive B cells, and CD4+ T cells under a specialized follicle associated epithelium (FAE). To trigger protective immunity, antigens have to cross the mucosal epithelial barrier. This is achieved by the specialized epithelial M cells of the FAE that are able to take up and transport macromolecules and microorganisms from the environment into the underlying organized lymphoid tissue. The ontogeny of M cells remains controversial: some data are in favor of a distinct cell lineage, while others provide evidence for the conversion of differentiated enterocytes into M cells. In this study we mapped the proliferative, M cells and apoptotic compartments along the FAE. Enterocytes acquire transient M cell features as they leave the crypt and regain enterocyte properties as they move towards the apoptotic compartment at the apex of the FAE, favouring the hypothesis of a plastic phenotype. The follicle-associated epithelium (FAE) is found exclusively over lymphoid follicles in mucosal tissues, including Peyer?s patches. The enterocytes over Peyer?s patches express a distinct phenotype when compared to the villi enterocytes, characterized by the down regulation of digestive and defense functions and the constitutive expression of chemokines, i.e. CCL20 and CCL25. The purpose of this study was to investigate and identify the potential cells and/or molecules instructing FAE differentiation. Contact between the epithelial and the mesenchymal cell compartment is required for gut morphogenesis. Extracellular matrix molecules (ECM) can activate key regulatory genes which in turn control cell adhesion and differentiation. In the gut, mesenchymal cells differentiate into myofibroblats that participate to the elaboration of ECM. We have described a differential expression of extracellular matrix components under the FAE, correlating with the absence of subepithelial myofibroblats. Molecular mechanisms of FAE differenciation. Different studies proposed an influence of the luminal compartment in the differentiation and/or the maturation of PP. CCL20, a chemokine able to recruit cells that initiate adaptive immunity constitutes our first positive FAE molecular marker. We have shown that CCL20 gene expression is inducible in vitro and in vivo in intestinal epithelium by flagellin, a component of bacterial flagella. This effect was not restricted to the FAE. Lymphotoxin ß (LTß) signaling is critical for PPs organogenesis as LT deficient mice as well as LTß-receptor-/- mice lack PPs and most of the lymph nodes (LN). The continuous signaling via LTßR-expressing cells appears necessary for the maintenance throughout the life of PP architecture. We obtained in vitro and in vivo evidence that LTß signalling is involved in CCL20 gene expression.

Cost information in engineering design -Potentials and limitations of activity-based costing

The purpose of this thesis is to analyse activity-based costing (ABC) and possible modified versions ofit in engineering design context. The design engineers need cost information attheir decision-making level and the cost information should also have a strong future orientation. These demands are high because traditional management accounting has concentrated on the direct actual costs of the products. However, cost accounting has progressed as ABC was introduced late 1980s and adopted widely bycompanies in the 1990s. The ABC has been a success, but it has gained also criticism. In some cases the ambitious ABC systems have become too complex to build,use and update. This study can be called an action-oriented case study with some normative features. In this thesis theoretical concepts are assessed and allowed to unfold gradually through interaction with data from three cases. The theoretical starting points are ABC and theory of engineering design process (chapter2). Concepts and research results from these theoretical approaches are summarized in two hypotheses (chapter 2.3). The hypotheses are analysed with two cases (chapter 3). After the two case analyses, the ABC part is extended to cover alsoother modern cost accounting methods, e.g. process costing and feature costing (chapter 4.1). The ideas from this second theoretical part are operationalized with the third case (chapter 4.2). The knowledge from the theory and three cases is summarized in the created framework (chapter 4.3). With the created frameworkit is possible to analyse ABC and its modifications in the engineering design context. The framework collects the factors that guide the choice of the costing method to be used in engineering design. It also illuminates the contents of various ABC-related costing methods. However, the framework needs to be further tested. On the basis of the three cases it can be said that ABC should be used cautiously when formulating cost information for engineering design. It is suitable when the manufacturing can be considered simple, or when the design engineers are not cost conscious, and in the beginning of the design process when doing adaptive or variant design. If the design engineers need cost information for the embodiment or detailed design, or if manufacturing can be considered complex, or when design engineers are cost conscious, the ABC has to be always evaluated critically.

Artificially Intelligent and Adaptive Methods for Prediction and Analysis of Superheater Fireside Corrosion in Fluidized Bed Boilers

Superheater corrosion causes vast annual losses for the power companies. With a reliable corrosion prediction method, the plants can be designed accordingly, and knowledge of fuel selection and determination of process conditions may be utilized to minimize superheater corrosion. Growing interest to use recycled fuels creates additional demands for the prediction of corrosion potential. Models depending on corrosion theories will fail, if relations between the inputs and the output are poorly known. A prediction model based on fuzzy logic and an artificial neural network is able to improve its performance as the amount of data increases. The corrosion rate of a superheater material can most reliably be detected with a test done in a test combustor or in a commercial boiler. The steel samples can be located in a special, temperature-controlled probe, and exposed to the corrosive environment for a desired time. These tests give information about the average corrosion potential in that environment. Samples may also be cut from superheaters during shutdowns. The analysis ofsamples taken from probes or superheaters after exposure to corrosive environment is a demanding task: if the corrosive contaminants can be reliably analyzed, the corrosion chemistry can be determined, and an estimate of the material lifetime can be given. In cases where the reason for corrosion is not clear, the determination of the corrosion chemistry and the lifetime estimation is more demanding. In order to provide a laboratory tool for the analysis and prediction, a newapproach was chosen. During this study, the following tools were generated: · Amodel for the prediction of superheater fireside corrosion, based on fuzzy logic and an artificial neural network, build upon a corrosion database developed offuel and bed material analyses, and measured corrosion data. The developed model predicts superheater corrosion with high accuracy at the early stages of a project. · An adaptive corrosion analysis tool based on image analysis, constructedas an expert system. This system utilizes implementation of user-defined algorithms, which allows the development of an artificially intelligent system for thetask. According to the results of the analyses, several new rules were developed for the determination of the degree and type of corrosion. By combining these two tools, a user-friendly expert system for the prediction and analyses of superheater fireside corrosion was developed. This tool may also be used for the minimization of corrosion risks by the design of fluidized bed boilers.

Converter-flux-based current control of voltage source PWM rectifiers - analysis and implementation

Pulsewidth-modulated (PWM) rectifier technology is increasingly used in industrial applications like variable-speed motor drives, since it offers several desired features such as sinusoidal input currents, controllable power factor, bidirectional power flow and high quality DC output voltage. To achieve these features,however, an effective control system with fast and accurate current and DC voltage responses is required. From various control strategies proposed to meet these control objectives, in most cases the commonly known principle of the synchronous-frame current vector control along with some space-vector PWM scheme have been applied. Recently, however, new control approaches analogous to the well-established direct torque control (DTC) method for electrical machines have also emerged to implement a high-performance PWM rectifier. In this thesis the concepts of classical synchronous-frame current control and DTC-based PWM rectifier control are combined and a new converter-flux-based current control (CFCC) scheme is introduced. To achieve sufficient dynamic performance and to ensure a stable operation, the proposed control system is thoroughly analysed and simple rules for the controller design are suggested. Special attention is paid to the estimationof the converter flux, which is the key element of converter-flux-based control. Discrete-time implementation is also discussed. Line-voltage-sensorless reactive reactive power control methods for the L- and LCL-type line filters are presented. For the L-filter an open-loop control law for the d-axis current referenceis proposed. In the case of the LCL-filter the combined open-loop control and feedback control is proposed. The influence of the erroneous filter parameter estimates on the accuracy of the developed control schemes is also discussed. A newzero vector selection rule for suppressing the zero-sequence current in parallel-connected PWM rectifiers is proposed. With this method a truly standalone and independent control of the converter units is allowed and traditional transformer isolation and synchronised-control-based solutions are avoided. The implementation requires only one additional current sensor. The proposed schemes are evaluated by the simulations and laboratory experiments. A satisfactory performance and good agreement between the theory and practice are demonstrated.

Permanent magnet synchronous motor for industrial inverter applications - analysis and design

During the latest few years the need for new motor types has grown, since both high efficiency and an accurate dynamic performance are demanded in industrial applications. For this reason, new effective control systems such as direct torque control (DTC) have been developed. Permanent magnet synchronous motors (PMSM) are well suitable for new adjustable speed AC inverter drives, because their efficiency and power factor are not depending on the pole pair number and speed to the same extent as it is the case in induction motors. Therefore, an induction motor (IM) with a mechanical gearbox can often be replaced with a direct PM motor drive. Space as well as costs will be saved, because the efficiency increases and the cost of maintenance decreases as well. This thesis deals with design criterion, analytical calculation and analysis of the permanent magnet synchronous motor for both sinusoidal air-gap flux density and rectangular air-gapflux density. It is examined how the air-gap flux, flux densities, inductances and torque can be estimated analytically for salient pole and non-salient pole motors. It has been sought by means of analytical calculations for the ultimate construction for machines rotating at relative low 300 rpm to 600 rpm speeds, which are suitable speeds e.g. in Pulp&Paper industry. The calculations are verified by using Finite Element calculations and by measuring of prototype motor. The prototype motor is a 45 kW, 600 rpm PMSM with buried V-magnets, which is a very appropriate construction for high torque motors with a high performance. With the purposebuilt prototype machine it is possible not only to verify the analytical calculations but also to show whether the 600 rpm PMSM can replace the 1500 rpm IM with a gear. It can also be tested if the outer dimensions of the PMSM may be the same as for the IM and if the PMSM in this case can produce a 2.5 fold torque, in consequence of which it may be possible to achieve the same power. The thesis also considers the question how to design a permanent magnet synchronous motor for relatively low speed applications that require a high motor torqueand efficiency as well as bearable costs of permanent magnet materials. It is shown how a selection of different parameters affects the motor properties. Key words: Permanent magnet synchronous motor, PMSM, surface magnets, buried magnets

Direct torque control of permanent magnet synchronous machines - analysis and implementation

Thedirect torque control (DTC) has become an accepted vector control method besidethe current vector control. The DTC was first applied to asynchronous machines,and has later been applied also to synchronous machines. This thesis analyses the application of the DTC to permanent magnet synchronous machines (PMSM). In order to take the full advantage of the DTC, the PMSM has to be properly dimensioned. Therefore the effect of the motor parameters is analysed taking the control principle into account. Based on the analysis, a parameter selection procedure is presented. The analysis and the selection procedure utilize nonlinear optimization methods. The key element of a direct torque controlled drive is the estimation of the stator flux linkage. Different estimation methods - a combination of current and voltage models and improved integration methods - are analysed. The effect of an incorrect measured rotor angle in the current model is analysed andan error detection and compensation method is presented. The dynamic performance of an earlier presented sensorless flux estimation method is made better by improving the dynamic performance of the low-pass filter used and by adapting the correction of the flux linkage to torque changes. A method for the estimation ofthe initial angle of the rotor is presented. The method is based on measuring the inductance of the machine in several directions and fitting the measurements into a model. The model is nonlinear with respect to the rotor angle and therefore a nonlinear least squares optimization method is needed in the procedure. A commonly used current vector control scheme is the minimum current control. In the DTC the stator flux linkage reference is usually kept constant. Achieving the minimum current requires the control of the reference. An on-line method to perform the minimization of the current by controlling the stator flux linkage reference is presented. Also, the control of the reference above the base speed is considered. A new estimation flux linkage is introduced for the estimation of the parameters of the machine model. In order to utilize the flux linkage estimates in off-line parameter estimation, the integration methods are improved. An adaptive correction is used in the same way as in the estimation of the controller stator flux linkage. The presented parameter estimation methods are then used in aself-commissioning scheme. The proposed methods are tested with a laboratory drive, which consists of a commercial inverter hardware with a modified software and several prototype PMSMs.

Induction motor versus permanent magnet synchronous motor in motion control applications: a comparative study

High dynamic performance of an electric motor is a fundamental prerequisite in motion control applications, also known as servo drives. Recent developments in the field of microprocessors and power electronics have enabled faster and faster movements with an electric motor. In such a dynamically demanding application, the dimensioning of the motor differs substantially from the industrial motor design, where feasible characteristics of the motor are for example high efficiency, a high power factor, and a low price. In motion control instead, such characteristics as high overloading capability, high-speed operation, high torque density and low inertia are required. The thesis investigates how the dimensioning of a high-performance servomotor differs from the dimensioning of industrial motors. The two most common servomotor types are examined; an induction motor and apermanent magnet synchronous motor. The suitability of these two motor types indynamically demanding servo applications is assessed, and the design aspects that optimize the servo characteristics of the motors are analyzed. Operating characteristics of a high performance motor are studied, and some methods for improvements are suggested. The main focus is on the induction machine, which is frequently compared to the permanent magnet synchronous motor. A 4 kW prototype induction motor was designed and manufactured for the verification of the simulation results in the laboratory conditions. Also a dynamic simulation model for estimating the thermal behaviour of the induction motor in servo applications was constructed. The accuracy of the model was improved by coupling it with the electromagnetic motor model in order to take into account the variations in the motor electromagnetic characteristics due to the temperature rise.

Diseño e implementación de la base de datos de un sistema centralizado de control del gasto público de los parlamentos europeos

Diseño e implementación de la base de datos de un sistema centralizado de control del gasto público de los parlamentos europeos.

Diseño e implementación de un sistema de control del consumo energético

Implementación de una base de datos transaccional para el control del consumo eléctrico mediante contadores inteligentes. La base de datos propuesta permite desarrollar los diferentes compromisos de gestión de las compañías suministradoras, consumidores, contadores, consumos y núcleos energéticos (smart cities), proporcionando los procedimientos almacenados necesarios para su gestión. También se desarrolla la implementación de una base de datos analítica, data warehouse, para la explotación de los datos almacenados en la primera parte del proyecto. El objetivo es la implementación de las entidades necesarias para la explotación analítica de los datos mediante consultas sencillas.

A design for an advanced architecture of satellite ground segments

This project proposes a preliminary architectural design for a control and data processing center, also known as 'ground segment', for Earth observation satellites.

Use of physiological constraints to identify quantitative design principles for gene expression in yeast adaptation to heat shock

Background: Understanding the relationship between gene expression changes, enzyme activity shifts, and the corresponding physiological adaptive response of organisms to environmental cues is crucial in explaining how cells cope with stress. For example, adaptation of yeast to heat shock involves a characteristic profile of changes to the expression levels of genes coding for enzymes of the glycolytic pathway and some of its branches. The experimental determination of changes in gene expression profiles provides a descriptive picture of the adaptive response to stress. However, it does not explain why a particular profile is selected for any given response. Results: We used mathematical models and analysis of in silico gene expression profiles (GEPs) to understand how changes in gene expression correlate to an efficient response of yeast cells to heat shock. An exhaustive set of GEPs, matched with the corresponding set of enzyme activities, was simulated and analyzed. The effectiveness of each profile in the response to heat shock was evaluated according to relevant physiological and functional criteria. The small subset of GEPs that lead to effective physiological responses after heat shock was identified as the result of the tuning of several evolutionary criteria. The experimentally observed transcriptional changes in response to heat shock belong to this set and can be explained by quantitative design principles at the physiological level that ultimately constrain changes in gene expression. Conclusion: Our theoretical approach suggests a method for understanding the combined effect of changes in the expression of multiple genes on the activity of metabolic pathways, and consequently on the adaptation of cellular metabolism to heat shock. This method identifies quantitative design principles that facilitate understating the response of the cell to stress.

Additive effects of HLA alleles and innate immune genes determine viral outcome in HCV infection.

BACKGROUND: Chronic HCV infection is a leading cause of liver-related morbidity globally. The innate and adaptive immune responses are thought to be important in determining viral outcomes. Polymorphisms associated with the IFNL3 (IL28B) gene are strongly associated with spontaneous clearance and treatment outcomes. OBJECTIVE: This study investigates the importance of HLA genes in the context of genetic variation associated with the innate immune genes IFNL3 and KIR2DS3. DESIGN: We assess the collective influence of HLA and innate immune genes on viral outcomes in an Irish cohort of women (n=319) who had been infected from a single source as well as a more heterogeneous cohort (Swiss Cohort, n=461). In the Irish cohort, a number of HLA alleles are associated with different outcomes, and the impact of IFNL3-linked polymorphisms is profound. RESULTS: Logistic regression was performed on data from the Irish cohort, and indicates that the HLA-A*03 (OR 0.36 (0.15 to 0.89), p=0.027) -B*27 (OR 0.12 (0.03 to 0.45), p=<0.001), -DRB1*01:01 (OR 0.2 (0.07 to 0.61), p=0.005), -DRB1*04:01 (OR 0.31 (0.12 to 0.85, p=0.02) and the CC IFNL3 rs12979860 genotypes (OR 0.1 (0.04 to 0.23), p<0.001) are significantly associated with viral clearance. Furthermore, DQB1*02:01 (OR 4.2 (2.04 to 8.66), p=0.008), KIR2DS3 (OR 4.36 (1.62 to 11.74), p=0.004) and the rs12979860 IFNL3 'T' allele are associated with chronic infection. This study finds no interactive effect between IFNL3 and these Class I and II alleles in relation to viral clearance. There is a clear additive effect, however. Data from the Swiss cohort also confirms independent and additive effects of HLA Class I, II and IFNL3 genes in their prediction of viral outcome. CONCLUSIONS: This data supports a critical role for the adaptive immune response in the control of HCV in concert with the innate immune response.

Object-oriented development of client / server application: case study of service control software

Tässä työssä on esitetty sen ohjelmiston kehittämisen prosessi, joka on tarkoitettu annettavien palveluiden valvottavaksi käyttäen prototyyppimallia. Raportti sisältää vaatimusten, kohteisiin suunnatun analyysin ja suunnittelun, realisointiprosessien kuvauksen ja prototyypin testauksen. Ohjelmiston käyttöala – antavien palveluiden valvonta. Vaatimukset sovellukselle analysoitiin ohjelmistomarkkinoiden perusteella sekä ohjelmiston engineeringin periaatteiden mukaisesti. Ohjelmiston prototyyppi on realisoitu käyttäen asiakas-/palvelinhybridimallia sekä ralaatiokantaa. Kehitetty ohjelmisto on tarkoitettu venäläisille tietokonekerhoille, jotka erikoistuvat pelipalvelinten antamiseen.

Optimising approaches to active immunotherapy of cancer

The design of therapeutic cancer vaccines is aimed at inducing high numbers and potent T cells that are able to target and eradicate malignant cells. This calls for close collaboration between cells of the innate immune system, in particular dendritic cells (DCs), and cells of the adaptive immune system, notably CD4+ helper T cells and CD8+ cytotoxic T cells. Therapeutic vaccines are aided by adjuvants, which can be, for example, Toll¬like Receptor agonists or agents promoting the cytosolic delivery of antigens, among others. Vaccination with long synthetic peptides (LSPs) is a promising strategy, as the requirement for their intracellular processing will mainly target LSPs to professional antigen presenting cells (APCs), hence avoiding the immune tolerance elicited by the presentation of antigens by non-professional APCs. The unique property of antigen cross-processing and cross-presentation activity by DCs plays an important role in eliciting antitumour immunity given that antigens from engulfed dead tumour cells require this distinct biological process to be processed and presented to CD8+T cells in the context of MHC class I molecules. DCs expressing the XCR1 chemokine receptor are characterised by their superior capability of antigen cross- presentation and priming of highly cytotoxic T lymphocyte (CTL) responses. Recently, XCR1 was found to be also expressed in tissue-residents DCs in humans, with a simitar transcriptional profile to that of cross- presenting murine DCs. This shed light into the value of harnessing this subtype of XCR1+ cross-presenting DCs for therapeutic vaccination of cancer. In this study, we explored ways of adjuvanting and optimising LSP therapeutic vaccinations by the use, in Part I, of the XCLl chemokine that selectively binds to the XCR1 receptor, as a mean to target antigen to the cross-presenting XCR1+ DCs; and in Part II, by the inclusion of Q.S21 in the LSP vaccine formulation, a saponin with adjuvant activity, as well as the ability to promote cytosolic delivery of LSP antigens due to its intrinsic cell membrane insertion activity. In Part I, we designed and produced XCLl-(OVA LSP)-Fc fusion proteins, and showed that their binding to XCR1+ DCs mediate their chemoattraction. In addition, therapeutic vaccinations adjuvanted with XCLl-(OVA LSP)-Fc fusion proteins significantly enhanced the OVA-specific CD8+ T cell response, and led to complete tumour regression in the EL4-OVA model, and significant control of tumour growth in the B16.0VA tumour model. With the aim to optimise the co-delivery of LSP antigen and XCLl to skin-draining lymph nodes we also tested immunisations using nanoparticle (NP)-conjugated OVA LSP in the presence or absence of XCLl chemokine. The NP-mediated delivery of LSP potentiated the CTL response seen in the blood of vaccinated mice, and NP-OVA LSP vaccine in the presence of XCLl led to higher blood frequencies of OVA-specific memory-precursor effector cells. Nevertheless, in these settings, the addition XCLl to NP-OVA LSP vaccine formulation did not increase its antitumour therapeutic effect. In the Part II, we assessed in HLA-A2/DR1 mice the immunogenicity of the Melan-AA27L LSP or the Melan-A26. 35 AA27l short synthetic peptide (SSP) used in conjunction with the saponin adjuvant QS21, aiming to identify a potent adjuvant formulation that elicits a quantitatively and qualitatively strong immune response to tumour antigens. We showed a high CTL immune response elicited by the use of Melan-A LSP or SSP with QS21, which both exerted similar killing capacity upon in vivo transfer of target cells expressing the Melan-A peptide in the context of HLA-A2 molecules. However, the response generated by the LSP immunisation comprised higher percentages of CD8+T cells of the central memory phenotype (CD44hl CD62L+ and CCR7+ CD62L+) than those of SSP immunisation, and most importantly, the strong LSP+QS21 response was strictly CD4+T cell-dependent, as shown upon CD4 T cell depletion. Altogether, these results suggest that both XCLl and QS21 may enhance the ability of LSP to prime CD8 specific T cell responses, and promote a long-term memory response. Therefore, these observations may have important implications for the design of protein or LSP-based cancer vaccines for specific immunotherapy of cancer -- Les vacans thérapeutiques contre le cancer visent à induire une forte et durable réponse immunitaire contre des cellules cancéreuses résiduelles. Cette réponse requiert la collaboration entre le système immunitaire inné, en particulier les cellules dendrites (DCs), et le système immunitaire adaptatif, en l'occurrence les lymphocytes TCD4 hdper et CD8 cytotoxiques. La mise au point d'adjuvants et de molécules mimant un agent pathogène tels les ligands TLRs ou d'autres agents facilitant l'internalisation d'antigènes, est essentielle pour casser la tolérance du système immunitaire contre les cellules cancéreuses afin de générer une réponse effectrice et mémoire contre la tumeur. L'utilisation de longs peptides synthétiques (LSPs) est une approche prometteuse du fait que leur présentation en tant qu'antigénes requiert leur internalisation et leur transformation par les cellules dendrites (DCs, qui sont les mieux à même d'éviter la tolérance immunitaire. Récemment une sous-population de DCs exprimant le récepteur XCR1 a été décrite comme ayant une capacité supérieure dans la cross-présentation d'antigènes, d'où un intérêt à développer des vaccins ciblant les DCs exprimant le XCR1. Durant ma thèse de doctorat, j'ai exploré différentes approches pour optimiser les vaccins avec LSPs. La première partie visait à cibler les XCR1-DCs à l'aide de la chemokine XCL1 spécifique du récepteur XCR1, soit sou s la forme de protéine de fusion XCL1-OVA LSP-Fc, soit associée à des nanoparticules. La deuxième partie a consisté à tester l'association des LSPs avec I adjuvant QS21 dérivant d'une saponine dans le but d'optimiser l'internalisation cytosolique des longs peptides. Les protéines de fusion XCLl-OVA-Fc développées dans la première partie de mon travail, ont démontré leur capacité de liaison spécifique sur les XCRl-DCs associée à leur capacité de chemo-attractio. Lorsque inclues dans une mmunisation de souris porteuse de tumeurs établies, ces protéines de fusion XCL1-0VA LSP-Fc et XCLl-Fc plus OVA LSP ont induites une forte réponse CDS OVA spécifique permettant la complète régression des tumeurs de modèle EL4- 0VA et un retard de croissance significatif de tumeurs de type B16-0VA. Dans le but d'optimiser le drainage des LSPs vers es noyaux lymphatiques, nous avons également testé les LSPs fixés de manière covalente à des nanoparticules co- injectees ou non avec la chemokine XCL1. Cette formulation a également permis une forte réponse CD8 accompagnée d'un effet thérapeutique significatif, mais l'addition de la chemokine XCL1 n'a pas ajouté d'effet anti-tumeur supplémentaire. Dans la deuxième partie de ma thèse, j'ai comparé l'immunogénicité de l'antigène humain Melan A soit sous la forme d un LSP incluant un épitope CD4 et CD8 ou sous la forme d'un peptide ne contenant que l'épitope CD8 (SSP) Les peptides ont été formulés avec l'adjuvant QS21 et testés dans un modèle de souris transgéniques pour les MHC let II humains, respectivement le HLA-A2 et DR1. Les deux peptides LSP et SSP ont généré une forte réponse CD8 similaire assoc.ee a une capacité cytotoxique équivalente lors du transfert in vivo de cellules cibles présentant le peptide SSP' Cependant les souris immunisées avec le Melan A LSP présentaient un pourcentage plus élevé de CD8 ayant un Phénotype «centra, memory» (CD44h' CD62L+ and CCR7+ CD62L+) que les souris immunisées avec le SSP, même dix mois après I'immunisation. Par ailleurs, la réponse CD8 au Melan A LSP était strictement dépendante des lymphocytes CD4, contrairement à l'immunisation par le Melan A SSP qui n'était pas affectée. Dans l'ensemble ces résultats suggèrent que la chemokine XCL1 et l'adjuvant QS21 améliorent la réponse CD8 à un long peptide synthétique, favorisant ainsi le développement d'une réponse anti-tumeur mémoire durable. Ces observations pourraient être utiles au développement de nouveau vaccins thérapeutiques contre les tumeurs.