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Indiana University-Purdue University Indianapolis (IUPUI) / Recent studies in anesthetized rats suggest that autonomic effects relating to thermoregulation that are evoked from the preoptic area (POA) may be mediated through activation of neurons in the dorsomedial hypothalamus (DMH). Disinhibition of neurons in the DMH produces not only cardiovascular changes but also increases in plasma adrenocorticotropic hormone (ACTH) and locomotor activity mimicking those evoked by microinjection of muscimol, a GABAA receptor agonist and neuronal inhibitor, into the POA. Therefore, I tested the hypothesis that all of these effects evoked from the POA are mediated through neurons in the DMH by assessing the effect of bilateral microinjection of muscimol into the DMH on the changes evoked by microinjection of muscimol into the POA in conscious rats. In addition, I tested the hypothesis that neurons in the DMH mediate a specific response that is thought to signal through the POA, the activation of the HPA axis evoked by systemic administration of the inflammatory cytokine IL-1β. After injection of vehicle into the DMH, injection of muscimol into the POA elicited marked increases in heart rate, arterial pressure, body temperature, plasma ACTH and locomotor activity and also increased Fos expression in the hypothalamic paraventricular nucleus (PVN), a region known to control the release of ACTH from the adenohypophysis, and the raphe pallidus, a medullary region known to mediate POA-evoked sympathetic responses. Prior microinjection of muscimol into the DMH produced a modest depression of baseline heart rate, arterial pressure, and body temperature but completely abolished all changes evoked from the POA. Microinjection of muscimol just anterior to the DMH had no effect on POA-evoked autonomic and neuroendocrine changes. Inhibition of neuronal activity in the DMH only partially attenuated the increased activity of the HPA axis following systemic injections of IL-1β. Thus, neurons in the DMH mediate a diverse array of physiological and behavioral responses elicited from the POA, suggesting that the POA represents an important source of inhibitory tone to key neurons in the DMH. However, it is clear that the inflammatory cytokine IL-1β must employ other pathways that are DMH-, and possibly POA-, independent to activate the HPA axis.

<p>A novel two-loop estimation and control strategy is proposed to reduce the natural gas (NG) spark-ignition (SI) engine tail pipe emissions, with focus on the outer loop development. In the outer loop, an fractional oxidation state (FOS) estimator consisting of a three-way catalyst (TWC) model and an extended Kalman-filter is used to estimate the real-time TWC's FOS, and a robust controller is used to control the first-half TWC's FOS by manipulating the desired engine lambda (i.e., air–fuel equivalence ratio; lambda=1 at stoichiometry). The outer loop estimator and controller are combined with an industry-production baseline inner loop controller, which controls the engine $\lambda$ based on the desired lambda value. This novel two-loop control strategy reduces more CH4 and NOx emissions over no-outer-loop control strategy and the conventional two-loop control strategies through simulation. </p> <p><br></p> <p>Engine with and without fuel cut-off are both investigated. Although fuel cut-off brings better fuel economy, it also over-oxidizes the TWC during fuel cut events, which makes the FOS-based controller's competence in NOx reduction over non-FOS-based controllers less significant. By comparing simulation results with and without fuel cut-off, it shows huge potential for much better emission result if fuel cut-off's side effect can be alleviated. Considering that fuel cut-off generally being cutting engine fueling during zero load periods and introducing unreacted oxygen into the after-treatment system, the best way of dealing with the issue is to cut off or reduce the oxygen input to the TWC during those events. Several advanced engine technologies such as cylinder deactivation and exhaust gas re-circulation are good candidates to approach this issue. </p> <p><br></p> <p>An industry-production Cummins B6.7N natural gas SI engine was installed in the Ray W. Herrick Laboratories for study of variable valve actuation (VVA) technology, for the purpose of evaluating/improving SI engine's fuel efficiency, emission reduction, and engine knock resistance. A one-dimensional, physics-based natural gas SI engine model was investigated and calibrated in GT-Power software. To calculate the burn rates in the cylinder, three different pressure analysis methods were investigated and implemented. It is observed that all six cylinders' pressure curves are different, which in turn render different burn rates cylinder-to-cylinder. Cylinder with a higher peak cylinder pressure has a faster burn rate. Each operating condition has its unique pressure curve, and their burn rates are different under different operating conditions. Considering that the burn rate profile can vary cylinder-to-cylinder and operation-to-operation, to make the GT combustion model work for a larger range of loads, a fixed burn rate model may help in the preliminary research phase, but a predictive combustion model is more preferable.</p> <p><br></p> <p>The GT-Power model's VVA capability is investigated, where intake valve closure (IVC) modulation and cylinder de-activation (CDA) are built and analyzed. To mitigate TWC's over-oxidation issue during engine's fuel cut-off events, the CDA is implemented and simulated to demonstrate its benefit on further emission and fuel consumption reductions.</p>

No description available.

La mondialisation économique et l'internationalisation des échanges ont engendré l'ouverture des frontières et la mobilité professionnelle. Par conséquent, de nouveaux besoins communicatifs émergent. En effet, les institutions, les organismes, les administrations et les entreprises recrutent, aujourd'hui, des professionnels capables de communiquer en plusieurs langues lors de leurs activités professionnelles. Pour répondre à cette demande, des établissements scolaires et universitaires ont mis en œuvre des dispositifs d'enseignement bi-plurilingue. La présente thèse s'intéresse aux Filières Universitaires Francophones (FUF) bi-plurilingues, et a pour objectif d'analyser le dispositif Discipline(s) Non Linguistique(s) (DNL)/cours de français, censé garantir la réussite universitaire et professionnelle des étudiants allophones. Ainsi, nous avons mené une enquête de terrain au sein d'une FUF d'économie en Egypte pour y étudier les pratiques linguistiques et didactiques. Notre recherche montre que l'intégration d'un cours de Français sur Objectif Universitaire (FOU) et de Français sur Objectif Spécifique (FOS) dans le programme de formation des FUF vise la réussite des étudiants. Par ailleurs, les résultats de notre investigation nous ont conduite à élaborer différents outils permettant aux enseignants de français d'élaborer plus facilement des cours de FOS/FOU. Il s'agit précisément de la conception d'un référentiel de compétences langagières, d'un programme de formation de FOS/FOU et d'activités pédagogiques. / The economic globalization and internationalization of exchanges led to the opening of borders and professional mobility. As a result, new communication needs are emerging. Indeed, institutions, organizations, administrations and enterprises are nowadays recruiting professionals who can communicate in different languages during their workplace activities. To meet this demand, schools and universities have implemented bi-multilingual teaching. This thesis focuses on bi-multilingual French-language University Courses (FUF) and aims to analyze the framework including non-linguistic subject(s) (DNL) in French and French courses, which is intended to ensure the academic and professional success of allophone students. Thus, we conducted a field survey within the Economics courses of a FUF in Egypt so as to study the linguistic and teaching practices. Our research shows that the integration of French for Specific Purposes (FSP) and French for Academic Purposes (FAP) courses in the FUF’s academic program aims at student achievement. Furthermore, the results of our investigation led us to develop different tools which will enable French teachers to create FSP/FAP courses more easily. More specifically, it is the construction of a competency framework, the design of a training program and educational activities.

La pathologie athéromateuse avec ses complications cardio-vasculaires reste aujourd’hui une des principales causes de mortalité dans les pays développés. Dans ce contexte, l’élaboration de nouveaux bio-marqueurs de la maladie athéromateuse occupe une place importante. Les objectifs de ces bio-marqueurs sont : de définir les populations les plus à risque de développer une complication cardio-vasculaire, de stratifier les groupes de patients de manière à optimiser leur prise en charge clinique et thérapeutique , de dévoiler de nouvelles cibles thérapeutiques dans le traitement de la pathologie. Dans ce contexte, nous avons ciblé trois bio-marqueurs d’intérêt à savoir la longueur des télomères leucocytaires (LTL) et le niveau d’expression leucocytaire des gènes c-Fos (impliqué dans les processus inflammatoires et oxydatifs) et OGG1 (nécessaire à la réparation des lésions oxydatives de l’ADN). Nous avons donc dans une première partie de ce travail voulu vérifier l’hypothèse selon laquelle la LTL pouvait être préservée par la prise régulière de statine, une thérapeutique ayant déjà démontré ses bienfaits en terme de prévention primaire et secondaire des maladies cardio-vasculaires. De plus, nous nous sommes intéressés aux possibles relations entre les niveaux d’expression des gènes c-Fos et OGG1 et la LTL. Nous nous sommes placés dans un contexte de patients à haut risque cardiovasculaire que représentent les patients en phase aigue de l’infarctus du myocarde (IDM). Ce travail a permis de montrer que la prise régulière de statine pouvait préserver la longueur des télomères leucocytaires et ce particulièrement chez les sujets les plus jeunes (moins de 64 ans), suggérant un nouvel effet « pléïotrope » des statines. Ce travail a également permis d’identifier les gènes c-Fos et OGG1 comme étant des acteurs potentiels du maintien de l’intégrité des télomères. La seconde partie de notre travail a porté sur une étude plus approfondie du niveau de transcription du gène c-Fos en relation avec l’un des principaux facteurs de risque de la maladie athéromateuse que représente le statut tabagique chez des patients présentant une maladie coronaire. Ce travail a permis de mettre en évidence pour la première fois une relation entre le niveau d’expression de c-Fos et le statut tabagique des sujets, suggérant que l’une des voies possibles de toxicité du tabac pourrait faire intervenir les voies de signalisations impliquant c-Fos. Ainsi, ce travail de thèse a permis de mettre en évidence trois bio-marqueurs intéressants dans le domaine de la pathologie athéromateuse : 1- La longueur des télomères leucocytaires qui peut être une des voies d’action bénéfique des statines en prévention précoce des maladies cardio-vasculaires, 2- Le niveau d’expression du gène OGG1 comme étant un des acteurs potentiels du maintien de l’intégrité des télomères, 3- Le niveau d’expression du gène c-Fos comme marqueur cumulatif d’exposition tabagique et potentiel acteur des effets délétères du tabac. Restent à préciser les mécanismes cellulaires et moléculaires mis en jeu et ainsi développer des stratégies thérapeutiques adéquates afin d’optimiser la prise en charge des patients souffrant de pathologies athéromateuses. / Atherosclerosis with cardiovascular complications remains today one of the leading causes of death in developed countries. In this context, development of new biomarkers of atherosclerosis has an important place. Objectives of these biomarkers are: • to identify populations most at risk of developing cardiovascular complications, • to stratify patient groups to optimize their clinical management and therapeutic, • to reveal new therapeutic targets in the treatment of the disease. In this context, we identified three biomarkers of interest, leukocyte telomere length (LTL) and level of expression of leukocyte genes c-Fos (involved in inflammatory processes and oxidative) and OGG1 (necessary repair of oxidative DNA damage). We therefore first part of this study wanted to test the hypothesis that LTL may be maintained by regular use of statin therapy which has already demonstrated its benefits in terms of primary and secondary prevention of cardiovascular disease. In addition, we examined the possible relationship between gene expression levels of c-Fos and OGG1 and LTL. We placed in the context of patients at high cardiovascular risk posed by patients in acute phase of myocardial infarction (MI). This work has shown that regular use of statins could preserve leukocyte telomere length and particularly among the younger subjects (under 64), suggesting a new effect "pleiotropic" statin. This work has also identified the genes c-Fos and OGG1 as potential actors for the maintenance of telomere integrity. The second part of our work focused on further study of the level of transcription of c-Fos in connection with one of the main risk factors for atherosclerosis posed by smoking status in patients with coronary artery disease. This work has to show for the first time a relationship between the expression level of c-Fos and smoking status of subjects, suggesting that one possible way of tobacco toxicity may involve the signaling pathways involving c-Fos. Thus, this thesis has highlighted three biomarkers of interest in the area of atherosclerotic disease: 1. Leukocyte telomere length may be one way of beneficial action of statins in early prevention of cardiovascular disease, 2. The level of OGG1 gene expression as a potential actor for maintained the integrity of telomeres, 3. The level of expression of the gene c-Fos as a marker of cumulative smoking exposure and potential actor of deleterious effects of tobacco. Remains to clarify the cellular and molecular mechanisms brought into play and thus develop appropriate therapeutic strategies to optimize the management of patients with atherosclerotic disease.

Os carcinomas de cabeça e pescoço correspondem a 10% de todos dos tumores malignos, destes aproximadamente 40% se manifestam na boca e 90% correspondem ao carcinoma espinocelular. Os principais agentes carcinogênicos relacionados ao câncer bucal são o tabaco e o álcool. A cirurgia é o tratamento de eleição para o carcinoma de boca seguido dos tratamentos quimio e radioterápicos. O uso de lipossomas como vetor de quimioterápicos abre grandes perspectivas para o tratamento do câncer, pois possibilitam maior eficácia, reduzindo a toxicidade e a dosagem do fármaco. Neste projeto foram avaliados os efeitos pró apoptóticos \"in vitro\" da fosfoetanolamina sintética (FOS) e da sua formulação lipossomal DODAC/FOS em duas linhagens celulares de carcinoma espinocelular de língua humano, SCC-9 e SCC-25. A FOS, a formulação lipossomal DODAC/FOS e o carreador DODAC vazio apresentam diferentes significados em seu potencial citotóxico. A FOS aumentou significativamente a formação de lipoperóxidos pela membrana celular nas maiores concentrações estudadas. A análise das fases do ciclo celular mostrou aumento significativo da população de células com DNA fragmentado em ambas as linhagens celulares induzindo a morte celular por apoptose com aumento da expressão de Bad, Bax, citocromo c e diminuição de Bcl-2, como também alterou o potencial elétrico mitocondrial promovendo a ativação da caspase-3. A FOS e a formulação lipossomal DODAC/FOS induziram retração dos filamentos de actina e fragmentação do DNA. O conjunto de resultados mostra que o composto FOS e a sua formulação lipossomal DODAC/FOS atuam nos efeitos citotóxicos e antitumoral promovidos por estes alquilfosfoésteres, sendo capazes de induzir a morte celular por apoptose em diferentes apresentações / Head and neck carcinomas account for 10% of all malignant tumors, approximately 40% of these tumors manifest in the mouth and 90% correspond to squamous cell carcinoma. The main carcinogenic agents related to oral cancer are tobacco and alcohol. Surgery is the treatment of choice for oral carcinoma followed by chemo and radiotherapeutic treatments. The use of liposomes as a vector of chemotherapy offers great prospects for treatment of cancer, as they allow greater efficacy, reducing the toxicity and the dosage of drug. In this project, in vitro pro apoptotic effects of synthetic phosphoethanolamine (Pho-S) and DODAC/Pho-S liposomal formulation were evaluated in two human tongue squamous cell carcinoma cell lines, SCC-9 and SCC-25. Pho-S, DODAC/Pho-S liposomal formulation and the empty DODAC carrier have different meanings in their cytotoxic potential. Pho-S significantly increased the formation of lipoperoxides by cell membrane in higher concentrations studied. Analysis of the cell cycle phases showed a significant increase in the cell population with fragmented DNA in both cell lines inducing apoptosis cell death with increase expression of Bad, Bax, cytochrome c and decrease of Bcl-2, as well as altered the potential mitochondrial activation promoting caspase-3 activation. Pho-S and the DODAC/Pho-S liposomal formulation induced retraction of the actin filaments and DNA fragmentation. The set of results shows that the Pho-S compound and its liposomal formulation DODAC/Pho-S act on the cytotoxic and antitumor effects promoted by these alkylphosphoesters, being able to induce cell death by apoptosis in different presentations

A deeper understanding of both movement control and the effects of nociceptor inputs on our motor systems is critical for proper clinical diagnosis of musculo-skeletal dysfunctions and for development of novel rehabilitation schemes. In the jaw system, masticatory movements are produced by a central pattern generator (CPG) located in the brainstem. Considerable efforts have been made in deciphering this neuronal network. The present thesis contributes towards an increasingly detailed understanding of its essential elements, and presents a hypothesis of how deep somatic pain (i.e. muscle pain) may be evoked and interferes with the masticatory CPG circuitry. In Paper I, the expression of c-Fos-like protein was used as a molecular marker to visualize brainstem neurons that were active during induced fictive mastication in the anesthetized and paralyzed rabbit. Our findings provide a previously lacking detailed record of the neuronal populations that form the masticatory motor pattern. Certain cells were located in brainstem areas previously suggested to be involved in the masticatory CPG. However, it was a new finding that neurons in the dorsal part of the trigeminal main sensory nucleus (NVsnpr-d) may belong to this circuitry. Paper II focused on the discovered neurons in NVsnpr in an in vitro slice preparation from young rats.  Intracellular recordings allowed us to define two cell types based on their response to depolarizing current. Microstimulation applied to the trigeminal motor nucleus, its reticular border, the parvocellular reticular formation and the nucleus reticularis pontis caudalis, elicited postsynaptic potentials in 81% of the neurons tested. Responses obtained were predominately excitatory and sensitive to gluta-matergic antagonists DNQX or/and APV. Some inhibitory and biphasic responses were also evoked. Bicuculline methiodide or strychnine blocked the IPSPs indicating that they were mediated by GABAA or glycinergic receptors. About one third of the stimulations activated both types of neurons antidromically. Neurons in NVsnpr-d seem to gather all the conditions that can theoretically account for a role in masticatory rhythm generation. In Paper III, the masticatory model system was used to investigate the possible role of muscle spindle primary afferents in development of persistent musculoskeletal pain. Following intramuscular acidic (pH 4.0) saline injections of rat masseter muscles, in vitro whole cell recordings were done from jaw closing muscle spindle somata located in the trigeminal mesencephalic nucleus (NVmes). Compared to control neurons, the somata of afferents exposed to acid had more hyperpolarized membrane potentials, more hyperpolarized thresholds for firing, high frequency membrane oscillations and ectopic bursting of action potentials. These changes in membrane properties lasted for up to 35 days. Within the same time frame experi-mental animals showed hypersensitivity to touch on the skin covering the injected muscle. Similar saline injections also resulted in a significant increase of activity dependent c-Fos expression in NVmes neurons compared to controls. Immuno-fluorescence and lectin binding studies indicated that small-caliber muscle afferents containing known nociceptor markers (CGRP, SP, P2X3, TRPV1 and IB4) and expressing glutamate receptors are found close to the annulo-spiral endings of the NVmes afferents. Combined, our new observations support the hypothesis that excessive release of glutamate, within muscle spindles due to ectopically evoked antidromic action potentials, could lead to development of persistent musculoskeletal pain by activation and/ or sensitization of adjacent muscle afferent nociceptors.

Transcription factors are proteins that regulate transcription of genes by binding to specific DNA sequences proximal to the gene. The specificity and affinity of protein-DNA recognition is critical for proper gene regulation. This thesis explores the mechanisms of binding to the sequence 5’CACGTG, a common recognition sequence both in plants where it is known as the G-box and in mammalian cells where it is termed the E-box. This sequence is of clinical interest because it is the target of the transcription factor Myc, an oncogene linked to many cancers. A number of alpha-helical proteins with different dimerization elements, from the basic region-leucine zipper (bZIP), basic region helix-loop-helix leucine zipper (bHLHZ) and basic region helix-loop-helix-PAS (bHLH-PAS) protein families, are capable of binding to this sequence. The basic regions of all these protein families contain residues that contact DNA and determine DNA sequence specificity while the other subdomains are responsible for dimerization specificity. First, the influence of protein-DNA contacts on sequence specificity of the plant bZIP protein EmBP-1 was probed by point mutations in the basic region. Residues that contact the DNA outside the core G-box sequence and residues that contact the phosphate backbone were found to be important for sequence specificity. Second, the impact of the dimerization subdomains of bHLHZ protein Max, the required heterodimerization partner of the Myc protein, and bHLH-PAS protein Arnt was probed by mutation, deletion and inter-family subdomain swapping studies. All studied protein families are intrinsically disordered, forming structure upon dimerization and DNA binding. The dimerization domains were found to indirectly influence DNA binding by affecting folding, dimerization ability or proper orientation of the basic regions relative to DNA. Lastly, a new strategy for selection of G-box binding proteins in the Yeast One-hybrid system is explored. Together, these studies broaden our understanding of the structure-function relationship of the DNA-binding activities of these closely related families of transcription factors. The creation and characterization of mutants with altered specificity, affinity and dimerization specificity may also be useful for biotechnology applications.

Transcription factors are proteins that regulate transcription of genes by binding to specific DNA sequences proximal to the gene. The specificity and affinity of protein-DNA recognition is critical for proper gene regulation. This thesis explores the mechanisms of binding to the sequence 5’CACGTG, a common recognition sequence both in plants where it is known as the G-box and in mammalian cells where it is termed the E-box. This sequence is of clinical interest because it is the target of the transcription factor Myc, an oncogene linked to many cancers. A number of alpha-helical proteins with different dimerization elements, from the basic region-leucine zipper (bZIP), basic region helix-loop-helix leucine zipper (bHLHZ) and basic region helix-loop-helix-PAS (bHLH-PAS) protein families, are capable of binding to this sequence. The basic regions of all these protein families contain residues that contact DNA and determine DNA sequence specificity while the other subdomains are responsible for dimerization specificity. First, the influence of protein-DNA contacts on sequence specificity of the plant bZIP protein EmBP-1 was probed by point mutations in the basic region. Residues that contact the DNA outside the core G-box sequence and residues that contact the phosphate backbone were found to be important for sequence specificity. Second, the impact of the dimerization subdomains of bHLHZ protein Max, the required heterodimerization partner of the Myc protein, and bHLH-PAS protein Arnt was probed by mutation, deletion and inter-family subdomain swapping studies. All studied protein families are intrinsically disordered, forming structure upon dimerization and DNA binding. The dimerization domains were found to indirectly influence DNA binding by affecting folding, dimerization ability or proper orientation of the basic regions relative to DNA. Lastly, a new strategy for selection of G-box binding proteins in the Yeast One-hybrid system is explored. Together, these studies broaden our understanding of the structure-function relationship of the DNA-binding activities of these closely related families of transcription factors. The creation and characterization of mutants with altered specificity, affinity and dimerization specificity may also be useful for biotechnology applications.