Fasting and ketogenic diet prevent seizures in epileptic children, magnesium-deficient rats and other animal models of seizure disorders. This effect has been attributed to increased levels of circulating ketone bodies. The purpose of this study was to determine the role of serum ketone bodies, measured as beta-hydroxybutyrate (BHB), in preventing audiogenically-induced seizures in weanling rats fed a magnesium-deficient diet for 17 days. The effect on seizure susceptibility was investigated by feeding a magnesium-deficient diet to weanling rats for 17 days. Fasting and ketogenic diet (dietary medium chain triglycerides, MCT) markedly decreased seizure incidence that was associated with increased serum BHB level. Also, rats fasted for 24h or fed 28 percent dietary MCT had decreased seizure incidence as compared with rats fed 3 percent dietary MCT or rats fasted for 6h. These effects were not caused by differences in caloric density or percentage of calories from fat in the diets. Gavaging 2 mmoles of BHB resulted in lower seizure incidence; as compared with rats gavaged with 0.5 mmoles BHB when measured 30 min after dosing. In contrast, gavaging 5.6 mmoles of glucose resulted in increased seizure incidence in 24-h-fasted rats. Gavaging 5.6 mmoles of glucose with 0.5 mmole of BHB simultaneously resulted in higher seizure incidence than gavaging with 2.0 mmole BHB and 1.4 mmole glucose simultaneuosly. In addition, gavaging 5.6 mmoles of glucose with 2 mmoles of BHB resulted in higher seizure incidence than gavaging 2 mmoles of BHB alone, which markedly reduced seizure incidence in fasted animals. Fasting, ketogenic diet (MCT) and gavaging BHB increase serum BHB and decrease serum glucose concentrations . Gavaging glucose reduced serum BHB and increased serum glucose concentration. There was an inverse relationship between serum BHB and glucose in all treatments of this study. Although some treatments affected serum minerals, these effects were not consistent among experiments. Therefore, fasting, ketogenic diet (MCT) and gavaging BHB or glucose does not affect serum minerals markedly or consistently; and modifications in serum minerals caused by these treatments do not account for this effect on seizure incidence and severity. Finally, increases in serum BHB and decreases in serum glucose were consistently associated with dose-dependent reductions in seizure susceptibility of rats fed a magnesium-deficient diet for 17 days.

« Etude du comportement paramagnétique des actinides en solution avec des ligands polyaminocarboxylates cycliques »Le comportement paramagnétique des cations actinide (éléments 5f) peut être étudié via la spectroscopie RMN liquide en suivant deux axes de recherche complémentaires : les susceptibilités magnétiques et les déplacements chimiques.Dans un premier temps, lorsque les interactions entre le cation actinide et le ligand sont négligeables, la susceptibilité magnétique molaire est accessible par la méthode d’Evans. Cette méthode est applicable pour des échantillons en solution autour de la température ambiante. Elle a été confrontée à la mesure SQUID sur échantillon solide à très basses températures pour le complexe [NpO2(DPC)2Li2]. Les deux méthodes ont donné des susceptibilités magnétiques molaires du même ordre de grandeur même si ce composé n’est pas optimal pour la comparaison.La méthode d’Evans a été utilisée pour compléter les données expérimentales de la littérature. La mesure de la susceptibilité magnétique du cation PuVO2+ (5f3) en milieu non complexant a été mesurée au laboratoire. Les calculs de susceptibilités magnétiques molaires réalisés par la méthode SO-CASPT2 pour les cations actinide aux degrés d’oxydation (+IV), (+V) et (+VI) (AnIV = UIV, NpIV, PuIV et AnV/VI = NpV/VI, PuV/VI) en milieux non complexant puis complexants chlorure et nitrate ont été comparés avec les valeurs expérimentales. Les cations actinide ont montré une sensibilité à la nature et géométrie de leur première sphère de coordination. Il a été mis en évidence que le cation NpVI (5f1) possède un état fondamental sensiblement affecté par la modification de la symétrie du complexe. A partir des niveaux électroniques calculés, des premiers calculs de spectres d’absorption de ces mêmes complexes ont pu être réalisés. L’absorbance principale calculée est en bon accord avec les spectres d’absorption expérimentaux malgré un décalage systématique des spectres calculés vers le rouge, assimilable à un effet néphélauxétique.Dans un deuxième temps, l’utilisation de la Théorie de Bleaney a permis l’étude des déplacements chimiques et plus précisément, du terme de contact des complexes de symétrie C4 d’actinide au degré d’oxydation (+IV) avec le ligand DOTA (AnIV = ThIV, UIV, NpIV, PuIV). Cette contribution de contact a été accessible par la RMN de l’oxygène 17 (17O), atome directement lié au centre paramagnétique. Le DOTA a été enrichi en 17O avant la synthèse du complexe en phase organique DMSO/CHCl3. Ces complexes ont été caractérisés par spectrophotométrie UV-Visible-NIR et spectroscopie RMN 1H et 13C. Une difficulté de synthèse a été rencontrée pour le complexe de ThIV-D17OTA, composante diamagnétique nécessaire à l’extraction des termes de contact purement paramagnétiques. D’autres voies de synthèses ont été explorées.Mots Clés : Actinides, RMN, Paramagnétisme, Susceptibilité magnétique, Déplacement chimique, DOTA.2018 – Commissariat à l’Energie Atomique et aux Energies Alternatives – Laboratoire d’interactions Ligand-Actinide – France / “Study of actinide’s paramagnetic behavior in solution with cyclic polyaminocarboxylate ligands”The actinide cation’s (5f elements) paramagnetic behavior may be studied by liquid NMR spectroscopy. Two complementary lines of research have been pursued: molar magnetic susceptibility and chemical shift.Firstly, magnetic susceptibility is easy to determine by the Evans’ method when there is no interaction between actinide cations and ligands. This method, with samples in solution at room temperature, has been compared to SQUID measurements using solid samples at very low temperatures for the [NpO2(DPC)2Li2] complex. Both methods produce molar magnetic susceptibilities with the same order of magnitude even if this compound is not the best one to the comparison.The Evans’ method has been used to complete experimental data from literature. The molar magnetic susceptibility measurement in a non-complexing medium for the PuVO2+ (5f3) cation has been measured in the laboratory. Molar magnetic susceptibility calculations were carried out using the SO-CASPT2 method for (+IV), (+V) and (+VI) actinide cations (AnIV= UIV, NpIV, PuIV and AnV/VI: NpV/VI, PuV/VI) in a non-complexing medium, then in chloride and nitrate complexing media. They have been compared with experimental values. The molar magnetic susceptibilities of actinide cations have been shown to be sensitive to the nature and geometry of their first coordination sphere. It has been revealed that the fundamental state of NpVI (5f1) cation is affected by changing the symmetry of the complex. From calculated electronic states, first absorption spectra calculations of these complexes have been carried out. A good matching between major calculated and experimental absorbances has been obtained. A red-shift was applied to the calculated absorption spectra to fit better with the experimental ones. This shift may be related to a nephelauxetic effect.Secondly, the use of Bleaney’s Theory has allowed the study of chemical shifts. And precisely, this work has been focused on the contact contribution for C4 symmetry AnIV complexed with DOTA ligand (AnIV= ThIV, UIV, NpIV, PuIV). This contact contribution is observable via NMR of oxygen-17 (17O) because oxygen atoms are directly linked to the paramagnetic cation. Therefore, the DOTA ligand was enriched in 17O before the actinide complex synthesis in a DMSO/CHCl3 organic phase. These complexes have been characterized by UV-Visible-NIR spectrophotometry and 1H, 13C NMR spectroscopy. But, some synthesis difficulties have been encountered to the diamagnetic ThIV-D17OTA (5f0) complex. This diamagnetic component is required to extract pure paramagnetic contact contribution. In that case, other ways of synthesis have been investigated.Keywords: Actinides, NMR, Paramagnetism, Magnetic susceptibility, Chemical shift, DOTA ligand.2018 – Commissariat à l’Energie Atomique et aux Energies Alternatives – Laboratoire d’interactions Ligand-Actinide – France

Le paludisme reste la parasitose avec les taux de morbidité et mortalité les plus élevés et son impact socioéconomique constitue un frein au développement. Il y a eu une coévolution entre l'hôte humain, le vecteur et le Plasmodium avec parfois des adaptations spécifiques de résistance. Cela s'est traduit aujourd'hui par la résistance du Plasmodium aux produits antipaludiques et des difficultés de développement de vaccin efficace. L'exploration de nouveaux axes de recherche s'avère donc pertinent pour la compréhension de certaines adaptations pouvant jouer un rôle dans la susceptibilité au paludisme. Des différences de susceptibilités au paludisme ont été décrites chez les Peulh et Dogons symatriques au Mali. La plupart des études faites pour comprendre cette différence de susceptibilité ont porté sur l'immunité. Dans ce travail, nous avons fait une approche novatrice plus globale, en étudiant l'interaction entre l'environnement, le système immunitaire et la susceptibilité au paludisme. Nous nous sommes ainsi intéressés à la relation entre l'alimentation, le métabolisme et l'immunité qui est un exemple d'interaction entre l'environnement et la biologie. Nos travaux ont permis de décrire des différences entre Peulh et Dogons du Mali en termes de taux sanguins d'AGE et sRAGE, ainsi que dans expression et le polymorphisme du récepteur RAGE. Cela pourrait avoir des implications sur le plan immunitaire et donc dans la susceptibilité au paludisme. Ces résultats constituent d'importantes données de base pour soutenir une nouvelle voie de recherche sur le paludisme en combinant l'alimentation, le métabolisme, en associant le microbiote intestinal qui suscite aussi actuellement beaucoup d’intérêt dans le paludisme / Malaria remains the parasitic disease with the highest rates of morbidity and mortality and its socio-economic impact is an obstacle to development.There has been a coevolution between human host, the vector and Plasmodium with sometimes specific adaptations of resistance, leading today into resistance of Plasmodium to antimalarial products and the difficulties to develop an effective vaccine. The exploration of new areas of research is therefore relevant for the understanding of some adaptations that may have implications in the susceptibility to malaria.Differences in susceptibility to malaria have been described in symmetric Fulani and Dogon in Mali. Most of the studies carried out to understand this difference in susceptibility have focused on immunity. In this work, we have implemented a more global and innovative approach, studying the inteplay between the environment, the immune system and susceptibility to malaria. We investigated the relationship between diet, metabolism and immunity, which is an example of interaction between environment and biology.In our study, we described differences between Fulani and Dogons of Mali in terms of blood levels of AGE and sRAGE, as well as in expression and polymorphism of the RAGE receptor. This could have implications for the immune system and therefore for susceptibility to malaria. These results provide important baseline data for supporting a new malaria research approach by combining diet, metabolism, and gut microbiota which is also currently of great interest in malaria

Suite à la découverte des antibiotiques, les succès thérapeutiques ont laissé présager un avenir où les maladies infectieuses d’origine bactérienne seraient éradiquées. Cependant, en moins d’un siècle, l’utilisation massive des antibiotiques à large spectre a conduit à l’émergence de résistances réduisant ainsi les options thérapeutiques. Mon projet de recherche vise à comprendre les altérations métaboliques et morphologiques bactériennes induites précocement par les antibiotiques et à contribuer au développement de tests diagnostiques rapides et fiables pour favoriser la mise en place d’antibiothérapies plus ciblées. Grâce au suivi des modifications des divers paramètres métaboliques et morphologiques des bactéries après traitement aux antibiotiques, nous avons montré l’intérêt des marqueurs de viabilité tels que le DiBAC4(3), le TOPRO®-3 ou encore l’Alexa FluorTM Hydrazide pour la détection rapide (<3h) de la sensibilité des bactéries aux antibiotiques. Nous avons notamment montré, pour la première fois, que la carbonylation des protéines, qui est induite dans des conditions de stress oxydatif et de vieillissement cellulaire, est un marqueur précoce universel de la sensibilité aux antibiotiques bactéricides. Suite à cette première partie de l’étude, nous avons souhaité comprendre les mécanismes mis en jeu par les bactéries en réponse au stress létal causé pas les antibiotiques. Au cours de nos expériences, il a été observé que lorsque les conditions ne permettaient plus la survie de l’organisme, un signal de fluorescence intrinsèquement lié à la bactérie permettait de prédire l’issue fatale après seulement 2 heures d’incubation avec l’antibiotique. En effet, suite à un traitement avec un antibiotique bactéricide ciblant la synthèse du peptidoglycane bactérien (ampicilline), nous avons observé une fluorescence maximale des cellules à la dose d’antibiotique correspondant à la Concentration Minimale Inhibitrice (CMI). L’augmentation de la fluorescence des cellules bactériennes a aussi été observé lors du traitement létal avec un agent biocide (hypochlorite de sodium). Cependant, ce phénomène n’est plus observable avec des antibiotiques bactériostatiques ou bactéricides qui inhibent la synthèse protéique indiquant l’importance d’un métabolisme bactérien actif. Les corrélations de propriétés spectrales nous ont permis de suspecter les molécules de flavines comme étant responsables du phénomène d’autofluorescence observé. De plus, nous avons montré une suractivation de la voie de biosynthèse des cofacteurs de type flavines et des flavoprotéines en présence d’ampicilline. Finalement, nous avons effectué des expériences de tri et de survie cellulaire de populations bactériennes traitées à l’ampicilline. Nos résultats ont montré que les cellules très fluorescentes ont une survie moyenne 5 fois supérieure aux cellules peu fluorescentes. Ceci suggère que le signal de fluorescence observé est une réponse cellulaire médiée par les composés flavonoïdes pour tenter de survivre au traitement antibiotique. Des travaux exploratoires suggèrent que le phénomène étudié chez les bactéries est conservé chez les levures et chez les cellules humaines. Ces résultats ouvrent de nouvelles perspectives dans la compréhension de la physiologie bactérienne, l’étude de la réponse bactérienne face à un stress exogène et la surveillance rapide de la viabilité des cellules. / Following the discovery of antibiotics, the therapeutic successes foreshadowed a future where infectious diseases of bacterial origin would be eradicated. However, in less than a century, the massive use of broad-spectrum antibiotics led to the emergence of resistance thus reducing therapeutic options. My research project aims to understand early bacterial metabolic and morphological changes induced by antibiotics and to contribute to the development of rapid and reliable diagnostic tests to promote the implementation of more targeted antibiotic treatments. By monitoring changes in various metabolic and morphological parameters of bacteria after antibiotic treatment, we have shown the interest of viability markers such as DiBAC4(3), TOPRO®-3 or Alexa FluorTM Hydrazide for rapid detection (<3h) of bacterial susceptibility to antibiotics. In particular, we have shown for the first time that protein carbonylation, which is induced under conditions of oxidative stress and cellular aging, is a universal early marker of bactericidal antibiotic susceptibility. Following this first part of the study, we wanted to understand the mechanisms involved in bacterial response to lethal stress caused by antibiotics. Following this first part of the study, we wanted to understand the bacterial mechanisms involved in response to lethal stress caused by antibiotics. In our experiments, it was observed that when the conditions no longer allowed the organism survival, a fluorescence signal intrinsically linked to the bacterium allowed to predict the fatal outcome after only 2 hours of incubation. Indeed, following a treatment with a bactericidal antibiotic targeting the synthesis of bacterial peptidoglycan (ampicillin), we observed a maximum fluorescence of the cells at the dose of antibiotic corresponding to the Minimum Inhibitory Concentration (MIC). The fluorescence increase of bacterial cells was also observed during the lethal treatment with a biocidal agent (sodium hypochlorite). However, this phenomenon is no longer observable with bacteriostatic or bactericidal antibiotics that inhibit protein synthesis indicating active bacterial metabolism importance. The correlations of spectral properties allowed us to suspect the flavin molecules as responsible for the observed autofluorescence phenomenon. In addition, we showed an overactivation of the biosynthesis pathway of flavin-type cofactors and flavoproteins occurring during ampicillin treatment. Finally, we performed cell sorting and cell survival experiments of ampicillin-treated bacterial populations. Our results showed that highly fluorescent cells have an average survival 5 times higher than low fluorescent cells. This suggests that the fluorescence signal observed is a cellular response mediated by flavonoid compounds in an attempt to survive to antibiotic treatment. Exploratory work suggests that the phenomenon studied in bacteria is conserved among yeasts and human cells. These results open new perspectives in bacterial physiology understanding, the study of bacterial response to exogenous stress and the rapid monitoring of cell viability.

Phishing is a social engineering attack to deceive and persuade people to divulge private information like usernames and passwords, account details (including bank account details), and social security numbers. Phishers typically utilize e-mail, chat, text messages, or social media. Despite the presence of automatic anti-phishing filters, phishing messages reach online users' inboxes. Understanding the influence of phishing techniques and individual differences on susceptibility and detection accuracy is an important step toward creating comprehensive behavioral and organizational anti-phishing awareness programs. This dissertation seeks to achieve a dual purpose in a series of three essays. Essay 1 seeks to explore the nature of phishing threats that including identifying attack intentions, and psychological and design techniques of phishing attacks. Essay 2 seeks to understand the relative influence of attack techniques and individual phishing experiential traits on people's phishing susceptibility. Essay 3 seeks to understand an individual's cognitive and affective differences that differentiate between an individual's phishing detection accuracy.

<p>IIn the first study, we investigated the functional implications of prolonged TLR signalling on IFN-γ mediated killing of mycobacteria by murine macrophages <i>in vitro</i>. TLR2, but not TLR4 ligation interfered with IFN-γ mediated killing of mycobacteria in macrophages. In terms of mechanisms, neither TNF nor nitric oxide (NO) production was significantly affected, and the refractoriness induced could be reversed with increasing amounts of IFN-γ In the second study, we aimed to identify immunological markers of diagnostic importance in both the respiratory tract and serum during pulmonary mycobacterial infection in mice. We found that increased levels of immunological markers in the respiratory tract, but not serum, correlated better with active mycobacterial infection in the lungs, suggesting that the immune response in the respiratory tract is more reflective of the infection status and pathology than the systemic response. Finally, we investigated the level and nature of immune responses to pulmonary mycobacterial infection in BALB/c and C57BL/6 mice, two mouse strains known to exhibit different susceptibilities to infection with several intracellular pathogens, including mycobacteria. We showed that increased susceptibility of BALB/c mice to early mycobacterial infection was associated with reduced Th1 immune responses, and increased sTNFR secretion in the lung. Moreover, BALB/c mice recruited fewer monocytes/macrophages to the lung, and although IFN-γ stimulation of infected bone marrow derived macrophages in both mouse strains resulted in induction of antimycobacterial activity, BALB/c mice had a reduced capacity to kill ingested bacteria. The work presented in this thesis provide further insight into the mechanisms involved in the host-pathogen interaction; from persistence, to the immunological processes induced by the pathogen, to susceptibility of the host to infection.</p>

<p>This thesis examined neurotoxic effects of nicotine exposure during a defined critical period of neonatal brain development in mice.</p><p>In our environment there are numerous hazardous contaminants that an individual can be exposed to during its entire lifetime. In many mammalian species the neonatal period is characterised by a rapid development of the brain. The present studies have identified a defined critical period during the neonatal brain development in mice, where exposure to low doses of nicotine causes permanent disturbances in the cholinergic nicotinic receptors and altered behaviour response to nicotine at adult age. This adult reaction to nicotine, a hypoactive response, was the opposite of that observed in control animals and animals exposed to nicotine before or after this period. Animals showing a hypoactive response to nicotine lacked nicotinic low affinity binding sites in the cerebral cortex. Furthermore, neonatal exposure to nicotine affected learning and memory in adult animals, an effect that was time-dependent. This thesis also showed that neonatal exposure to nicotine increased adult susceptibility to a repeated exposure of nicotine, manifested as an even more pronounced effect in spontaneous behaviour after challenging doses of nicotine. In these animals the nicotinic receptors in the cerebral cortex, assayed by a-bungarotoxin, was decreased. </p><p>Neonatal exposure to nicotine was also shown to increase adult susceptibility to the organophosphate paraoxon, a known cholinergic agent, and to the brominated flame retardant 2,2´,4,4´,5-pentabromodiphenyl ether, a novel environmental agent, at adult age. This was seen at doses that did not affect behaviour in control animals, and was manifested as deranged spontaneous behaviour and reduced habituation, aberrations that also worsened with age. </p><p>The results indicate that differences in adult susceptibility to environmental pollutants are not necessarily an inherited condition. Rather they may well be acquired by low dose exposure to toxic agents during early life.</p>

Myxobolus cerebralis, a myxozoan parasite of salmonids, is the causative agent of whirling disease. The parasite is considered widespread throughout northeastern Oregon in the Grande Ronde and Imnaha River basins where threatened and endangered salmonid populations exist. The work presented in this thesis comprises several studies that assess the effects of M. cerebralis on resident and anadromous salmonids in Oregon. Laboratory challenges to determine the susceptibility of indigenous Deschutes River, Oregon, salmonids to M. cerebralis were conducted as part of a study to assess the risk of reintroducing anadromous salmon above a migration barrier on that river. This study was the first to assess the susceptibility of kokanee salmon Oncorhynchus nerka to M. cerebralis, and results contribute to the understanding of salmonid susceptibility as it relates to species and age. Further, this study demonstrates that the indigenous salmonids present in the river are susceptible to infection, but resident rainbow trout Oncorhynchus mykiss would be most at risk should introduction of M. cerebralis occur in this system. The susceptibility of chinook salmon Oncorhynchus tshawytscha to M. cerebralis was assessed following laboratory challenges at different ages to different parasite levels. Results from this study indicate that chinook salmon are more resistant to M. cerebralis infection than susceptible rainbow trout; resistance to disease developed in chinook salmon exposed after 3 weeks of age. Sustained exposures to a low parasite dose were performed to model the conditions chinook salmon would encounter in a natural exposure. Following continuous exposure to low parasite densities, chinook salmon were very resistant to infection and disease. Managed populations of chinook salmon and steelhead Oncorhynchus mykiss juveniles are held in acclimation facilities on their natal streams before release to commence their seaward migration. Rainbow trout fry were held at each of the acclimation facilities to detect the presence of M. cerebralis and to assess the prevalence of exposure during the acclimation period. Results from these exposures indicate that the Wallowa acclimation facility is a high-risk site for parasite exposure of steelhead juveniles. Further, detection was confirmed in several rivers and streams where the presence of M. cerebralis has been suggested. Finally, a preliminary study on the effect of M. cerebralis on survival of steelhead juveniles upon transfer to saltwater was conducted. Results from this study indicate that M. cerebralis exposure and infection may increase mortality among juvenile steelhead during saltwater adaptation. / Graduation date: 2003

The anisotropy of magnetic susceptibility (AMS) was investigated in three Chinese Loess Plateau sedimentary sections along a W–E transect. Previously published models assumed that winter monsoons were responsible for the magnetic fabric formation of loess sequences. In our new interpretation, the stronger summer monsoons from the southeast played the major role in magnetic fabric orientation in the studied west and central parts of the Chinese Loess Plateau. The AMS was generated during the rainy summer monsoon when the sedimentary particles including magnetite were rearranged, settled, and fixed. We reconstruct the summer paleomonsoon routes for the last 130 kyr. These winds prevail from SE to NW but appear to be affected by regional topographic factors. Evidence in the world’s ocean current system indicates an abrupt cooling from 34.1 to 33.6 Ma across the Eocene-Oligocene boundary (EOB) at 33.9 Ma. I describe and date with magnetostratigraphy a section from the north Junggar Basin (Burqin section). Three fossil assemblages revealed through the EOB (34.8, 33.7, and 30.4 Ma) demonstrate that perissodactyl faunas were abruptly replaced by rodent/lagomorph-dominant faunas during climate cooling, and the changes in mammalian communities were accelerated by aridification in central Asia. Paleomagnetic studies of two sections of the northern Junggar Basin, China, are presented from Burqin and Tieersihabahe. Our paleomagnetic results demonstrate counterclockwise tectonic rotations in Burqin and Tieersihabahe (–17.2 ± 9.6° and –11.8 ± 6.1°, respectively) as well as considerable northward latitudinal displacement (12.2 ± 6.5° and 9.7 ± 4.1°, respectively) with respect to Europe. These results are consistent with the motions of contiguous blocks in the same geological time intervals (India, north and south China, Tarim, Amuria, and Kazakhstan). No significant intracontinental shortening or vertical-axis rotation is observed for the Junggar block from 40 Ma to 20 Ma. Our results reveal that the major compression and rotation between Junggar and northern Europe occurred after 20 Ma due to continuous penetration of India into Asia. We interpret the uplift of the Altay Mountains and the formation of the Lake Baikal rift system to be due to such intracontinental compression and relative rotations. / Geophysics

No description available.