A Doença Hepática Gordurosa Não Alcoólica (DHGNA) é atualmente uma das formas mais comuns de doença hepática, e está diretamente relacionada com a obesidade. Estudos indicam uma prevalência por volta de 30% na população ocidental e 11% na população oriental. A DGHNA possui um largo espectro abrangendo desde casos de esteatose simples sem inflamação, até casos com esteatohepatite e fibrose, podendo evoluir para cirrose e carcinoma hepatocelular. A fisiopatogênese da DHGNA é baseada em múltiplos eventos: resistência insulínica, aumento da lipólise periférica, aumento da síntese de novo de lipídeos, estresse oxidativo, endotoxemia crônica no desencadeamento da inflamação e fibrose entre outros. A etapa inicial caracteriza-se pelo acúmulo de ácidos graxos no hepatócito, suplantando sua capacidade de metabolização e exportação conseqüente à ação lipogênica da insulina, desta forma o metabolismo de ácidos graxos está intimamente ligado ao desenvolvimento da DHGNA. O Yo Jyo Hen Shi Ko (YHK) é um composto natural usado na medicina japonesa para tratamento de doenças hepáticas e apresenta propriedades antioxidantes, antiinflamatórias e hipolipemiantes. O presente estudo teve como objetivo avaliar o efeito do YHK no metabolismo hepático de lipídeos. Para tanto, foram utilizados camundongos obesos (ob/ob) com esteatohepatite não alcoólica (ENA) induzida por dieta deficiente em colina e metionina (DCM) e foram analisados no tecido hepático, genes relacionados com a síntese de novo de lipídeos (SREBP1c, FASn), genes relacionados com a oxidação e exportação de lipídeos (CPT1a e SCD-1, MTP), assim como genes relacionados com o armazenamento de lipídeos (Perilipina e ADFP). O YHK apresentou um efeito citoprotetor hepático com melhora dos parâmetros histológicos neste modelo experimental de ENA. Associadamente, houve redução na expressão de genes relacionados à síntese de novo como SREBP e da FASn, quando se comparou o grupo tratado com DCM+YHK com o grupo não tratado DCM. Em contrapartida, houve aumento na expressão da MTP e da SCD-1 ocasionando uma maior exportação de triglicerídeos hepáticos nos animais que utilizaram o YHK. Ainda, o YHK modulou as proteínas Perilipina e ADFP. Por outro lado, não houve modificação na oxidação de lipídeos.. Conclui-se que o YHK pode ser uma droga promissora no tratamento da DHGNA, já que age modulando genes envolvidos na síntese e exportação de lipídeos hepáticos, reduzindo o acúmulo de gordura no hepatócito / Nonalcoholic fatty liver disease (NAFLD) is currently one of the most common forms of liver disease, related directly to the increase of obesity in the world. Previous studies indicate a prevalence of around 30% in the western population and 11% in the eastern. This disease covers cases from simple steatosis without inflammation to cases of steato hepatitis (NASH) and fibrosis and it may lead to liver cirrhosis and hepatocellular carcinoma. The pathophysiology of NAFLD is based on multiple events: insulin resistance, increased peripheral lipolysis, increased de novo lipogenesis, oxidative stress, endotoxemia in triggering chronic inflammation and fibrosis and others. The initial stage of the disease is characterized by the accumulation of fatty acids in hepatocytes caused by the lipogenic action of insulin. This condition results in the surpassing of the cells ability to metabolize and export. This way, the metabolism of fatty acids is closely linked to the development of NAFLD. The Yo Jyo Hen Shi Ko (YHK) is a natural compound used in Japanese medicine for the treatment of liver disease and it has antioxidant, anti-inflammatory and lipid lowering properties. This study aimed to evaluate the effect of YHK in the hepatic metabolism of lipids. An experimental model was designed using obese mice (ob/ob) affected by NASH induced by a deficient diet in choline and methionine (MCD). Then, genes from its hepatic tissue related to de novo lipogenesis (SREBP1c, FASN), to lipid oxidation and exportation (CPT1A and SCD-1, MTP) as well as genes related to lipid storage (Perilipin and ADFP) were analyzed. The YHK presented a cytoprotective effect, improving the hepatic histological parameters in this experimental model. Additionally, when comparing the group treated with MCD + YHK (diet + YHK) to the untreated MCD group (diet) there was a reduction in the expression of genes related to de novo synthesis like SREBP1c and FASn. However, an increased expression of MTP and SCD-1 were observed leading to a greater liver exportation of fatty acids in animals that were treated with YHK. Moreover, the YHK modulated the proteins Perilipin and ADFP. On the other hand, there was no changing in lipid oxidation. In summary, the YHK can be a promising drug for the treatment of NAFLD, as it acts by modulating genes involved in the synthesis and exportation of hepatic lipids, reducing the accumulation of fat in hepatocytes

No description available.

A Doença Hepática Gordurosa Não Alcoólica (DHGNA) é atualmente uma das formas mais comuns de doença hepática, e está diretamente relacionada com a obesidade. Estudos indicam uma prevalência por volta de 30% na população ocidental e 11% na população oriental. A DGHNA possui um largo espectro abrangendo desde casos de esteatose simples sem inflamação, até casos com esteatohepatite e fibrose, podendo evoluir para cirrose e carcinoma hepatocelular. A fisiopatogênese da DHGNA é baseada em múltiplos eventos: resistência insulínica, aumento da lipólise periférica, aumento da síntese de novo de lipídeos, estresse oxidativo, endotoxemia crônica no desencadeamento da inflamação e fibrose entre outros. A etapa inicial caracteriza-se pelo acúmulo de ácidos graxos no hepatócito, suplantando sua capacidade de metabolização e exportação conseqüente à ação lipogênica da insulina, desta forma o metabolismo de ácidos graxos está intimamente ligado ao desenvolvimento da DHGNA. O Yo Jyo Hen Shi Ko (YHK) é um composto natural usado na medicina japonesa para tratamento de doenças hepáticas e apresenta propriedades antioxidantes, antiinflamatórias e hipolipemiantes. O presente estudo teve como objetivo avaliar o efeito do YHK no metabolismo hepático de lipídeos. Para tanto, foram utilizados camundongos obesos (ob/ob) com esteatohepatite não alcoólica (ENA) induzida por dieta deficiente em colina e metionina (DCM) e foram analisados no tecido hepático, genes relacionados com a síntese de novo de lipídeos (SREBP1c, FASn), genes relacionados com a oxidação e exportação de lipídeos (CPT1a e SCD-1, MTP), assim como genes relacionados com o armazenamento de lipídeos (Perilipina e ADFP). O YHK apresentou um efeito citoprotetor hepático com melhora dos parâmetros histológicos neste modelo experimental de ENA. Associadamente, houve redução na expressão de genes relacionados à síntese de novo como SREBP e da FASn, quando se comparou o grupo tratado com DCM+YHK com o grupo não tratado DCM. Em contrapartida, houve aumento na expressão da MTP e da SCD-1 ocasionando uma maior exportação de triglicerídeos hepáticos nos animais que utilizaram o YHK. Ainda, o YHK modulou as proteínas Perilipina e ADFP. Por outro lado, não houve modificação na oxidação de lipídeos.. Conclui-se que o YHK pode ser uma droga promissora no tratamento da DHGNA, já que age modulando genes envolvidos na síntese e exportação de lipídeos hepáticos, reduzindo o acúmulo de gordura no hepatócito / Nonalcoholic fatty liver disease (NAFLD) is currently one of the most common forms of liver disease, related directly to the increase of obesity in the world. Previous studies indicate a prevalence of around 30% in the western population and 11% in the eastern. This disease covers cases from simple steatosis without inflammation to cases of steato hepatitis (NASH) and fibrosis and it may lead to liver cirrhosis and hepatocellular carcinoma. The pathophysiology of NAFLD is based on multiple events: insulin resistance, increased peripheral lipolysis, increased de novo lipogenesis, oxidative stress, endotoxemia in triggering chronic inflammation and fibrosis and others. The initial stage of the disease is characterized by the accumulation of fatty acids in hepatocytes caused by the lipogenic action of insulin. This condition results in the surpassing of the cells ability to metabolize and export. This way, the metabolism of fatty acids is closely linked to the development of NAFLD. The Yo Jyo Hen Shi Ko (YHK) is a natural compound used in Japanese medicine for the treatment of liver disease and it has antioxidant, anti-inflammatory and lipid lowering properties. This study aimed to evaluate the effect of YHK in the hepatic metabolism of lipids. An experimental model was designed using obese mice (ob/ob) affected by NASH induced by a deficient diet in choline and methionine (MCD). Then, genes from its hepatic tissue related to de novo lipogenesis (SREBP1c, FASN), to lipid oxidation and exportation (CPT1A and SCD-1, MTP) as well as genes related to lipid storage (Perilipin and ADFP) were analyzed. The YHK presented a cytoprotective effect, improving the hepatic histological parameters in this experimental model. Additionally, when comparing the group treated with MCD + YHK (diet + YHK) to the untreated MCD group (diet) there was a reduction in the expression of genes related to de novo synthesis like SREBP1c and FASn. However, an increased expression of MTP and SCD-1 were observed leading to a greater liver exportation of fatty acids in animals that were treated with YHK. Moreover, the YHK modulated the proteins Perilipin and ADFP. On the other hand, there was no changing in lipid oxidation. In summary, the YHK can be a promising drug for the treatment of NAFLD, as it acts by modulating genes involved in the synthesis and exportation of hepatic lipids, reducing the accumulation of fat in hepatocytes

Please read the abstract in the section 00front of this document / Thesis (DPhil (Educational Psychology))--University of Pretoria, 2008. / Educational Psychology / unrestricted

With the publication of the famous Erdős-Ko-Rado Theorem in 1961, intersection problems became a popular area of combinatorics. A family of combinatorial objects is t-intersecting if any two of its elements mutually t-intersect, where the latter concept needs to be specified separately in each instance. This thesis is split into two parts; the first is concerned with intersecting injections while the second investigates intersecting posets. We classify maximum 1-intersecting families of injections from {1, ..., k} to {1, ..., n}, a generalisation of the corresponding result on permutations from the early 2000s. Moreover, we obtain classifications in the general t>1 case for different parameter limits: if n is large in terms of k and t, then the so-called fix-families, consisting of all injections which map some fixed set of t points to the same image points, are the only t-intersecting injection families of maximal size. By way of contrast, fixing the differences k-t and n-k while increasing k leads to optimal families which are equivalent to one of the so-called saturation families, consisting of all injections fixing at least r+t of the first 2r+t points, where r=|_ (k-t)/2 _|. Furthermore we demonstrate that, among injection families with t-intersecting and left-compressed fixed point sets, for some value of r the saturation family has maximal size . The concept that two posets intersect if they share a comparison is new. We begin by classifying maximum intersecting families in several isomorphism classes of posets which are linear, or almost linear. Then we study the union of the almost linear classes, and derive a bound for an intersecting family by adapting Katona's elegant cycle method to posets. The thesis ends with an investigation of the intersection structure of poset classes whose elements are close to the antichain. The overarching theme of this thesis is fixing versus saturation: we compare the sizes and structures of intersecting families obtained from these two distinct principles in the context of various classes of combinatorial objects.

The problems we study in this thesis arise in computer science, extremal set theory and quantum computing. The first common feature of these problems is that each can be reduced to characterizing the independent sets of maximum size in a suitable graph. A second common feature is that the size of these independent sets meets an eigenvalue bound due to Delsarte and Hoffman. Thirdly, the graphs that arise belong to association schemes that have already been studied in other contexts. Our first problem involves covering arrays on graphs, which arises in computer science. The goal is to find a smallest covering array on a given graph <i>G</i>. It is known that this is equivalent to determining whether <i>G</i> has a homomorphism into a <i>covering array graph</i>, <i>CAG(n,g)</i>. Thus our question: Are covering array graphs cores? A covering array graph has as vertex set the partitions of <i>{1,. . . ,n}</i> into <i>g</i> cells each of size at least <i>g</i>, with two vertices being adjacent if their meet has size <i>g²</i>. We determine that <i>CAG(9,3)</i> is a core. We also determine some partial results on the family of graphs <i>CAG(g²,g)</i>. The key to our method is characterizing the independent sets that meet the Delsarte-Hoffman bound---we call these sets <i>ratio-tight</i>. It turns out that <i>CAG(9,3)</i> sits inside an association scheme, which will be useful but apparently not essential. We then turn our attention to our next problem: the Erdos-Ko-Rado theorem and its <i>q</i>-analogue. We are motivated by a desire to find a unifying proof that will cover both versions. The EKR theorem gives the maximum number of pairwise disjoint <i>k</i>-sets of a fixed <i>v</i>-set, and characterizes the extremal cases. Its <i>q</i>-analogue does the same for <i>k</i>-dimensional subspaces of a fixed <i>v</i>-dimensional space over <i>GF(q)</i>. We find that the methods we developed for covering array graphs apply to the EKR theorem. Moreover, unlike most other proofs of EKR, our argument applies equally well to the <i>q</i>-analogue. We provide a proof of the characterization of the extremal cases for the <i>q</i>-analogue when <i>v=2k</i>; no such proof has appeared before. Again, the graphs we consider sit inside of well-known association schemes; this time the schemes play a more central role. Finally, we deal with the problem in quantum computing. There are tasks that can be performed using quantum entanglement yet apparently are beyond the reach of methods using classical physics only. One particular task can be solved classically if and only if the graph &Omega;(<i>n</i>) has chromatic number <i>n</i>. The graph &Omega;(<i>n</i>) has as vertex set the set of all <i>?? 1</i> vectors of length <i>n</i>, with two vertices adjacent if they are orthogonal. We find that <i>n</i> is a trivial upper bound on the chromatic number, and that this bound holds with equality if and only if the Delsarte-Hoffman bound on independent sets does too. We are thus led to characterize the ratio-tight independent sets. We are then able to leverage our result using a recursive argument to show that <i>&chi;</i>(&Omega;(<i>n</i>)) > <i>n</i> for all <i>n</i> > 8. It is notable that the reduction to independent sets, the characterization of ratio-tight sets, and the recursive argument all follow from different proofs of the Delsarte-Hoffman bound. Furthermore, &Omega;(<i>n</i>) also sits inside a well-known association scheme, which again plays a central role in our approach.

L’autisme est un trouble envahissant du développement défini uniquement sur des critères comportementaux et l’âge d’apparition. Le X fragile est une pathologie d’origine monogénique dont 15-25% des patients présente le diagnostique complet de l’autisme et dont de nombreux symptômes chevauchent avec l’autisme. Une souris Fmr1 KO a été créée et validée comme modèle pour le X fragile. A l’instar de la variabilité des phénotypes du X fragile chez l’humain, les données préliminaires montrent que la mutation nulle Fmr1 chez la souris interagit avec l'arrière fond génétique. Les travaux présentés visaient à déterminer les caractéristiques autistiques exprimées par les souris Fmr1 KO, ainsi que l’interaction de la mutation nulle avec le fond génétique (souches C57BL/6J, FVB.129P2tm1Cgr /J et leurs hybrides). Les résultats de ces travaux montrent notamment que les souris Fmr1 KO présentent un évitement initial d’approche sociale, des altérations principalement qualitatives des vocalisations, de l’hyperactivité et une augmentation de l’activité diurne. La mutation interagit avec le fond génétique et les résultats actuels indiquent que les KO de fond FVB.129P2tm1Cgr /J ont le phénotype le plus marqué. / Autism is a pervasive developmental disorder defined by behavioural criteria and age of onset. Fragile X is a disorder due to the silencing of the Fmr1 gene. About 15-25% of Fragile X patients are diagnosed as autistic and many symptoms overlap between the two disorders. A mouse Fmr1 KO was created and validated as a model for Fragile X Syndrome. Preliminary data also show that the null mutation interacts with the genetic background. The work presented in this thesis aimed to determine the autistic features expressed in Fmr1 KO mice, as well as the influence of the genetic background (C57BL/6J and FVB.129P2tm1Cgr/J strains, and their reciprocal hybrids) on the expression of the Fmr1 mutation. Our results show an initial inhibition of social approach in Fmr1 KO mice and a qualitative alteration of ultrasonic vocalizations in isolated pups, as well as an increase in activity, especially during the diurnal period. The Fmr1 mutation interacts with the genetic background and the results indicate that KO on the FVB.129P2tm1Cgr/J background show the most marked phenotype.

Au cours de ce travail, nous avons utilisé des souris ayant une délétion totale (KO) ou partielle (hétérozygotes) du gène codant la protéine STOP. La souris KO STOP constitue un modèle reconnu pour l’étude de la physiopathologie de la schizophrénie (SCH). Ce travail a permis d’étendre les données disponibles en mettant en évidence chez la souris KO STOP des troubles comportementaux qui miment les symptômes apparentés à l’ensemble des dimensions de la SCH. La comparaison des déficits chez des souris KO STOP générées à partir de différentes souches a permis de montrer que la délétion du gène STOP induit un phénotype robuste. De plus, notre travail permet de suggérer que, de par leur construction et leur phénotype, la souris hétérozygote STOP évoque la vulnérabilité à la SCH et pourrait constituer un modèle animal pertinent pour étudier les facteurs qui, interagissant avec une vulnérabilité génétique, favoriserait la décompensation psychotique. Dans cette optique, nous avons étudié l’influence de différents types de stress chroniques appliqués à différents moments clés du développement sur le phénotype de nos modèles animaux. Aucun des stress utilisés (isolement, stress chronique multiple, privation maternelle) n’a modifié le phénotype des souris hétérozygotes STOP à l’âge adulte, ni dans le sens de l’émergence ni dans celui d’une aggravation de troubles apparentés à la symptomatologie de la SCH. Ces résultats posent la question du type de stress, de son intensité et de la fenêtre temporelle où il doit être appliqué qui, associé à une altération génique donnée, validerait le modèle physiopathologique actuel basé sur une interaction délétère entre vulnérabilité et stress / In this work, we used mice with total (STOP null) or partial deletion (heterozygous) for the gene encoding the STOP protein. STOP null mice represent a recognized model for studying the physiopathology of schizophrenia (SCH). This work allowed us to extend the available phenotype by showing that STOP null mice exhibit various behavioural impairments mimicking symptoms corresponding to all SCH dimensions. By comparing the alterations present in STOP null mice generated from various strains, we showed that the STOP deletion induces a robust phenotype linked to SCH. In addition, through their construct and phenotype validity, the present work allows us to suggest that the STOP heterozygous mice evoke SCH vulnerability and could be a relevant model for studying the parameters which could favour SCH when interacting with a genetic vulnerability. In this context, the effects of chronic stress applied at different key steps of the mouse development were studied on the phenotype of our animal models. Any stress paradigm used (short-term isolation, chronic multiple stress, maternal deprivation) has been not able to alter the phenotype of STOP heterozygous mice measured in adulthood, neither by inducing nor by worsening alterations linked to SCH. According to the current SCH physiopathology hypothesis based on a deleterious interaction between susceptibility to SCH and stress, our findings raise the question regarding the type of stress paradigm, including stress intensity and the time window where it is applied, that could induce frank psychosis when interacting with a specific genetic alteration

Un des défis majeurs de l’immunologie antitumorale repose sur l’induction efficace et prolongée de laphase effectrice de la réponse immune antitumorale. Une meilleure compréhension des mécanismesimpliqués dans la potentialisation de l’activité antitumorale des effecteurs immunitaires, en particulier lesCTL infiltrant la tumeur représente donc un enjeu considérable dans le développement de nouvellesapproches d’immunothérapie visant à induire une réponse immunitaire spécifique efficace contre latumeur. Dans ce contexte, nous nous sommes particulièrement intéressés à étudier le rôle de CD5 dans lecontrôle de la progression tumorale, en particulier dans la potentialisation de l’activité T cytotoxique desCTL infiltrant le mélanome B16 in vivo. Nos résultats ont montré un ralentissement significatif de lacroissance tumorale chez des souris déficientes pour l’expression de CD5 comparées à leurs équivalentessauvages. Le contrôle de la progression de la tumeur chez les souris CD5-/- ne semble pas corréler avec unrecrutement plus important de lymphocytes T, mais avec une efficacité accrue de leur réactivité vis-à-visdu mélanome B16. Nous avons montré aussi que cette réponse est transitoire et qu’un échappementtumoral au système immunitaire ait lieu à un stade plus tardif de la progression de la tumeur. Cetéchappement tumoral semble être associé à une augmentation de la mort par AICD des TIL CD8+/CD5-par rapport aux TIL CD8+/CD5+ et ce par induction de FasL à la surface des TIL. La modulation de la voieFas/FasL in vivo avec un adénovirus Fas-Fc protège les lymphocytes T CD8+/CD5- infiltrant la tumeur dela mort par apoptose et empêche ainsi l’échappement tumoral. De plus, l’analyse du répertoirelymphocytaire T spécifique du mélanome B16 dans les souris CD5-/- suggère que le contrôle de laprogression de la tumeur serait lié à une meilleure prolifération de lymphocytes T CD5-/- spécifiques insitu. Nos résultats montrent aussi que l’immunisation des souris CD5-/- en utilisant des Ag tumorauxassociés au mélanome B16 contribue à la potentialisation de la réponse immunitaire antitumorale.L’ensemble de nos résultats soulignent un intérêt particulier du ciblage de CD5 pour améliorer lesapproches d’immunothérapie antitumorale actuelles. / A major challenge in tumor immunology is based on effective and prolonged induction of the effectorphase of antitumor immune response. A better understanding of the mechanisms involved in potentiatingthe antitumor activity of immune effectors, particularly the CTL infiltrating the tumor represents aconsiderable challenge in developing new approaches to immunotherapy. In this context we areparticularly interested in studying the role of CD5 in the control of tumor progression, particularly inpotentiating the cytotoxic activity of CTLs infiltrating B16 melanoma. Our results showed a significantdelay in tumor growth in CD5-/- mice as compared with wild type mice. The control of tumor growth inCD5-/- mice does not seem to correlate with a higher recruitment of T cells, but with increased cytotoxicityof infiltrating T cells against B16 cells. We have also shown that this response is transient and that thetumor escape from immune system takes place at a later stage of tumor progression. This tumor escapeappears to be associated with increased death by AICD of TIL CD8+ from CD5-/- mice as compared withTIL CD8+ from wild type mice wich correlated with the induction of FasL on the surface of TIL. In vivomodulation of Fas/FasL with an adenovirus AdFas-Fc protects tumor infiltrating T CD8+/CD5- fromapoptosis and thereby prevents the tumor escape. In addition, analysis of specific T lymphocyte repertoirein CD5-/- mice suggests that the control of tumor progression could be linked to a greater in situproliferation of specific CD5- T lymphocytes. Our results also show that immunization of CD5-/- miceusing different melanoma associated antigens contributes to the potentiation of antitumor immuneresponse. All these results highlight a particular interest in targeting of CD5 to improve currentapproaches to tumor immunotherapy.

本論文之研究動機有三：一是希望藉著對諸葛亮傳說內容的探討，可發掘其中所蘊含的民間旺盛的文學創造力；二是希望藉由對諸葛亮傳說的探討，能更瞭解諸葛亮在民間豐富的形象與評價；三是希望藉著對諸葛亮傳說中所包藏的民俗意識，加以分析探討，以便能更瞭解民間的思想與文化。本論文之論述範圍，主要以80年代中國大陸所搜集整理出版的傳說集子為對象。由於傳說與歷史的關係密切，而三國人物的傳說又常與《三國演義》的成書有關，因而在本論文的研究方法上，首先採取比較研究法，把傳說與歷史小說做比對分析；又由於傳說本身常富涵一些民間文化與思想，因而我們又採取民俗學的角度切入，仔細而深刻的探討這些文化思想，並試著闡釋民俗與傳說的連繫方式。本論文除第一章〈緒論〉與第六章〈結論〉外，共分為四章：第二章為〈三顧茅廬前的諸葛亮傳說〉，主要探討有關諸葛亮的少年時期，我們分為求學、娶親與得寶三部份述說。這時期的傳說內容常為正史或小說所忽略，大部份為人民自己的想像創造，因而我們的探討便較傾向傳說內容所包含的民間文化與思想。第三章為〈三顧茅廬後的諸葛亮傳說〉，主要探討有關諸葛亮的青壯時期的傳說，包括三顧茅廬、借箭、借東風與空城計四個部份。此部份為史家或小說家所刻意渲染的，因而我們的探討重點在傳說與史實小說的比較分析。第四章為〈諸葛亮之死與死後的傳說〉，主要探討的範圍包括諸葛爭壽、遣計埋墳與諸葛亮墓的傳說。這部份的傳說內容主要突顯了諸葛亮過人的智慧，其神機妙算幾乎如同神仙一般。第五章為〈有關諸葛亮的地方風物傳說〉，主要探討的範圍包括地方傳說與物產傳說。