Objective. Wilson disease is a copper storage disorder caused by mutations in the ATP7B gene leading to liver cirrhosis. It has previously been shown that lentiviral vectors can govern an efficient ...delivery and stable expression of a transgene. The aim of this pilot study was to prove the principle of a lentiviral gene transfer in the Long-Evans cinnamon (LEC) rat, an animal model of Wilson disease. Material and methods. LEC rats were treated either by systemic application of lentiviral vectors or by intrasplenic transplantation of LEC-rat hepatocytes lentivirally transduced with ATP7B. The ATP7B gene expression was analyzed by RT-PCR and immunofluorescence analysis. The therapeutic effect was assessed by analysis of liver histology, serum ceruloplasmin oxidase activity, and liver copper content. Results, Hepatic expression of the transgene was detected at different time-points post-treatment and lasted for up to 24 weeks (end of experiment). Liver copper levels were lowered in all treatment groups compared to untreated LEC rats. Twenty-four weeks after treatment, the area of the examined liver-tissue sections occupied by fibrosis was 48.3-57.9% in untreated LEC rats and 10.7-19.8% in rats treated with cell therapy. In systemically treated rats, only small fibrous septa could be observed. Conclusions. These data prove for the first time that lentiviral ATP7B gene transfer is feasible in Wilson disease. In our pilot study the systemic approach was more promising in ameliorating disease progression than the transplantation of lentivirally transduced hepatocytes.
RANKL et RANK sont membres de la superfamille des TNF et de la superfamille des TNF-récepteurs, respectivement. Ils sont connus pour jouer un rôle important dans la régulation de la masse osseuse et ...dans le développement et la fonction du système immunitaire. Cependant des questions restent. Nous avons utilisé des souris génétiquement modifiées pour répondre à certaines de ces questions, en particulier en utilisant une souris dont les cellules stromales réticulaires marginales manquent RANKL dans les ganglions lymphatiques. Les résultats obtenus lors de cette thèse fournissent de nouvelles informations importantes sur l'impact positif de RANKL stromal sur les macrophages des ganglions lymphatiques concomitantes avec une fonction des cellules B amélioré et une pathogénicité virale réduit. Nous avons constaté que RANKL stromal régule l'expression de lymphotoxine et CXCL13, deux molécules clés de l'homéostasie des cellules B et de l'intégrité cellulaire des organes lymphoïdes secondaires. L’activité du RANKL semble suivre une hiérarchie temporelle sur lymphotoxine/TNFα, vu que le phénotype causé par le déficit en RANKL a une pénétrance augmenté avec l'âge. De plus, nous démontrons que RANKL active les cellules endotheliales lymphatiques des ganglions lymphatiques et on a trouvé que l'intégrine ITGA2b est un nouvel indicateur pour les cellules endotheliales lymphatiques activés. Ainsi, avec MAdCAM-1, ITGA2b sert comme un nouveau marqueur pour les cellules endothéliales lymphatiques qui sont constitutivement activés par le RANKL stromal. Au total, les données confirment l'importance de RANKL pour l'homéostasie des ganglions lymphatiques et dévoile les mécanismes ci-inconnus des fonctions de RANKL. À la lumière de cela et le fait que RANKL est sensible aux hormones féminines, nous avons étudié le rôle de RANKL dans le syndrome de Sjögren, une maladie inflammatoire chronique des glandes salivaires et lacrymales avec une forte polarisation de sexe féminin. Nous apportons la preuve que la neutralisation du RANKL réduit la taille des organes lymphoïdes tertiaire. En perspective, une éventuelle diaphonie entre les cellules endothéliales lymphatiques et les macrophages ou les cellules réticulaires marginales reste à clarifier. En outre, d'autres travaux sont nécessaires pour élucider le mécanisme par lequel RANKL stimule les maladies inflammatoires chroniques présentant des structures lymphoïdes tertiaires, afin de faire RANKL une nouvelle cible pour la thérapie.
RANKL and RANK are members of the TNF-superfamily and TNF-receptor superfamily, respectively. They are known to play an important role in the regulation of bone mass and in the development and the function of the immune system. However questions still remain. We have used genetically modified mice to address some of these questions, in particular by using a mouse whose lymph node marginal reticular stromal cells lack RANKL. The results obtained during this PhD provide important new insights into the positive impact of stromal RANKL on lymph node macrophages concomitant with enhanced B cell function and reduced viral pathogenicity. We found that stromal RANKL regulates lymphotoxin and CXCL13 expression, two key molecules for B cell homeostasis and secondarylymphoid organ cellular integrity. RANKL activity seems to follow a temporal hierarchy over lymphotoxin/TNFα, as the phenotype caused by stromal RANKL-deficiency has increased penetrance with age. Furthermore, we demonstrate that RANKL activates lymph node lymphatic endothelial cells and found that the integrin ITGA2b is a new indicator for activated lymphatic endothelial cells. Thus, together with MAdCAM-1, ITGA2b serves as a novel marker for those lymphatic endothelial cells that are constitutively activated by stromal RANKL. Altogether, the data reinforce the importance of RANKL for the lymph node homeostasis and uncover here to unknown mechanisms of RANKL functions.In light of this and the fact that RANKL is responsive to female hormones, we studied the role of RANKL in the Sjögrens syndrome, a chronic inflammatory disease of salivary and lacrimal glands with a strong female sex bias. We provide evidence that RANKL neutralization reduces tertiary lymphoid organ size. On the perspective side, a possible cross talk between lymph node lymphatic endothelial cells and macrophages or marginal reticular cells remains to be clarified.Furthermore, further work is required to elucidate the mechanism by which RANKL stimulates chronic inflammatory diseases presenting tertiary lymphoid structures, in order to make RANKL a new target for therapy.
Oksidatif stres fazla oksidant bileşiğin yapılması ve antioksidant koruma mekanizmasının azlığı sonucu oluşarak doku hasarlarına yol açar. Oksidatif stres sonucu oluşan okside-düşük dansiteli ...lipoprotein oxidized low-density lipoprotein ox-LDL , reseptörü lektin benzeri ox-LDL reseptör-1 lectin-like receptor for ox-LDL-1 LOX-1 ’e bağlanır. ox-LDL ve LOX-1 endotel disfonksiyonu, monosit adezyonu, düz kas hücre proliferasyon, migrasyon ve apoptozis, yağ hücre yapımı ve trombosit aktivasyonu ile ilgili mekanizmalarda görev alır. ox-LDL, ateroskleroz, diabetes mellitus, yaşlanma, metabolik sendrom, kardiovasküler, ve serebrovasküler, böbrek ve karaciğer hastalıklarında artarak hastalıkların patogenezlerinde aktif rol alır. Bu derlemede, ox-LDL ve reseptörü LOX-1 etkileri incelenmiştir
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
This paper deals with the teaching / learning of the French L2 lexicon within the framework of the Explicative and Combinatory Lexicology. Recognizing the importance of learning some basic ...meta-lexical notions, we sketch out a progressive approach for teaching a sample of notions concerning some semantic relations. Our proposal is based on the results of a test submitted to a group of Italian-speaking students at the academic level, although the progression we suggest is designed to be adapted to audiences of different levels.
Die vorliegende Arbeit behandelt die "Unfrisierten Gedanken" von Stanisław Jerzy Lec. Der Untersuchung der Aphorismen Lec' im dritten Kapitel geht eine theoretische Begründung unseres ...Aphorismusverständnisses im zweiten Kapitel voraus sowie im ersten Kapitel ein Überblick über die Geschichte des Aphorismus in Polen.
En tant que syntagmes sémantiquement non-compositionnels, les locutions sont des unités lexicales à part entière, qui doivent avoir leur propre entrée dans un modèle du lexique. Elles doivent donc ...recevoir une définition lexicographique, ainsi qu’une description de leurscaractéristiques grammaticales. De plus, en vertu de leur signifiant syntagmatique, les locutionstémoignent – à des degrés divers – d’une flexibilité formelle (passivation, insertion de modificateurs, substitution de certains constituants, etc.).Notre thèse défend l’idée selon laquelle une description des locutions combinant à la fois l’identification des unités lexicales qui les composent et l’identification des relations de dépendance syntaxique qui unissent les unités constituantes, permettra de prédire leurs différents emplois possibles dans la phrase. Une telle description n’est possible que dans un modèle du lexique décrivant précisément la combinatoire des lexies. Notre recherche, basée sur les principes de la Lexicologie Explicative et Combinatoire, exploite et enrichit les données du Réseau Lexical du Français (RL-fr), ressource en cours de développement à l’ATILF.La thèse a deux principaux apports. Le premier est le développement d’un modèle de description lexico-syntaxique relativement fine des locutions du français. Le second est l’identification et l’étude de différentes variations structurales, syntaxiques et lexicales liées à la flexibilité formelle des locutions. Les variations des locutions sont mises en corrélation avec leurs structures lexico-syntaxiques, mais également avec leurs définitions lexicographiques. Ceci nous conduit à introduire la notion de projection structurale, centrale dans le continuum de la flexibilité formelle des locutions
As semantically non-compositional phrases, idioms are lexical units. Consequently, they must have their own entries in a lexical resource, with a lexicographic definition and grammatical characteristics. Furthermore, because of their phrasal signifier, idioms show – to varying degrees – a formal flexibility (passivization, attachment of modifiers, substitution of components,etc.)Our thesis defends the view that a description of idioms that combine identification of their lexical components and identification of dependency links between these components will permit to predict their formal variations. Such a description is possible only in a model of lexicon that describes precisely combinatorial proprieties of lexical units. Our thesis, based on the Explanatory Combinatorial Lexicology’s framework, exploits and enhances the data of the French Lexical Network (fr-LN). This resource is being developed at the laboratory ATILF (Nancy, France).The thesis makes two principal contributions to the study of phraseology. The first contribution is the development of a precise description of idioms’ lexico-syntactic structures. The second contribution is the indentification and the study of structural, syntactic and lexical variations linked to idioms’ formal flexibility. Idioms’ formal variations are correlated with their lexico-syntactic structures, but also with their lexicographic definitions. This work leads us to introduce the notion of structural projection, that plays a central role in the continuum of idiom’s formal flexibility
The aim of the research was to verify the effects of the yeast Saccharomyces cerevisiae during the first five months of lactation in Summer time. The 18 cows of Control group were fed the same ...unifeed offered to the 17 cows of Yeast group (added with 10 g/head/day of Yea-Sacc1026, Alltech Biotechnology Center, USA), from the day 44 until the day 156 of lactation. Dry matter intake was higher in Yeast group (21.56 kg vs 21.00 kg, P0.05) and during June, July, August and October the difference of the intake touched 1 kg/day (P0.01). FCM production showed better results in Yeast group (29.49 kg vs 27.84 kg, +5.9%). Fat and protein content were favourably influenced by the addition of Saccharomyces cerevisiae in the diet (3.47% vs 3.35%, +3.6%, for fat and 3.10% vs 3.06%, +1.3%, for protein), but the differences were not significant at statistical analysis. The unifeed inclusion of Saccharomyces cerevisiae during the first five months of lactation in Summer time permitted to reduce the negative influence of heat stress in cows: DM intake increased significantly and this allowed to obtain better results in FCM production and milk quality
Lo scopo della ricerca era di verificare gli effetti del lievito Saccharomyces cerevisiae durante il periodo estivo, quando maggiormente si verificano gli effetti negativi dovuti allo stress da caldo, sulla produzione e le caratteristiche qualitative del latte nei primi cinque mesi di lattazione. Sono state utilizzate 35 bovine di razza Frisona Italiana, allevate in stabulazione libera con area di riposo su lettiera permanente, suddivise in 2 gruppi sperimentali (18 vacche per il gruppo Controllo e 17 per il gruppo Lievito), omogenei in base alla produzione di latte e all'ordine di parto. L'alimentazione (unifeed) somministrata agli animali differiva solamente per l'integrazione al gruppo Lievito di 10 g/capo/giorno di Saccharomyces cerevisiae, somministrato a partire da 44 e fino a 156 giorni di lattazione. L'ingestione media di sostanza secca è risultata significativamente superiore (P0,05) nelle bovine del gruppo Lievito rispetto a quelle del gruppo Controllo (21,56 kg vs 21,00 kg di SS), con differenze maggiori (P0,01) nei mesi di giugno, luglio, agosto e ottobre, dove si è notato un aumento di circa 1 kg in più di SS. La produzione di latte corretta al 4% di grasso (FCM) ha evidenziato una maggior produzione media giornaliera a favore del gruppo Lievito (29,49 kg vs 27,84 kg), corrispondente al 5,9% in più. Anche il grasso e le proteine del latte sono state favorevolmente influenzate dall'aggiunta di Lievito (3,47% vs 3,35% per il grasso, pari a +3,6%, e 3,10% vs 3,06% per le proteine, pari a + 1,3%), differenze però non significative all'analisi statistica. La maggior assunzione di SS registrata nelle vacche del gruppo Lievito ha evidenziato come l'apporto del lievito Saccharomyces cerevisiae permetta alle bovine di adattarsi meglio allo stress da caldo, consentendo di ottenere migliori produzioni quali-quantitative di latte
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