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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
1

Développement d'une stratégie thérapeutique anti-inflammatoire en pathologie pulmonaire basée sur l'administration d'anti-protéases / Development of an anti-inflammatory therapeutic strategy for the treatment of long diseases based on the administration of anti-proteases

Baranger, Kévin 15 December 2008 (has links)
Les travaux de cette thèse ont porté sur l’étude des propriétés fonctionnelles d’inhibiteurs recombinants polyvalents ciblant les trois protéases à sérine du neutrophile (élastase, protéase 3, cathepsine G), libérées massivement au cours des inflammations pulmonaires. Ces inhibiteurs, dérivés de molécules naturelles (élafine, trappine-2, SLPI), interagissent fortement avec les trois protéases à sérine, sous forme soluble ou liée aux membranes des neutrophiles et possèdent des propriétés anti-bactériennes indépendantes de leurs capacités inhibitrices. De plus, nous avons montré que ces inhibiteurs peuvent être ancrés à différentes protéines de structure par transglutamination tout en conservant leurs propriétés inhibitrices. Par leurs différentes propriétés, ces inhibiteurs représentent des molécules particulièrement attractives dans le cadre du développement d’une stratégie thérapeutique basée sur l’administration d’anti-protéases par aérosol pour le traitement de maladies pulmonaires inflammatoires. / In this study, we have analysed the properties of recombinant polyvalent inhibitors of the three neutrophil serine proteinases (elastase, proteinase 3, cathepsin G), massively released during inflammatory events in various lung diseases. These inhibitors, derived from natural endogeneous inhibitors (elafin, trappin-2, SLPI), interact tightly with both free and membrane-bound neutrophil serine proteinases and possess antimicrobial properties that are independent from their inhibitory capacity. We have also shown that these polyvalent inhibitors can be covalently bound to the extracellular matrix proteins by a transglutaminase and that they retain their inhibitory properties in these conditions. With their various biological properties, these inhibitors are attractive molecules for the development of an aerosol-based therapeutic strategy for the treatment of inflammatory lung diseases.
2

Impact d'un inhibiteur de protéases à sérine, le TFPI-2, sur le microenvironnement tumoral pulmonaire / Impact of a serine proteinase inhibitor expression, TFPI-2 (Tissue Factor Pathway Inhibtor-2 on the tumoral pulmonary microenvironment

Gaud, Guillaume 11 February 2009 (has links)
Le TFPI-2 (Tissue factor pathway inhibitor 2 est un inhibiteur de la plasmine qui peut limiter la génération de métalloprotéases (MMP) et réduire ainsi le potentiel invasif des cellules tumorales, essentiel à la formation de métastases. Deux clones cellulaires inactivés pour le TFPI-2 par une stratégie d’ARN interférence ont été réalisés (miRNA-1b et -2b). Ces clones ont un pourcentage de migration et d’invasion 2 à 3 fois supérieur au clone contrôle, associé à une plus grande adhérence à la laminine et au collagène IV et à une augmentation de l’expression des MMP-1 et –3. En cocultures directes avec des fibroblastes pulmonaires sains, une augmentation des MMP-3, -7 et–13 a été observée avec les clones miRNA-1b et -2b. En présence des milieux conditionnés des ces clones, une potentialisation de la surexpression des MMP-1, -3, -7 a été observée. Cette étude nous a permis de démontrer que le TFPI-2 a un impact sur les gènes impliqués dans le remodelage de la MEC, notamment lors des interactions entre les cellules tumorales et les cellules stromales. / TFPI-2 (Tissue factor pathway inhibitor-2), an inhibitor of serine proteinases, particularly plasmin, can indirectly regulate the activation of MMPs, thus regulating ECM degradation and tumour cell invasion. Our results demonstrated that TFPI-2 silencing was associated with a 2 and 3-fold increase in invasive ability through basement membrane components, for clones NCI-H460 miRNA-1b and -2 respectively, associated with an increased in the relative attachment towards laminin and collagen IV and MMP-1 and MMP–3 overexpression. In direct coculture with fibroblasts, an increase in MMP-3, -7 and -13 transcriptional expression was observed when CCD19-Lu cells were cocultured with both miRNA-1b or -2b clones. In indirect coculture, allowing contact between fibroblasts and NCI-H460 clones conditioned media, an increase in MMP-1, -3 and -7 fibroblastic expression was measured. This study has demonstrated that TFPI-2 can influence ECM remodelling-associated genes and then act as a pericellular proteolysis inhibitor, particularly at the tumour-stroma interface.
3

Studies toward the enantioselective total synthesis of pectenotoxin 2

Bondar, Dmitriy A., January 2005 (has links)
Thesis (Ph. D.)--Ohio State University, 2005. / Title from first page of PDF file. Document formatted into pages; contains xviii, 211 p.; also includes graphics Includes bibliographical references (p. 128-134). Available online via OhioLINK's ETD Center
4

Precise orbit determination of global navigation satellite system of second generation (GNSS-2) orbit determination of IGSO, GEO and MEO satellites /

Su, Hua. January 2000 (has links)
München, Univ. der Bundeswehr, Diss., 2000. / Computerdatei im Fernzugriff.
5

Precise orbit determination of global navigation satellite system of second generation (GNSS-2) orbit determination of IGSO, GEO and MEO satellites /

Su, Hua. January 2000 (has links)
München, Univ. der Bundeswehr, Diss., 2000. / Computerdatei im Fernzugriff.
6

Precise orbit determination of global navigation satellite system of second generation (GNSS-2) orbit determination of IGSO, GEO and MEO satellites /

Su, Hua. January 2000 (has links) (PDF)
München, University der Bundeswehr, Diss., 2000.
7

Evaluation d'une stratégie thérapeutique dans la broncho-pneumopathie chronique obstructive basée sur l'administration d'anti-protéases par voie aérosol / Evaluation of therapeutic strategy for COFB based on aerosol delivery of protease inhibitors

Tanga, Annabelle 02 April 2012 (has links)
Il est bien établi que l’inflammation joue un rôle central dans la pathogenèse de la broncho-pneumopathie chronique obstructive (BPCO). Celle-ci va entraîner un déséquilibre marqué de la balance protéases-antiprotéases avec comme conséquence une libération massive des protéases à sérine du neutrophile (NSPs) : élastase (HNE), protéase 3 (Pr3) et cathepsine G (CG). Outre la dégradation de la matrice extracellulaire, ces protéases stimulent la sécrétion de cytokines pro-inflammatoires, contribuant ainsi au maintien d’une inflammation chronique. Dans une optique de ciblage de ces protéases dans la BPCO, nous avons évalué la capacité de la trappine-2 A62L (T2 A62L), un inhibiteur recombinant dérivé de trappine-2 (T2) capable d’inhiber les trois NSPs, à protéger l’épithélium alvéolaire des effets délétères engendrés par les NSPs. Dans notre étude nous avons montré que la T2 A62L inhibe significativement le détachement cellulaire et la dégradation des protéines de jonctions cellulaires (E-cadhérine, ß-caténine et Zonula Occludens-1) des cellules épithéliales alvéolaires (A549), induits par chacune des NSPs ou par des neutrophiles activés. / Inflammation has been demonstrated to play a central role in chronic obstructive pulmonary diseases (COPD). Neutrophil influx leads to a massive release of neutrophil serine proteases elastase (NSPs): elastase (HNE), proteinase 3 (Pr3) and cathepsin (CG) thereby leading to a protease/anti-protease imbalance. Besides the proteolytic damages to the lung extracellular matrix proteins, these proteases stimulate secretion of pro-inflammatory cytokines and therefore contribute to the perpetuation of inflammation. In order to target these proteases in COPD, we have examined the capacity of trappin-2 A62L (A62L T2), a genetically modified inhibitor which is able to inhibit all three serine neutrophil proteinases at the same time to protect the alveolar epithelium of the deleterious effects caused by the NSPS. In our study, we showed that T2 A62L significantly inhibits cell detachment and degradation of cell junction proteins (E-cadherin, ß-catenin and ZO-1, zonula occludens-1) of alveolar epithelial cells (A549) induced by each individual NSPS or by activated neutrophils. In addition to their antiproteolytic action T2 and T2 A62L reduced proinflammatory cytokines IL-6 and IL-8 release by A549 cells, previously stimulated by HNE or Escherichia coli lipopolysaccharide (LPS).
8

Estudos visando a sintese de derivados do acido 4-amino-3- (4clorofenil) butirico (BACLOFEN) / Studies towards the synthesis of derived of the 4-amine-3- (4chlorophenyl) butryric acid (BACLOFEN)

Melgar, Gliseida Zelayaran 16 November 2000 (has links)
Orientador: Fernando Antonio Santos Coelho / Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Quimica / Made available in DSpace on 2018-08-08T23:27:59Z (GMT). No. of bitstreams: 1 Melgar_GliseidaZelayaran_M.pdf: 8149347 bytes, checksum: 2b29b731feb41c073037e3801e461f87 (MD5) Previous issue date: 2000 / Resumo: O ácido g-aminobutírico (GABA) é o mais importante neurotransmissor inibitório presente no Sistema Nervoso Central. Ele sozinho é responsável por 34% de todas as sinapses que ocorrem no cérebro. A ação do GABA no SNC é realizada através da interação com dois tipos diferentes de receptores, classificados por Hill e Bowery como GABAA e GABAB. Esses receptores apresentam diferentes propriedades de ligação e, conduzem quando ativados, a efeitos biológicos diferentes. O ácido 4-amino-3(R)-4-clorofenilbutírico (baclofen) é um agonista seletivo para o receptor GABAB, que apresenta um certo grau de lipofilicidade, podendo com isso atravessar a barreira hematoencefálica. A necessidade de se desenvolver substâncias que podem atuar como antagonistas seletivos levou ao desenvolvimento do faclofen, do saclofen e do hidroxisaclofen. Nesse trabalho avaliamos a utilização de duas estratégias sintéticas numa nova abordagem para a preparação de derivados conhecidos e não conhecidos do Baclofen. Exploramos inicialmente uma estratégia já conhecida em nosso laboratório, que se baseava no emprego de uma a,a'-diclorociclobutanona, obtida através de uma reação de ciclo adição [2+2]. Essa última foi transformada na lactona 7. Várias tentativas de abertura dessa lactona foram realizadas, conduzindo a g-dicloroéster 1, o álcool éster sililado 9, o diol 11 e o g-iodoéster 15. De todas as tentativas, aquela que forneceu o intermediario 15 foi a de melhor rendimento. Esse último pode ser transformado no amino álcool 18, importante intermediário para a síntese de homólogos do Baclofen. Além disso, avaliamos também o aduto de Baylis-Hillman 19, como matéria prima para a preparação de derivados do Baclofen. Esse foi reduzido quimiosseletivamente para fornecer o diol 28. Proteção desse diol forneceu o cetal 36, que teve a dupla ligação submetida a uma reação de clivagem oxidativa com OsO4/NaIO4 para fornecer a acetona 37 com 78% de rendimento. A adição de um reagente organolítio derivado do 4-bromoclorobenzeno sobre a carbonila de 37 forneceu o intermediário para a síntese dos derivados hidroxilados do Baclofen. Essa segunda abordagem nos permitiu estabelecer uma nova aproximação à síntese total de derivados do Baclofen, uma importante classe de compostos terapêuticos / Abstract: The g-aminobutiric acid (GABA) is the most important inhibitory neurotransmitter present in the mammalian central nervous system (CNS). This acid is responsable for 30% of all the synapses occuring in the human brain. The action of GABA in the SNC is carried out through the interaction with two different types of receptors, classified by Hill and Bowery as GABAA and GABAB. These receptors present different binding properties, which led to different biological effect when activated. There are in the literature several examples of substances acting on GABAA receptor, however there are only few examples acting on GABAB. The 3-(R)-4-amino-3-(4chlorophenyl)butanoic acid or Baclofen is the only therapeutically available GABAB agonist known. This compound is used on the treatment of spasticity, a serious disease characterized by an increase muscle tone usually perceived as muscle tightness or achiness in the limbs and associated normally with multiple sclerosis (MS). Besides Baclofen there are others known substances acting on GABAB receptors as antagonist. In this class we can notice phaclophen, saclophen and hydroxysaclophen. In this work we describe our results concerning the exploitation of two strategies aiming to the preparation of intermediates to the synthesis of Baclofen derivatives. Initially we have explored a strategy will documented in our laboratory, based on the [2+2] cycloaddition reaction the a,a'-dichlorocyclobutanone, obtained from the cycloaddition was transformed in the lactone 7, by ring expansion. The opening of the lactone was very troublesome and led to the g-dicloroester 1, the silylated alcohol ester 9, the diol 11 and the g-iodoester 15. The g-iodoester 15 easily obtained from 7 by treatment with TMSI was transformed into the amino alcohol 18, an important intermediate for the synthesis of Baclofen homologue series.We have also evaluated the potentiality of the Baylis-Hillman adduct 19, as starting material for the synthesis of Baclofen derivatives. The Baylis-Hillman adduct was chemoselectivily reduced to provide the diol 28, which was transformed to the ketal 36. The exocyclic double bond of 36 was transformed to ketone 37 in 78% yield, by oxidative cleavage with OsO4/NaIO4 The addition of the organolithium reagent derived of 4-bromoclorobenzene on the carbonyl of 37 led to the isomers 40 and 42. These intermediates can be used to the synthesis of hidroxylated derivatives of the Baclofen and the Baclofen itself. This second strategy has permitted to us establish a new approach to the total synthesis of Baclofen derived of this important class of therapeutically useful compounds / Mestrado / Quimica Organica / Mestre em Química
9

Sintese de um analogo ciclico da esfingosina / Synthesis of sphingosine of sphingosine cyclic analogous

Azevedo, Luiz Fabricio da Silva 21 February 2008 (has links)
Orientador: Carlos Roque Duarte Correia / Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Quimica / Made available in DSpace on 2018-08-11T11:57:03Z (GMT). No. of bitstreams: 1 Azevedo_LuizFabriciodaSilva_M.pdf: 1610950 bytes, checksum: 7d31330e73f1ffeb923f119448edcc2f (MD5) Previous issue date: 2008 / Resumo: Esfingolipídios são compostos naturais que apresentam uma miríade de atividades biológicas conhecidas. A esfingosina é o exemplo mais representativo desta classe de compostos. Este trabalho está relacionado com a síntese de um análogo cíclico da esfingosina. A primeira parte esteve relacionada com a preparação do hidroxilactol F. Inicialmente o enecarbamato B foi preparado a partir da 2-pirrolidinona A através de 2 metodologias; a mais eficiente realizada em "one-pot" com rendimento global de 60%. A funcionalização da dupla endociclica do enecarbamato B foi efetuada com sucesso a partir da reação de cicloadição do tipo [2+2] com dicloroceteno. Esta reação levou a formação da a, a-diclorobutanona C em excelente rendimento (90%). A remoção dos cloros de C com um liga de Zn/Cu em uma solução metanóica de NH4Cl, levou a obtenção da ciclobutanona D em moderado rendimento (50%). A irradiação ultravioleta na presença de ácido acético, seguida pela substituição do grupamento acetil, com BF3-OEt2, pelo grupamento tiofenol, e finalmente a eliminação em meio básico sob refluxo, forneceu o diidrofurano E em bom rendimento global (4 etapas em 53 %). A reação de diidroxilação do diidrofurano E com OsO4 realizada em bom rendimento (87%) completou a sintese do hidroxilactol F. A segunda parte deste trabalho esteve realizada com os estudos visandose à síntese de um análogo cíclico da esfingosina. A melhor rota encontrada foi a reação do hidroxilactol F com [Ph3PCH3]+Br- que levou a obtenção da olefina desejada em baixo rendimento. A reação de metátese com 1-octadeceno, realizada em bom rendimento (80%) e a desproteção de G com Et3SiH e CF3CO2H alcançada em bom rendimento (89%), completaram a síntese do composto. A síntese convergente do análogo cíclico da esfingosina, partindo-se da 2- pirrolidinona A foi alcançada em 14 etapas e com rendimento global de 14% / Abstract: Sphingosine are natural compounds that bear multiple known biological activities. The sphingosine molecule is representative of this class of biological compounds. The present study is related to the synthesis of a new cyclic analogue of sphingosine. The first part of this dissertation was focused on the synthesis of the hydroxy lactol F. The synthesis began with distinct methodologies: The most efficient one was realized by a ¿one-pot¿ procedure to provide the enecarbamate B in 60% overall yield. The endocyclic double bond funcionalization of B was performed with sucess employing a [2+2] cycloaddition reaction with dichloroketene. This reaction yielded the corresponding a,a-dichlorocyclobutanone C in excellent yields (90%). The removal of the chlorine atoms of C was carried out using a Zn/Cu alloy in a methanol solution of NH4Cl, to give the cyclobutanone D in moderate yieelds (50%). Ultraviolet irradiation of D in the presence of acetic acid, followed by replacement of the acethyl group by thiophenol, promoted by BF3-OEt2, and elimination in basic medium under reflux, provided the dihydrofuran intermediate E in good overall yields (53% over 4 steps). Finally, stereoselective dihydroxylation of E with OsO4 furnished the hydroxylactol F in 87% yield. In the second part of this dissertation we focused on the synthesis of the cyclic analogue of sphingosine. The best route examined involved the olefination of the intermediate hydrolactol F wiht [Ph3PCH3]+Br- to provide the desired trans olefin in low yields. Olefin metathesis of this olefin with 1-octadecene gave intermediate G in a good yield of 80%. Next, the Boc protected olefin G was deprotected with Et3SiH and CF3CO2H to provide the desired cyclic analogue of sphingosine in 89% yield. The stereocontrolled total synthesis of this new cyclic analogue of sphingosine was accomplished from 2-pyrrolidinone A in 11 steps with an overall yield of 14% / Mestrado / Quimica Organica / Mestre em Química
10

Analyse protéomique des endosulfatases humaines HSulfs, enzymes clés de la modulation de la sulfatation de l’héparane sulfate / Proteomic analysis of human endosulfatases HSulfs, key enzymes in the modulation of the sulfation pattern of heparan sulfate

Seffouh, Ilham 31 August 2018 (has links)
Les 6-O-endosulfatases HSulf-1 et HSulf-2 (HSulfs) catalysent l'hydrolyse régio-sélective du groupe 6-O sulfate des résidus glucosamine sulfatés de l'héparane sulfate (HS), assurant ainsi une modification post-synthétique unique de ce glycosaminoglycane constitutif des protéoglycanes de la surface cellulaire. Par cette action, les HSulfs modulent les propriétés d'interaction de HS avec un grand nombre de ligands, faisant de ces enzymes des acteurs cruciaux dans de nombreux processus physiopathologiques. De nombreuses études ont souligné le rôle physiologique de HSulf-2 ainsi que son implication dans des processus pathologiques, en particulier du cancer. HSulf-2 est ainsi proposée comme une cible thérapeutique prometteuse dans la recherche anti-cancéreuse. Néanmoins, à l'heure actuelle, aucune structure cristallographique d'endosulfatase Sulf-2 n'a été décrite. Dans le présent travail de thèse, nous présentons la première caractérisation par spectrométrie de masse (MS) de HSulf-2. Une masse moléculaire moyenne de 133115 g.mol-1 a été déterminée pour l'enzyme entière par MS MALDI-TOF. Cette masse expérimentale plus élevée que la masse théorique (98169,86 g.mol-1) déduite de la séquence d'acides aminés, souligne la contribution significative de modifications post-traductionnelles (MPTs) à la masse moléculaire totale de HSulf-2. La séquence protéique de HSulf-2 a été confirmée par analyse nano-LC-MS/MS, ce qui a permis de localiser quatre sites de N-glycosylation (N108, N147, N174 et N217) sur les sept sites potentiels de la chaîne longue. Outre cette N-glycosylation, nous avons également identifié une nouvelle MPT de type O-glycosylation. En combinant différentes approches d'électrophorèse (SDS-PAGE / C-PAGE) et de MS (MALDI-TOF et HILIC-ESI-MS) nous avons montré que cette PTM est constituée d'une chaîne de glycosaminoglycane (GAG) appartenant à la famille des chondroïtine sulfate/dermatane sulfate. L'analyse par MALDI-TOF de la forme modifiée HSulf-2 dans laquelle les deux seuls sites d'ancrage possibles de ce GAG ont été substitués, a permis de déduire une contribution globale des MPTs de 34964 g.mol-1, dont 24727 g.mol-1 pour la seule chaîne de GAG. Cette dernière est greffée de manière covalente au niveau du domaine HD de la chaîne courte. Elle représente une modification inédite pour une enzyme, premier exemple connu d'un protéoglycane de ce type. Plusieurs N-glycosylations réparties sur les deux chaînes longue et courte comptent pour les 10237 g.mol-1 restant. L'ensemble de ces résultats fournissent les bases bioanalytiques solides pour la poursuite de la caractérisation structurale des enzymes HSulfs, visant à comprendre le rôle des MPTs, à élucider l'organisation des deux chaînes de HSulf-2, et à en déchiffrer leur rôle dans la liaison au substrat et dans la formation de la poche catalytique afin de développer un inhibiteur spécifique des HSulfs. / The human 6-O-endosulfatases HSulf-1 and -2 (HSulfs) catalyze the regio-selective hydrolysis of the 6-O-sulfate group of glucosamine residues within sulfated domains of heparan sulfate (HS), thereby ensuring a unique and original post-biosynthetic modification of the cell surface proteoglycans. Through their activity, the HSulfs enzymes modulate the interaction properties of HS and they are thus involved in crucial physiological processes as well as in pathological conditions, particularly in cancer. Therefore, HSulf-2 is considered as a valuable therapeutic target in cancer research. There is no crystallographic structure available for HSulfs so that their structural organization in two chains remains poorly understood. In this study, we report the first characterization by mass spectrometry (MS) of HSulf-2. An average molecular weight of 133115 g.mol-1 was determined for the whole enzyme by MALDI-TOF MS, i.e. higher than the naked amino acid backbone (98170 g.mol-1), highlighting a significant contribution of post-translational modifications (PTMs). The HSulf-2 protein sequence was determined by nano-LC-MS/MS, revealing four glycosylated sites at Asn 108, 147, 174 and 217. Besides, a unique O-glycosylation has been evidenced. By combining electrophoresis methods (SDS-PAGE / C-PAGE) and MS analysis (MALDI-TOF / HILIC-ESI-MS), we have identified this PTM as a glycosaminoglycan (GAG) of chondroitin sulfate/dermatan sulfate type. The MALDI-TOF analysis of the HSulf-2 modified form in which the two GAG binding sites have been impaired indicated a contribution of 34964 g.mol-1 for the whole PTMs, including 24727 g.mol-1 for the GAG chain only. This GAG chain is covalently linked to the HD domain within the C-terminus of HSulf-2. It is an unprecedented post-translational modification of an enzyme, providing the first example of a catalytic proteoglycan. N-glycans dispatched on both HSulf-2 long (N-terminus) and short (C-terminus) chains account for the remaining PTMs mass contribution 10237 g.mol-1. Overall, these results provide a bioanalytical platform for further structural investigations of the HSulf enzymes, aiming at deciphering the role PTMs and of each chain in the substrate binding and specificities and in the catalytic activities, and for the discovery of specific HSulfs inhibitors.

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