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HIGH PERFORMANCE BLENDS AND COMPOSITES: PART (I) CLAY AEROGEL/POLYMER COMPOSITES PART (II) MECHANISTIC INVESTIGATION OF COLOR GENERATION IN PET/MXD6 BARRIER BLENDSBandi, Suneel A. 12 July 2006 (has links)
No description available.
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Identification of microorganisms in food ecosystems and characterization of physical and molecular events involved in biofilm developmentLuo, Hongliang 02 December 2005 (has links)
No description available.
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<b>BIFUNCTIONAL CHEMICAL CONJUGATION STRATEGIES FOR IMMUNOMODULATION</b>Ahad Hossain (18424803) 23 April 2024 (has links)
<p dir="ltr">Immunotherapy has revolutionized the field of oncology. While a lot of antibodies and small molecule inhibitors have been developed for this, a lot of targets remain undruggable in humans.</p><p dir="ltr">Targeted protein degradation has opened a new horizon in drug discovery where we can target these undruggable proteins. Proteolysis targeting chimeras using the ubiquitin-proteasomal system is one of the most popular TPD strategies that complement lysosomal degradation strategies to degrade intracellular proteins, typically using bifunctional small molecule degraders. Recently, large biomolecular and antibody conjugates have been developed for degrading membrane and extracellular proteins in cells, such as lysosomal targeting chimeras (LYTACs) and genetically encoded LYTACS, among several others. However, larger molecules have limitations in penetrating solid tumors. This dissertation work focused on the development of bifunctional small molecule degraders for programmed death-ligand 1 (PD-L1), a transmembrane protein ligand for the immune checkpoint programmed cell death 1 (PD-1). PD-L1 is highly expressed on several tumors, such as triple-negative breast cancer (TNBC), non-small cell lung carcinoma, and renal cancer, and is known to suppress cancer-killing immune cells via interaction with PD-1 on T-cells. In addition, PD-L1 is also present on macrophages in the tumor microenvironments leading to further immune suppression and acquired resistance to anti-PD-1 therapy is associated with the upregulation of alternative immune checkpoints, thereby reducing anti-tumor efficacy. We have designed and synthesized bifunctional small molecules as PD-L1 degraders with different recruiters and linkers guided by computational studies with known PD-1/PD-L1 structures to show both cell surface and total protein degradation in human TNBC cells. In a separate project, we also developed small molecule conjugates to degrade an intracellular integral membrane protein of the endoplasmic reticulum with an unknown 3D structure, namely Diglyceride acyltransferase 2 (DGAT2). Recently, our lab identified DGAT2 as a new target for combating Alzheimer’s disease. Specifically, DGAT2 catalyzes triacylglycerol (TAG) synthesis using diacylglycerol and fatty acyl CoA as substrates. The accumulation of TAGs, mechanistically linked to DGAT2, results in “fat” or lipid droplets (LDs) inside the cells. Our lab showed that microglial cells (resident immune cells in the brain) accumulate LDs in the postmortem brains of human patients and mouse models (5xFAD) of Alzheimer’s disease and that the LD accumulation is driven by amyloid-beta (Ab) – a hallmark of Alzheimer’s disease – via DGAT2 pathway. Further, these LD-laden microglia have phagocytic defects and are spared Aβ thereby affecting plaque accumulation and clearance. Inhibiting DGAT2 reduces the amount of TAG in the brain, which in turn reduces LDs and restores microglial ability to phagocytose Ab. However, commercially available DGAT2 inhibitors were unable to reduce LD load in older 5xFAD mice. Using AlphaFold’s models of DGAT2, we designed and identified sites to synthesize bifunctional DGAT2 degraders that resulted in reduced LDs in mouse primary microglial cells and enhanced phagocytosis of Aβ plaques in vivo in aged 5xFAD mice. Our approach shows a framework to develop bifunctional small molecule degraders for membrane proteins to potentially combat immune dysregulation in chronic diseases.</p>
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SUMO-1 conjugation blocks beta-amyloid-induced astrocyte reactivity.Hoppe, J.B., Rattray, Marcus, Tu, H., Salbego, C.G., Cimarosti, H. 06 1900 (has links)
No / Astrocyte reactivity is implicated in the neuronal loss underlying Alzheimer's disease. Curcumin has been shown to reduce astrocyte reactivity, though the exact pathways underlying these effects are incompletely understood. Here we investigated the role of the small ubiquitin-like modifier (SUMO) conjugation in mediating this effect of curcumin. In beta-amyloid (Aβ)-treated astrocytes, morphological changes and increased glial fibrillary acidic protein (GFAP) confirmed reactivity, which was accompanied by c-jun N-terminal kinase activation. Moreover, the levels of SUMO-1 conjugated proteins, as well as the conjugating enzyme, Ubc9, were decreased, with concomitant treatment with curcumin preventing these effects. Increasing SUMOylation in astrocytes, by over-expression of constitutively active SUMO-1, but not its inactive mutant, abrogated Aβ-induced increase in GFAP, suggesting astrocytes require SUMO-1 conjugation to remain non-reactive.
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Development of multifunctional microgels for novel biomedical applicationsKodlekere, Purva Ganesh 07 January 2016 (has links)
A range of microgels with two different functionalities were synthesized, and their utility in novel bioapplications was examined. Cationic microgels with varying properties were developed by tuning synthesis conditions. Their size and primary amine content was analyzed, and one microgel system was selected as a model construct. Its primary amine groups were conjugated to two dyes with properties favorable for utilization as contrast agents in photoacoustic imaging. The concentration of contrast agent in single particles was determined. The implications of a high local dye concentration in the generation of high intensity photoacoustic signals, are discussed. The second bioapplication involved the targeted delivery of fibrinolytics to fibrin clots, in order to bring about dissolution of abnormal thrombi. For this purpose, core/shell microgels with carboxylic acid groups in their shells were synthesized in three size ranges. Following this, their dimension based differential localization in and around porous fibrin clots was examined. Fibrin-specific peptides were then conjugated onto the shells of these particles and the conjugates were shown to demonstrate strong interactions with the fibrin clots. The microgels conjugated to the peptide with the highest binding affinity to fibrin, were observed to bring about disruption of fibrin clots, merely through interference in the dynamic interactions among clot fibers, due to the equilibrium nature of the fibrin polymer. The implications of these novel results and future studies required to facilitate a better understanding of the phenomena involved, are discussed.
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A new perspective on the importance of glycine N-acyltransferase in the detoxification of benzoic acid / Christoffel Petrus Stephanus BadenhorstBadenhorst, Christoffel Petrus Stephanus January 2014 (has links)
Despite being the first biochemical reaction to be discovered, the glycine conjugation pathway remains poorly
characterised. It has generally been assumed that glycine conjugation serves to increase the water solubility of
organic acids, such as benzoic acid and isovaleric acid, in order to facilitate urinary excretion of these compounds.
However, it was recently suggested that the conjugation of glycine to benzoate should be viewed as a
neuroregulatory process that prevents the accumulation of glycine, a neurotransmitter, to toxic levels. The true
importance of glycine conjugation in metabolism is therefore not well understood. However, no genetic defect of
glycine conjugation has ever been reported. This seems to suggest that glycine conjugation is a fundamentally
important metabolic process, whatever its function may be. Therefore, a major objective of this thesis was to
develop a deeper understanding of glycine conjugation and its metabolic significance. A review of the literature on
GLYAT and glycine conjugation suggested that the primary purpose of glycine conjugation is indeed to detoxify
benzoate and other aromatic acids of dietary origin. However, the commonly held assumption, that glycine
conjugation increases the water solubility of aromatic acids in order to facilitate urinary excretion, seems to be
incorrect. A better explanation for the detoxification of benzoate by means of glycine conjugation is based on
hydrophilicity, not water solubility. Because of its lipophilic nature, benzoic acid is capable of passively diffusing
across the mitochondrial inner membrane into the matrix space, where it accumulates due to the pH gradient
over the inner membrane. Although benzoate can be exported from the matrix by organic anion transporters, this
process would likely be futile because benzoic acid can simply diffuse back into the matrix. Hippurate, however, is
significantly less lipophilic and therefore less capable of diffusing into the matrix. It is therefore not transport out
of the mitochondrial matrix that is facilitated by glycine conjugation, but rather the ability of the glycine
conjugates to re-enter the matrix that is decreased.
The conversion of benzoate to hippurate is a two-step process. First, benzoate is activated by an ATP-dependent
acid:CoA ligase (ACSM2A) to form the more reactive benzoyl-CoA. Second, glycine N-acyltransferase (GLYAT)
catalyses the formation of hippurate and CoASH from benzoyl-CoA and glycine. Another major objective of this thesis was to gain a better understanding of the structure and function of the GLYAT enzyme. While the substrate
selectivity and enzyme kinetics of GLYAT have been investigated to some extent, almost nothing has been
published on the structure, active site, or catalytic mechanism of GLYAT. Furthermore, while interindividual
variation in the rate of glycine conjugation has been reported by several researchers, it is not known if, or how,
genetic variation in the human GLYAT gene contributes to this interindividual variation. To address these issues,
systems for the bacterial expression of recombinant bovine GLYAT and recombinant human GLYAT were
developed. Because no crystal structure of GLYAT has been reported, homology modelling was used to generate a
molecular model of bovine GLYAT. By comparing the molecular model to other acyltransferases for which the
catalytic residues were known, Glu227 of bovine GLYAT was identified as a potential catalytic residue. Site directed
mutagenesis was used to generate an E227Q mutant recombinant bovine GLYAT lacking the proposed catalytic
residue. Characterisation of this mutant suggested that Glu227 was indeed the catalytic residue, and the GLYAT
catalytic mechanism was elucidated. The molecular model was also used to identify Asn131 of bovine GLYAT as a
potential active site residue. Site-directed mutagenesis was used to generate an N131C mutant, which was
sensitive to inhibition by the sulfhydryl reagent DTNB. This suggests that the Asn131 residue of bovine GLYAT may
be situated in the active site of bovine GLYAT, but more work is needed to confirm this result. Finally, site-directed
mutagenesis was used to generate variants of recombinant human GLYAT corresponding to six of the known SNPs
in the human GLYAT gene. Expression and characterisation of the recombinant human GLYAT variants revealed
that the enzyme activity and KM (benzoyl-CoA) parameter of the recombinant human GLYAT were influenced by
SNPs in the human GLYAT gene. This suggests that genetic variation in the human GLYAT gene could partly explain
the interindividual variation in the rate of glycine conjugation observed in humans. Interestingly, the SNPs that
negatively influenced enzyme activity also had low allele frequencies, suggesting that there may be some selective
advantage to having high GLYAT activity. / PhD (Biochemistry), North-West University, Potchefstroom Campus, 2014
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Avaliação imunológica de vacina de polissacarídeo meningocócico C conjugado e encapsulado em lipossomo / Immunological evaluation of meningococcal polysaccharide C conjugate vaccine and encapsulated liposomeBrito, Glauber da Costa de 12 December 2002 (has links)
A tecnologia de conjugação melhorou a imunogeniddade de vacinas constituídas de polissacarídeo, especialmente em crianças. Polissacarídeos conjugados a proteínas carregadoras, como o toxóide tetânico, induzem resposta imunológica dependente de célula T e memória imunológica de longa duração. No entanto, esta tecnologia apresenta custo elevado. Assim, foi investigada a capaddade dos lipossomos de aumentar a resposta imunológica ao polissacarídeo C de Neisseria meningitidis (PSC). Camundongos foram imunizados com Iipossomos contendo PSC, conjugado toxóide tetânico-PSC ou PSC livre como controle, com dose de reforço constituída de PSC livre. Foram gerados anticorpos IgG e IgM contra PSC nos camundongos imunizados com conjugado ou Iipossomo. Os resultados mostram que lipossomos contendo PSC têm potencial para substituir a vadna conjugada toxóide tetânico-PSC. / Conjugation technology has improved the immunogenicity of polysaccharide vaccines, specially in small children. Polysaccharides conjugated to various carrier proteins, e.g. tetanus toxoid, stimulate a T cell-dependent antibody response and induce a long-term immunological memory. However, protein-polysaccharide conjugation technology is expensive and this could constitute an important drawback. Thus, immunopotentiation of Neisseria meningitidis serogroup C polysaccharide (PSC) by use of liposomes as an alternative to protein-polysaccharide C conjugates was investigated. Mice were immunized with liposomes containing PSC or tetanus toxoid-PSC conjugate or free PSC as control and boosted with free PSC. Immunogenicity of these different preparations was compared with each other. Conjugate and liposome containing PSC induced both IgG and IgM antibodies against the polysaccharide. These results show that liposomes containing entrapped PSC have potential to be used as an alternative to tetanus toxoid-PSC conjugate vaccine.
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As formas verbais finitas do hebraico bíblico: qatal, yiqtol, wayyiqtol e weqatal e seus respectivos usos na narrativa e poesia bíblica / The biblical hebrew verbal finite forms: qatal, yiqtol, weqatal e wayyiqtol and its respective uses in biblical narrative and poetryPerin, Tiago Rebello 20 May 2016 (has links)
O sistema verbal do hebraico bíblico tem sido objeto de debate desde o início dos estudos gramaticais até os dias atuais. As conjugações de sufixo e prefixo, com ou sem a presença do waw prefixado (respectivamente, as formas verbais: qatal, yiqtol, weqatal e wayyiqtol) tomam uma parte central nesse debate devido à grande amplitude de significados que possuem na Bíblia Hebraica. A presente pesquisa propõe-se a apresentar as várias correntes teóricas acerca da interpretação do significado e relação dessas quatro formas verbais e também o uso das mesmas nos textos narrativos e poéticos da Bíblia Hebraica. / The verbal system of Biblical Hebrew has been the subject of debate since the beginning of grammatical studies until today. The suffix and prefix conjugations, with or without the presence of prefixed waw (respectively, the verbal forms: qatal, yiqtol, weqatal e wayyiqtol) take a central part in this debate because of the wide range of meaning that they have in the Hebrew Bible. This research aims to present the various theoretical perspectives about the interpretation of the meaning and relationship of these four verbal forms and also the use of each of them in narrative and poetic texts of the Hebrew Bible.
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Untersuchungen zum Aufbau, zur Funktion und zur Verbreitung von genomischen Inseln in der Gattung LegionellaLautner, Monika 25 February 2013 (has links)
Der Austausch von genetischem Material über horizontalen Gentransfer, stellt einen wichtigen Mechanismus in der bakteriellen Evolution dar. Legionella pneumophila Stämme codieren für verschiedene Typ IV Sekretionssysteme (T4SS) und integrative konjugative Elemente, die zur genomischen Variabilität der intrazellulären Erreger beitragen. L. pneumophila Corby codiert auf der genomischen Insel Trb-1 für ein funktionelles Konjugations- und T4ASS. Trb-1 ist innerhalb des tRNAPro Gens integriert und kann in einer chromosomalen oder zirkulären episomalen Form existieren. Zusätzlich zu den trb/tra Genen sind auf der Insel eine Integrase (int-1) und die Gene lvrRABC der Legionella vir Region (lvr) lokalisiert. Durch die Deletion von int-1 konnte gezeigt werden, dass die Exzision von Trb-1 unter Beteiligung der Integrase erfolgt. Zudem wurde in dieser Arbeit zum ersten Mal demonstriert, dass die lvr-Region, vor allem der putative Phagen-Repressor LvrR an der Regulation der Exzision von Trb-1 beteiligt ist. Die Konjugation von Trb-1 in L. oakridgensis, hatte keinen Effekt auf die in vivo Fitness der Transkonjuganten in humanen Makrophagen. Die genomischen Inseln LpcGI-1 und LpcGI-2 codieren für ein neues putatives GI-T4SS. Für LpcGI-2 konnte erstmals gezeigt werden, dass das T4SS funktionell ist und die Konjugation der genomischen Insel in einen anderen L. pneumophila Stamm vermitteln kann. LpcGI-2 kann anschließend ortsspezifisch in das Genom der Transkonjuganten integriert werden. LpcGI-1 und LpcGI-2 werden vom tRNAThr bzw. tRNAMet Gen flankiert und können in verschiedenen chromosomalen und zirkulären, episomalen Formen existieren. Die Exzision von LpcGI-2 erfolgt ähnlich zu Trb-1, in Abhängigkeit einer ortsspezifischen Integrase. Im Genom von Lp Corby wurden zwei weitere genomische Inseln (LpcGI-Asn und LpcGI-Phe) identifiziert. In silico Analysen zeigten zudem, dass genomische Inseln mit einer Ähnlichkeit zu Trb-1, LpcGI-2 bzw. LpcGI-1 im Genus Legionella verbreitet sind. / Exchange of genetic information by horizontal gene transfer is an important mechanism for the evolution of bacterial genomes. Legionella pneumophila strains encode different type IV secretion systems and integrative conjugative elements contribute to the variability of the intracellular pathogen. The genomic island Trb-1 of L. pneumophila Corby encodes a functional conjugation and T4ASS. Trb-1 is integrated within the tRNAPro gene and can exist in a chromosomal or an episomal circular form. In addition to the trb/tra genes, a site-specific integrase (int-1) and a Legionella vir region (lvrRABC) are also localized on the genomic island. By deleting the int-1 gene, it could be demonstrated that the excision and of Trb-1 is integrase dependent. Furthermore, in this work it was shown for the first time that the lvr region and especially the putative phage repressor LvrR, is involved in the regulation of Trb-1 excision. Conjugation of Trb-1 in L. oakridgensis does not influence the in vivo fitness of the transconjugants in human macrophages. The genomic islands LpcGI-1 and LpcGI-2 encode a new putative T4SS. For the first time it could be demonstrated, that the T4SS localized on LpcGI-2 is functional. Although LpcGI-2 could be mobilized and transferred via conjugation to another L. pneumophila strain, followed by the site-specific integration into the genome of the transconjugants. LpcGI-1 and LpcGI-2 are flanked by the tRNAThr or tRNAMet gene respectively. Both islands can exist in different chromosomal and episomal forms. The excision of LpcGI-2 occurs similar to Trb-1 in an integrase dependent manner. Two additional genomic islands (LpcGI-Asn and LpcGI-Phe) could be identified in the genome of Lp Corby. Moreover, data of the in silico analysis demonstrated, that genomic islands similar to Trb-1, LpcGI-2 and LpcGI-1 are distributed within the genus Legionella.
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A conjugação de \'ser\' e de \'ter\' em alguns livros didáticos de português língua estrangeira sob a ótica do pensamento complexo / Analisis of the way that the verb conjugation of \"ser\" (to be) and \"ter\" (to have) is presented by Portuguese as foreign language books visualized from the complex paradigmZampietro, Linei Matzenbacher 23 May 2007 (has links)
A partir de uma base teórica que cruza textos advindos do pensamento complexo (Filosofia), do paradigma funcional (Lingüística) e de autores diversos das áreas de Didática, Sociologia e Lingüística Aplicada, afinados de alguma maneira com o paradigma ou pensamento complexo, analisaremos a forma de como a conjugação verbal dos verbos \"ser\" e \"ter\" é introduzida em nosso corpus - quatro livros didáticos de português (do Brasil) para estrangeiros de grande circulação no sul e sudeste do País, e tentaremos obter por meio dessa análise uma visão do quanto cada obra de nosso corpus se aproxima de nossa base teórica. Tal base, resumida em \"quesitos\" no capítulo 5 a serem satisfeitos ou não pelo corpus analisado nos capítulos 6 e 7, encara o indivíduo/aprendiz como um ser extremamente complexo pois portador de nuances as mais diversas, que se não consideradas no processo de aquisição da linguagem, aquisição por si só também extremamente complexa, corremos o risco de se ver esse indivíduo frustrado em sua tentativa legítima de aprender o português como língua estrangeira. A título de sugestão de melhorias na forma como nosso corpus introduz e sedimenta os verbos \"ser\" e \"ter\", descreveremos como os equivalentes desses verbos no inglês são introduzidos pela série New Interchange, além, e principalmente, de oferecer sugestões de melhorias inspiradas em nossa base teórica e em nossa experiência na área de ensino de Português Língua Estrangeira. / From a theory basis that crosses texts from the complex paradigm (Philosophy), the functional paradigm (Linguistics) and several other authors from Didactics, Sociology and Applied Linguistics, anyhow affined with the paradigms above, we will make an analysis of the way that the verb conjugation of \"ser\" (to be) and \"ter\" (to have) is presented by our corpus - four Portuguese as foreign language books largely sold in the South and Southeast of Brazil - and try to visualize through this analysis in which degree each of these books gets close to our theory basis. The result of this \"texts crossing\" is summarized in quests form in chapter 5 to be met or not by our corpus analyzed in chapters 6 and 7. Such theory basis considers the individual/learner as an extremely complex being, a carrier of many different aspects that, once not taken into account in the language acquisition process, such acquisition extremely complex itself, one takes the risk to have this individual frustrated in his legitimate try to learn Portuguese as a foreign language. As an improvement suggestion on how verbal conjugation of \"ser\" and \"ter\" could be presented by the Portuguese as foreign language books focused in this dissertation, we will describe how the verb conjugation of \"be\" and \"have\" is presented by the New Interchange series, besides offering improvement suggestions inspired by our theory basis and by our own experience in the field of teaching Portuguese as foreign language.
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