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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.
31

Role of variant sialylation in regulating tumor cell behavior

Shaikh, Faheem M. January 2008 (has links) (PDF)
Thesis (Ph. D.)--University of Alabama at Birmingham, 2008. / Title from first page of PDF file (viewed Oct. 9, 2008). Includes bibliographical references (p. 89-101).
32

Macrophage Recognition of Xenogeneic Erythrocytes

Goding, Linda M. January 2007 (has links)
No description available.
33

TAILORING DRUG-CARRIER INTERACTIONS IN POLY(SIALIC ACID) MICELLES FOR USE AS CANCER THERAPEUTIC CARRIERS

Pawlish, Gerald Joseph January 2018 (has links)
Although great progress has been made, cancer still remains one of the most prevalent maladies plaguing mankind. New treatment methodologies using nanoparticles have come to the forefront by allowing for enhanced delivery of therapeutics to the tumor site. The design of the nanoparticle should allow for long circulation times, tumor-specific targeting and efficient release at the site of action. This requires that both the external shell and internal core of the nanoparticle be carefully selected to meet the maximal criteria of each of these steps. Poly(sialic acid) (PSA), a naturally occurring polysaccharide, meets all of the benchmarks of an effective exterior coating yet remains relatively unexplored in the field of drug delivery. Due to stealth properties, natural tumor targeting ability, and inherent pH-responsive elements, PSA has frequently been viewed as a “next-generation” surface coating. Just as important, the internal composition of the carrier should aid in effective drug loading but also rapid release. The selection of the core containing groups as well as therapeutic should be maximized in order to customize the carrier to drug. Here, we have developed PSA micelles composed of various internal groups selected to maximize drug loading and facilitate release. Loading of the chemotherapeutic doxorubicin was optimized through variations in non-covalent bonding forces between drug and carrier. Furthermore, PSA micelles composed of internal pH-responsive groups of varying hydrophobicity were also developed to tailor micelle swelling points at conditions analogous towards those found upon cellular uptake. Both of these were effective delivery platforms towards MCF-7 human breast adenocarcinoma cells. / Bioengineering
34

Selective synthesis of Neu5Ac2en and its oxazoline derivative using BF3.Et2O

Ribeiro Morais, Goreti, Oliveira, Rudi S., Falconer, Robert A. 22 January 2009 (has links)
No / Application of the Lewis acid BF3·Et2O to the selective synthesis of 5-acetamido-2,6-anhydro-3,5-dideoxy-d-glycero-d-galacto-non-2-enonic acid (Neu5Ac2en) and the related oxazoline, methyl 7,8,9-tri-O-acetyl-2,3,4,5-tetradeoxy-2,3-didehydro-2,3-trideoxy-4',5'-dihydro-2'-methyloxazolo[5,4-d]- d-glycero-d-talo-non-2-enonate is described.
35

Exploring and Exploiting Acceptor Preferences of the Human Polysialyltransferases as a Basis for an Inhibitor Screen

Ehrit, J., Keys, T.G., Sutherland, Mark, Wolf, S., Meier, C., Falconer, Robert A., Gerardy-Schahn, R. 24 May 2017 (has links)
Yes / α2,8-Linked polysialic acid (polySia) is an oncofoetal antigen with high abundance during embryonic development. It reappears in malignant tumours of neuroendocrine origin. Two polysialyltransferases (polySTs) ST8SiaII and IV are responsible for polySia biosynthesis. During development, both enzymes are essential to control polySia expression. However, in tumours ST8SiaII is the prevalent enzyme. Consequently, ST8SiaII is an attractive target for novel cancer therapeutics. A major challenge is the high structural and functional conservation of ST8SiaII and -IV. An assay system that enables differential testing of ST8SiaII and -IV would be of high value to search for specific inhibitors. Here we exploited the different modes of acceptor recognition and elongation for this purpose. With DMB-DP3 and DMB-DP12 (fluorescently labelled sialic acid oligomers with a degree of polymerisation of 3 and 12, respectively) we identified stark differences between the two enzymes. The new acceptors enabled the simple comparative testing of the polyST initial transfer rate for a series of CMP-activated and N-substituted sialic acid derivatives. Of these derivatives, the non-transferable CMP-Neu5Cyclo was found to be a new, competitive ST8SiaII inhibitor.
36

Production of Sialic Acid Analogs in Engineered E. coli: Characterization of Amino Sugar Recycling

Villegas-Peñaranda, Luis Roberto 06 November 2019 (has links)
This research focused on the study of the amino sugar recycling and sialic acid degradation pathway as a possible entry point for N-acyl glucosamines for the production of sialic acid analogs. Meeting this objective would allow the development of a bacterial strain capable of producing non-natural nonulosonic acids that could be used in the development of medicines, vaccines or useful compounds for the study of interactions between pathogenic organisms and their host. The first step was to understand how N-acetyl-D-glucosamine-6-phosphate deacetylase reacts to different types of substrates in order to determine its tolerance to the size of acyl groups in acyl amino sugars. This was achieved by studying the enzymatic activity in an in vitro system. We determine that the enzyme has a preference for small and slightly bulky acyl groups. Then, an in silico docking modeling and an in vivo system experiment were carried out. These experiments allowed to confirm the previous results. The second project was carried out due to the uncertainty of whether the kinase involved in the catabolic pathway would be able to phosphorylate the substrates. By quantifying residual ATP, the high specificity of N-acetyl-D-glucosamine kinase could be verified. This result led us to think about the design of an organic synthesis strategy that would allow the phosphorylation of glucosamine in carbon 6. A simple synthetic route was designed based on the protection of the two most reactive moieties of the amino sugars and the reactivity of the hydroxy group on carbon 6. However, we had problems with the purification step of the final product due to its high polarity. The next stage of this investigation was to confirm the transformation of GlcNAc into ManNAc. For this, an NMR analysis was designed that would detect the presence of both sugars in the reaction system. The epimerization of ManNAc to GlcNAc was detected successfully. Notwithstanding, the reverse reaction could not be detected. Based on the results obtained in the previous stage, we realized that an error was made in the epimerization reaction since we placed the wrong kinase because we did not take into account its substrate specificity. Finally, we tried to produce sialic acid analogs in a fermentative system using different genetic variants of Escherichia coli. Two of the expected analogs, Neu5Pr and Neu5nBu, were obtained. In addition, NagA activity towards substrates with small acyl groups was confirmed.
37

Multivalent sialic acid binding proteins as novel therapeutics for influenza and parainfluenza infection

Alias, Nadiawati January 2014 (has links)
In nature, proteins with weak binding affinity often use a multivalency approach to enhance protein affinity via an avidity effect. Interested in this multivalency approach, we have isolated a carbohydrate binding module (CBM) that recognises sialic acid (known as a CBM40 domain) from both Vibrio cholerae (Vc) and Streptococcus pneumoniae (Sp) NanA sialidases, and generated multivalent polypeptides from them using molecular biology. Multivalent CBM40 constructs were designed either using a tandem repeat approach to produce trimeric or tetrameric forms that we call Vc3CBM and Vc4CBM, respectively, or through the addition of a trimerization domain derived from Pseudomonas aeruginosa pseudaminidase to produce three trimeric forms of proteins known as Vc-CBMTD (WT), Vc-CBMTD (Mutant) and Sp-CBMTD). Due to the position and flexibility of the linker between the trimerization domain and the CBM40 domain, site directed mutagenesis was employed to introduce a disulphide bond between the monomers at positions S164C and T83C of the CBM40 domain in order to promote a stable orientation of the binding site for easier access of sialic acids. Data from isothermal titration calorimetry (ITC) reveals that interaction of multivalent CBM40 proteins with α(2,3)-sialyllactose was mainly enthalpy driven with entropy contributing unfavorably to the interaction suggesting that these proteins establish a strong binding affinity to their ligand minimizing dissociation to produce stable multivalent molecules. However, using surface plasmon resonance (SPR), a mixed balance of entropy and enthalpy contributions was found with all constructs as determined by Van't Hoff plots. This proved that binding does not occur through a simple protein-ligand interaction but through disruption of hydrophobic and/or ionic hydration that provide the driving force to the process. Interestingly, the valency of multiple-linked polypeptides also plays an important part in the protein stabilization. However, little is known about their detailed structure when in multivalent form, as attempts to crystallize the whole protein molecule of Vc-CBMTD (WT) failed due to linker and domain flexibility. Only the trimerization domain (TD) part from Pseudomonas aeruginosa pseudaminidase was successfully crystallized and structure was determined to 3.0 Å without its CBM40 domain attached. In this thesis, we have also reported on the potential anti-influenza and anti- parainfluenza properties of these proteins, which were found to block attachment and inhibit infection of several influenza A and parainfluenza virus strains in vitro. As widely mentioned in literature, terminal sialic acids on the cell surface of mammalian host tissue provide a target for various pathogenic organisms to bind. Levels of viral inhibition were greatest against A/Udorn/72 H3N2 virus for Vc4CBM and Vc3CBM constructs with the lowest EC50 of 0.59 µM and 0.94 µM respectively, however most of the multivalent proteins tested were also effective against A/WSN/33 H1N1 and A/PR8/34 H1N1 subtypes. For parainfluenza virus, all constructs containing V. cholerae sialidase CBM40 domain showed great effect in inhibiting virus infection during cell protection assay. The best EC50 values were 0.2 µM from Vc-CBMTD (WT) followed by 1.17 µM from Vc4CBM and 1.78 µM from Vc-CBMTD (Mutant) which was against hPIV2, hPIV3 and hPIV5 infections respectively. Only a construct from S. pneumoniae sialidase known as Sp-CBMTD showed negligible effect on cell protection. All constructs were further tested for cytotoxicity in mammalian cell culture as well as undergoing an inhibition study on viral replication proteins. For the in vivo study, we also demonstrated the effectiveness of Vc4CBM to protect cotton rats and mice from hPIV3 and Streptococcus pneumoniae infections, when given intranasally in advance or on the day of infection. Therefore, these novel multivalent proteins could be promising candidates as broad-spectrum inhibitors or as a prophylactic treatment for both influenza and parainfluenza associated diseases.
38

Risk factors for cardiovascular events and incident hospital-treated diabetes in the population

Khalili, Payam January 2012 (has links)
Background: Cardiovascular disease (CVD) is the leading cause of death worldwide. Well-established risk factors for CVD include increasing age, male sex, sedentary lifestyle, obesity, smoking, diabetes, hypertension, dyslipidaemia and low socio-economic status. Traditional risk factors do, however, not fully explain cardiovascular risk in general. In this thesis we focused on two conventional risk factors (smoking, blood pressure), and two unconventional risk markers (adiponectin, an adipocyte derived protein; and sialic acid (SA), a marker of systemic inflammation) for prediction of CVD events. Aims: In Paper I we examined to what degree smoking habits modify the risk of CVD in relation to systolic blood pressure levels in middle-aged men. In Paper II we investigated the predictive role of adiponectin for risk of CVD as well as the cross-sectional associations between adiponectin and markers of glucose metabolism, also in men. In Paper III we examined if increasing pulse pressure (PP) and increasing levels of SA both increase the risk of CVD and whether their effects act in synergism. In Paper IV the association of SA with risk of incident diabetes mellitus and related complications, resulting in hospitalization, was studied. Subjects and Methods: Two large-scale, population-based, screening studies with long follow-up periods have been used. The Malmö Preventive Project (MPP) was used with 22,444 individuals in Paper I and a sub cohort of 3,885 individuals in Paper II. The Värmland Health Survey (VHS) was used in Papers III and IV with 37,843 and 87,035 individuals, respectively. Results: CVD risk increases with increasing systolic blood pressure levels and this risk is almost doubled in smokers. Total adiponectin level is not associated with increased risk of future CVD but it is inversely associated with markers of glucose metabolism. PP and SA both contribute to risk of future CVD. Adjustment for mean arterial pressure reduces the risk induced by PP. Elevated SA contributes to increased risk of incident diabetes and related complications leading to hospitalization.
39

Design, synthesis and biological evaluation of inhibitors of polysialyltransferases PST and STX : design, synthesis and biological evaluation of a range of N-modified mannosamines, sialic acids and analogues from in silico screening as inhibitors of PolySia-NCAM biosynthesis with anti-migration activity

Springett, Bradley Ross January 2013 (has links)
Polysialylated NCAM (polySia-NCAM) is re-expressed in a number of tumours, including small cell lung carcinoma and neuroblastoma and is strongly associated with aggressive, invasive and metastatic tumours in the clinic. SiRNA knockdown of the polysialyltransferases (polySTs), the enzymes responsible for polysialylation of neural cell adhesion molecule (NCAM), has been shown to abolish cell migration. PolySia-NCAM is thus a highly attractive novel therapeutic target. A library of potential polyST inhibitors has been synthesised, using substrate-based design and computational chemistry. Compounds synthesised include N-acylmannosamine analogues, thio-linked CMP-sialic acid analogues, N-acyl modified sialic acids and compounds incorporating elements of both approaches. Novel methodology development in the synthesis of many of the compounds is described, notably a novel route to N-acyl sialosides. In addition, compounds identified from in silico screening were considered. Routes to synthesis and isolation of analogues of biologically active compounds are described. Using an enzyme assay, compounds were evaluated for their ability to reduce polySia synthesis through polyST inhibition. Effects of agents on polySia expression in cells, and the ability of compounds to reduce cell migration in vitro was studied using a wound healing ‘scratch assay’. The data from these experiments revealed a number of potent modulators of polySia assembly and their efficacy in reducing cell migration, as well as the limits of the biosynthetic pathway to accept unnatural sialic acid precursors. This is the first example of polyST inhibition modulating tumour cell migration, and points to the potential of the polysialyltransferases as a therapeutic target in metastatic tumours.
40

The preparation and evaluation of N-acetylneuraminic acid derivatives as probes of sialic acid-recognizing proteins

Ciccotosto, Silvana January 2004 (has links)
Abstract not available

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