• Refine Query
  • Source
  • Publication year
  • to
  • Language
  • 75
  • 9
  • 7
  • 6
  • 4
  • 1
  • 1
  • 1
  • 1
  • Tagged with
  • 210
  • 74
  • 52
  • 51
  • 44
  • 42
  • 33
  • 32
  • 29
  • 28
  • 26
  • 26
  • 26
  • 26
  • 23
  • 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.
41

SYNTHESIS AND CHARACTERIZATION OF ANTIOXIDANT CONJUGATED POLY(ΒETA-AMINO ESTER) MICRO/NANOGELS FOR THE SUPPRESSION OF OXIDATIVE STRESS

Gupta, Prachi 01 January 2016 (has links)
Oxidative stress is a pathophysiological condition defined by an increased production of reactive oxygen species (ROS), which can result in the growth arrest of cells followed by cell disintegration or necrosis. A number of small molecule antioxidants (e.g. curcumin, quercetin and resveratrol) are capable of directly scavenging ROS, thereby short-circuiting the self-propagating oxidative stress state. However, poor solubility and rapid 1st pass metabolism results in overall low bioavailability and acts as a barrier for its use as a drug to suppress oxidative stress efficiently. To overcome this limitation, these small molecule antioxidants were covalently conjugated into poly(β-amino ester) (PβAE) cross-linked networks to formulate prodrug gel microparticles and nanoparticles (nanogels). Being hydrolytically degradable in nature, these PβAE crosslinked systems released antioxidants in their original structural form in a sustained controlled fashion. Both quercetin and curcumin-PβAE nanogels showed prolonged suppression of cellular oxidative stress induced by H2O2. Curcumin PβAE nanogels also demonstrated protection against mitochondrial oxidative stress induced by H2O2 and polychlorinated biphenyls. Curcumin-PβAE gel microparticles were also developed as a platform to treat oral mucositis through a local antioxidant delivery route. The same synthesis chemistry was transferred to formulate resveratrol PβAE gel microparticles for topical applications, to treat UV radiation induced oxidative stress. Both formulations showed suppression of induced oxidative stress. An in vivo trial with curcumin-PβAE microparticles further showed relatively reduced the severity of induced oral mucositis (OM) in hamster check pouch as compared to placebo.
42

TARGETED POLYMERIC BIOMATERIALS FOR THE PREVENTION OF POST SURGICAL ADHESIONS

Medley, John M. 01 January 2010 (has links)
Despite recent advances in surgical technique and the development of numerous therapeutic agents, the formation post surgical adhesions (PSA) continues to cause complications for many patients. In this research, we have employed a rational system to develop a novel treatment to address this clinical need. Based on an understanding of the biochemical events that lead to PSA formation, a series of targeted polymeric biomaterials was designed to interrupt the fibrin gel matrix propagation and suppress PSA formation. Using group transfer polymerization, a series of well controlled block copolymers of polyacrylic acid and poly(ethylene glycol-methacrylate) based materials was synthesized. Subsequent functionalization with the pentapeptide Cys-Arg-Glu-Lys-Ala (CREKA) was employed to target the materials to fibrin as a marker of pro-adhesive sites. While preliminary testing of the untargeted materials verified their ability to suppress non-specific protein adsorption to model surfaces, numerous in vitro tests were conducted to study the ability to inhibit fibrin gel propagation. The ability to inhibit both the rate and quantity of fibrinogen deposition to a fibrin coated surface has been demonstrated. In addition, the rate of fibrin gel propagation and the degree of cellular attachment can modulated. Taking advantage of the systematic variation in structure facilitated by the robust synthetic methodology employed, statistical analysis was used to elucidate the structureproperty relationships governing the performance of these materials. The most important factors that lead to enhanced performance in in vitro tests are the length of PEG chain and number of peptide units conjugated to the polymer: increasing PEG chain length and increasing the number of peptides conjugated to the polymer both improve performance in all tests. The synthetic methods that have been developed, in conjunction with the experimental results, will be used to direct future studies, including cytotoxicity and animal studies.
43

ENGINEERING NOVEL TERPENE PRODUCTION PLATFORMS IN THE YEAST SACCHAROMYCES CEREVISIAE

ZHUANG, XUN 01 January 2013 (has links)
The chemical diversity and biological activities of terpene and terpenoids have served in the development of new flavors, fragrances, medicines and pesticides. While terpenes are made predominantly by plants and microbes in small amounts and as components of complex mixtures, chemical synthesis of terpenes remains technically challenging, costly and inefficient. In this dissertation, methods to create new yeast lines possessing a dispensable mevalonate biosynthetic pathway wherein carbon flux can be diverted to build any chemical class of terpene product are described. The ability of this line to generate diterpenes was next investigated. Using a 5.5 L fed bath fermentation system, about 569 mg/L kaurene and approximately 207 mg/L abietadiene plus 136 mg/L additional isomers were achieved. To engineer more highly modified diterpenes might have greater industrial, agricultural or medicinal applications, kaurenoic acid production reached 514 mg/L with byproduct kaurene and kaurenal at 71.7mg/L and 20.1mg/L, respectively, in fed batch fermentation conditions. Furthermore, ZXM lines for engineer monoterpene and ZXB lines for engineer triterpene were generated by additional specific genomic modification, 84.76 ±13.2 mg/L linalool, 20.54±3.8 mg/L nerolidol and 297.7mg/L squalene were accumulate in ZXM144 line ana ZXB line, respectively, in shake flask conditions.
44

A non-contact laser ablation cell for mass spectrometry

Asogan, Dhinesh January 2011 (has links)
A common analytical problem in applying LA sampling concerns dealing with large planar samples, e.g. gel plates, Si wafers, tissue sections or geological samples. As the current state of the art stands, there are two solutions to this problem: either sub-sample the substrate or build a custom cell. Both have their inherent drawbacks. With sub-sampling, the main issue is to ensure that a representative is sample taken to correctly determine the analytes of interest. Constructing custom cells can be time consuming, even for research groups that are experienced or skilled, as they have to be validated before data can be published. There are various published designs and ideas that attempt to deal with the issue of large samples, all of which ultimately enclose the sample in a box. The work presented in this thesis shows a viable alternative to enclosed sampling chambers. The non-contact cell is an open cell that uses novel gas dynamics to remove the necessity for an enclosed box and, therefore, enables samples of any arbitrary size to be sampled. The upper size limit of a sample is set by the travel of the XY stages on the laser ablation system, not the dimensions of the ablation cell.
45

An Expedited, Regiospecific para-Bromination of Activated Aryls

Dudley, Kathryn E 01 April 2017 (has links)
Electrophilic Aromatic Substitution (EAS) is one of the most frequently used aryl substitution methods. Aside from the fact that most EAS reactions require an acid and an oxidizer to proceed, the reactions involving activated aryls typically produce a mixture of ortho- and para- products as well as an ortho-/para- disubstituted product. Regiospecificity in aromatic substitution is key in the production of many compounds in a variety of disciplines. Since EAS is one of the most often used substitution methods, it is extremely important to develop an efficient method for regiospecific substitutions. Previous research developed a method of ortho-substitution by using hydrocarbon media, a less hazardous, greener medium, which was modified to develop a method of p-iodination (bromination), but with extensive time periods. The research presented here not only reveals an expedient, rapid method for regiospecific p-bromination, but also does so without the need for an acid or an oxidizer. The conditions for p-bromination involve the use of acetone (sometimes with cyclohexane) and NBS resulting in GC yields of p-brominated product approaching 100% in a cost and time efficient manner without the concerns of hazardous materials or byproducts like Br2 or HBr. The reaction mechanism is briefly examined as well.
46

Interaction Characteristics of Viral Protease Targets and Inhibitors : Perspectives for drug discovery and development of model systems

Shuman, Cynthia F January 2003 (has links)
Viral proteases are important targets for anti-viral drugs. Discovery of protease inhibitors as anti-viral drugs is aided by an understanding of the interactions between viral protease and inhibitors. This thesis addresses the characterization of protease-inhibitor interactions for application to drug discovery and model system development. The choice of a relevant target is essential to molecular interaction studies. Therefore, full-length NS3 protein of hepatitis C virus (HCV) was obtained, providing a more relevant target and a better model for the development of HCV protease inhibitors. In addition, resistance to anti-viral drugs, a serious problem in the treatment of AIDS, prompted the investigation of resistant variants of human immunodeficiency virus (HIV) protease. Drug resistance was initially explored by characterization of the interactions between a series of closely related inhibitors and resistant variants of HIV protease, using an inhibition assay to determine the inhibition dissociation constants (Ki). The relationship between structure, activity and resistance profiles was not clarified, indicating that the effect of structural changes in the inhibitors and the protease are not predictable and must be analyzed case wise. It was proposed that additional kinetic characterization of the interactions was required and a biosensor-based method allowing for determination of affinity, KD, and interaction rate constants, kon and koff, was adopted. The increased physiological relevance of this method was confirmed, and the affinity data have better correlation with cell culture data. In addition, interactions between clinical inhibitors of HIV protease and enzyme variants indicate that increased dissociation rates (koff) are associated with the development of resistance. Thermodynamic characterization of the interactions between HIV-1 protease and clinically relevant inhibitors revealed distinct energetic characteristics for inhibitors. The resolution of the energetics of association and dissociation identified an inhibitor with unique interaction characteristics and confirmed the validity of using this method for further characterization of molecular interactions. This work resulted in the development of model systems for the analysis of kinetics, resistance and thermodynamic characteristics of protein-inhibitor interactions. The results give increased understanding of the biomolecular interactions and can be applied to drug discovery.
47

Development of a suite of bioinformatics tools for the analysis and prediction of membrane protein structure

Togawa, Roberto Coiti January 2006 (has links)
This thesis describes the development of a novel approach for prediction of the three-dimensional structure of transmembrane regions of membrane proteins directly from amino acid sequence and basic transmembrane region topology. The development rationale employed involved a knowledge-based approach. Based on determined membrane protein structures, 20x20 association matrices were generated to summarise the distance associations between amino acid side chains on different alpha helical transmembrane regions of membrane proteins. Using these association matrices, combined with a knowledge-based scale for propensity for residue orientation in transmembrane segments (kPROT) (Pilpel et al., 1999), the software predicts the optimal orientations and associations of transmembrane regions and generates a 3D structural model of a gi ven membrane protein, based on the amino acid sequence composition of its transmembrane regions. During the development, several structural and biostatistical analyses of determined membrane protein structures were undertaken with the aim of ensuring a consistent and reliable association matrix upon which to base the predictions. Evaluation of the model structures obtained for the protein sequences of a dataset of 17 membrane proteins of detennined structure based on cross-validated leave-one-out testing revealed generally high accuracy of prediction, with over 80% of associations between transmembrane regions being correctly predicted. These results provide a promising basis for future development and refinement of the algorithm, and to this end, work is underway using evolutionary computing approaches. As it stands, the approach gives scope for significant immediate benefit to researchers as a valuable starting point in the prediction of structure for membrane proteins of hitherto unknown structure.
48

ENGINEERING SURFACES TO SUPPORT NEURAL STEM CELLS (HNSC’S) AND HEPATOCYTES ADHESION AND GROWTH.

Sharma, Karan, Wen, Xuejun 01 January 2016 (has links)
In a 2D cell culture, the cells are mainly grown on flat surfaces which are usually made of polystyrene plastic. Cells are able to attach to these surfaces, forming individual cell formations or colonies. In this study, we have been looked at many different platforms to improve cell growth, adhesion, attachment and proliferation on two different promising cell lines. These cell lines are the human neural stem cells (hNSCs) and human liver hepatocellular carcinoma cells (HepG2). Researchers have been very interested in studying these cell lines in the recent years as they have very useful potentials in the long run to aid and cure many of the disorders, diseases and possibly replace infected or injured organs as well. This can be done using actual clinical applications for cell therapies and tissue transplantation. Based on the studies conducted for this thesis, we have been able to show that cells can be maintained in a 2D culture setting with increasing growth and adhesion factors. The conditions used for these studies were a way to not use the traditional materials for cell attachment and growth. This was pursued due to the fact that most stem cells for their continuity require a microenvironment that will support their physical and chemical properties of an effective extra cellular matrix (ECM). To reiterate, presently most ECM molecules are human or animal derived for effective cell culture applications but not clinical. This is a major problem as each batch varies, they are difficult to isolate and most contain biological components that have been known to limit their use in clinical applications. Hence, this study concentrated on developing synthetic polymer based ECMs as they do not have the problems of the human or animal derived ECMs, but also as they are relatively low-cost, reliable and easily fabricated. Through many experimental trials we have successfully developed synthetic polymer based ECM molecules that sustain stem cell growth for HepG2 liver hepatocellular carcinoma and hNSC human neural stem cell lines. The different substrates developed were a peptide fabricated in our lab; different concentrations and solutions of Poly 4-vinylphenol (P4VP) that were used on a flat hollow fiber membrane made using Polyacrylonitrile (PAN) doped in a solution containing PAN/N, N-dimethylformamide (DMF) having a high biocompatibility. This hollow fiber membrane study was maintained with eight different conditions over a period of 6 weeks.
49

DESIGN, SYNTHESIS, AND BIOLOGICAL EVALUATION OF POTENT HIV-1 PROTEASE INHIBITORS WITH NOVEL BICYCLIC OXAZOLIDINONE AND BIS SQUARAMIDE SCAFFOLDS

Jacqueline N Williams (6859052) 16 August 2019 (has links)
<p>In 2018, the World Health Organization (WHO) reported approximately 37 million people are living with the Human Immunodeficiency Virus (HIV). Suppressing replication of the virus down to undetectable levels was achieved by combination antiretroviral therapy (cART) which effectively reduced the mortality and morbidity rates of HIV positive individuals. Despite the improvements towards combatting HIV/AIDS, no successful treatment exists to eradicate the virus from an infected individual. Treatment regimens are lifelong and prompt less than desirable side effects including but not limited to; drug-drug interactions, toxicity, systemic organ complications, central nervous system HIV triggered disorders and most importantly, drug resistance. Current therapies are becoming ineffective against highly resistant HIV strains making the ability to treat long-term viral suppression a growing issue. Therefore, potent and more effective HIV inhibitors provide the best chance for long-term successful cART. </p> <p>HIV-1 protease (PR) enzyme plays a critical role in the life cycle and replication of HIV. Significant advancements were achieved through structure-based design and X-ray crystallographic analysis of protease-bound to HIV-1 and brought about several FDA protease inhibitors (PI). Highly mutated HIV-1 variants create a challenge for current and future treatment regimens. This thesis work focuses on the design, synthesis, and evaluation of two new classes of potent HIV-1 PIs that exhibit a novel bicyclic oxazolidinone feature as the P2 ligand and a novel bis squaramide scaffold as the P2/P3 ligand. Several inhibitors displayed good to excellent activity toward HIV-1 protease and significant antiviral activity in MT-4 cells. Inhibitors 1.65g and 1.65h were further evaluated against a panel of highly resistant multidrug-resistant HIV-1 variants and displayed antiviral activity similar to Darunavir. X-ray crystal structures of inhibitor 1.65a and inhibitor 1.65i were co-crystallized with wild type HIV-1 protease and solved at a 1.22 Å and 1.30 Å resolution and maintained strong hydrogen bond with the backbone of the PR enzyme. </p>
50

EVALUATION OF STAPHYLOCOCCUS AURUES RNPA PROTEIN AS AN ANTIBACTERIAL TARGET

Lisha Ha (5930654) 13 August 2019 (has links)
<p><i>Staphylococcus aureus</i> (<i>S. aureus</i>) is a Gram-positive pathogen that causes a wide range of infections in both hospitals and communities, of which the total mortality rate is higher than AIDS, tuberculosis, and viral hepatitis combined. The drug resistant <i>S. aureus </i>is a member of the “ESKAPE” pathogens that require immediate and sustained actions of novel method to combat. However, the current antimicrobial development against <i>S. aureus</i> is in stagnation, which underscores the urgent need for novel antimicrobial scaffolds and targets. <i>S. aureus</i> Ribonuclease P protein (RnpA) is an essential protein that plays important roles in both tRNA maturation and mRNA degradation pathways. The goal of this research was to evaluate RnpA as an antimicrobial target using biophysical methods. The crystal structures of wild-type RnpA in three different constructs were determined, among which the tag-free RnpA construct has a structural model of 2.0 Å resolution and R<sub>crys</sub>/R<sub>free</sub>= 0.214/0.234, and its crystals are reproducible. This crystal structure of tag-free <i>S. aureus </i>RnpA shows a globular representation with key structural motifs, including the “RNR” Ribonuclease P RNA binding region and a substrate binding central cleft, which shares high similarity to previously solved RnpA structures from other species despite of their low sequence identity. Meanwhile, in a screen of <i>S. aureus </i>RnpA mutants performed by our collaborator, RnpA<sup>P89A</sup> was found lacking the mRNA degradation activity while retaining the tRNA maturation function, and causing defects in cell viability. We therefore studied this mutant using differential scanning fluorimetry, crystallography, and circular dichroism. It was shown that RnpA<sup>P89A</sup> is thermally less stable than wild-type RnpA by ~2.0 ˚C, but no secondary structural or 3D conformational differences were found between the two proteins. Although the mutant RnpA<sup>P89A</sup> requires further characterization, the results of the studies in this thesis have begun to shed light on the relatively new role of <i>S. aureus </i>RnpA in mRNA degradation, and will serve as useful tools in future structure-based drug discovery for multi-drug resistant <i>S. aureus </i>treatment. </p>

Page generated in 0.0723 seconds