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Nichols, Alexander J. "Optical Molecular Sensing in Complex Biological Environments". Thesis, Harvard University, 2014. http://nrs.harvard.edu/urn-3:HUL.InstRepos:14226087.
Pełny tekst źródłaPokhrel, Laxman. "Design, synthesis, and biological evaluation of tricyclic pyrones and thiouridine nucleosides". Diss., Kansas State University, 2013. http://hdl.handle.net/2097/16233.
Pełny tekst źródłaDepartment of Chemistry
Duy H. Hua
The first chapter in this thesis includes the design, synthesis, and evaluation of anti-Alzheimer and anti-norovirus activities of tricyclic pyrones (TPs). Alzheimer’s disease is a major cause of dementia and sixth leading cause of death; it is a growing problem all over the world. On the other hand, norovirus, a highly contagious agent is responsible for more than 90% of non-bacterial gastroenteritis causing severity mainly in the closed environments. No drugs exist to eradicate the symptoms developed by both of these disorders. Studies have shown that the development of Alzheimer’s disease and the infection of norovirus are dependent on cholesterol metabolism. More specifically, the inhibition of acyl-CoA: cholesterol acyltrasferase (ACAT) led to the reduction of plaques in Alzheimer’s disease as well as reduced the infection of norovirus. Mimicking the structure of CP2, a TP with promising anti-Alzheimer activities, a library of tricyclic pyrones containing phenyl, naphthyl, heterocyclic, and dipeptidyl moieties were synthesized and evaluated for their anti-Alzheimer and anti-norovirus efficacies. Several TPs containing phenyl and naphthyl groups showed sub-micromolar to nanomolar potencies for the protection of neuronal MC65 cells from Aβ-oligomers induced death. Similarly, the TPs containing pyrrolyl, imidazolyl, and quinolinyl moieties were effective to inhibit the norovirus replication in low micromolar range. The most effective TPs from MC65 cells protection assay were also effective in the inhibition ACAT and up-regulation ABCA1 gene. The second chapter in this thesis includes the design, synthesis, and anti-norovirus activity of thiouridine nucleosides. Many nucleosides have demonstrated effective inhibition of viral RNA polymerase, and some are progressing at different level of clinical trials for the treatment of hepatitis C virus. Some of the nucleosides, including 2’-C-methyl and 2’-amino substituted analogs, were found to effectively inhibit the norovirus replication. In the search of more potent anti-noroviral compounds, two thiouridine nucleosides were synthesized and evaluated as anti-norovirus agents. Both of these analogs were ineffective up to 50 μM for the inhibition of norovirus replication in cell based assay. Proposed work of converting these nucleosides to their phosphoramidate derivatives is also described.
Njaria, Paul Magutu. "Antimycobacterial 2-aminoquinazolinones and benzoxazole-based oximes: synthesis, biological evaluation, physicochemical profiling and supramolecular derivatization". Doctoral thesis, University of Cape Town, 2017. http://hdl.handle.net/11427/26954.
Pełny tekst źródłaForsyth, Andrea N. "Synthesis and Biological Evaluation of Rigid Analogues of Methamphetamines". ScholarWorks@UNO, 2012. http://scholarworks.uno.edu/td/1436.
Pełny tekst źródłaZhu, Chongyu. "Polymeric drug delivery systems for biological antimicrobial agents". Thesis, University of Warwick, 2017. http://wrap.warwick.ac.uk/91996/.
Pełny tekst źródłaShi, Fengjian. "LASER ELECTROSPRAY MASS SPECTROMETRY: INSTRUMENTATION AND APPLICATION FOR DIRECT ANALYSIS AND MOLECULAR IMAGING OF BIOLOGICAL TISSUE". Diss., Temple University Libraries, 2017. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/445496.
Pełny tekst źródłaPh.D.
This dissertation elucidates the instrumentation and application of a hybrid ambient ionization source, laser electrospray mass spectrometry (LEMS), for the direct analysis and molecular imaging of biological tissue without matrix deposition. In LEMS, laser pulses from a Ti:Sapphire laser amplifier (60 fs, 800 nm, and 1 mJ) interact with surface analytes and transfer them from the condensed phase into the gas phase without the requirement of either exogenous matrix or endogenous water in the sample. The laser vaporized analytes are captured and ionized by an electrospray source, and finally detected by a mass analyzer. It was found that a turn-key, robust femtosecond fiber laser with longer wavelength, longer duration, and lower pulse energy at 1042 nm, 425 fs, and 50 µJ, respectively, provided comparable results with the Ti:Sapphire laser. Vaporization of intact, dried or aqueous cytochrome c and lysozyme samples was demonstrated by the fiber laser. A charge states distribution at lower charge states indicating folded conformation of proteins and the hemoglobin α subunit-heme complex from whole blood was observed. Endogenous anthocyanins, sugars, and other metabolites were detected and revealed the anticipated metabolite profile for the flower petal and leaf samples by the fiber laser. Phospholipids, especially phosphatidylcholine, were identified from a fresh mouse brain section sample. These lipid features were suppressed in both the fiber laser and Ti:Sapphire LEMS measurement in the presence of optimal cutting temperature compounds which are commonly used in animal tissue cryosectioning. This dissertation also details the design of an automated mass spectrometry imaging source based on the Ti:Sapphire LEMS. The laser, translation stage, and mass analyzer are synchronized and controlled using a customized user interface to enable step-by-step scanning of the area of interest on a given tissue sample. The imaging source is coupled with a high resolution accurate mass quadrupole time-of-flight (QTOF) mass analyzer with tandem mass analysis capability. A lateral resolution of 60 µm was demonstrated on a patterned ink film by LEMS imaging. Plant metabolites including sugar and anthocyanins were directly imaged from a leaf sample. Small metabolites, lipids and proteins were simultaneously imaged from a single tissue section of a pig liver sample. Biomarkers of blood-brain barrier damage and traumatic brain injury (TBI) that occurred during the injury were detected and imaged from a TBI mouse brain. The loading values from principal component analysis (PCA) were shown to be useful for identification of features of interest from the large LEMS imaging dataset.
Temple University--Theses
Jaramillo, Forcada Tatiana. "Synthesis and biological evaluation of natural and synthetic ganoderic acids". Thesis, University of Nottingham, 2017. http://eprints.nottingham.ac.uk/43313/.
Pełny tekst źródłaPetersson, Nina. "Optimisation of capillary gel electrophoresis method for enhanced separation of mRNA shortmers". Thesis, Uppsala universitet, Institutionen för kemi - BMC, 2018. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-351119.
Pełny tekst źródłaVerma, Abha. "Design, Synthesis and Biological Evaluation of Novel Cannabinoid Antagonist". ScholarWorks@UNO, 2012. http://scholarworks.uno.edu/td/1527.
Pełny tekst źródłaMuth, Aaron. "Design, Synthesis, and Biological Evaluation of Novel Polyamine Transport System Probes and their Application to Human Cancers". Doctoral diss., University of Central Florida, 2012. http://digital.library.ucf.edu/cdm/ref/collection/ETD/id/5348.
Pełny tekst źródłaPh.D.
Doctorate
Chemistry
Sciences
Chemistry
Komati, Rajesh. "Cu (II) Catalyzed Gateways In The Synthesis of Acridine Derivatives and Their Biological Evaluation as Anti-Cancer Drugs". ScholarWorks@UNO, 2014. http://scholarworks.uno.edu/td/1818.
Pełny tekst źródłaJagu, Elodie. "Design, synthesis and biological evaluation of new polyamine derivatives as antikinetoplastid agents". Thesis, Université Paris-Saclay (ComUE), 2016. http://www.theses.fr/2016SACLS589/document.
Pełny tekst źródłaThis project is at the interface of chemistry and biology and relies on the expertise of two different teams. This thesis involves the design and development of inhibitors directed against Kinetoplastids. It is urgent to develop new therapeutic strategies to respond to drug resistance and toxicity of currently used drugs against these parasites. Polyamine metabolism and transporter have been demonstrated as essential for parasite growth. Therefore, these systems are potential drug targets for development of antikinetoplastid compounds. We chose to synthesize polyamine derivatives and evaluate their biological activity against Kinetoplatids. Fifty-four compounds, divided into three chemical series, have been synthesized and evaluated. Many have shown a micromolar biological activity in vitro against parasite. In vivo evaluation is foreseen for the most promising derivative
Akin, Myles. "Site specific thermodynamic study of OH radical addition to DNA bases". Thesis, Georgia Institute of Technology, 2010. http://hdl.handle.net/1853/33919.
Pełny tekst źródłaSingh, Shilpa. "SYNTHESIS AND BIOLOGICAL EVALUATION OF SECOND GENERATION ANIBAMINE ANALOGUES AS NOVEL ANTI-PROSTATE CANCER AGENTS". VCU Scholars Compass, 2012. http://scholarscompass.vcu.edu/etd/359.
Pełny tekst źródłaWazeerud-Din, Idris. "Synthetic Approaches towards Novel Isoform Selective PI3K Inhibitors and Their Biological Activities against Prostate Cancer Cells". DigitalCommons@Robert W. Woodruff Library, Atlanta University Center, 2018. http://digitalcommons.auctr.edu/cauetds/143.
Pełny tekst źródłaSherwood, Alexander M. "Design, Synthesis and Biological Evaluation of Novel Compounds with CNS-Activity Targeting Cannabinoid and Biogenic Amine Receptors". ScholarWorks@UNO, 2014. http://scholarworks.uno.edu/td/1831.
Pełny tekst źródłaApsunde, Tushar D. "Synthesis and Biological Evaluation of N-heterocycles for Activity on Monoamine Transporters and Exploration of Iridium Chemistry for Synthesis of Medicinally Important Molecules". ScholarWorks@UNO, 2014. http://scholarworks.uno.edu/td/1862.
Pełny tekst źródłaBoff, Bastien. "Synthesis, physicochemical and biological evaluation studies of ruthenium(II) and osmium(II) anticancer organometallic complexes". Phd thesis, Université de Strasbourg, 2012. http://tel.archives-ouvertes.fr/tel-00796216.
Pełny tekst źródłaObeng, Samuel. "Design, Synthesis, and Biological Screening of Selective Mu Opioid Receptor Ligands as Potential Treatments for Opioid Addiction". VCU Scholars Compass, 2017. http://scholarscompass.vcu.edu/etd/4771.
Pełny tekst źródłaBatra, Sumit. "Innovative Purification Protocol for Heparin Binding Proteins: Relevance in Biopharmaceutical and Biomedical Applications". TopSCHOLAR®, 2011. http://digitalcommons.wku.edu/theses/1062.
Pełny tekst źródłaLoe, Ashley M. "TOWARDS AN UNDERSTANDING OF PHARMACOLOGICALLY INDUCED INTRACELLULAR CHANGES IN NICOTINIC ACETYLCHOLINE RECEPTORS: A FLUORESCENCE MICROSCOPY APPROACH". UKnowledge, 2016. http://uknowledge.uky.edu/chemistry_etds/69.
Pełny tekst źródłaNgo, Huy. "SYNTHESIS AND BIOLOGICAL EVALUATION OF NOVEL DRUG CANDIDATES TO ADDRESS DRUG RESISTANCE IN TUBERCULOSIS AND FUNGAL DISEASES". UKnowledge, 2018. https://uknowledge.uky.edu/pharmacy_etds/95.
Pełny tekst źródłaKhalaf, Ali. "Design, synthesis and biological evaluation of new platelet aggregation inhibitors and novel methodologies for the preparation of CF₂R containing molecules". Phd thesis, Université Rennes 1, 2013. http://tel.archives-ouvertes.fr/tel-00861475.
Pełny tekst źródłaBoibessot, Thibaut. "Approche pluridisciplinaire de la problématique de la résistance bactérienne : conception, synthèse, évaluation de l'activité biologique et de la biodégradabilité de nouveaux agents antibactériens". Thesis, Nîmes, 2016. http://www.theses.fr/2016NIME0002/document.
Pełny tekst źródłaOver the two past decades, the massive use of antibiotics has led to the emergence of resistant bacterial strains against most families of antibiotics available on the pharmaceutical market. The emergence of multiresistant and totoresistant bacterial strains particularly in hospitals, which create increasing problem in the development of new therapeutics and constitutes serious public health threat problems. During my PhD, two approaches were discussed.The first approach of this project consist in targeting the DapF and MurE enzymes, which are implicated in the biochemical pathway for peptidoglycan biosynthesis, a key component of the bacterial cell wall. Consequently, we prepared amino acids derivatives with triazolyl and alkynyl groups, sterically hindered analogs of 2,6-diaminopimelic acid (meso-DAP).The second approach is the development of antibiotic adjuvants, to target specific proteins implicated in the development of bacterial resistance mechanisms (Histidine kinases, HKs). This work has enabled the development of thirty-three thiophene derivatives, eight of them have biological activity against three HKs (1.63 < IC50 (μM) < 243.9). In addition, among the eight molecules with biological activity, two of them present inhibition of bacterial growth (bactericide) against both gram-positive and/or gram-negative bacteria (B. subtilis, S. aureus, B. anthracis, E. coli…) and one of them restores the sensibility of bacterial strains (E. coli producing extended spectrum of β-lactamases (ESBL) and S. aureus resistant to methicillin (MRSA)) to the appropriate antibiotic (cefotaxim)
Avedis, Ani. "A high-throughput method for screening of protein binding behavior of multimodal anionic exchange ligands". Thesis, Uppsala universitet, Analytisk farmaceutisk kemi, 2021. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-434809.
Pełny tekst źródłaAggrawal, Manali. "Study of DNA damage on DNA G-quadruplexes and biophysical evaluation of the effects of modified bases (lesions) on their conformation and stability". Scholarly Commons, 2014. https://scholarlycommons.pacific.edu/uop_etds/134.
Pełny tekst źródłaArikatla, Swetha. "Effect of Tumor Microenvironmental Conditions on Non Small Cell Lung Cancer". Scholarly Commons, 2017. https://scholarlycommons.pacific.edu/uop_etds/126.
Pełny tekst źródłaMarahatta, Ram Prasad. "Folding of Bovine Pancreatic Trypsin Inhibitor (BPTI) is Faster using Aromatic Thiols and their Corresponding Disulfides". FIU Digital Commons, 2017. https://digitalcommons.fiu.edu/etd/3530.
Pełny tekst źródłaZhang, Changfeng. "Investigation of the endoplsmic reticulum calcium stores for their potential roles in neuroprotection using the NG115-401L neuronal cell line model". Scholarly Commons, 2014. https://scholarlycommons.pacific.edu/uop_etds/142.
Pełny tekst źródłaWang, Yu. "Mechanistic study of aryl hydrocarbon receptor nuclear translocator (ARNT)-mediated signaling". Scholarly Commons, 2013. https://scholarlycommons.pacific.edu/uop_etds/151.
Pełny tekst źródłaSilva, Amauri Francisco da. "Cálculo de potenciais de redução em meio aprótico (dmf) de adutos da reação de Morita-Baylis-Hillman com potencialidades biológicas anti-leishmania". Universidade Federal da Paraíba, 2015. http://tede.biblioteca.ufpb.br:8080/handle/tede/9221.
Pełny tekst źródłaMade available in DSpace on 2017-08-04T17:21:10Z (GMT). No. of bitstreams: 1 arquivototal.pdf: 15443881 bytes, checksum: a81c2afaef7e1fccdeb2543bc340d5a1 (MD5) Previous issue date: 2015-08-10
Nitroaromatic compounds derived from Morita-Baylis-Hillman reaction (RMBH) have been tested in the treatment of most neglected diseases such as malaria, Chagas disease and leishmaniasis. An important experimental observation is the relation between biological activity (measured by IC50) and reduction potential of these compounds (estimated by the cathodic and anodic peak potentials determined by electroanalytical techniques), the latter directly connected to the reduction of the nitro group (-NO2 ). For this reason, electrochemical methods have been used in order to mimic the enzymatic bioreduction of these compounds, as reported by Vasconcellos et al. (J. Braz. Chem. Soc. 23:894, 2012). The objective of this work was to develop a computational protocol to predict the reduction potential in aprotic media to support the molecular modeling of new compounds with desired pharmacological activity. The developed direct protocol (for aprotic solvents) consists of performing DFT calculations with B98, PBE1PBE or M06-2X functionals with 6-31+G(d,p) basis set and C-PCM solvation method (with standard cavitation method UFF/VdW). The results show that it is possible to predict the experimental variation of the reduction potential of at least 70 % of confidence (in a range of experimental data of only 140 mV) with absolute average errors less than 45 mV (much less than the experimental uncertainty of the absolute reaction potential of hydrogen electrode, approximately 400 mV) and standard deviation of about 35 mV (inferior to 1,0 kcal/mol). The application of direct protocol for a series of 65 uncorrelated molecules, whose reduction potentials vary in a range of more than 6 V, provided a model with more than 99% of predictive power. From the application of the protocol to a series of 40 molecules, for which experimental results are not available, it was possible to predict that some of these structures may have more favorable potentials to bioreduction process than the systems used in the calibration step, which makes them candidates for new drugs.
Compostos nitroaromáticos derivados da reação de Morita-Baylis-Hillman (RMBH) vêm sendo testados no tratamento de doenças extremamente negligenciadas, tais como malária, doença de Chagas e leishmanioses. Uma importante observação experimental consiste na relação entre a atividade biológica (medida pelo IC50) e o potencial de redução (estimado pelos potencias de pico anódico e catódico determinados por técnicas eletroanalíticas) destes compostos, este último diretamente ligado à redução do grupo nitro (-NO2). Por esta razão, métodos eletroquímicos têm sido utilizados com o intuito de simular a biorredução enzimática destes compostos, como reportado por Vasconcellos e colaboradores (J. Braz. Chem. Soc. 23:894, 2012). O objetivo deste trabalho foi o de desenvolver um protocolo computacional para a predição de potenciais de redução em meio aprótico para auxiliar a modelagem molecular de novos compostos com a atividade farmacológica desejada. O protocolo direto desenvolvido (para solventes apróticos) consiste na realização de cálculos DFT com os funcionais B98, PBE1PBE ou M06-2X, com o conjunto de funções de base 6-31+G(d,p) e método de solvatação C-PCM (com o método de cavitação padrão UFF/VdW). Os resultados mostram que é possível prever a variação experimental do potencial de redução com pelo menos 70 % de confiança (em uma faixa de valores experimentais de apenas 140 mV) e erros médios absolutos inferiores a 45 mV (muito inferior à incerteza experimental do potencial de redução absoluto do eletrodo de hidrogênio, que é de cerca de 400 mV) e desvio-padrão de cerca de 35 mV (inferior a 1,0 kcal/mol). A aplicação do protocolo direto a uma série de 65 moléculas não-correlacionadas, cujos potenciais de redução variam em uma faixa de mais de 6 V, forneceu um modelo com mais de 99 % de poder preditivo. A partir da aplicação do protocolo a uma série de 40 moléculas, para as quais ainda não estão disponíveis resultados experimentais, foi possível prever que algumas destas estruturas podem possuir potenciais mais favoráveis ao processo de biorredução que os estudados na etapa de calibração, o que as tornam candidatos à novos fármacos.
Sun, Hongzhe. "Biological chemistry of bismuth drugs". Thesis, Birkbeck (University of London), 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.244018.
Pełny tekst źródłaFraga, Keith Jeffrey. "Explorations into protein structure with the knob-socket model". Scholarly Commons, 2016. https://scholarlycommons.pacific.edu/uop_etds/264.
Pełny tekst źródłaCox, Kaleb Woodrow. "Synthesis and Biological Activity of Indolinones". Wright State University / OhioLINK, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=wright1421165680.
Pełny tekst źródłaViscardi, Ariel. "Avaliação da atividade antiproliferativa de extratos hidroalcoólicos de plantas em linhagens celulares humanas de câncer de mama, fígado e próstata". Universidade de São Paulo, 2018. http://www.teses.usp.br/teses/disponiveis/82/82131/tde-29082018-140818/.
Pełny tekst źródłaCancer is one of the most common diseases overworld. Studying the therapeutics of it is important to understand the biological mechanisms and targets behind this disease. Although conventional treatments show a good outcome against some types of cancer, they also currently cause undesired responses, such as molecular damage, neoplastic cell resistance and strong side effects, increasing recurrence of neoplasms, metastasis formation, and patient mortality. Therefore, the search for new alternatives is a challenge for Modern Science to improve or replace conventional treatments. In view of their antiproliferative effects medicinal plants have become the focus of many cancer studies as an alternative. The aim of the present study was to evaluate the cytotoxic and antiproliferative effect of 59 plant extracts in human cancer cell lines as breast cancer (MDA-MB-231 and MCF7), prostate cancer (PC-3 and DU 145) and liver cancer (HepG2). Initially, the extracts were screened in two different dilutions 100x and 1000x by MTT to analyze the cellular viability and cytotoxicity effects of them. To 59 extracts analyzed, 35 were effective against at least one of the tested lineages. The next step involved studying those pre-selective extracts through response curves to quantify the selectivity of these extracts for each cell lineage tested. For this stage, 31 extracts were selected. In breast cancer, for MDA-MB-231, nine extracts were selective and for MCF7 were six extracts. In prostate cancer, for PC-3, fifteen extracts were selective and for DU 145 were sixteen extracts. For liver cancer (HepG2) only seven extracts were selective. Comparing all the cancer lineages we can see a greater sensitivity of prostate cancer lineages compared to breast cancer and liver cancer in response of these tested extracts. Of all the results presented, silk cotton (Calotropis procera), chamomile (Matricaria chamomilla), winter\'s bark (Drimys winteri), bitter melon (Momordica charantia L.), corn silk (Zea mays), graviola (Annona muricata), purple trumpet tree (Tabebuia sp.), malva - folhas (Malva sylvestris) e unha de gato (Uncaria tomentosa) silk cotton (Calotropis procera), chamomile (Matricaria chamomilla), graviola (Annona muricata) and mallow-leaves (Malva sylvestris) were the most effective extracts reaching different cell types and present high selectivity indices. With the accomplishment of this work we can conclude that the natural extracts of plants presented antiproliferative activity in cancer lines and their phytochemicals can be used to study new herbal medicines. The next step, then, is to understand the molecular mechanisms where they act.
Murthi, Krishna Kumar. "Chapter 1. Spatol: Synthesis and biological chemistry of allylic diepoxides. Chapter 2. Levuglandins: Detection and biological chemistry". Case Western Reserve University School of Graduate Studies / OhioLINK, 1992. http://rave.ohiolink.edu/etdc/view?acc_num=case1059672042.
Pełny tekst źródłaCatti, Federica. "4,5-dihydropyrazoles : novel chemistry and biological activity". Thesis, St Andrews, 2007. http://hdl.handle.net/10023/351.
Pełny tekst źródłaEvans, Louise A. "Electroanalytical chemistry for biological and environmental applications". Thesis, University of Hull, 2008. http://hydra.hull.ac.uk/resources/hull:1616.
Pełny tekst źródłaDavidson, Nicola E. "Glucosinolates and isothiocyanates : chemistry and biological activity". Thesis, University of St Andrews, 1999. http://hdl.handle.net/10023/14230.
Pełny tekst źródłaBunyapaiboonsri, Taridaporn. "Dynamic combinatorial chemistry : Exploration using biological receptors". Université Louis Pasteur (Strasbourg) (1971-2008), 2003. http://www.theses.fr/2003STR13065.
Pełny tekst źródłaDynamic combinatorial chemistry (DCC) has recently been introduced as a new and attractive approach for generating and screening large numbers of library compounds in one step. Based upon the reversible interconnection between library components, the self-adjusting process give access to selection and amplification of the best binder in the presence of a target. In this thesis, two biological targets were chosen to explore the DCC approach. The reversibility of the system was achieved using disulfide interchange or reversible acyl hydrazone formation. Firstly, a dynamic library of acetylcholinesterase inhibitors was generated through disulfide exchange. The reversibility of the system was observed by NMR spectroscopy. Upon scrambling 5 initial homodisulfides in the presence of a reducing agent, a 15-compound library was produced. The library components were analyzed by ESI-MS and CE. Secondly, a dynamic combinatorial library of acetylcholinesterase inhibitors was further generated through reversible acyl hydrazone formation. The pre-equilibrated process was applied to produce a dynamic library composed of 66 possible species, from a set of 13 initial aldehyde and hydrazide building blocks. Using a technique called dynamic deconvolution, a highly potent inhibitor was identified with IC50 in the nanomolar range. Finally, the pre-equilibrated process combined with the dynamic deconvolution technique was further studied to identify HPr kinase/phosphatase inhibitors. From a set of 21 initial aldehyde and hydrazide builiding blocks, a dynamic library of 440 possible compounds was formed in one operation. A bis-cationic heterocyclic ligand was identified as a relatively potent inhibitor, displaying an IC50 in the micromolar range
Mukhitov, Nikita. "Microfluidic Methods for the Study of Biological Dynamics". Thesis, The Florida State University, 2018. http://pqdtopen.proquest.com/#viewpdf?dispub=10633959.
Pełny tekst źródłaThe work in this dissertation presents microfluidic methods developed for the study of biological dynamics. The requirements for the methods development was to create approaches with the ability to perform dynamic cell stimulation, measurement, and sample preparation. The methods presented herein were initially developed for the study of pancreatic islet biology but are expected to be translatable to other applications. In another study, a method to interface transmission electron microscopy (TEM) with microfluidics methods was developed.
The primary biological topic of interest investigated was the mechanisms of inter-islet synchronization. To test this, a microfluidic device fabricated from poly(dimethylsiloxane) (PDMS) was used to culture and stimulate pancreatic islets. Intracellular calcium ([Ca2+]i) imaging was performed with a fluorescent indicator, Fura-2-acetoxymethyl ester (Fura-2 AM). Under constant glucose (11 mM), islets demonstrated asynchronous and heterogeneous [Ca2+]i oscillations that drifted in period. However, when exposed to a glucose wave (11+/– 1 mM, 5 min period) islets were entrained to a common and consistent [Ca2+]i oscillation mode. The effect of islet entrainment on cellular function was investigated by measuring gene expression levels with microarray profiling. Calcium-dependent genes were found to be differentially expressed. Furthermore, it was speculated that islet entrained produced a beneficial effect on cell function and upkeep.
While [Ca2+]i imaging is an acceptable proxy measurement for insulin, it is not a viable reporter for other islet peptides and direct measurement is desired. Electrophoretic affinity assays can be performed on a microfluidic device in a serial manner to measure peptide release from an on-chip cell culture in near real-time. Successful analysis of electrophoretic affinity assays depends strongly on the preservation of the affinity complex during separations. Elevated separation temperatures due to Joule heating promotes complex dissociation leading to a reduction in sensitivity. To address this limitation, a method to cool a glass microfluidic chip for performing an affinity assay for insulin was achieved by a Peltier cooler localized over the separation channel. The Peltier cooler allowed for rapid stabilization of temperatures, with 21 °C the lowest temperature that was possible to use without producing detrimental thermal gradients throughout the device. Kinetic capillary electrophoresis analysis was utilized as a diagnostic of the affinity assay and indicated that optimal conditions were at the highest attainable separation voltage, 6 kV, and the lowest separation temperature, 21 °C, leading to 3.4% dissociation of the complex peak during the separation. These optimum conditions were used to generate a calibration curve and produced 1 nM limits of detection (LOD), representing a 10-fold improvement over non-thermostated conditions.
To date, most approaches for measurement of rapid changes in insulin levels rely on separations, making the assays difficult to translate to non-specialist laboratories. To enable rapid measurements of secretion dynamics from a single islet in a manner that will be more suitable for transfer to non-specialized laboratories, a microfluidic online fluorescence anisotropy immunoassay was developed. A single islet was housed inside a microfluidic chamber and stimulated with varying glucose levels from a gravity-based perfusion system. The total effluent of the islet chamber containing the islet secretions was mixed with gravity-driven solutions of insulin antibody and cyanine-5 (Cy5) labeled insulin. After mixing was complete, a linearly polarized 635 nm laser was used to excite the immunoassay mixture and the emission was split into parallel and perpendicular components for determination of anisotropy. Key factors for reproducible anisotropy measurements, including temperature homogeneity and flow rate stability were optimized, which resulted in a 4 nM LOD for insulin with < 1% RSD of anisotropy values. The capability of this system for measuring insulin secretion from single islets was shown by stimulating an islet with varying glucose levels. As the entire analysis is performed optically, this system should be readily transferable to other laboratories.
To increase the number of analytes that can be simultaneously monitored by a fluorescence anisotropy immunoassay, frequency encoding was introduced. As a demonstration of the method, simultaneous competitive immunoassays for insulin and glucagon were performed by measuring the ratio of bound and free Cy5-insulin and fluorescein isothiocyanate (FITC)-glucagon in the presence of their respective antibodies. A vertically polarized 635 nm laser was pulsed at 73 Hz and used to excite Cy5-insulin, while a vertically polarized 488 nm laser pulsed at 137 Hz excited FITC-glucagon. The total emission was split into parallel and perpendicular polarizations and collected onto separate photomultiplier tubes. The signals from each channel were demodulated using a fast Fourier transform, resolving the contributions from each fluorophore. Anisotropy calculations were carried out using the magnitude of the peaks in the frequency domain. The method produced the expected shape of the calibration curves with LOD of 0.6 and 5 nM for insulin and glucagon, respectively. (Abstract shortened by ProQuest.)
Chavan, Archana G. "Exploring the molecular architecture of proteins| Method developments in structure prediction and design". Thesis, University of the Pacific, 2014. http://pqdtopen.proquest.com/#viewpdf?dispub=3609082.
Pełny tekst źródłaProteins are molecular machines of life in the truest sense. Being the expressors of genotype, proteins have been a focus in structural biology. Since the first characterization and structure determination of protein molecule more than half a century ago1, our understanding of protein structure is improving only incrementally. While computational analysis and experimental techniques have helped scientist view the structural features of proteins, our concepts about protein folding remain at the level of simple hydrophobic interactions packing side-chain at the core of the protein. Furthermore, because the rate of genome sequencing is far more rapid than protein structure characterization, much more needs to be achieved in the field of structural biology. As a step in this direction, my dissertation research uses computational analysis and experimental techniques to elucidate the fine structural features of the tertiary packing in proteins. With these set of studies, the knowledge of the field of structural biology extends to the fine details of higher order protein structure.
Higgs, Paul G. "Biological and synthetic polymer networks". Thesis, University of Cambridge, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.306415.
Pełny tekst źródłaWisner, Daniel A. "Biophysical studies of biological phosphates /". The Ohio State University, 1987. http://rave.ohiolink.edu/etdc/view?acc_num=osu148732651171337.
Pełny tekst źródłaLunn, Jennifer H. J. D. "The Architecture of Macromolecules: Their Functions as Sensor and Drug Delivery Reagents in Biological and Non-biological Environments". University of Cincinnati / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1421921436.
Pełny tekst źródłaFerguson, Ronald Dale 1966. "Design, synthesis and biological screening of combinatorial chemical libraries". Thesis, The University of Arizona, 1996. http://hdl.handle.net/10150/278584.
Pełny tekst źródłaMalvezzi, Alberto. "Modelos de virtual Screening de inibidores da cruzaína: desenvolvimento e validação experimental". Universidade de São Paulo, 2008. http://www.teses.usp.br/teses/disponiveis/46/46135/tde-10082016-115529/.
Pełny tekst źródłaIn order to search and identify new cruzain inhibitor(s) - a cysteine-protease of Trypanosoma cruzi, the etiologic agent of Chagas disease - two virtual screening schemes(Models I and II) were proposed, validated- and applied to the ZINC database (3.294.714 compounds). The proposed virtual screening models, bearing a sequence of different physicalchemical, pharmacophore and docking filters, as well as a visual inspection filter, were built from information taken from 13 cruzain complexes and from 20 complexes of other cysteine proteases, having their structures available in PDB. In a first step, a detailed recognition of the cruzain structural features and characteristics was performed through visual inspection of the enzyme environment; followed by the analysis of GRID generated molecular interaction fields; through the identification of molecular interaction properties exposed at the enzyme cavity surface, generated by the CAVBASE program; and by molecular dynamics simulations. The virtual screening Model I, - generated from the structural characteristics recognized from 13 PDB cruzain complexes - when applied to the ZINC database selected 10 compounds. For the experimental validation ofthe model, six ofthese compounds have been acquired and were tested as cruzain inhibitors. It was observed that three of the tested compounds (ZINC02470662, ZINC02682879 and ZINC03192044, respectively) did not show any significant cruzain inhibition, up to 7 mM. Meanwhile the other three tested compounds (ZINC02663001, ZINC01936854 and ZINC03326243, respectively) showed an unspecific cruzain inhibition, suggesting that an enzyme inhibition by promiscuous mechanism occurred. This mechanism was verified by the addition of 0.1% Triton X-100 on the enzymatic assay with a concomitant loss of cruzain inhibition activity. For these compounds, the confirmation of the promiscuous mechanism was also done, observing the loss of enzyme inhibition, after a ten times increase in the cruzain concentration on the enzymatic assay. The virtual screenmg Model II - generated from the structural characteristics recognized from 13 cruzain complexes and 20 complexes of other cysteine proteases, that have been identified on a search for cavities similar to cruzain - selected 55 compounds, when applied to the ZINC database. In order to experimentally validate the model, nineteen compounds have been acquired and were tested as cruzain inhibitors. It has been observed that one compound, ZINC01794422, showed a specific cruzain inhibition (Ki = 21 µM), while the other eighteen showed no significant inhibition, up to 592 µM concentration. The promiscuous mechanism of enzymatic inhibition was not observed, since 0.1% of Triton X-100 was added in ali assays. Additionally, Model II identified two other cruzain inhibitors (ZINC04899534 and ZINC01547017). However, these compounds have not been acquired or tested, since they are known cruzain inhibitors - already described in the literature and are structurally similar to the inhibitors used in the construction of the mode!. Referring to new inhibitors found, Model II showed a hit rate of 5,3%. This value is in agreement with those found in the literature, which ranges from 1 to 50%.
Zhang, Yizhe. "Drop-Based Microfluidics for Biological Applications". Thesis, Harvard University, 2015. http://nrs.harvard.edu/urn-3:HUL.InstRepos:17467232.
Pełny tekst źródłaChemical Physics
Zimmer, John P. (John Philip). "Quantum dot-based nanomaterials for biological imaging". Thesis, Massachusetts Institute of Technology, 2006. http://hdl.handle.net/1721.1/37888.
Pełny tekst źródłaVita.
Includes bibliographical references.
Quantum dot-based fluorescent probes were synthesized and applied to biological imaging in two distinct size regimes: (1) 100-1000 nm and (2) < 10 nm in diameter. The larger diameter range was accessed by doping CdSe/ZnS or CdS/ZnS quantum dots (QDs) into shells grown on the surfaces of pre-formed sub-micron SiO2 microspheres. The smaller diameter range was accessed with two different materials: very small InAs/ZnSe QDs and CdSe/ZnS QDs, each water solubilized with small molecule ligands chosen for their ability not only to stabilize QDs in water but also to minimize the total hydrodynamic size of the QD-ligand conjugates. Indium arsenide QDs were synthesized because nanocrystals of this material can be tuned to fluoresce in the near infrared (NIR) portion of the electromagnetic spectrum, especially in the 700-900 nm window where many tissues in the body absorb and scatter minimally, while maintaining core sizes of 2 nm or less. The QD-containing microspheres were used to image tumor vasculature in living animals, and to generate maps of size-dependent extravasation. With subcutaneously delivered nAs/ZnSe QDs, multiple lymph node mapping was demonstrated in vivo for the first time with nanocrystals. When administered intravenously, < 10 nm QDs escaped from the vasculature, or were efficiently cleared from circulation by the kidney. Both of these behaviors, previously unreported, mark key milestones in the realization of an ideal fluorescent QD probe for imaging specific compartments in vivo. Also presented in this thesis is the growth of single-crystalline cobalt nanorods through the oriented attachment of spherical cobalt nanocrystal monomers.
(cont.) When administered intravenously, < 10 nm QDs escaped from the vasculature, or were efficiently cleared from circulation by the kidney. Both of these behaviors, previously unreported, mark key milestones in the realization of an ideal fluorescent QD probe for imaging specific compartments in vivo. Also presented in this thesis is the growth of single-crystalline cobalt nanorods through the oriented attachment of spherical cobalt nanocrystal monomers.
by John P. Zimmer.
Ph.D.
Garnett, Emily R. (Emily Rose). "Biological Functions of ribonuclease 1 and angiogenin". Thesis, Massachusetts Institute of Technology, 2018. http://hdl.handle.net/1721.1/118260.
Pełny tekst źródłaCataloged from PDF version of thesis.
Includes bibliographical references (pages 128-142).
Pancreatic-type ribonucleases (ptRNases) are a large family of vertebrate-specific secretory endoribonucleases. They catalyze degradation of many RNA substrates, mediating a variety of biological functions. The homology shared by ptRNases has enabled extensive biochemical characterization and evolutionary study of these enzymes, yet understanding of their biological roles is still incomplete. The goal of this thesis is to identify novel physiological functions for two ptRNases, RNase 1 and angiogenin, through characterization of murine model systems. In Chapter 1, I introduce the ptRNase superfamily and highlight evidence of biological function for RNase 1 and angiogenin that has motivated and informed our study of these enzymes. Extracellular RNA drives blood coagulation, which is preventable by administration of RNase A. In Chapter 2, I demonstrate that loss of RNase 1, a nonspecific and extracellular ptRNase similar to RNase A, results in the potentiation of blood coagulation by activation of coagulation factors in mice. Angiogenin is a ptRNase with unique angiogenic activity and suggested biological function in cancer and amyotrophic lateral sclerosis, as well as in cellular growth and quiescence. My studies demonstrate a fundamental role for angiogenin. In Chapter 3, I find that this enzyme is essential for the development of mice, with heterozygosity for angiogenin resulting in impaired vascularization of the placenta and reduced survival of offspring. Biological study of ptRNases is hampered by the high degree of conservation of the family, which engenders antibody nonspecificity. In Chapter 4, I describe efforts to generate novel specific anti-ptRNase antibodies by producing tagged ptRNases for use in an antibody phage-display workflow. Finally, Chapter 5 outlines future directions for the study of RNase 1 and angiogenin. Taken together, this thesis reveals a more complete picture of the physiological niches of these two enzymes, confirming some previously suspected roles, ascribing new ones, and providing groundwork for future characterization of the biology of these and other ptRNases.
by Emily R. Garnett.
Ph. D. in Biological Chemistry