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Articles 1 - 21 of 21
Full-Text Articles in Chemicals and Drugs
Reactive Chemistries For Protein Labeling, Degradation, And Stimuli Responsive Delivery, Myrat Kurbanov
Reactive Chemistries For Protein Labeling, Degradation, And Stimuli Responsive Delivery, Myrat Kurbanov
Doctoral Dissertations
Reactive chemistries for protein chemical modification play an instrumental role in chemical biology, proteomics, and therapeutics. Depending on the application, the selectivity of these modifications can range from precise modification of an amino acid sequence by genetic manipulation of protein expression machinery to a stochastic modification of lysine residues on the protein surface. Ligand-Directed (LD) chemistry is one of the few methods for targeted modification of endogenous proteins without genetic engineering. However, current LD strategies are limited by stringent amino acid selectivity. To bridge this gap, this thesis focuses on the development of highly reactive LD Triggerable Michael Acceptors (LD-TMAcs) …
Chemical Modification And Evaluation Of Cells Towards Use As Delivery Tools, Bishnu Prasad Joshi
Chemical Modification And Evaluation Of Cells Towards Use As Delivery Tools, Bishnu Prasad Joshi
Doctoral Dissertations
CHEMICAL MODIFICATION AND EVALUATION OF CELLS TOWARDS USE AS DELIVERY TOOLS SEPTEMBER 2023 BISHNU PRASAD JOSHI M.S., SRI SATHYA SAI INSTITUTE OF HIGHER LEARNING Ph.D., UNIVERSITY OF MASSACHUSETTS AMHERST Directed by: Professor Michelle E. Farkas Endogenous cells are being studied for use in various applications, such as next generation therapeutics and drug delivery vehicles. This is on account of their biocompatibility, amenable distribution profiles, and in many instances, recruitment to and localization of diseased tissues. Multiple cell types have been employed, including macrophages, stem cells, red blood cells, and T cells. Most examples of cell-based delivery utilize phagocytosed entities as …
Transition Metal Catalyst (Tmc)-Embedded Bioorthogonal Nanozymes For Anticancer Therapeutics, Xianzhi Zhang
Transition Metal Catalyst (Tmc)-Embedded Bioorthogonal Nanozymes For Anticancer Therapeutics, Xianzhi Zhang
Doctoral Dissertations
Bioorthogonal chemistry offers versatile strategies for monitoring and modulating biomolecules in their native environments through abiotic chemical reactions. Bioorthogonal catalysis via transition metal catalysts (TMCs) provides the controlled activation of anticancer therapeutics, which mimics the enzymatic amplifications. However, the direct use of TMCs in living systems faces challenges such as instability, poor solubility, and low biocompatibility. Engineering the structure of TMCs can partially solve the problems, but the rapid clearance of small molecules hurdles the in vivo applications. Therefore, embedding TMCs in/onto nanomaterials to obtain bioorthogonal nanozymes enhances stability, solubility, biocompatibility, and the presence of the catalysts in biological environments …
Mechanism-Driven Approaches And Novel Constructs For High Purity Rna Synthesis, Kithmie Malagodapathiranage
Mechanism-Driven Approaches And Novel Constructs For High Purity Rna Synthesis, Kithmie Malagodapathiranage
Doctoral Dissertations
RNA is poised to revolutionize medicine. By simply changing the sequence, one therapeutic can be converted into a wholly new one, with little or no change in manufacturing and formulation. While a single mRNA vaccine produced at massive scale can treat billions, the re-codability of RNA will also enable the widespread growth of personalized medicines. T7 RNA polymerase is highly efficient at the synthesis of therapeutic RNA, but is known to produce unintended RNA impurities during synthesis. These products arise from the encoded RNA rebinding the enzyme such that its 3’ end serves as a primer for extension. This leads …
Mechanisms Of Cigarette Smoke-Induced Mitochondrial Dysfunction In Striated Muscle And Aorta, Stephen T. Decker
Mechanisms Of Cigarette Smoke-Induced Mitochondrial Dysfunction In Striated Muscle And Aorta, Stephen T. Decker
Doctoral Dissertations
Cigarette Smoke is a significant cause of morbidity and mortality in the United States, accounting for over 480,000 annual deaths. Of these deaths, the most common cause of mortality in chronic smokers is cardiometabolic diseases. Likewise, a significant portion of smokers experience some form of cardiac, vascular, or metabolic dysfunction throughout their lifetime. More specifically, smoking is shown to induce mitochondrial dysfunction in these tissues, causing an increase in oxidative damage and poor overall health. However, despite the advances in the health outcomes related to cigarette smoke exposure, the mechanisms underlying mitochondrial dysfunction in striated muscle and the vasculature remain …
Frontiers In The Self-Assembly Of Charged Macromolecules, Khatcher O. Margossian
Frontiers In The Self-Assembly Of Charged Macromolecules, Khatcher O. Margossian
Doctoral Dissertations
The self-assembly of charged macromolecules forms the basis of all life on earth. From the synthesis and replication of nucleic acids, to the association of DNA to chromatin, to the targeting of RNA to various cellular compartments, to the astonishingly consistent folding of proteins, all life depends on the physics of the organization and dynamics of charged polymers. In this dissertation, I address several of the newest challenges in the assembly of these types of materials. First, I describe the exciting new physics of the complexation between polyzwitterions and polyelectrolytes. These materials open new questions and possibilities within the context …
Biomedical Applications Of Protein Films And Polymeric Nanomaterials, Sanjana Gopalakrishnan
Biomedical Applications Of Protein Films And Polymeric Nanomaterials, Sanjana Gopalakrishnan
Doctoral Dissertations
Biomaterials are widely applied for the diagnosis and treatment of numerous diseases. In addition to fulfilling specific biological functions, biomaterials must also be non-toxic, biocompatible, and sterilizable to be regarded as safe-for-use. Polymers are excellent candidates for fabricating functional biomaterials due to their wide availability and varied properties and may be natural or synthetic. Polymer precursors are fabricated into coatings, foams, scaffolds, gels, composites, and nanomaterials for several biomedical applications. This dissertation focuses on two types of polymeric biomaterials – protein-based materials and synthetic polymeric nanoparticles. Proteins are biopolymers that naturally occur with a variety of structural and functional properties. …
Controlling Myosin’S Function Via Interactions Between The Substrate And The Active Site, Mike K. Woodward
Controlling Myosin’S Function Via Interactions Between The Substrate And The Active Site, Mike K. Woodward
Doctoral Dissertations
Molecular motors, such as myosin, have evolved to transduce chemical energy from ATP into mechanical work to drive essential cellular processes, from muscle contraction to vesicular transport. Dysfunction in these motors is a root cause of many pathologies necessitating the application of intrinsic control over molecular motor function. We hypothesized that altering the myosin’s energy substrate via minor positional changes to the triphosphate portion of the molecule will allow us to control the protein and affect its in vitro function. We utilized positional isomers of a synthetic non-nucleoside triphosphate, azobenzene triphosphate, and assessed whether myosin’s force- and motion-generating capacity could …
Deciphering Protein Higher-Order Structure And Interactions Via Diethylpyrocarbonate Labeling-Mass Spectrometry, Xiao Pan
Doctoral Dissertations
The study of protein higher-order structures is vital because it is closely related to the investigation of protein folding, aggregation, interaction and protein therapeutics. Consequently, numerous biochemical and biophysical tools have been developed to study protein higher-order structures in many different situations. The combination of covalent labeling (CL) and mass spectrometry (MS) has emerged as a powerful tool for studying protein structures and offers many advantages over other traditional techniques, such as better structural coverage, high throughput, high sensitivity, and the ability to study proteins in mixtures. This dissertation focuses on diethylpyrocarbonate (DEPC) as an effective CL reagent that can …
Polymer-Based Strategies For Therapeutic Delivery To Bacterial Biofilms, Cheng-Hsuan Li
Polymer-Based Strategies For Therapeutic Delivery To Bacterial Biofilms, Cheng-Hsuan Li
Doctoral Dissertations
Bacterial infections are emerging threat to public health. Antibiotics once provided front-line treatments to bacterial infections; however, bacteria adapted to resist antibiotics through drug resistance mechanisms and biofilm formation. In this dissertation, I describe polymer-based strategies for therapeutic delivery as treatments of bacterial biofilm infections. Initially, I developed a functional polymer for delivering hydrophobic carvacrol (the primary constituent of oregano oil) to the bacterial biofilms. This strategy incorporates a cross-linking strategy to fabricate a robust yet biodegradable nanoemulsion, improving antimicrobial activity of carvacrol and overcoming antimicrobial resistance development. Next, I demonstrated that this functional polymer-based emulsion platform provides a general …
Design Of Resposive Oligomeric And Polymeric Interfaces For Sensing And Controlled Release Applications, . Manisha
Doctoral Dissertations
Nature has designed magnificent responsive systems by constructing several interacting molecular level networks for the recognition and propagation of chemical and biochemical information. One of the eminent characteristics of these systems is their capability to quickly transduce molecular scale recognition events into macroscopic or visually observable responses. Inspired by these systems present in nature, we became interested in developing artificial responsive systems with similar capabilities. This dissertation will feature four such systems that employ amphiphilic oligomers and polymers which were chosen as the scaffolds because of their high thermodynamic stability, low critical aggregation concentrations, convenient handles to incorporate functional group …
Structural Analysis Of Protein Therapeutics Using Covalent Labeling – Mass Spectrometry, Patanachai Limpikirati
Structural Analysis Of Protein Therapeutics Using Covalent Labeling – Mass Spectrometry, Patanachai Limpikirati
Doctoral Dissertations
Using mass spectrometry (MS) to obtain information about a higher order structure of protein requires that a protein’s structural properties are encoded into the mass of that protein. Covalent labeling (CL) with reagents that can irreversibly modify solvent accessible amino acid side chains is an effective way to encode structural information into the mass of a protein, as this information can be read-out in a straightforward manner using standard MS-based proteomics techniques. The differential reactivity of proteins under two or more conditions can be used to distinguish protein topologies, conformations, and/or binding sites. CL-MS methods have been effectively used for …
Engineered Nanoparticles For Site-Specific Bioorthogonal Catalysis: Imaging And Therapy, Riddha Das
Engineered Nanoparticles For Site-Specific Bioorthogonal Catalysis: Imaging And Therapy, Riddha Das
Doctoral Dissertations
Bioorthogonal catalysis offers a strategy for chemical transformations complementary to bioprocesses and has proven to be a powerful tool in biochemistry and medical sciences. Transition metal catalysts (TMCs) have emerged as a powerful tool to execute selective chemical transformations, however, lack of biocompatibility and stability limits their use in biological applications. Incorporation of TMCs into nanoparticle monolayers provides a versatile strategy for the generation of bioorthogonal nanocatalysts known as “nanozymes”. We have fabricated a family of nanozymes using gold nanoparticles (AuNPs) as scaffolds featuring diverse chemical functional groups for controlled localization of nanozymes in biological environments, providing unique strategies for …
Cytochrome P450 Monooxygenase-Mediated Lipid Metabolism In Obesity And Colon Tumorigenesis, Weicang Wang
Cytochrome P450 Monooxygenase-Mediated Lipid Metabolism In Obesity And Colon Tumorigenesis, Weicang Wang
Doctoral Dissertations
Colon cancer is a major public health issue: it is expected to have 140,250 new cases and 50,630 deaths during 2018, making colon cancer the third most common type of cancer and the second leading cause of cancer death in the United States. Obesity is associated with enhanced colonic inflammation, which is a major risk factor of colorectal cancer. Currently, more than 35% of adults and nearly 17% of children are obese. Considering the obesity and colon cancer epidemic in the United States, there is an urgent need to identify novel therapeutic targets for obesity and colon cancer. Here, using …
Protein Detection And Structural Characterization By Mass Spectrometry Using Supramolecular Assemblies And Small Molecules, Bo Zhao
Doctoral Dissertations
Mass spectrometry (MS) has played an increasingly prominent role in proteomics and structure biology because it shows superior capabilities in identification, quantification and structural characterization of proteins. To realize its full potential in protein analysis, significant progress has been made in developing innovative techniques and reagents that can couple to MS detection. This dissertation demonstrates the use of polymeric supramolecular assemblies for enhanced protein detection in complex biological mixtures by MS. An amphiphilic random co-polymer scaffold is developed to form functional supramolecular assemblies for protein/ peptide enrichment. The influences of charge density and functional group pKa on host-guest interactions …
Hormonal Contraceptive Use Among Active Duty Army Servicewomen. Trends And Implications For Risk Of Musculoskeletal Injury., Melanie K. Hosker
Hormonal Contraceptive Use Among Active Duty Army Servicewomen. Trends And Implications For Risk Of Musculoskeletal Injury., Melanie K. Hosker
Doctoral Dissertations
Almost 40% of servicewomen use hormonal contraception every year, and 60% will use a contraceptive method in their military career. Rates of contraceptive use and musculoskeletal injury are higher among servicewomen as compared to civilians. Gender differences in rates of musculoskeletal injury have led investigators to question the role of sex hormones, including contraception. Recent studies suggest that hormonal contraceptives may decreased risk of anterior cruciate ligament (ACL) injury, potentially decreasing early onset osteoarthritis (OA). We utilized the Total Army Injury and Health Outcome Database, which prospectively captured demographics, clinical and pharmacy records on over 5.6 million Army soldiers since …
Microtransplantation Of Rat Brain Neurolemma Into Xenopus Laevis Oocytes To Study The Effect Of Environmental Toxicants On Endogenous Voltage-Sensitive Ion Channels, Edwin Murenzi
Masters Theses
Microtransplantation of mammalian neurolemma into Xenopus laevis oocytes has been used to study ion channels in terms of their structure and function in the central nervous system. Use of microtransplanted neurolemma is advantageous in that tissue can be obtained from various sources, ion channels and receptors are present in their native configuration and they can be used to evaluate numerous channelpathies caused by environmental toxicants. Here we show that Xenopus oocytes injected with fragments of rat brain neurolemma successfully express functional native ion channels that are assembled in their own plasma membrane. Using a high throughput two electrode voltage clamp …
Colicins - A Sound Antimicrobial Approach For The Prevention Of Catheter-Associated Urinary Tract Infections, Sandra M. Roy
Colicins - A Sound Antimicrobial Approach For The Prevention Of Catheter-Associated Urinary Tract Infections, Sandra M. Roy
Doctoral Dissertations
The emergence and spread of antibiotic resistance has created one of the greatest challenges in fighting infectious disease. We address the rise of antibiotic-resistant pathogens by examining the evolutionary history of a class of resistance determinants, the SHV b-lactamases. We isolated the genes that encode the SHV beta-lactamases (blaSHV genes) from clinical settings and from an environment essentially devoid of antibiotic use. Our data suggests that, counter to current dogma, the use of antibiotics in the clinic is not creating these resistance genes; genes for antibiotic resistance already exist in nature and our use of antibiotics in clinical …
Mimicking The Arterial Microenvironment With Peg-Pc To Investigate The Roles Of Physicochemical Stimuli In Smc Phenotype And Behavior, William G. Herrick
Mimicking The Arterial Microenvironment With Peg-Pc To Investigate The Roles Of Physicochemical Stimuli In Smc Phenotype And Behavior, William G. Herrick
Doctoral Dissertations
The goal of this dissertation was to parse the roles of physical, mechanical and chemical cues in the phenotype plasticity of smooth muscle cells (SMCs) in atherosclerosis. We first developed and characterized a novel synthetic hydrogel with desirable traits for studying mechanotransduction in vitro. This hydrogel, PEG-PC, is a co-polymer of poly(ethylene glycol) and phosphorylcholine with an incredible range of Young’s moduli (~1 kPa - 9 MPa) that enables reproduction of nearly any tissue stiffness, exceptional optical and anti-fouling properties, and support for covalent attachment of extracellular matrix (ECM) proteins. To our knowledge, this combination of mechanical range, low …
Dried Whole Plant Artemisia Annua As A Novel Antimalarial Therapy, Mostafa A. Elfawal
Dried Whole Plant Artemisia Annua As A Novel Antimalarial Therapy, Mostafa A. Elfawal
Doctoral Dissertations
Dried Whole plant Artemisia annua as a novel antimalarial therapy September 2014 Mostafa Ahmed Elfawal Ph.D., UNIVERSITY OF MASSACHUSETTS AMHERST Directed by: Professor Stephen M. Rich Malaria is one of the worst vector-borne parasitic diseases in the developing world. The World Health Organization (WHO) estimated that 215 million cases of malaria occurred, with >655,000 deaths; half the world’s population is at risk of contracting the disease. Drugs are primary weapons for reducing malaria in human populations. Successful drugs are highly efficacious and inexpensive to manufacture synthetically. However, emergence of resistant parasites has repeatedly curtailed the lifespan of each drug that …
Ligand-Receptor Interactions For Supramolecular Disassembly With Applications In Screening And Drug Delivery, Diego Amado Torres
Ligand-Receptor Interactions For Supramolecular Disassembly With Applications In Screening And Drug Delivery, Diego Amado Torres
Doctoral Dissertations
Proteins have the capacity to bind specific sets of compounds known as ligands, these are small molecules with a recurrent theme in their molecular design that is a characteristic exploited here to (i) identify particular affinities of small molecules for proteins with the aim of using them as ligands, inhibitors, or targeting moieties in more complex systems by means of a methodology that screens small molecules based on protein affinity; (ii) decorate a self-assembling supramolecular system at different positions, making it responsive to a complementary protein with the aim of exploring differences in disassembly and sensitivity of the release of …