Life Sciences Commons^™

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

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 …

Head Stabilization And Cortical Activation In Contact Sport Athletes During Walking Under Different Visual Task Constraints, Sam Zeff

Doctoral Dissertations

Contact sport participation exposes athletes to repetitive sub-concussive head impacts, which have been shown to elicit cortical neurophysiologic, cognitive, and motor performance alterations that have the potential to disrupt visual perception. Despite the growing concern regarding sub-concussive impacts, our understanding of their implications on motor performance and risk for further injury is limited. A stable head provides a consistent perceptual platform for the visual and vestibular sensory systems, but the effects of contact sport participation on head stability and visual perception remain poorly understood. The goal of this dissertation was to understand whether contact sport participation modifies athletes’ ability to …

Role Of Fat Content On The Structure And Function Of Human Skeletal Muscle, Joseph A. Gordon Iii

Doctoral Dissertations

Muscle size does not fully explain variations in muscle strength. Fat content has been implicated in muscle weakness, though this relationship remains unclear. The relationship between fat and strength may vary between scales (e.g., cellular, organ, and organism). The goal of this dissertation was to clarify the role of fat in the structure and function of muscle using in vitro and in vivo techniques across multiple scales in adults 21-45 years old. Study 1 tested the agreement of intramyocellular lipid (IMCL) content between oil red o (ORO) and magnetic resonance spectroscopy (MRS) techniques. These measures of IMCL were also compared …

Evaluation Of Treatment Options And Investigation Of Pathogenesis Of Chytridiomycosis In North American Salamanders, Anastasia Elaine Towe

Doctoral Dissertations

Chytridiomycosis, a cutaneous fungal disease caused by two related fungi, Batrachochytrium dendrobatidis (Bd) and Batrachochytrium salamandrivorans (Bsal), is a major cause of amphibian population declines worldwide. Bd has a broad distribution, covering every continent except for Antarctica. Meanwhile, Bsal is currently restricted to Europe and Asia. Treatment options for both Bd and Bsal remain a major area of concern for wild populations. Recently, implants for long-term, parenteral antifungal drug administration have shown some promise in fungal diseases in wildlife. We investigated the safety and efficacy of an intracoelomic implant of the antifungal drug terbinafine in greater …

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 …

Bifidobacterial Metabolism Of Fucosylated Human Milk Oligosaccharides Influences Structure And Function Of The Infant Gut Microbiome, Liv R. Dedon

Doctoral Dissertations

Human milk contains human milk oligosaccharides (HMOs) that are indigestible and pass intact through the infant gastrointestinal tract where they are available for microbial metabolism. HMOs incorporate the same monosaccharide building blocks but vary structurally in primary sequence of monomeric components. Primary sequences are further diversified by degree of polymerization, branching, and secondary modifications such as fucosylation. Fucosylated HMOs (fHMOs) are highly abundant and can account for over 30% of total HMOs. Infant-colonizing Bifidobacterium longum subsp. infantis (B. infantis) possesses a specialized gene cluster conveying the ability to metabolize fHMOs. This study presents an in-depth analysis of B. …

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 …

Sphenoidal Sinuses And Spherical Harmonics: Variation And Covariation Of The Most Morphologically Diverse And Least Understood Paranasal Sinus, Katharine Grace Josephine Ryan

Doctoral Dissertations

Understanding the shape variation of the human sphenoidal sinus is important to several areas of research. This includes clinical investigation (sinus pathology and safe endoscopic endonasal surgical practice) and paranasal sinus evolution (for which there is still no consensus). Yet, the sphenoidal sinus has high morphological variation, prohibiting its quantification through traditional geometric morphometric landmarking methods. The sphenoid body, and thus also the sinus contained within, is located directly at the developmental center of the basicranium in humans, where the three cranial fossae meet at the midline, and adjacent to the three synchondroses which are the sites of cranial base …

Identification Of The Type Eleven Secretion System (T11ss) And Characterization Of T11ss-Dependent Effector Proteins, Alex S. Grossman

Doctoral Dissertations

Host-associated microbes live in dangerous environments as a result of host immune killing, nutrient provisioning, and physiological conditions. Bacteria have evolved a host of surface and secreted proteins to help interact with this host environment and overcome nutrient limitation. The studies included within this dissertation describe the identification of a novel bacterial secretion system which has evolved to transport these symbiosis mediating proteins. This system, termed the type eleven secretion system (T11SS), is present throughout the Gram negative phylum Proteobacteria, including many human pathogens such as Neisseria meningitidis, Acinetobacter baumanii, Haemophilus haemolyticus, and Proteus vulgaris. Furthermore, …

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

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

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 …

Quality Of Life For Women With Chronic Lyme Disease: A Socioeconomic Investigation, Dale M. Jones

Doctoral Dissertations

This is a mixed methods investigation of how chronic Lyme disease, including Lyme-like diseases and co-infections, affects the quality of life of women who have chronic Lyme. Both quantitative and qualitative methods were used during three phases of research: a 91-question survey instrument followed by focus group discussions and written narratives. The research considered the socioeconomic impact on quality of life in five areas: obtaining a diagnosis, relationships and personal support systems, struggles with the medical system, the ability to work, and access to treatment. There were 500 responses to the survey, of which 373 were analyzed; 11 participants in …

Cat Covid, Cmv And Chemokines, Oh My!, Trevor Hancock

Doctoral Dissertations

Cytomegalovirus (CMV) is an important pathogen infecting most humans worldwide. CMV infection within immunocompromised individuals can cause severe morbidity and potential mortality. Disease during CMV infection is due to virus dissemination and subsequent inflammation. Host immune cells lie at the intersection potentially mediating both. The CMV-encoded viral chemokine vCXCL-1 is a proposed virulence factor in mouse models increasing immune cell recruitment and disease. However, the primary immune cell mediator is undetermined. To identify targets, Chapter 2 examines CXCR2 expression (receptor for vCXCL-1) among various mouse tissues and human peripheral blood under steady-state conditions. In vitro, isoforms of HCMV’s vCXCL-1 …

Design And Development Of The Urban Population Health Observatory To Improve Disease Surveillance And Response, Whitney Brakefield

Doctoral Dissertations

Chronic and infectious diseases have a profound impact on the quality and length of life of populations that suffer from these conditions. Scientists, physicians, and health officials are seeking innovative approaches to decrease the morbidity and mortality of deadly diseases. Incorporating artificial intelligence and data science techniques across the health science domain could improve disease surveillance, intervention planning, and policymaking. In this dissertation, we describe the design and development of the Urban Population Health Observatory (UPHO), an explainable knowledge-based multimodal big data analytics platform. A common challenge for conducting multimodal big data analytics is integrating multidimensional heterogeneous data sources, which …

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 …

Oxybenzone And The Mammary Gland: Impact Of An Environmental Pollutant On Health, Disease & Ethical Decision-Making, Klara Matouskova

Doctoral Dissertations

The environmental pollutant and common sunscreen compound oxybenzone is a benzophenone type UV light chemical filter used in industrial and consumer goods. This chemical widely contaminates human tissues, non-human species, and environmental matrices. In this dissertation, oxybenzone is investigated for its effects on the mouse mammary gland in the offspring following perinatal exposure; after perinatal and prepubertal exposures as a dual environmental insult during two sensitive times of development; and in adults after exposure during pregnancy & lactation as an environmental factor potentially increasing the tissue susceptibility to mammary tumors. Chapter 1 introduces the mammary gland. Chapter 2 reviews UV …

Investigating The Developmental Impacts Of 3,3’-Dichlorobiphenyl (Pcb-11) In Zebrafish (Danio Rerio), Monika A. Roy

Doctoral Dissertations

The environmental pollutant 3,3’-dichlorobiphenyl (PCB-11) is a lower-chlorinated polychlorinated biphenyl (PCB) congener present in air and water samples. Both PCB-11 and its metabolite, 4-PCB-11-Sulfate, are detected in humans, including in pregnant women. The work conducted for this dissertation takes a developmental toxicology approach and uses zebrafish (Danio rerio) to investigate PCB-11’s potential impacts to the liver and pancreas. Chapter 1 introduces PCBs and the current knowledge gaps. Chapter 2 investigates PCB-11 interactions in short-term 4-day exposures with the Aryl hydrocarbon receptor (Ahr) pathway in both 0-20 mM individual and mixture exposures with other Ahr agonists. In Chapter 3, …

Anti-Inflammatory And Chemopreventive Activity Of Lunasin From Tofu Whey For The Management Of Gastrointestinal Diseases, Cindy Andrea Nieto Veloza

Doctoral Dissertations

Gastrointestinal diseases such as inflammatory bowel diseases (IBD) and colorectal cancer (CRC) are pathological conditions associated with chronic inflammation, characterized by intestinal damage, debilitating symptoms, and detrimental health consequences. The increased risk of CRC in IBD patients, and the adverse effects associated with current therapeutic strategies, point out the need for safer alternatives to reduce chronic inflammation in the bowel. Lunasin is a bioactive peptide naturally occurring in soybeans, with chemopreventive and anti-inflammatory properties demonstrated in several extra-intestinal diseases. However, to date, there is no evidence of the biological activity of lunasin on the gastrointestinal tract as a target site. …

Using A Cognitive Behavioral Approach In Individual Counseling With Patients Undergoing Bariatric Surgery, Nina Marie Ditommaso

Doctoral Dissertations

Morbid obesity is linked to physical and psychological well-being. Bariatric surgery has shown tremendous success with rapid weight loss in the patient population with morbid obesity. These patients experience issues with weight regain post-surgery, which can be linked to psychological and social factors. Despite this, mental health counseling is rarely offered in bariatric surgery programs. The primary investigator used a six-session Cognitive Behavioral Therapy (CBT) approach in individual counseling with patients following bariatric surgery. The primary investigator used a single case research design to treat four participants. The primary investigator measured the effectiveness of a six-session CBT treatment, assessing for …

Interactions Between Titanium Dioxide Nanoparticles (Nps) And Mucin, . Boimin

Doctoral Dissertations

Titanium dioxide nanoparticles (TiO₂ NPs) are widely used in many food, consumer, and industrial products. However, little is known about the overall effects of TiO₂ NPs on the environment or human health. In order to elucidate the fate, transformation, transport, and toxicological impact of TiO₂ NPs, a better understanding is needed of how the physicochemical properties of TiO₂ NPs (e.g. size, charge, curvature, hydrophobicity, and surface functionality) interact with their microenvironments (e.g. pH, temperature, bile acids, microbiome, enzymes, surface-active components, and biopolymers). Living organisms including humans have a natural mechanism to protect themselves from physical, biological, …

Prevalence Of Rats And Rodent Borne Pathogens Across Post-Katrina New Orleans, Bruno Marco Ghersi

Doctoral Dissertations

Disasters are happening at an increasingly higher rate and intensity a trend that is expected to continue as more humans migrate to coastal urban areas. Disasters, and as importantly, disaster recovery can affect how native and pest populations will recover. My aim was to improve understanding of disease risk by evaluating the socioecological conditions that have shaped commensal rat recovery and distribution, as well as the pathogens they carry, across New Orleans after Hurricane Katrina. I first estimated relative abundance and distribution of commensal rats from rodent trapping conducted between mid-2014 and early-2017 across 96 sites in 10 areas of …

A Review Of Horticultural Therapy And Horticultural Therapy Education In The United States: Addressing Challenges And Opportunities, Derrick R. Stowell

Doctoral Dissertations

The Horticultural Therapy (HT) profession has been formally organized in the United States since 1973. Despite the long history of horticulture being used as therapy, the profession of HT in the United States has not advanced as quickly as other allied healthcare professions. This study will review the current challenges and opportunities for HT and HT education in the United States.

A qualitative study of the status of the profession was conducted to determine what challenges and opportunities the profession of HT currently has and how the profession can meet those challenges and opportunities. The study sample was recruited from …

Examining The Physical Activity Levels Of Youth With Intellectual And Developmental Disabilities During Physical Education And Recess, Vincenzo Nocera

Doctoral Dissertations

Introduction: It is currently believed that children with intellectual and/or developmental disabilities (IDD) are less physically active than their peers. The school setting may offer a promising solution to allow children with and without IDD to engage in physical activity (PA). However, the current school-based PA levels of this population remain unclear. Therefore, the purpose of this investigation was to compare the PA levels and related context of youth with and without IDD during the total school day, physical education, and recess. Methods: A total of 13 children (n = 3 with IDD) enrolled in first- and second grade participated …

Redox Signaling In The Zebrafish Embryo And Implications For Endocrine Pancreas Morphogenesis, Archit Rastogi

Doctoral Dissertations

The glutathione (GSH) system evolved to combat oxygen toxicity in nearly all living organisms, and serves as the predominant cellular redox buffer in vertebrates. This dissertation explores the roles of GSH during embryogenesis using the zebrafish (Danio rerio). The first agnostic in vivo characterization of GSH utilization in the embryo revealed strict spatiotemporal GSH profiles in developing organ systems. Interruption of these GSH profiles by exogenous xenobiotics led to organ specific adverse developmental outcomes; pancreatic β-cells were found to be especially susceptible and developed atypical morphologies following redox active xenobiotic exposures. Pancreatic β-cells lacked expression of Nrf2a (Nuclear …

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

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

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 pK_a on host-guest interactions …