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Articles 391 - 420 of 838
Full-Text Articles in Biology
Phenotyping And Preclinical Meta-Analysis Of Behavioral Outcomes From Complete Freund’S Adjuvant-Induced Inflammatory Pain In The Rodent Hind-Paw, Dominika J. Burek
Phenotyping And Preclinical Meta-Analysis Of Behavioral Outcomes From Complete Freund’S Adjuvant-Induced Inflammatory Pain In The Rodent Hind-Paw, Dominika J. Burek
Arts & Sciences Graduate Student Theses and Dissertations
Pain and opioid use disorder prevalence, diagnoses of mental health disorders, and rate of suicide have all skyrocketed over the last 30 years as a matrix of public health crises. Each reduces quality of life and installs risk of the others; together, they have burdened our country with nearly unmanageable healthcare challenges. Although the critical demand for novel and more effective therapeutics has been clear for decades, relatively little progress has been made to address pain and its comorbidities. Repeated clinical trial failures have called into question the preclinical evidence upon which they are based. Preclinical models of pain-induced negative …
The Immunoregulation Of Autoimmune Diabetes, Hao Hu
The Immunoregulation Of Autoimmune Diabetes, Hao Hu
Arts & Sciences Graduate Student Theses and Dissertations
How autoimmune diseases are regulated is a long-term research topic in the autoimmunity field. We use autoimmune diabetes as a model to study this. Autoimmune diabetes is a T cell-dependent autoimmune syndrome. The functions of T cells are regulated during their development and activation. Developmentally, T cells will undergo a stringent thymic selection: a process that self-reactive T cells are tolerized to become thymic derived Tregs or can be deleted by apoptosis based on binding affinity and avidity between the TCRs and self-peptide:MHC complexes. After T cells mature, they can also be tolerized in the periphery in many other ways, …
Copper-Mediated Regulation Of A Traditional Iron Uptake System In Uropathogenic Escherichia Coli., George Lwanga Katumba
Copper-Mediated Regulation Of A Traditional Iron Uptake System In Uropathogenic Escherichia Coli., George Lwanga Katumba
Arts & Sciences Graduate Student Theses and Dissertations
Transition metals constitute an important part of the host-pathogen interface. Iron is an essential nutrient that functions as a cofactor for numerous bacterial and host proteins, as either a ligand for oxygen in carrier proteins or an enzyme catalytic site due to its natural redox properties. As part of the innate immune response, infected hosts sequester iron from pathogens to limit their growth, a phenomenon known as nutritional immunity. On the other hand, copper ions are deployed at infection sites as a potent antimicrobial agent to kill bacteria. The ability to survive within multiple, often harsh, microenvironments is fundamental to …
The Evolutionary History Of Camelina Crantz (Brassicaceae) And Domestication Of The Biofuel Crop, C. Sativa (L.) Crantz, Jordan Brock
The Evolutionary History Of Camelina Crantz (Brassicaceae) And Domestication Of The Biofuel Crop, C. Sativa (L.) Crantz, Jordan Brock
Arts & Sciences Graduate Student Theses and Dissertations
The mustard family, Brassicaceae, is a large and economically important group of plants comprising ~350 genera and ~4060 species. Within the family, one genus, Camelina, has been neglected and nearly forgotten until recent decades. This genus comprises between 7 – 9 species, and includes Camelina sativa, an ancient oilseed crop cultivated for thousands of years in Europe. An allohexaploid, C. sativa contains high levels of omega-3 fatty acids and a seed oil composition amenable for production of aviation jet fuel. With a short generation time and ability to be cultivated on marginal soils with few inputs, C. sativa is set …
Precision Diffusion Imaging To Analyze Individual-Specific Plasticity, Nicole Andrea Seider
Precision Diffusion Imaging To Analyze Individual-Specific Plasticity, Nicole Andrea Seider
Arts & Sciences Graduate Student Theses and Dissertations
Diffusion weighted imaging (DWI) is used to non-invasively infer and characterize the structure and integrity of the brain’s white matter fibers. Individual-specific precision diffusion imaging can identify additional organizational detail important for understanding basic brain connectivity and for advancing clinical applications of DWI in neuromodulation and neurosurgical planning. The reliability of individual specific DWI and data requirements for various analytic methodologies must first be systematically assessed. The reliability and accuracy of precision diffusion imaging was evaluated as a function of data quantity and analysis method, using both simulations and highly sampled individual-specific data (Chapter 2). Parameter estimation methods that allowed …
Testing Janzen’S Physiological Barrier Hypothesis Through Experimental Evolution And Biogeographic Studies On Sister Species Pairs, Vincent John Fasanello
Testing Janzen’S Physiological Barrier Hypothesis Through Experimental Evolution And Biogeographic Studies On Sister Species Pairs, Vincent John Fasanello
Arts & Sciences Graduate Student Theses and Dissertations
Background: Janzen’s physiological barrier hypothesis suggests that variation in the effectiveness of physiological barriers to dispersal underlies global patterns of speciation and biodiversity. He noted that because a species’ physiology often evolves to match the range of conditions it has experienced in evolutionary history, it is likely that lineages that occupy habitats with wider ranges of temperature variation will tend to be better at dispersing across thermal gradients and will therefore be less likely to speciate as a result of mountain barriers. Despite decades of research into different aspects of this fundamental hypothesis, its assumptions and predictions remain largely untested.Methods: …
Chemical Damage To Mrna And Its Impact On Ribosome Quality-Control And Stress-Response Pathways In Eukaryotic Cells, Liewei Yan
Arts & Sciences Graduate Student Theses and Dissertations
Ribosome often faces defective adducts that disrupt its movement along the mRNA template. These adducts are primarily caused by chemical damage to mRNA and are highly detrimental to the decoding process on the ribosome. Hence, unless dealt with, chemical damage to RNA has been hypothesized to lead to the production of toxic protein products. Even more detrimental is the ability of damaged mRNA to drastically affect ribosome homeostasis through stalling. This in turn would lead to greatly diminished translation capacity of cells. Therefore, the inability of cells to recognize and resolve translational-stalling events is detrimental to proteostasis and could even …
The Regulation Of Plasmodium Falciparum Metabolism By Haloacid Dehalogenase Proteins, Philip Frasse
The Regulation Of Plasmodium Falciparum Metabolism By Haloacid Dehalogenase Proteins, Philip Frasse
Arts & Sciences Graduate Student Theses and Dissertations
Malaria is an enormous financial and public health burden for much of the world, infecting over 200 million and killing over 400,000 people every year. While much progress has been made combating malaria in the past few decades, those advances have slowed in recent years, partially due to the emergence of resistance to all known antimalarials used to date. To achieve the goal of eliminating malaria as a major global health problem, new therapeutics need to be developed, targeting novel categories of parasite biology. One poorly understood area of parasite biology is the regulation of various metabolic pathways. We have …
Rna Polymerase Binding Protein A (Rbpa) Regulation Of Mycobacteria Transcription And Sensitivity To Fidaxomicin, Jerome Prusa
Rna Polymerase Binding Protein A (Rbpa) Regulation Of Mycobacteria Transcription And Sensitivity To Fidaxomicin, Jerome Prusa
Arts & Sciences Graduate Student Theses and Dissertations
Mycobacterium tuberculosis is the causative agent of the disease tuberculosis (TB) and remains one of the deadliest microorganisms on the planet. The effort to eradicate M. tuberculosis would benefit from the development of novel therapeutics, which requires a detailed understanding of M. tuberculosis physiology. Like all living organisms, M. tuberculosis gene expression requires transcription. Transcription in the phylum Actinobacteria, which includes mycobacteria, is unique because it includes RNA Polymerase Binding Protein A (RbpA) that is essential in both M. tuberculosis and the nonpathogenic model organism Mycobacterium smegmatis. RbpA increases the housekeeping A and housekeeping like B interactions with the RNA …
Functional Optical Imaging Of The Developing Mouse Cortex In Health And Disease, Rachel Marlene Rahn
Functional Optical Imaging Of The Developing Mouse Cortex In Health And Disease, Rachel Marlene Rahn
Arts & Sciences Graduate Student Theses and Dissertations
Neurodevelopmental disorders (NDDs) are a heterogeneous family of disorders characterized by the presence of abnormal developmental trajectories. Functional connectivity (FC) neuroimaging provides a minimally-invasive method by which to investigate the progression of these disorders and identify potential biomarkers of disease-related dysfunction for use in therapeutics’ development. My thesis work therefore took several approaches to the question of how the functional connectome reflects developmental change as well as system-wide perturbations from environmental or genetic factors. I explored the use of optical fluorescence and intrinsic signal imaging to characterize FC and stimulation-derived responses in a NDD model of perinatal exposure to selective …
Exploring The Intrinsic And Extrinsic Factors That Regulate Breast Cancer Cell Dormancy, Qihao Ren
Exploring The Intrinsic And Extrinsic Factors That Regulate Breast Cancer Cell Dormancy, Qihao Ren
Arts & Sciences Graduate Student Theses and Dissertations
Breast cancer can recur in patients months to decades after initial diagnosis and treatment. There is mounting evidence that dormant breast disseminated tumor cells (DTCs) exist in distant organs, whose reactivation results in cancer recurrence. However, the mechanisms that control tumor cell dormancy remain poorly understood, making it difficult to predict which patients will recur and develop cancer recurrence. Unfortunately, the extreme rarity of dormant DTCs has been the major obstacle to their study. To overcome this challenge, we developed an efficient system to isolate and study rare dormant tumor cells from metastatic organs. Using this system and single cell …
Association Of Structural Variation (Sv) With Cardiometabolic Traits In Finns, Lei Chen
Association Of Structural Variation (Sv) With Cardiometabolic Traits In Finns, Lei Chen
Arts & Sciences Graduate Student Theses and Dissertations
Cardiovascular diseases (CVDs) are known to be associated with a variety of quantitative risk factors such as cholesterol, metabolites, and insulin. Understanding the genetic basis of these quantitative traits can shed light on the etiology, prevention, diagnosis, and treatment of disease. However most prior trait-mapping studies have focused on single nucleotide variants (SNVs) and Indels, with the contribution of structural variation (SV) remaining unknown. In this thesis, we present the results of a study examining genetic association between SVs and cardiometabolic traits in the Finnish population. In the first chapter, we used sensitive methods to identify and genotype 129,166 high-confidence …
Role Of 4r Tau In Astrocyte-Mediated Neuronal Toxicity And The Progression Of Neurodegenerative Disease, Lubov Alexandra Ezerskiy
Role Of 4r Tau In Astrocyte-Mediated Neuronal Toxicity And The Progression Of Neurodegenerative Disease, Lubov Alexandra Ezerskiy
Arts & Sciences Graduate Student Theses and Dissertations
The microtubule-binding protein tau is associated with neurodegenerative diseases, including Alzheimer’s disease, progressive supranuclear palsy, and a subset of frontotemporal dementias. In these tauopathies, tau becomes hyperphosphorylated and forms intracellular neurofibrillary tau tangles, contributing to synaptic dysfunction, neuronal death, and severe astrogliosis. Tau can be classified as having a 3-repeat (3R) or 4-repeat (4R) structure, resulting from alternative splicing of exon 10 within the MAPT gene. While the higher deposition of 4R tau characterizes many primary tauopathies, the role of 4R tau in neurodegenerative disease pathogenesis remains unclear. To investigate the role of tau isoforms in disease, we created tau …
Investigation Of Ifnγ-Induced Control Of Intracellular Pathogens, Michael Mcallaster
Investigation Of Ifnγ-Induced Control Of Intracellular Pathogens, Michael Mcallaster
Arts & Sciences Graduate Student Theses and Dissertations
Genes required for the lysosomal degradation pathway of autophagy play key roles in topologically distinct cellular processes with significant physiologic importance. One of the first-described of these ATG gene-dependent processes is the requirement for a subset of ATG genes in interferon-γ (IFNγ)-induced inhibition of norovirus and Toxoplasma gondii replication. In this dissertation we identified novel components that are required for or that negatively regulate this immune mechanism. Enzymes involved in the conjugation of UFM1 to target proteins including UFC1 and UBA5, negatively regulated IFNγ-induced inhibition of norovirus replication via effects of Ern1. We identified and confirmed that IFNγ-induced inhibition of …
Vestibulospinal Circuit In The Larval Zebrafish, Zhikai Liu
Vestibulospinal Circuit In The Larval Zebrafish, Zhikai Liu
Arts & Sciences Graduate Student Theses and Dissertations
The vestibular system sense gravity and self-motion to help animals maintain body balance. Although vestibular signals inform the brain of the directions and speed of our body movements, it still remains unclear how these sensory information are processed and organized in the central nervous system. My thesis aims to illustrate neural computation underlying central vestibular tuning and the topographic organization of the vestibular circuits. First I established a novel approach to perform whole-cell recording of synaptic inputs in vivo during multi-axis movements in the central vestibular neurons. This technical advance allowed me to simultaneously measure presynaptic and postsynaptic tuning, along …
Exploring Β-Cell Function And Heterogeneity In Obese Sm/J Mice, Mario Alejandro Miranda
Exploring Β-Cell Function And Heterogeneity In Obese Sm/J Mice, Mario Alejandro Miranda
Arts & Sciences Graduate Student Theses and Dissertations
Pancreatic β-cells perform glucose-stimulated insulin secretion, a process required to maintain systemic glucose homeostasis. Obesity promotes glycemic and inflammatory stress, causing β-cell death and dysfunction, resulting in diabetes. Efforts to improve β-cell function in obesity have been hampered by observations that β-cells are highly heterogeneous, varying in morphology, function, and gene expression. There is great need to understand the breadth of β-cell heterogeneity in health and obesity to improve diabetic therapies.High fat-fed SM/J mice spontaneously transition from hyperglycemic-obese to normoglycemic-obese with age, providing a unique opportunity to study β-cell adaptation. Here, we show that as they resolve hyperglycemia, obese SM/J …
Metabolic Control And Immune Barriers Of Hematopoietic Stem Cells, Hannah Pizzato
Metabolic Control And Immune Barriers Of Hematopoietic Stem Cells, Hannah Pizzato
Arts & Sciences Graduate Student Theses and Dissertations
Hematopoietic stem cells (HSCs) have the unique ability to self-renew for life, to differentiate into mature blood lineages, and to readily engraft upon intravenous transplantation. As such, they are the only types of stem cells in routine clinical use. Understanding HSCs and hematopoietic development can provide many lessons for other types of stem cells as they near clinical utility. Through bone marrow transplantation, it was discovered that cells exist with regenerative potential. This led to the search to purify these cells and to determine the function of other hematopoietic cells. By isolating and transplanting cells expressing different combinations of surface …
The Evolving Mammalian 3d Epigenome, Mayank Choudhary Nishikant Choudhary
The Evolving Mammalian 3d Epigenome, Mayank Choudhary Nishikant Choudhary
Arts & Sciences Graduate Student Theses and Dissertations
One of life’s greatest mysteries is how a 6ft long-strand of DNA (our genome) fits inside the nucleus of a cell that’s less than a tenth of the width of a strand of hair. Adding to that, this genome has functioned faithfully with high fidelity over hundreds of millions of years of evolution is simply mind boggling. Moreover, within our genomes, we find millions of copies of strange genetic hitchhikers that were once thought to be purely self-seeking and parasitic. Critical advances in technology, assay development, sequencing, and computation have brought us today at an opportune moment in space and …
Investigating The Role Of Bladder Epithelial Stem Cells In Bladder Mucosal Remodeling And Defense Against Infection, Seongmi Kim Russell
Investigating The Role Of Bladder Epithelial Stem Cells In Bladder Mucosal Remodeling And Defense Against Infection, Seongmi Kim Russell
Arts & Sciences Graduate Student Theses and Dissertations
Urinary tract infections (UTIs) can be highly recurrent, and the mechanism(s) governing recurrence susceptibility are mostly unknown. Here I demonstrate bladder epithelial (urothelial)-intrinsic trained immunity as part of a differential mucosal remodeling response to an initial UTI. I established urothelial stem cell (USC) lines from isogenic mice with different UTI histories (naïve, chronic, or self-resolving) and discovered 2880 differential genome-accessible regions, indicating differential epigenetic reprogramming dependent on infection history. Differentiation of USC lines in vitro resulted in polarized urothelial cultures that recapitulated distinct remodeling morphologies seen in vivo and exhibited altered gene expression, including genes involved in cell death pathways. …
Regulation Of Host-Microbe Interactions In Autoimmunity And Antiviral Immunity By Cytosolic Nucleic Acid Sensing And Interferon Signaling, Derek Jerome Platt
Regulation Of Host-Microbe Interactions In Autoimmunity And Antiviral Immunity By Cytosolic Nucleic Acid Sensing And Interferon Signaling, Derek Jerome Platt
Arts & Sciences Graduate Student Theses and Dissertations
Cytosolic nucleic acid sensing and interferon (IFN) signaling are central to the host immune response to microbial pathogens. However, dysregulation of immunological pathways such as these can result in devastating autoimmune disease. In order to provide a robust immune response to pathogen without causing harm to self, the host immune system must engage in a delicate balancing act, interacting with microbes and determining whether they are commensal or pathogenic. The cGAS-STING pathway is a key regulator of host-microbe interactions by cytosolic nucleic sensing and IFN signaling. Loss of function in the cGAS-STING pathway leads to increased susceptibility to pathogenic threats, …
Discovery Of Sex Differences In Response To P53 Loss And Gain-Of-Function In Glioblastoma, Nathan Cuyle Rockwell
Discovery Of Sex Differences In Response To P53 Loss And Gain-Of-Function In Glioblastoma, Nathan Cuyle Rockwell
Arts & Sciences Graduate Student Theses and Dissertations
The tumor suppressor TP53 (p53) is the most frequently mutated gene in cancer and among the most mutated genes in brain cancer. Functionally, p53 is a transcription factor that, when activated by an array of stress stimuli, regulates a complex transcriptional program that contributes to a variety of antiproliferative pathways. The loss of p53 function (LOF), either through mutation, deletion, or inhibition by alterations in the proteins that regulate p53, removes an essential barrier to the unfettered proliferation and genomic instability that drive transformation. Unlike most tumor suppressors, many p53 mutations are missense mutations that lead to stable expression of …
The Origins & Functional Effects Of Postzygotic Mutations Throughout The Human Lifespan, Nicole Briana Rockweiler
The Origins & Functional Effects Of Postzygotic Mutations Throughout The Human Lifespan, Nicole Briana Rockweiler
Arts & Sciences Graduate Student Theses and Dissertations
Mosaicism is pervasive in humans and yet we understand little of its causes and functional consequences across the lifespan. To help solve these mysteries, we developed a suite of tools, called Lachesis, to analyze postzygotic mutations (PZMs). LachesisDetect is a novel and accurate method to detect PZMs with VAFs as low as 0.04% from bulk RNA-seq samples. LachesisMap is an innovative supervised method to reconstruct postzygotic mutation phylogenies from putative prenatal PZMs. We applied Lachesis to 17,382 samples derived from 948 donors across 54 diverse tissues and cell types from the NIH’s Genotype-Tissue Expression (GTEx) project to produce the most …
Uncovering A Myc-Driven Tumor-Suppressive Program In Proliferating Lymphocytes, Elena Tonc
Uncovering A Myc-Driven Tumor-Suppressive Program In Proliferating Lymphocytes, Elena Tonc
Arts & Sciences Graduate Student Theses and Dissertations
Rapid cell proliferation is a hallmark feature of adaptive immune cells lymphocytes. It is essential for the establishment of diverse antigen receptor repertoires and amplification of antigen-specific immune responses. While such proliferation is beneficial for host protection from infections and cancers, it inevitably elevates the risk of oncogenic transformation. In developing and germinal center B lymphocytes, the risk is further increased by endogenous, genomic insults due to antigen receptor rearrangements and somatic mutations, with which expression of the proto-oncogene c-MYC is closely associated. Nonetheless, frequencies of cancers originated from B lymphocytes are relatively low, suggesting that they are protected from …
Investigating The Differentiation And Functional Maturation Of Stem Cell-Derived Β Cells, Leonardo Velazco-Cruz
Investigating The Differentiation And Functional Maturation Of Stem Cell-Derived Β Cells, Leonardo Velazco-Cruz
Arts & Sciences Graduate Student Theses and Dissertations
Diabetes mellitus is a chronic and global disease rapidly growing in prevalence. Diabetes can be characterized by the dysfunction or death of the glucose sensing insulin secreting cell. cells are located within the islet of Langerhans (islet), a tissue within the pancreas. Human islets are critical for the study and treatment of diabetes. However, they can only be obtained from cadaveric organ donors. These cadaveric islets do not proliferate and can only be maintained in vitro for short periods of time, making their availability rare and fleeting. Stem cell-derived -like cells can be generated in indefinite amounts and …
Peripheral Nerve Macrophages And Their Implications In Neuroimmunity, Peter Leon Wang
Peripheral Nerve Macrophages And Their Implications In Neuroimmunity, Peter Leon Wang
Arts & Sciences Graduate Student Theses and Dissertations
Macrophages are innate immune cells that protect against pathogens and maintain tissue integrity. In vertebrates, macrophages reside in every tissue where they perform specific functions from early development through adulthood. While macrophages provide important functions across all tissues, a major focus in recent years has been the role of resident brain macrophages, known as microglia, in neurodegeneration. As microglia have been shown to affect brain development, homeostasis, and disease, they demonstrate how immune cells critically mediate neurological health and point to the broader significance of neuroimmune interactions, or the coordinated actions of the nervous and immune systems for maintaining tissue …
Disentangling Glial Diversity In Peripheral Nerves At Single Nuclei Resolution, Aldrin Kay Yuen Yim
Disentangling Glial Diversity In Peripheral Nerves At Single Nuclei Resolution, Aldrin Kay Yuen Yim
Arts & Sciences Graduate Student Theses and Dissertations
The ability to discern gene expression at single cell level is revolutionizing our understanding of both basic biology and human health. Peripheral nerves are essential communicators between the outside world and the CNS, as evidenced by the devastating effects of diseases that disrupt them, such as ALS, Charcot-Marie-Tooth Syndrome and diabetic neuropathy. Understanding peripheral nerve dysfunction at a mechanistic level is of considerable interest due to the increasing prevalence and associated patient care costs of these disorders. Although most research of the peripheral nerve has focused on glial-axonal interactions, the important contributions of other cell types besides Schwann cells, such …
Type I Interferon Regulation Of Chikungunya Virus Pathogenesis, Marissa Christine Locke
Type I Interferon Regulation Of Chikungunya Virus Pathogenesis, Marissa Christine Locke
Arts & Sciences Graduate Student Theses and Dissertations
Chikungunya virus (CHIKV) is an arthritogenic alphavirus that acutely causes fever as well as severe joint and muscle pain. Chronic musculoskeletal pain persists in a substantial fraction of patients for months to years after the initial infection, yet we still have a poor understanding of the mechanisms responsible for chronic disease. While replicating virus has not been detected in joint-associated tissues of patients with persistent arthritis nor in various animal models at convalescent time points, viral RNA is detected months after acute infection. However, there has been a lack of tools to study the mechanisms of chronic CHIKV disease. To …
Linking Neuronal Protein Phosphatase 2a To The Dlk Stress Kinase Signaling Cascade, Margaret Hayne
Linking Neuronal Protein Phosphatase 2a To The Dlk Stress Kinase Signaling Cascade, Margaret Hayne
Arts & Sciences Graduate Student Theses and Dissertations
Neurons are constantly responding to internal and external cues as they adapt through signaling cascades and transcriptional programs. I have identified a role for the dual leucine zipper kinase (DLK) and the transcriptional program it controls in neuronal inhibition of the protein phosphatase PP2A. PP2A is an essential phosphatase, expressed in all cell types and required for survival. There is a reduction in PP2A activity in Alzheimer’s disease patient brains which is linked to increased phosphorylation of the microtubule associated protein Tau and ultimately cell death. Here, I have demonstrated that PP2A acts to restrain the DLK stress response and …
Dendritic Processing And Efficient Coding In The Retina, Jen-Chun Hsiang
Dendritic Processing And Efficient Coding In The Retina, Jen-Chun Hsiang
Arts & Sciences Graduate Student Theses and Dissertations
In early sensory systems, a copious amount of information needs to be simultaneously processed to extract salient stimulus features and compress representations for efficient transmission. My thesis addresses how the retina processes visual information to detect specific motion patterns and efficiently encode our environment for perception. Around 40 retinal ganglion cell (RGC) types in mammals send specific feature representations through their axons from the retina to the brain. RGCs are the sole source of visual information to the brain. Recent studies suggest that amacrine cells (ACs) generate feature-selective responses of RGCs, but little is known about their neuronal computations. We …
Computational Approaches For Screening Drugs For Bioactivation, Reactive Metabolite Formation, And Toxicity, Noah Flynn
Computational Approaches For Screening Drugs For Bioactivation, Reactive Metabolite Formation, And Toxicity, Noah Flynn
Arts & Sciences Graduate Student Theses and Dissertations
Cytochrome P450 enzymes aid in the elimination of a preponderance of small molecule drugs, but can generate reactive metabolites that may adversely conjugate to protein and DNA, in a process known as bioactivation, and prompt adverse reaction, drug candidate attrition, or market withdrawal. Experimental assays are low-throughput and expensive to perform, so they are often reserved until later stages of the drug development pipeline when the drug candidate pools are already significantly narrowed. Reactive metabolites also elude in vivo detection, as they are transitory and generally do not circulate. In contrast, computational methods are high-throughput and cheap to screen millions …