Biology Commons^™

Modeling The Bioactivation And Subsequent Reactivity Of Drugs, Tyler Brian Hughes

Arts & Sciences Graduate Student Theses and Dissertations

Metabolism can convert drugs to harmful reactive metabolites that conjugate to DNA and off-target proteins. Reactive metabolites are a significant driver of both drug candidate attrition and withdrawal from the market of already approved drugs. Unfortunately, reactive metabolites are difficult to study in vivo, because they are transitory and generally do not circulate. Instead, this work computationally models both metabolism and reactivity. Using deep learning, predictive models were developed for the metabolic formation of quinones and epoxides, which together account for about half of known reactive metabolites. Additionally, an accurate model of DNA and protein reactivity was constructed, which predicts …

Protein Structure-Guided Approaches To Identify Functional Mutations In Cancer, Sohini Sengupta

Arts & Sciences Graduate Student Theses and Dissertations

Distinguishing driver mutations from passenger mutations within tumor cells continues to be a major challenge in cancer genomics. Many computational tools have been developed to address this challenge; however, they rely heavily on primary protein sequence context and frequency/mutation rate. Rare driver mutations not found in many cancer patients may be missed with these traditional approaches. Additionally, the structural context of mutations on tertiary/quaternary protein structures is not taken into account and may play a more prominent role in determining phenotype and function. This dissertation first presents a novel computational tool called HotSpot3D, which identifies regions of protein structures that …

Prokaryotic Diversity And Aqueous Geochemistry Of Subsurface Environments Of The Death Valley Regional Flow System, Joshua David Sackett

UNLV Theses, Dissertations, Professional Papers, and Capstones

This dissertation summarizes over four years of effort towards the completion of a Ph.D. in Biological Sciences. The work presented in this document covers a broad range of topics, but a central unifying theme is prokaryotic life in the continental subsurface. The work presented in each chapter relied heavily on cultivation-independent methods for assessing prokaryotic communities, including prokaryotic community structure reconstruction from high-throughput sequencing of 16S rRNA gene libraries and single-cell genome analysis of novel uncultivated bacteria.

Chapter 2 examines the aqueous geochemistry and prokaryotic diversity of Devils Hole, a cavernous limnocrene and sole natural habitat for the critically endangered …

A Force Sensor That Converts Fluorescence Signal Into Force Measurement Utilizing Short Looped Dna, Golam Mustafa, Cho-Ying Chuang, William A. Roy, Mohamed M. Farhath, Nilisha Pokhrel, Yue Ma, Kazuo Nagawawa, Edwin Antony, Matthew J. Comstock, Soumitra Basu, Hamza Balci

Biological Sciences Faculty Research and Publications

A force sensor concept is presented where fluorescence signal is converted into force information via single-molecule Förster resonance energy transfer (smFRET). The basic design of the sensor is a ~100 base pair (bp) long double stranded DNA (dsDNA) that is restricted to a looped conformation by a nucleic acid secondary structure (NAS) that bridges its ends. The looped dsDNA generates a tension across the NAS and unfolds it when the tension is high enough. The FRET efficiency between donor and acceptor (D&A) fluorophores placed across the NAS reports on its folding state. Three dsDNA constructs with different lengths were bridged …

A Mouse Model Of Börjeson-Forssman-Lehmann Syndrome Reveals A Potential Link With Autism Spectrum Disorder, Cheng Cheng

Arts & Sciences Graduate Student Theses and Dissertations

ABSTRACT OF THE DISSERTATIONA Mouse Model of Börjeson-Forssman-Lehmann Syndrome reveals a potential link with Autism Spectrum DisorderByCheng ChengDoctor of Philosophy in Biology and Biomedical SciencesDevelopmental, Regenerative and Stem Cell BiologyWashington University in St. Louis, 2018Dr. Azad Bonni, ChairIntellectual disability (ID) is a prevalent neurodevelopmental disorder that affects 1% to 3% of the general population. ID is characterized by developmental deficiencies in cognitive function and adaptive behaviors. Lacking effective treatments, ID currently presents an immense burden to affected families and the economy. Therefore, there is an urgent need to elucidate the pathogenesis of ID. Human genetic studies have associated ID with …

Combining Footprinting Mass Spectrometry And Molecular Dynamics Simulation For Structural Studies In Membrane Proteins, Fengbo Zhou

Arts & Sciences Graduate Student Theses and Dissertations

Membrane proteins are essential in many cellular processes and represent ~60% of all current drug targets. Due to technical limits, membrane proteins of various types were not studied extensively in the past and the biochemistry and functionality of them remain unclear. The structural biology methodologies require pure isolated protein samples for us to resolve their structure and study their biochemical functions. For such in vitro studies, however, membrane proteins often become unstable when isolated from their native lipid bilayer environment. To overcome the challenge, I employed a novel methodology of solubilizing membrane proteins in solution without detergent. I reconstituted ferroportin, …

The Role Of Fibrillin-1 In Eye Development And Disease, Wendell Brooks Jones

Arts & Sciences Graduate Student Theses and Dissertations

The ciliary zonule of the human eye consists of a circumferential array of fibers that connect the ocular lens to the nonpigmented ciliary epithelium (NPCE) located at the inner wall of the eye. Zonular fibers consist of bundles of beaded filaments called microfibrils. Microfibrils are major structural elements of the extracellular matrix and are present in pure form in the ciliary zonule. Microfibrils are composed principally of fibrillin-1 (FBN-1); a large extracellular matrix glycoprotein. In humans, mutations in FBN1 underlie Marfan syndrome; a pleiotropic connective tissue disorder that profoundly affects the eye. Ocular manifestations include ectopia lentis (dislocated lenses), cataracts, …

Sequence Analysis Methods For The Design Of Cancer Vaccines That Target Tumor-Specific Mutant Antigens (Neoantigens), Jasreet Hundal

Arts & Sciences Graduate Student Theses and Dissertations

The human adaptive immune system is programmed to distinguish between self and non-self proteins and if trained to recognize markers unique to a cancer, it may be possible to stimulate the selective destruction of cancer cells. Therapeutic cancer vaccines aim to boost the immune system by selectively increasing the population of T cells specifically targeted to the tumor-unique antigens, thereby initiating cancer cell death.. In the past, this approach has primarily focused on targeted selection of ‘shared’ tumor antigens, found across many patients. The advent of massively parallel sequencing and specialized analytical approaches has enabled more efficient characterization of tumor-specific …

The Essential Roles Of The Chromatin Factor Gon4l In Heart Development, Terin Elise Budine

Arts & Sciences Graduate Student Theses and Dissertations

Heart development and the genetic pathways underlying it are highly conserved among vertebrates. During heart development, an embryo must induce mesoderm formation, pattern the mesoderm, specify cardiomyocytes, increase the population of cardiomyocytes through proliferation, and pattern the cardiac chambers. It is becoming increasingly clear that chromatin modifications help mediate the complex processes of heart development by providing spatiotemporal regulation of gene expression. My thesis work focuses on characterizing functions of the chromatin factor Gonad-4-like (Gon4l), encoded by the gene ugly duckling (udu), in zebrafish heart development. Previous works established a requirement for Gon4l in the formation of many mesoderm derivatives …

Genetic Basis Of Thermal Divergence In Saccharomyces Species, Xueying C. Li

Arts & Sciences Graduate Student Theses and Dissertations

The genetic architecture of phenotypic divergence is a central question in evolutionary biology. Genetic architecture is impacted by whether evolution occurs through accumulation of many small-effect or a few large-effect changes, the relative contribution of coding and cis-regulatory changes, and the prevalence of epistatic effects. Our empirical understanding of the genetic basis of evolutionary change remains incomplete, largely because reproductive barriers limit genetic analysis to those phenotypes that distinguish closely related species. In this dissertation, I use hybrid genetic analysis to examine the basis of thermal divergence between two post-zygotically isolated species, Saccharomyces cerevisiae and S. uvarum. S. cerevisiae is …

A Recombinant Virus And Reporter Mouse System To Study Chronic Chikungunya Virus Pathogenesis, Alissa Roxanne Young

Arts & Sciences Graduate Student Theses and Dissertations

Chikungunya virus (CHIKV) is an arthritogenic alphavirus that during acute disease causes fever as well as severe joint and muscle pain. Chronic joint and muscle pain persists in a significant subset of patients, yet we still have a poor understanding of what drives this chronic disease. While replicating virus has not been detected in the joints of patients with chronic arthritis or in various animal models at chronic time points, persistent viral RNA can be detected for months after acute infection.To identify the cells that could be contributing to chronic CHIKV pathogenesis, we developed recombinant viruses that express Cre recombinase …

Mechanistic Characterization Of Resistome And Microbiome Dynamics Across Diverse Microbial Habitats, Andrew John Gasparrini

Arts & Sciences Graduate Student Theses and Dissertations

Increasing antibiotic resistance in pathogens is a serious public health challenge, with over two million antibiotic resistant infections in the United States leading to at least 23,000 deaths and an estimated $55 billion in excess healthcare and societal costs. Antibiotic resistance has risen steadily in both pathogenic and benign bacteria since antibiotics’ introduction to agriculture and medicine 70 years ago. A dramatic reduction in the number of antibiotics approved for human use has accompanied this rise in antibiotic resistance, leading to the alarming prospect of a post-antibiotic era. Understanding the evolutionary origins, genetic contexts, and molecular mechanisms of antibiotic resistance …

The Role Of Apolipoprotein E In Regulating Tau Pathogenesis And Neurodegeneration In A Tauopathy Mouse Model, Yang Shi

Arts & Sciences Graduate Student Theses and Dissertations

APOE4 is the strongest genetic risk factor for late-onset Alzheimer's disease (AD). APOE4 increases brain amyloid-β (Aβ) pathology relative to other APOE isoforms. However, whether APOE independently influences tau pathology, the other pathological hallmark of AD and other tauopathies, or tau-mediated neurodegeneration, is not clear. By generating P301S tau transgenic mice on either a human APOE knock in (KI) or APOE knockout (KO) background, we show that the presence of human APOE, regardless of APOE isoforms, leads to various degrees of brain atrophy in 9-month old P301S mice, whereas APOE ablation strongly protects against neurodegeneration. In particular, P301S/E4 mice develop …

A Tail Of Two Pancancer Projects: Somatic Variant Identification And Driver Gene Discovery Using Tcga, Matthew Hawkins Bailey

Arts & Sciences Graduate Student Theses and Dissertations

The implementation of next-generation genomic sequencing has exploded over the past dozen years. Large consortia, such as The Cancer Genome Atlas (TCGA); the International Cancer Genetics Consortium (ICGC); and the Pediatric Cancer Genome Projects (PCGP), made great strides in democratizing big data for the scientific community. These data sets provide a rich resource to build tools for somatic variant discovery and exploratory analysis. Public repositories hold the answer to many novel biological and clinical revelations i.e., the discovery of complex indels, splice creating mutations, alternative super enhancer binding sites, machine learning models to predict mutation impact, and cancer subtype classification …

Neural Mechanisms Of Drosophila Circadian Rhythms, Xitong Liang

Arts & Sciences Graduate Student Theses and Dissertations

Animals show circadian rhythms in a variety of physiological functions and behaviors. In Drosophila melanogaster, behavioral rhythms are driven by circadian clock genes that are oscillating in ~150 circadian pacemaker neurons. To explain how circadian neurons encode time and regulate different behavioral rhythms, I performed 24-hour in vivo whole-brain calcium imaging using light-sheet microscopy. First, I found that different groups of circadian neurons show circadian rhythms in spontaneous neural activity with diverse phases. The neural activity phases of the M and E pacemaker groups, which are associated with the morning and evening locomotor activities respectively, occur ~4 hours before their …

Using Clay Models To Measure Seasonal Predation On Eastern Red-Backed Salamanders, Emma Perry

Honors Program Theses and Projects

One of the many gaps we have in our knowledge of salamanders is that of predation. Most studies suggest that salamanders are eaten mainly by birds and snakes, but there are still several unanswered questions: What other types of animals tend to prey on salamanders? Is there any difference in predator type during different times of the year? In order to answer these questions, I studied predation on one particular species of salamander, Plethodon cinereus (eastern red-backed salamander). Models of the two primary color morphs of P. cinereus (striped and unstriped) were created using impressionable clay to determine types and …

Miniscule Differences Between Sex Chromosomes In The Giant Genome Of A Salamander, Melissa C. Keinath, Nataliya Y. Timoshevskaya, Vladimir A. Timoshevskiy, S. Randal Voss, Jeramiah J. Smith

Biology Faculty Publications

In the Mexican axolotl (Ambystoma mexicanum), sex is determined by a single Mendelian factor, yet its sex chromosomes do not exhibit morphological differentiation typical of many vertebrate taxa that possess a single sex-determining locus. As sex chromosomes are theorized to differentiate rapidly, species with undifferentiated sex chromosomes provide the opportunity to reconstruct early events in sex chromosome evolution. Whole genome sequencing of 48 salamanders, targeted chromosome sequencing and in situ hybridization were used to identify the homomorphic sex chromosome that carries an A. mexicanum sex-determining factor and sequences that are present only on the W chromosome. Altogether, …

Regulation Of Canonical And Non-Canonical Hippo Pathway Components In Mitosis And Cancer, Seth Stauffer

Theses & Dissertations

The Hippo pathway is conserved regulator of organ size through control of proliferation, apoptosis, and stem-cell self-renewal. In addition to this important function, many of the canonical signaling members have also been shown to be regulated during mitosis. Importantly, Hippo pathway components are frequently dysregulated in cancers and have attracted attention as possible targets for improved cancer therapeutics. Further exploration of Hippo-YAP (yes-associated protein) signaling has revealed new regulators and effectors outside the canonical signaling network and has revealed a larger non-canonical network of signaling proteins in which canonical Hippo pathway components crosstalk with important cellular homeostasis and apoptosis signaling …

Employing Natural History Collections In The Aid Of Conservation: Streamlining An Approach To Model Species Distributions En Masse For The Preservation Of Biodiversity, Alice Fornari

Master's Projects and Capstones

Using species distribution models (SDMs) in Natural History Collections (NHCs) can influence how humans implement conservation changes in flora and fauna communities and ecosystems. Through the use of legacy data (old NHCs and their associated locality/collection information), data correction (background data or pseudo absences added to presence-only data), and the SDM software, Maxent (and its associated geographic information systems or GIS projected models), it has been shown that it is feasible to create a low budget protocol/setup to project the past, present and future of species population changes. This has been done in the past few decades as more collections …

Gene Flow Mediates The Role Of Sex Chromosome Meiotic Drive During Complex Speciation, Colin D. Meiklejohn, Emily L. Landeen, Kathleen E. Gordon, Thomas Rzatkiewicz, Sarah B. Kingan, Anthony J. Geneva, Jeffrey P. Vedanayagam, Christina A. Muirhead, Daniel Garrigan, Daven C. Presgraves, David L. Stern

School of Biological Sciences: Faculty Publications

During speciation, sex chromosomes often accumulate interspecific genetic incompatibilities faster than the rest of the genome. The drive theory posits that sex chromosomes are susceptible to recurrent bouts of meiotic drive and suppression, causing the evolutionary build- up of divergent cryptic sex-linked drive systems and, incidentally, genetic incompatibilities. To assess the role of drive during speciation, we combine high-resolution genetic mapping of X-linked hybrid male sterility with population genomics analyses of divergence and recent gene flow between the fruitfly species, Drosophila mauritiana and D. simulans. Our findings reveal a high density of genetic incompatibilities and a corresponding dearth of gene …

Chronoecology Of A Cave Dwelling Spider, Meta Ovalis, Rebecca Steele

3 Minute Thesis Competition

No abstract provided.

Shedding Light On The Role Of Opaque1 In Asymmetric Cell Division In Maize, Janette Yuseil Mendoza

Biology ETDs

Asymmetric cell division (ACD) is important for cell fate and tissue patterning. Many aspects of ACD in plants, however, are still unclear. The process of ACD can be broadly broken down into three phases: (1) cell polarization, (2) division plane establishment and maintenance, and (3) cell division and cytokinesis. Stomatal development in maize has proven to be a useful model for understanding the ACD mechanism. Previous studies have identified several proteins important for all three phases of ACD. Actin is important in each of the phases of ACD, suggesting an actin motor such as myosin may also be important for …

Physella Acuta, Comparative Immunology And Evolutionary Aspects Of Gastropod Immune Function, Jonathan H. Schultz

Biology ETDs

Gastropod immunobiology has benefitted from investigations focused on the planorbid snail Biomphalaria glabrata, intermediate host for the human parasite Schistosoma mansoni. Though such concentrated efforts have elucidated fascinating aspects of invertebrate immunity, they have not provided full knowledge regarding the evolution of immune function among other gastropod species. This dissertation presents the importance of making strategic choices regarding which organisms to select for comparative immunology. Herein, the choice was made to investigate the immunobiology of Physella acuta, a freshwater snail species of the Physidae, a sister family to Planorbidae to which B. glabrata belongs. Benefiting greatly from …

Effect Of Temperature Change On Synaptic Transmission At Crayfish Neuromuscular Junctions, Yuechen Zhu, Leo De Castro, Robin L. Cooper

Biology Faculty Publications

Ectothermic animals in areas characterised by seasonal changes are susceptible to extreme fluctuations in temperature. To survive through varied temperatures, ectotherms have developed unique strategies. This study focuses on synaptic transmission function at cold temperatures, as it is a vital component of ectothermic animals' survival. For determining how synaptic transmission is influenced by an acute change in temperature (20°C to 10°C within a minute) and chronic cold (10°C), the crayfish (Procambarus clarkii) neuromuscular junction (NMJ) was used as a model. To simulate chronic cold conditions, crayfish were acclimated to 15°C for 1 week and then to 10°C for …

Cryo-Em Structures Of Eastern Equine Encephalitis Virus Reveal Mechanisms Of Virus Disassembly And Antibody Neutralization, Saif Hasan, Chengqun Sun, Arthur S. Kim, Yasunori Watanabe, Chun-Liang Chen, Thomas Klose, Geeta Buda, Max Crispin, Michael S. Diamond, William B. Klimstra, Michael G. Rossmann

Department of Biological Sciences Faculty Publications

Alphaviruses are enveloped pathogens that cause arthritis and encephalitis. Here, we report a 4.4-Å cryoelectron microscopy (cryo-EM) structure of eastern equine encephalitis virus (EEEV), an alphavirus that causes fatal encephalitis in humans. Our analysis provides insights into viral entry into host cells. The envelope protein E2 showed a binding site for the cellular attachment factor heparan sulfate. The presence of a cryptic E2 glycan suggests how EEEV escapes surveillance by lectin-expressing myeloid lineage cells, which are sentinels of the immune system. A mechanism for nucleocapsid core release and disassembly upon viral entry was inferred based on pH changes and capsid …

Molecular Machinery Of Auxin Synthesis,Secretion, And Perception In The Unicellular Chlorophyte Alga Chlorella Sorokiniana Utex 1230, Maya Khasin, Rebecca E. Cahoon, Kenneth Nickerson, Wayne R. Riekhof

School of Biological Sciences: Faculty Publications

Indole-3-acetic acid is a ubiquitous small molecule found in all domains of life. It is the predominant and most active auxin in seed plants, where it coordinates a variety of complex growth and development processes. The potential origin of auxin signaling in algae remains a matter of some controversy. In order to clarify the evolutionary context of algal auxin signaling, we undertook a genomic survey to assess whether auxin acts as a signaling molecule in the emerging model chlorophyte Chlorella sorokiniana UTEX 1230. C. sorokiniana produces the auxin indole-3-acetic acid (IAA), which was present in both the cell pellet and …

Census Study Of Ducks, Swans And Geese From High-Altitude Wetlands Of Pakistan, Fakhra Nazir, Inayatullah Malik, Safdar Ali Shah

Journal of Bioresource Management

The family Anatidae consists of aquatic birds such as ducks, geese and swans of varied sizes that belong to the order Anseriformes (Carboneras, 1992). The Anatidae comprise of approximately 148 species (Johnsgard, 2010). This family is commonly found across the globe except for in Antarctica. Data on ecology and population of these water birds was taken from protected areas of Pir Lasura National Park (June-July 2009), Banjosa Game Reserve (May-June 2009), Dhirkot National Park (February 2008), Pir Chanasi National park (April-May 2010) and Tolipir National Park (April-May 2008). Only four species from the family Anatidae were found in the study …

Checklist Of Zooplanktons In Different Rivers Of Bajwat Area, Zahid Bhatti, Muhammad Asif Gondal, Asad Ghufran, Andleeb Batool

Journal of Bioresource Management

Zooplanktons are important fish and waterfowl food. Limnological studies of Marala Wetlands, a complex created by three rivers, i.e., Jammu Tawi, Chenab and Manawar Tawi, entering Bajwat area located 25 km from North of Sialkot city from state of Jammu and Kashmir, were carried out between October, 2000 to September 2001. This survey was carried out to create a checklist of zooplanktons existing in the study site which would help in future studies relating to aquatic biodiversity and ecological studies of wetlands. A minimum of 25 species of zooplanktons were present in the wetland area, which can be included into …

Accumulation And Transmission Dynamics Of A Naturally-Occurring Mtdna Deletion In Caenorhabditis Briggsae, Jennifer Anne Sullins

Dissertations and Theses

Maintaining mitochondrial genome sequence integrity is essential for preserving normal mitochondrial function. Several human diseases have been associated with heteroplasmic mitochondrial genome mutations, but few genetic systems can simultaneously represent pathogenic mitochondrial genome evolution and inheritance. The nematode Caenorhabditis briggsae is one such model. Natural C. briggsae isolates are globally-distributed and phylogenetically grouped into three distinct clades, with isolates exhibiting varying levels of a large-scale mtDNA deletion, nad5∆. Furthermore, a small subset of clade II isolates exhibits putative compensatory mutations that may reduce the risk of deletion formation and accumulation in those populations. In this thesis, the author characterizes the …

Reproductive Life History And Shell Shape Variation Of Three Species Of Elimia (Pleuroceridae) In The Lower Etowah River Basin, Ellen Winant

Master of Science in Integrative Biology Theses

Pleurocerid snail diversity in the Southeastern United States is thought to be high, but estimates of overall diversity are compromised by uncertain taxonomy. This is particularly true for the genus Elimia, where reliance on conchological characters described by early naturalists for species designation failed to recognize significant variability in shell morphology. In this study we examine three putative species of Elimia to determine if quantifiable conchological characters are associated with differences in life history characteristics. Individuals of E. modesta, E. carinocostata, and E. cariniferawere collected from nine sites in three streams in the lower Etowah River …