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Articles 1 - 30 of 698
Full-Text Articles in Life Sciences
On The Origins Of Genetic Novelty In Drosophila, Eric Bo Zheng
On The Origins Of Genetic Novelty In Drosophila, Eric Bo Zheng
Student Theses and Dissertations
Evolution is at its heart the study of variation: which variants survive and even thrive across generations, and why? Behind this lies the fundamental question of the origins of novelty, for there cannot be variation without a source of new variants. Understanding how novelty emerges, then, is a crucial problem of basic relevance in evolutionary biology. In this thesis, I examine two aspects regarding the origins of novelty: first, how new proteins originate and subsequently evolve; second, how chromatin accessibility maintains evolutionary lability while remaining conserved across broad sequence divergence. The study of the origins of new genes has flourished …
Replaying Life's Tape With Intraclonal Germinal Center Evolution, Tatsuya Araki
Replaying Life's Tape With Intraclonal Germinal Center Evolution, Tatsuya Araki
Student Theses and Dissertations
Because high-affinity antibodies produced by germinal centers (GCs) are critical in protecting against the ever-increasing array of pathogens, understanding how GC response allows our immune system to recognize a variety of pathogens and develop specific and effective immunity against each pathogen encounters are important. We gained insight into how GCs modulate clonal diversity in recent years, including a discovery that individual B cells clones can occasionally undergo “clonal bursts” that eliminate clonal diversity through massive proliferation. However, it remains unclear what are the factors driving such bursts, or whether GCs respond reproducibly to similar magnitude increases in affinity, mainly because …
Interrogation And Manipulation Of The Igg Fc Glycan, Aaron Keshav Gupta
Interrogation And Manipulation Of The Igg Fc Glycan, Aaron Keshav Gupta
Student Theses and Dissertations
Antibody signaling is a cardinal feature of successful adaptive immune responses. The magnitude and direction of this signaling is determined by the structure of a given antibody’s fragment crystallizable (Fc) domain, which interfaces with cells of the immune system. Often considered a constant region, the immunoglobulin G (IgG) Fc protein backbone and conserved N-linked glycan combine to introduce structural diversity in IgG molecules that in turn, triggers divergent humoral responses. These N-glycans are variably constructed, ultimately leading to families of highly related, but non-equivalent glycoproteins known as glycoforms. Despite burgeoning interest in understanding the complexities of IgG Fc glycoforms and …
Deep Molecular Characterization Of Human Cortical Cell-Types, Christina Pressl
Deep Molecular Characterization Of Human Cortical Cell-Types, Christina Pressl
Student Theses and Dissertations
Human cortical cytoarchitecture is as beautiful as it is complex. Harboring dozens of morphologically, functionally, and molecularly distinct cell-types, the neocortex is organized into cytoarchitectonically and functionally diverse regions. In concert, the diverse cell-types that are found within the diverse cortical regions build the center of all higher cognitive functions, including but not limited to sensory processing, instruction and execution of motor movements, abstract thinking, perception, as well as speech processing and production. Over the past decades, detailed knowledge on the molecular characteristics of cortical cell-types has been obtained from genetically engineered animal models. These deep insights into the molecular …
Antibody-Effector Functions In Antiviral Response, Kevin Shuolong Kao
Antibody-Effector Functions In Antiviral Response, Kevin Shuolong Kao
Student Theses and Dissertations
Antibodies are a fundamental component of the adaptive arm of the immune system. Interactions of the antibody’s fragment crystallizable (Fc) domain with Fc receptors (FcR) on effector leukocytes is essential for proper immunological function and bridges the humoral with the cellular components of immunity. While the Fc domain of immunoglobulin G (IgG) has historically been considered to be relatively constant, recent studies have demonstrated that in conjunction with IgG subclasses, the single conserved N-linked glycan present on the CH2 domain imparts a considerable amount of heterogeneity in the molecule. Given the stepwise construction of this N-glycan structures, families of highly …
Enrichment And Transcriptome Analysis Of Cd4+ T Cell Clones Harboring Intact Hiv-1 Proviruses, Georg Hartmut Johannes Weymar
Enrichment And Transcriptome Analysis Of Cd4+ T Cell Clones Harboring Intact Hiv-1 Proviruses, Georg Hartmut Johannes Weymar
Student Theses and Dissertations
More than 40 years after its onset, the Human Immunodeficiency Virus Type 1 (HIV-1) epidemic remains a major global health burden. HIV-1 is a retrovirus that infects and destroys predominantly CD4+ T cells. Since CD4+ T cells are crucial for the innate and adaptive immune system, their progressive loss in the course of HIV-1 infection leads to the Acquired Immune Deficiency Syndrome (AIDS). Antiretroviral therapy can suppress the virus in people living with HIV and prevent progression to AIDS, but does not provide a cure. Therefore, lifelong antiretroviral therapy is necessary. The barrier to HIV-1 cure is the HIV-1 reservoir, …
Inter-Organellar Nucleic Acid Communication By A Mitochondrial Trna Regulates Nuclear Transcription, Christopher Rouya
Inter-Organellar Nucleic Acid Communication By A Mitochondrial Trna Regulates Nuclear Transcription, Christopher Rouya
Student Theses and Dissertations
Balancing metabolic demands with transcriptional output requires efficient communication between mitochondria and the nucleus. However, the mitochondrial factors that mediate signals to the nucleus remain poorly defined. In eukaryotes, the mitochondrial genome encodes transfer RNAs (mito-tRNAs) that function in mitochondrial-specific translation. Here, we report the detection of multiple mito-tRNAs within the nucleus of human cells. Focused studies of one such nuclear-transported mito-tRNA-asparagine (mito-tRNA-Asn) revealed that its cognate charging enzyme (NARS2) is also present in the nucleus. Nuclear localization of mito-tRNA-Asn and NARS2 was dependent on the VDAC1 mitochondrial channel and importin-α nuclear transport factor, respectively. Mito-tRNA-Asn promoted the interaction of …
A Gain-Of-Function Role Of Apolipoprotein E2 In Melanoma Progression, Nneoma Adaku
A Gain-Of-Function Role Of Apolipoprotein E2 In Melanoma Progression, Nneoma Adaku
Student Theses and Dissertations
Genetic polymorphism of the secreted lipid transporter apolipoprotein E (APOE) plays important roles in the development of atherosclerosis and Alzheimer’s disease. More recently, three common APOE alleles have been implicated as modulators of melanoma progression and survival. Melanoma patients born with a copy of the APOE4 allele exhibit improved disease survival and responses to immunotherapy. Conversely, APOE2 allele carriers experience substantially worsened survival outcomes compared to APOE4 carriers and APOE3 homozygotes. These survival differences are partly governed by effects on the immune system, as the APOE4 genotype augments anti-tumor immunity. However, APOE variants also exert direct suppressive effects on melanoma …
Rarely Acquired Type Ii-A Crispr-Cas Spacers Mediate Anti-Viral Immunity Through The Targeting Of A Non-Canonical Pam Sequence, Claire T. Kenney
Rarely Acquired Type Ii-A Crispr-Cas Spacers Mediate Anti-Viral Immunity Through The Targeting Of A Non-Canonical Pam Sequence, Claire T. Kenney
Student Theses and Dissertations
Viruses that infect prokaryotes, called bacteriophages or phages, are thought to outnumber bacteria by a ratio of 10:1 and provide a constant threat to their hosts. In response, bacteria have evolved numerous defense mechanisms, attacking all major steps of the phage infection and replication cycle. In turn, phages have evolved their own counter defenses. One phage defense system, only recently characterized, has proved revolutionary for our understanding of prokaryote-phage dynamics and our ability to edit genomes of nearly any cell type. CRISPR-Cas (Clustered Regularly Interspaced Short Palindromic Repeats and CRISPR-associated genes) functions as an adaptive immune system by identifying and …
Anteromedial Thalamus Gates The Selection & Stabilization Of Long-Term Memories, Andrew Toader
Anteromedial Thalamus Gates The Selection & Stabilization Of Long-Term Memories, Andrew Toader
Student Theses and Dissertations
The hippocampus is necessary for the initial encoding and recent storage of memories. Under the standard model of systems consolidation, it is thought that the memory trace eventually reorganizes from the hippocampus to a distributed cortical network, with the anterior cingulate cortex playing a central role in remote memory retrieval. However, little is known about the mechanisms responsible for coordinating this process. Additionally, the intermediate memory representations in the brain and the circuits that might gate and select memories for permanent storage remain unknown. To facilitate the longitudinal tracking of memory circuits in the brain, we first developed a novel …
Mechanical Manipulation Of Eukaryotic Chromatin By Dna-Binding Proteins, Tuan Nguyen
Mechanical Manipulation Of Eukaryotic Chromatin By Dna-Binding Proteins, Tuan Nguyen
Student Theses and Dissertations
The eukaryotic genome is organized in many length scales, reflecting the intricacy associated with evolution of complex biological processes. This organization serves to exert spatiotemporal control of many DNA-transacting processes such as gene expression. Despite emerging progress, the biophysical mechanism underpinning eukaryotic genome organization remains an outstanding question in the field. In this thesis, I describe mechanistic insights on genome organization and its regulation through leveraging single-molecule biophysical techniques. In Chapter 2, I characterize the dynamic interplay of Sox2 and H1 DNA binding activity. Both families constitute large classes of chromatin and DNA binding proteins that have been historically thought …
Using Chemical Probes To Examine Cellular Activities, Megan Elizabeth Kelley
Using Chemical Probes To Examine Cellular Activities, Megan Elizabeth Kelley
Student Theses and Dissertations
Chemical probes are valuable tools for investigating rapid cellular processes, such as anaphase in cell division, by allowing for the modulation of protein activity over the course of minutes. In addition, resistance to chemical probes by mutation can provide insight into inhibitor binding interactions and may provide morphological pharmacodynamic markers that allow for the identification of drug resistance or sensitivity. Here, I present a two-part thesis in which I (i) explore the role of spastin during late anaphase and nuclear envelope reformation using our recently developed spastin inhibitor and (ii) use inhibitor resistance to identify morphological markers of drug resistance …
Life On The Edge: Insights Into The Neural And Behavioral Algorithms Of Plume Tracking, Andrew Siliciano
Life On The Edge: Insights Into The Neural And Behavioral Algorithms Of Plume Tracking, Andrew Siliciano
Student Theses and Dissertations
Animals use turbulent odor plumes as chemical beacons to navigate long distances. What are the neural and behavioral algorithms that underlie such a navigational feat? While plume navigation has been conventionally described as a simple sensory reflex, animals may instead rely on their memories of past plume encounters and current assessment of the wind direction to pursue a dynamic odor source. Differentiating between these strategies has been challenging due to the fact that plumes are invisible and spatially complex, precluding an understanding of the exact sensory experience of an animal. We have been leveraging the concise architecture of the Drosophila …
Structures, Functions, And Druggability Of The Sars-Cov-2 Replication–Transcription Complex, Brandon F. Malone
Structures, Functions, And Druggability Of The Sars-Cov-2 Replication–Transcription Complex, Brandon F. Malone
Student Theses and Dissertations
Since its emergence in late 2019, the COVID-19 pandemic continues to devastate communities worldwide. Despite the successes in both identifying new therapeutics and immunization strategies that have alleviated the toll on livelihoods, the threat of novel coronavirus (CoV) variants triggering future pandemics necessitates research into the lifecycle of the causative agent, SARS-CoV-2, and more broadly related CoVs. An essential aspect of viral propagation is the replication process in which viral enzymes orchestrate the production of nascent viral RNA genomes. CoV RNA synthesis is mediated by the RNA-dependent RNA polymerase (RdRp) which requires a coterie of viral nucleic acid-metabolizing enzymes to …
Transgenic Tools In Ants And The Representation Of Alarm Pheromones In The Ant Antennial Lobe, Taylor Eco Hart
Transgenic Tools In Ants And The Representation Of Alarm Pheromones In The Ant Antennial Lobe, Taylor Eco Hart
Student Theses and Dissertations
For decades, ants have served as major study species for ethologists, theorists, geneticists, and chemical ecologists, who have been drawn to understand how their unique features contribute to the evolution and maintenance of insect societies. These features, especially their extreme morphological plasticity, collective behavior, and complex chemical communication, together with their small sizes and relatively simple brains, make ants intriguing model systems for many topics in neurobiology. While many ant species possess brains no larger than the wellcharacterized vinegar fly, the primary olfactory processing centers (antennal lobes) contain an order of magnitude more functional units compared to the vinegar fly, …
Bioorthogonal Tethering Of Drug Fragments To Engineered G Protein-Coupled Receptors, Jordan M. Mattheisen
Bioorthogonal Tethering Of Drug Fragments To Engineered G Protein-Coupled Receptors, Jordan M. Mattheisen
Student Theses and Dissertations
G protein-coupled receptors (GPCRs) modulate diverse cellular signaling pathways and are important drug targets. Despite the availability of high-resolution structures for nearly 100 discrete GPCRs in complex with various ligands, discovering allosteric drugs that can modulate receptor signaling remains challenging. In principle, allosteric ligands have certain advantages because they bind to pockets on the receptor that do not directly impact the orthosteric site for agonist ligands, but still tune downstream signaling pathways. But identifying and validating allosteric ligands remains difficult partly due to the dynamic nature of GPCRs in native membranes. Of the more than 3700 distinct FDA-approved drugs, there …
Dissecting Host-Viral Interactons Through Focused Or Unbiased High-Throughput Genetic Approaches, Daniel Poston
Dissecting Host-Viral Interactons Through Focused Or Unbiased High-Throughput Genetic Approaches, Daniel Poston
Student Theses and Dissertations
In the world around us, viruses surround and vastly outnumber us. Indeed, there are roughly 1 sextillion—or one thousand million million million—times as many viral particles as humans on earth (1). While most of these viruses do not cause disease in humans, those that do present a grave and increasing threat to human health. Fundamental studies in host-viral interactions are thus critical to further our understanding of the parameters of viral infection and elucidate potential new treatments. Since, as obligate intracellular parasites, viruses rely on host resources at every step of the viral lifecycle, in-depth knowledge of how viruses hijack …
Multiplexed Mapping Of The Interactome Of G Protein-Coupled Receptors And Receptor Activity-Modifying Proteins, Ilana Beth Kotliar
Multiplexed Mapping Of The Interactome Of G Protein-Coupled Receptors And Receptor Activity-Modifying Proteins, Ilana Beth Kotliar
Student Theses and Dissertations
Receptor activity-modifying proteins (RAMPs) have emerged as modulators of many aspects of G protein-coupled receptor (GPCR) biology and pharmacology. The RAMP family was discovered more than two decades ago and GPCR-RAMP interactions and their functional consequences on receptor trafficking and ligand selectivity have been documented for several GPCRs, mostly belonging to the secretin family. However, the pervasiveness of GPCR-RAMP interactions and the mechanisms of their effects are not well understood. Recent bioinformatics and experimental studies suggest that GPCR-RAMP interactions might be much more widespread than previously anticipated. However, potential direct interactions among the three known RAMPs (RAMP1, RAMP2 and RAMP3) …
Sex Differences And The Evolution Of Gene Expression, Samuel Khodursky
Sex Differences And The Evolution Of Gene Expression, Samuel Khodursky
Student Theses and Dissertations
Phenotypic sex differences are essential byproducts and drivers of evolution in sexually reproducing species. Knowing how sex differences arise and how they influence evolution is central to our understanding of evolution. Although many facets of sex differences have been explored, many remain unknown. Here I focus on sex differences and the evolution of gene expression in three parts. First, I examine the evolutionary properties of genes with sex differences in mean expression levels in the Drosophila brain – a surprisingly understudied organ in this context. Second, I identify and characterize genes with sex differences in gene expression variability in human …
The Search For Regulatory Mutations In Gitelman Syndrome, Renan Eduardo Aparicio
The Search For Regulatory Mutations In Gitelman Syndrome, Renan Eduardo Aparicio
Student Theses and Dissertations
The development of whole exome and whole genome sequencing technologies has allowed geneticists to gradually uncover a wide spectrum of rare, deleterious mutations with large effect sizes, which are responsible for Mendelian diseases. Roughly 70% of human genes are single copy and have orthologs across the vertebrate lineage, suggesting that they are under purifying selection. This suggests that at least 10,000 genes will have Mendelian phenotypes when mutated but have yet to be discovered1. Exhaustive research efforts have been directed at finely categorizing the coding, and more recently noncoding, genome. The actual number of large effect noncoding mutations, and of …
Dna Methylation And Dna Methyltransferases In The Clonal Raider Ant, Ooceraea Biroi, Ivasyk Iryna
Dna Methylation And Dna Methyltransferases In The Clonal Raider Ant, Ooceraea Biroi, Ivasyk Iryna
Student Theses and Dissertations
DNA methylation and DNA methyltransferase enzymes (DNMTs) are ubiquitous and predate the origin of eukaryotes. In animals, DNA methylation primarily is carried out by DNMT1, which targets hemi – methylated DNA and maintains methylation patterns through cycles of cell replication, and DNMT3, the de novo methyltransferase. These genes are essential to mammalian development, and mutations lead to embryonic (DNMT1 and DNMT3b) or post – natal (DNMT3a) lethality. Studies of DNA methylation and DNMTs in invertebrates have been limited to non – traditional model organisms because Caenorhabditis elegans and Drosophila melanogaster lack the DNMT enzymes, and their DNA has no detectable …
Novel Optical Tools To Investigate Presenilin Control Of Neurotransmission, Ryan J. Farrell
Novel Optical Tools To Investigate Presenilin Control Of Neurotransmission, Ryan J. Farrell
Student Theses and Dissertations
Neurotransmission is a critical function for neurons that underlies the complex processes of the brain. Deficits in synaptic function often manifest in neurodegenerative diseases, motivating the study of control points of neurotransmission. The Endoplasmic Reticulum (ER) has recently been described as one such control point, as ER Ca2+ levels can regulate the magnitude of synaptic vesicle exocytosis. Here we investigate the controversial hypothesis that Presenilins are ER Ca2+ leak channels to determine if a role in ER Ca2+ leak can explain the previously described regulation of neurotransmission by Presenilins. While Presenilins are best known for their involvement in Alzheimer’s Disease, …
Integration Sites In The Persistence Of Latent Hiv-1, Amy S. Huang
Integration Sites In The Persistence Of Latent Hiv-1, Amy S. Huang
Student Theses and Dissertations
Human immunodeficiency virus (HIV-1), the pathogen that causes acquired immune deficiency syndrome (AIDS), remains one of the world’s most pressing health issues. Since the beginning of the HIV/AIDS epidemic, over 32M people have succumbed to AIDS-related illnesses. Despite remarkable advances in HIV-1 biology, neither a vaccine or cure have been achieved. While antiretroviral therapy (ART) has significantly improved disease outcomes for people with HIV-1 and reduced transmission, treatment is often accompanied by long-term side effects or stigma, or impeded by limited access to health care. Furthermore, because viral load quickly rebounds upon treatment interruption, ART is required to be a …
Modulation Of Prefrontal Cortex Activity And Sociability By Local Interneurons Expressing Corticotropi-Releasing Hormone, Michael Riad
Modulation Of Prefrontal Cortex Activity And Sociability By Local Interneurons Expressing Corticotropi-Releasing Hormone, Michael Riad
Student Theses and Dissertations
The cerebral cortex is composed primarily of two neuronal cell types: excitatory pyramidal cells and inhibitory interneurons. Their neurochemical diversity and complex organization into interconnected laminar and columnar circuits imbues the cortex with countless computational and functional possibilities. At the behavioral level, changes in the molecular profile and electrophysiological activity of cortical neurons produce noticeable changes in perception, learning and memory, motor skills, and executive cognitive functions. In the initial chapter of this thesis, I briefly cover the history and progress of cell type studies in cerebral cortex and provide frameworks for understanding and interrogating interneuron diversity. We next apply …
Biased Constitutive Activity In The Uveal Melanoma Oncogene Cysltr2 Is Unique In Cysltr2 Germline And Pan-Cancer Human Variome, Mizuho Horioka-Duplix
Biased Constitutive Activity In The Uveal Melanoma Oncogene Cysltr2 Is Unique In Cysltr2 Germline And Pan-Cancer Human Variome, Mizuho Horioka-Duplix
Student Theses and Dissertations
Uveal melanoma is the most common eye cancer in adults and is clinically and genetically distinct from skin cutaneous melanoma. In a subset of cases, the oncogenic driver is an activating mutation in CYSLTR2, the gene encoding the G protein-coupled receptor (GPCR) cysteinylleukotriene receptor 2. The mutant CYSLTR2 encodes for CysLTR2-L129Q receptor, with the substitution of Leu to Gln at position 129 (3.43). The ability of CysLTR2-L129Q to cause malignant transformation has been hypothesized to result from constitutive activity, but how the receptor could escape desensitization is unknown. In this work, we characterized the functional properties of CysLTR2-L129Q. CysLTR2 signals …
New Roles For The Integrated Stress Response In Cancer And Proteostasis, Brian Hurwitz
New Roles For The Integrated Stress Response In Cancer And Proteostasis, Brian Hurwitz
Student Theses and Dissertations
The integrated stress response (ISR) is a highly conserved pathway that senses diverse stresses and responds by limiting total protein synthesis and redirecting translation to stress response transcripts. The ISR has the potential to modify a broad range of processes in cancer, but the major cancer-relevant functions of the pathway have remained elusive due to the complex and redundant nature of the upstream kinases that sense stress and activate the pathway. To overcome this challenge, we genetically targeted the central, regulatory node of the pathway, eIF2α-serine 51, directly, in primary squamous cell carcinoma cells to generate "ISR-null" SCCs. We surprisingly …
Reproductive Resilience Of Aedes Aegypti Mosquitoes, Krithika Venkataraman
Reproductive Resilience Of Aedes Aegypti Mosquitoes, Krithika Venkataraman
Student Theses and Dissertations
Female Aedes aegypti mosquitoes impose a severe global public health burden as vectors of viruses that cause dengue, chikungunya, yellow fever, and Zika, and parasites that cause lymphatic filariasis. Under optimal environmental conditions, Aedes aegypti females have access to human hosts that provide blood proteins required for egg development, conspecific males that provide sperm required for fertilization, and freshwater in natural or manmade containers that serves as an egg-laying substrate suitable for offspring survival during larval and pupal stages. As global temperatures rise, Aedes aegypti females are faced with climate challenges like intense droughts and intermittent bouts of precipitation, which …
B Cell Receptor Signalng In Germinal Centers, Spencer T. Chen
B Cell Receptor Signalng In Germinal Centers, Spencer T. Chen
Student Theses and Dissertations
Germinal centers (GC) are sites of B cell clonal expansion, diversification, and antibody affinity selection. This process is limited and directed by T follicular helper cells that provide helper signals to B cells that endocytose, process, and present cognate antigens in proportion to receptor affinity. GCs play a crucial role in immunity by generating an evolving B cell pool that serves as the origin of protective memory B and plasma cells. Therefore, understanding how the GC reaction is controlled and how high-affinity clones are selected within the GC is fundamental to our understanding of adaptive immunity and of crucial importance …
Non-Canonical Odor Coding Ensures Robust Mosquito Attraction To Humans, Margaret Herre
Non-Canonical Odor Coding Ensures Robust Mosquito Attraction To Humans, Margaret Herre
Student Theses and Dissertations
Aedes aegypti mosquitoes spread deadly diseases, including dengue, Zika, yellow fever, and chikungunya. Only female mosquitoes bite, and they do so because they require a blood-meal for reproduction. Aedes aegypti prefer to bite human hosts, which contributes to their effectiveness as a deadly disease vector. Mosquitoes rely heavily on chemosensory cues, including carbon dioxide (CO2) emitted from breath and human body odor, which is a mixture of more than 200 different individual odorants. Although the exact odor profile of people varies considerably, Aedes aegypti are incredibly reliable in finding humans to bite, despite widespread efforts to by humans to mask …
Transcriptomic And Proteomic Studies Of Intercellular Communication Between Melanocytes And Keratinocytes In Human Skin, Gabriella Stephanne Spitz-Becker
Transcriptomic And Proteomic Studies Of Intercellular Communication Between Melanocytes And Keratinocytes In Human Skin, Gabriella Stephanne Spitz-Becker
Student Theses and Dissertations
The epidermis is a stratified epithelium composed of multiple cell types. Keratinocytes are the most prevalent cells in the epidermis and provide the barrier function of the skin. Interspersed amongst the keratinocytes in the basal layer of the epidermis are melanocytes, the pigment producing cells of the epidermis. Melanocytes produce melanin pigment which resides in melanosomes, organelles that are transferred to keratinocytes. In my thesis work, I focused on identifying downstream results of intercellular communication between melanocytes and keratinocytes for each of these cell types. I characterized the transcriptomes of human melanocytes and keratinocytes that were freshly derived from human …