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Full-Text Articles in Life Sciences
A High-Throughput Approach To Uncover Novel Roles Of Apobec2, A Functional Orphan Of The Aid/Apobec Family, Linda Molla
A High-Throughput Approach To Uncover Novel Roles Of Apobec2, A Functional Orphan Of The Aid/Apobec Family, Linda Molla
Student Theses and Dissertations
APOBEC2 is a member of the AID/APOBEC cytidine deaminase family of proteins. Unlike most of AID/APOBEC, however, APOBEC2’s function remains elusive. Previous research has implicated APOBEC2 in diverse organisms and cellular processes such as muscle biology (in Mus musculus), regeneration (in Danio rerio), and development (in Xenopus laevis). APOBEC2 has also been implicated in cancer. However the enzymatic activity, substrate or physiological target(s) of APOBEC2 are unknown. For this thesis, I have combined Next Generation Sequencing (NGS) techniques with state-of-the-art molecular biology to determine the physiological targets of APOBEC2. Using a cell culture muscle differentiation system, and RNA sequencing (RNA-Seq) …
Dopaminergic Modulation Shapes Sensorimotor Processing In The Drosophila Mushroom Body, Raphael Cohn
Dopaminergic Modulation Shapes Sensorimotor Processing In The Drosophila Mushroom Body, Raphael Cohn
Student Theses and Dissertations
To survive in a complex and dynamic environment, animals must adapt their behavior based on their current needs and prior experiences. This flexibility is often mediated by neuromodulation within neural circuits that link sensory representations to alternative behavioral responses depending on contextual cues and learned associations. In Drosophila, the mushroom body is a prominent neural structure essential for olfactory learning. Dopaminergic neurons convey salient information about reward and punishment to the mushroom body in order to adjust synaptic connectivity between Kenyon cells, the neurons representing olfactory stimuli, and the mushroom body output neurons that ultimately influence behavior. However, we still …
Single Cell Analysis Of The Hiv-1 Latent Reservoir, Lillian Brumer Cohn
Single Cell Analysis Of The Hiv-1 Latent Reservoir, Lillian Brumer Cohn
Student Theses and Dissertations
Human immunodeficiency virus type 1 (HIV-1), the virus that causes acquired immune deficiency syndrome (AIDS), is one of the world’s most serious health and development challenges. Worldwide there are approximately 36.7 million people living with HIV, and tens of millions have died of AIDS-related causes since the beginning of the epidemic. Treatment of HIV-1 infection with combinations of antiretroviral drugs has significantly reduced the death rate and improved the quality of life of HIV-1 infected individuals. Despite over thirty years of HIV-1 research, however, both a cure and a vaccine remain elusive. Complete eradication of HIV-1 by antiretroviral drugs is …
Characterizing Human Transfer Rnas By Hydro-Trnaseq And Par-Clip, Tasos Gogakos
Characterizing Human Transfer Rnas By Hydro-Trnaseq And Par-Clip, Tasos Gogakos
Student Theses and Dissertations
The participation of tRNAs in fundamental aspects of biology and disease necessitates an accurate, experimentally confirmed annotation of tRNA genes, and curation of precursor and mature tRNA sequences. This has been challenging, mainly because RNA secondary structure and nucleotide modifications, together with tRNA gene multiplicity, complicate sequencing and read mapping efforts. To address these issues, I developed hydro-tRNAseq, a method based on partial alkaline RNA hydrolysis that generates fragments amenable for sequencing. To identify transcribed tRNA genes, I further complemented this approach with Photoactivatable Crosslinking and Immunoprecipitation (PAR-CLIP) of SSB/La, a conserved protein involved in pre-tRNA processing. My results show …
Control Of Salmonella Virulence By Microbiota-Derived And Dietary Fatty Acids, Zhenrun J. Zhang
Control Of Salmonella Virulence By Microbiota-Derived And Dietary Fatty Acids, Zhenrun J. Zhang
Student Theses and Dissertations
The intestinal microbiota plays critical roles in human physiology and diseases. While recent research has revealed many mechanisms by which gut microbiota influences host immunity to defend against invading pathogens, how microbiota directly antagonizes pathogen virulence is less studied. In particular, gut microbiota produces large amounts and varieties of small molecules that may impact both host immunity and pathogen virulence. In this thesis, I describe how fatty acids, derived from both gut microbiota and diet, contribute to attenuation of virulence of enteric pathogen Salmonella. In Chapter 1, I review how dietary and microbiota metabolites affect different aspects of host-microbe interactions. …
Investigating Genetic (In)Compatibility Between Temperate Phages And Crispr-Cas Systems In Staphylococcus Aureus, Gregory W. Goldberg
Investigating Genetic (In)Compatibility Between Temperate Phages And Crispr-Cas Systems In Staphylococcus Aureus, Gregory W. Goldberg
Student Theses and Dissertations
Prokaryotic organisms employ various mechanisms for defending against parasitism by viruses and other mobile genetic elements. One form of defense comprises the adaptive immune systems derived from clustered, regularly interspaced, short palindromic repeat (CRISPR) loci and CRISPR-associated (cas) genes. CRISPR-Cas immune systems enable the acquisition of heritable resistance to specific mobile genetic elements on the basis of nucleic acid sequence recognition, but do not necessarily discriminate between target elements which are burdensome and those which are beneficial. My thesis is concerned with the consequences of CRISPR-Cas immunity directed at a particular breed of bacterial DNA viruses, known as temperate phages, …
Targeting The Cd4 Binding Site Of Hiv, Lotta Von Boehmer
Targeting The Cd4 Binding Site Of Hiv, Lotta Von Boehmer
Student Theses and Dissertations
The immunologic obstacles to develop a broadly neutralizing antibody (bNAb) against HIV by vaccine mandate for methodical testing in order to understand and direct the immune response. A mouse model with the predicted human heavy chain variable domain of a bNAb precursor or mature version introduced into the mouse heavy chain immunoglobulin locus proved to be very useful. The immunoglobulin heavy-chain of the predicted germline (GLVH) or mature mutated (MuVH) version of 3BNC60 was knocked into the JH4 locus in mice. 3BNC60 is a bNAb that targets the CD4 binding site (CD4bs) of HIV-11,2 and belongs to the IgHV1-2 …
Netrin Guides Spinal Commissural Axons To The Midline At Long Range Through The Receptors Dcc And Neogenin, Sze Sing Shaun Teo
Netrin Guides Spinal Commissural Axons To The Midline At Long Range Through The Receptors Dcc And Neogenin, Sze Sing Shaun Teo
Student Theses and Dissertations
During neurodevelopment, commissural axons are guided to the ventral midline in a remarkably precise and stereotyped way. Netrin, a secreted laminin-related protein, provides the major attractive cue for midline guidance. It is thought to act at long-range, functioning either in solution (chemotaxis) or bound to surfaces (haptotaxis). A gradient of Netrin-1 along the dorsal-ventral axis of the spinal cord is thought to attract commissural axons to the midline, with the floor plate being a major source of diffusible Netrin. However, this view has recently been challenged. To address this controversy and determine what role, if any, floor plate-derived Netrin-1 plays …
Characterization And Reconstitution Of S-Palmitoylated Ifitm3 Antiviral Activity, Avital Percher
Characterization And Reconstitution Of S-Palmitoylated Ifitm3 Antiviral Activity, Avital Percher
Student Theses and Dissertations
To rapidly detect early stage infections the innate immune system maintains an assortment of pathogen recognition mechanisms interspersed throughout both the extracellular and intracellular environments. These sensors recognize key components of viral, bacterial and fungal pathogens, and stimulate an inflammatory response which leads to the expression of an extensive network of host defense proteins. One such canonical network is regulated by type I interferon. This pathway responds to viral infections by upregulating hundreds of interferon stimulated genes (ISG) critical for host immunity. One of the more pivotal proteins for viral control is interferon-induced transmembrane protein 3 (IFITM3). IFITM3 is a …
Robustness Enhancement Of Sensory Transduction By Hair Bundles, Andrew Robert Milewski
Robustness Enhancement Of Sensory Transduction By Hair Bundles, Andrew Robert Milewski
Student Theses and Dissertations
How do biological systems ensure robustness of function despite developmental and environmental variation? Our sense of hearing boasts exquisite sensitivity, precise frequency discrimination, and a broad dynamic range. Experiments and modeling imply, however, that the auditory system achieves this performance for only a narrow range of parameter values. Although the operation of some systems appears to require precise control over parameter values, I describe how the function of the ear might instead be made robust to parameter perturbation. The sensory hair cells of the cochlea are physiologically vulnerable: small changes in parameter values could compromise hair cells' ability to detect …
Cell Type Specific Roles Of Serotonin Receptor 4 In The Hippocampus And Neocortex In Emotion And Cognition, Remzi Karayol
Cell Type Specific Roles Of Serotonin Receptor 4 In The Hippocampus And Neocortex In Emotion And Cognition, Remzi Karayol
Student Theses and Dissertations
Anxiety and mood disorders are the most prevalent classes of mental disorders. However, current treatments for these debilitating diseases are limited due to their delayed onset of action and numerous side effects, emphasizing the need for faster acting and more efficacious therapies. Preclinical studies indicate a critical role for Serotonin Receptor 4 (5-HT4R, product of the Htr4 gene) in this direction as drugs that activate this receptor show fast-acting antidepressant-like properties. Unfortunately, 5-HT4R is widely expressed in the periphery, limiting its use as a direct therapeutic target due to various side effects. Understanding the cell type …
Cell Cycle Control By Cyclin-Cdks In Chlamydomonas Reinhardtii, Kenneth C. Atkins
Cell Cycle Control By Cyclin-Cdks In Chlamydomonas Reinhardtii, Kenneth C. Atkins
Student Theses and Dissertations
The cell cycle consists of a series of events, including replication and segregation of the genome, that occurs in order to ensure successful reproduction of cells. In fungi and animals, this process is carefully regulated by a set of protein complexes with alternating, oscillating activity. A well established model has been developed for animals and fungi in which the activities of various cyclin-dependent kinases (CDKs) and the anaphase promoting complex (APC) drive the events of the cell cycle at the appropriate time and in the appropriate order. While this model has been extremely useful for understanding cell division in these …
Components Required For The Death And Degradation Of The Linker Cell In C. Elegans, Lena Marlise Kutscher
Components Required For The Death And Degradation Of The Linker Cell In C. Elegans, Lena Marlise Kutscher
Student Theses and Dissertations
Programmed cell death (PCD) is an important process in the development of multicellular organisms. Apoptosis, a form of PCD characterized morphologically by chromatin condensation, membrane blebbing, and cytoplasm compaction, and molecularly by the activation of caspase proteases, has been extensively investigated. Studies in C. elegans, Drosophila, mice, and the developing chick have revealed, however, that developmental PCD also occurs through other mechanisms, morphologically and molecularly distinct from apoptosis. One prominent cell death program, linker cell-type death (LCD), is morphologically conserved, and independent of the key genes that drive apoptosis. Instead, LCD functions, in part, through the stressrelated protein HSF-1, and …
Biological Consequences Of Atypical Phage Conversion In Gram-Positive Pathogens, Douglas R. Deutsch
Biological Consequences Of Atypical Phage Conversion In Gram-Positive Pathogens, Douglas R. Deutsch
Student Theses and Dissertations
Temperate bacteriophage have a complex, dynamic relationship with bacteria: parasitizing in the lytic cycle, but often increasing bacteria’s fitness as lysogens. The phage-bacteria relationship is vast and has evolved over more than an estimated three billion years, and there are likely many uncharacterized, intricate events between host and phage with important impacts on bacterial pathogenesis. This Thesis explores some of these lesser-studied phage-bacteria interactions, describing atypical mechanisms (“conversion events”) by which phage shape the populations of Bacillus anthracis and Staphylococcus aureus, driving their increased diversity and likely impacting their natural behaviors. In B. anthracis, phage contributions to virulence are largely …
Identification And Characterization Of Hells-Cdca7, A Nucleosome Remodeling Complex Required For Mitotic Chromosome Structure, Christopher Jenness
Identification And Characterization Of Hells-Cdca7, A Nucleosome Remodeling Complex Required For Mitotic Chromosome Structure, Christopher Jenness
Student Theses and Dissertations
The major components of mitotic chromosomes including histones, topoisomerase II and condensin are known to compact and shape the chromatin into rod-like chromatids. However, a complete picture of the proteins involved in shaping mitotic chromatin is unsettled. Here, I perform mass spectrometry on chromatin isolated from Xenopus egg extracts. By comparing interphase and M phase, I reveal how the chromatin proteome is affected by the cell cycle. I find that although topoisomerase II associates with chromatin throughout the cell cycle, its catalytic activity is greatly enhanced in mitosis where it can act on nucleosomal substrates. In contrast, condensin is specifically …
Daple Orients And Patterns Sensory Hair Bundles In The Inner Ear, Kimberly Siletti
Daple Orients And Patterns Sensory Hair Bundles In The Inner Ear, Kimberly Siletti
Student Theses and Dissertations
The planar orientation of mammalian cells necessitates the integration of diverse pathways. In the inner ear, at least two systems regulate the planar polarity of the hair bundle. The core planar cell polarity (PCP) proteins coordinate the orientations of hair cells across the epithelial plane. The cell-intrinsic patterning of each hair bundle is implemented independently by a G-protein complex comprising the alpha subunit of heterotrimeric G-protein (Gαi) and Leu-Gly-Asn repeat-enriched protein (LGN). Classically known for orienting the mitotic spindle, these proteins form an apical blueprint for hair-bundle development. Although the primary cilium also participates in each of these pathways, the …
Modeling Alzheimer's Disease In Induced Pluripotent Stem Cells, Andrew Gregg
Modeling Alzheimer's Disease In Induced Pluripotent Stem Cells, Andrew Gregg
Student Theses and Dissertations
Alzheimer’s disease (AD) is the most common cause of dementia worldwide, and is now the 5th leading cause of death in the United States. The pathologic hallmarks of AD include the deposition of extracellular plaques of aggregated amyloid-β (Aβ) and intracellular neurofibrillary tangles of tau aggregates (NFTs). Autosomal dominant inheritance of AD has been attributed to genetic mutations in three key genes: amyloid precursor protein (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN-2). Together, these pathologic findings and genetics provided the framework for the amyloid cascade hypothesis, which states that Aβ deposition is a necessary, early event that is upstream of the …
The Role Of Neuronal Pentraxin 1 In Promoting Pancreatic Cancer Progression, Yuehyi Gloria Wu
The Role Of Neuronal Pentraxin 1 In Promoting Pancreatic Cancer Progression, Yuehyi Gloria Wu
Student Theses and Dissertations
Pancreatic cancer is a deadly malignancy because it is usually diagnosed at an advanced stage and does not respond to the majority of treatments. More than 80% of patients present with advanced stage disease at the time of diagnosis and metastatic pancreatic cancer has a median survival of eight to eleven months under current standard of care. In the United States, pancreatic cancer is the fourth leading cause of cancer death. Efforts in using targeted agents to treat pancreatic cancer have mostly been fruitless. The dismal survival outcome of this disease and lack of success in clinical trials indicate the …
The Characterization Of A Novel Complex Implicated In The Initiation Of Apoptosis, Thomas Hsiao
The Characterization Of A Novel Complex Implicated In The Initiation Of Apoptosis, Thomas Hsiao
Student Theses and Dissertations
Apoptosis, which is one of many different types of programmed cell death, is widely utilized as a mechanism to eliminate unwanted cells. The ability of cells to undergo apoptosis is required not only for development in many organisms, but also to maintain proper homeostasis; too little apoptosis can result in cancer whereas too much can lead to degenerative diseases. Apoptosis has been well studied at events that take place at or downstream of the mitochondria; these steps are rigorous and predictable, making them easy to study. However, little is known about early, decision-making events that occur upstream of the mitochondria. …
Chemical Approaches To Dynein Inhibition, Jonathan Baruch Steinman
Chemical Approaches To Dynein Inhibition, Jonathan Baruch Steinman
Student Theses and Dissertations
Cells utilize energy to maintain order within the cytoplasm. Motor proteins are the enzymes that convert the chemical energy contained in adenosine triphosphate (ATP) into directed movement along polarized filaments of actin and tubulin within cells. Dyneins are the primary enzymes that drive motion toward the stable “minus ends” of tubulin-containing filaments known as microtubules. This protein family is divided into two sub-families. Axonemal dyneins drive flagellar beating while cytoplasmic dyneins (hereafter, dyneins) are required a wide array of cellular processes including moving RNAs, proteins, and whole organelles and for the formation, maintenance, and positioning of the mitotic spindle, the …
Surface Coat Replacement Dynamics And Antigen Glycosylation In T. Brucei Influence Evasion Of The Host Antibody Response, Jason M. Pinger
Surface Coat Replacement Dynamics And Antigen Glycosylation In T. Brucei Influence Evasion Of The Host Antibody Response, Jason M. Pinger
Student Theses and Dissertations
The protozoan parasite Trypanosoma brucei, a causative agent of human and animal trypanosomiasis, evades host immunity through antigenic variation of its variant surface glycoprotein (VSG) coat. During infection, the VSG coat elicits a robust antibody response, but the parasite escapes antibody-mediated clearance by repeatedly accessing its large genomic VSG repertoire and switching expression to antigenically distinct VSGs. Much of our knowledge of the process of VSG switching and the extent of VSG diversity has come from genetic analyses, but deep understanding of the T. brucei host-pathogen interface also requires examination of these topics at the protein level. In this thesis, …
Making Ribosomes: Biochemical And Structural Studies Of Early Ribosome Biogenesis In Yeast, Malik Chaker-Margot
Making Ribosomes: Biochemical And Structural Studies Of Early Ribosome Biogenesis In Yeast, Malik Chaker-Margot
Student Theses and Dissertations
The ribosome is a complex macromolecule responsible for the synthesis of all proteins in the cell. In yeast, it is made of four ribosomal RNAs and 79 proteins, asymmetrically divided in a small and large subunit. In a growing yeast cell, more than 2000 ribosomes are assembled every minute. The ribosome is assembled through a highly complex process involving more than 200 trans-acting factors. Ribosome assembly begins in the nucleolus where RNA polymerase I transcribes a long polycistronic RNA, the 35S preribosomal RNA which contains the sequences for three of the four ribosomal RNAs, as well as spacer sequences which …
Neural Circuit Mechanisms Underlying Behavioral Evolution In Drosophila, Laura Fairbanks Seeholzer
Neural Circuit Mechanisms Underlying Behavioral Evolution In Drosophila, Laura Fairbanks Seeholzer
Student Theses and Dissertations
Courtship rituals serve to reinforce reproductive barriers between closely related species. Several species in the Drosophila melanogaster subgroup exhibit pre-mating isolation due, in part, to the fact that D. melanogaster females produce 7,11-heptacosadiene (7,11-HD), a pheromone that promotes courtship in D. melanogaster males but suppresses it in D. simulans, D. yakuba, and D. erecta males. Here we compare pheromone-processing pathways across species to define how males endow 7,11-HD with the opposite behavioral valence to underlie species discrimination. We first show that D. melanogaster and D. simulans males detect 7,11-HD using the homologous peripheral sensory neurons, but this signal is differentially …
A Role For Pi31-Mediated Proteasome Regulation In Proteostasis And Neuronal Health, Sandra Jones
A Role For Pi31-Mediated Proteasome Regulation In Proteostasis And Neuronal Health, Sandra Jones
Student Theses and Dissertations
The specific and timely degradation of proteins is achieved by the Ubiquitin-Proteasome System (UPS), which governs a variety of cellular processes such as apoptosis, cell cycle progression, protein quality control, and metabolism. Using this system, cells maintain homeostasis by quickly and irreversibly altering signaling pathways in response to changing environmental stimuli. Protein degradation by UPS requires two consecutive steps, 1) the covalent attachment of the substrate by ubiquitin and 2) the delivery of the substrate to the 26S proteasome for breakdown and recycling of reusable ubiquitin. The 26S proteasome is a 2.5- MDa multicatalytic protease consisting of two subcomplexes: a …
Igdb-2, An Ig/Fniii Protein, Binds The Ion Channel Lgc-34 And Controls Sensory Compartment Morphogenesis In C. Elegans, Wendy Wang
Student Theses and Dissertations
Sensory organ glia surround neuronal receptive endings (NREs), forming a specialized extracellular space, or compartment, important for neuronal activity, and reminiscent of glia-ensheathed synapses in the central nervous system. Sensory organ glia are conserved across organisms, but our current understanding of how they form sensory compartments is generally lacking. To date, the Caenorhabditis elegans amphid sensory organ has provided critical insight into some of these developmental processes. DAF-6, a Patched-related protein, was previously shown to be required in amphid glia to restrict sensory compartment size. LIT-1, a Nemo-like kinase, and SNX-1, a retromer component, antagonize DAF-6 and promote compartment expansion. …
Multi-Modal Effects Of The Repellent Deet Across Protostomia, Emily Jane Dennis
Multi-Modal Effects Of The Repellent Deet Across Protostomia, Emily Jane Dennis
Student Theses and Dissertations
DEET (N, N-diethyl-m-toluamide) is the most broadly effective and widely used personal repellent available, yet we do not understand what makes it so effective. Even in well-studied species like Drosophila melanogaster flies and Aedes aegypti mosquitoes, many mysteries remain as to how DEET can affect behavior in these species. For example, Ae. aegypti mosquitoes are attracted to human arms. When an arm is covered in DEET, wild-type mosquitoes are not attracted to the arm, while mutant mosquitoes that lack the odorant receptor co-receptor (orco), approach the arm, but rarely bite. We investigated this orco-independent DEET repellency in Ae. aegypti and …