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Full-Text Articles in Life Sciences
Effects Of Temporal And Spatial Context Within The Macaque Face-Processing System, Clark Andrew Fisher
Effects Of Temporal And Spatial Context Within The Macaque Face-Processing System, Clark Andrew Fisher
Student Theses and Dissertations
Temporal and spatial context play a key role in vision as a whole, and in face perception specifically. However, little is known about the neurophysiological mechanisms by which contextual cues exert their effects. Anatomically distinct face patches in the macaque brain analyze facial form, and studies of the activity within these patches have begun to clarify the neural machinery that underlies facial perception. This system provides a uniquely valuable opportunity to study how context affects the perception of form. We used functional magnetic resonance imaging (fMRI) to investigate the brain activity of macaque monkeys while they viewed faces placed in …
A New Role For Beta-Amyloid In Alzheimer's Disease: Initiation Of Thrombotic And Inflammatory Processes Via Coagulation Factor Xii And Fibrinogen, Daria Zamolodchikov
A New Role For Beta-Amyloid In Alzheimer's Disease: Initiation Of Thrombotic And Inflammatory Processes Via Coagulation Factor Xii And Fibrinogen, Daria Zamolodchikov
Student Theses and Dissertations
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with no effective therapies. While abundant genetic, histological, and experimental evidence links the beta-amyloid (Aβ) peptide to disease onset and progression, the mechanisms behind neuronal dysfunction in AD are not completely understood. It is now clear that AD is a complex, multifactorial disease characterized by vascular dysfunction, prothrombotic state, and inflammation, but whether these conditions are a cause or consequence of disease is debated. Prothrombotic and inflammatory states can contribute to alterations in cerebral blood flow resulting in hypoperfusion. Since neuronal function is dependent on an uninterrupted blood supply sustained by a …
The Effect Of Chronic Hypertension On Neuropathology In The Tgswdi Mouse Model Of Alzheimer's Disease, Anna Kruyer
The Effect Of Chronic Hypertension On Neuropathology In The Tgswdi Mouse Model Of Alzheimer's Disease, Anna Kruyer
Student Theses and Dissertations
Numerous epidemiological studies link vascular disorders, such as hypertension, diabetes and stroke, with Alzheimer’s disease. Hypertension, specifically, is an important modifiable risk factor for late onset Alzheimer’s disease. Despite the abundance of clinical data connecting these conditions, animal studies investigating the connection between the two are lacking. To examine the link between midlife hypertension and the onset of Alzheimer’s disease later in life, chronic hypertension was induced in the TgSwDI mouse model of Alzheimer’s disease in early adulthood using long-term administration of the eNOS inhibitor, N ω-Nitro-L-arginine methyl ester hydrochloride (L-NAME). L-NAME treatment accelerated cognitive deficits, microvascular deposition of the …
Neural Circuit Dependence Of Acute And Subacute Nociception In C. Elegans, Yifan Xu
Neural Circuit Dependence Of Acute And Subacute Nociception In C. Elegans, Yifan Xu
Student Theses and Dissertations
Nociception, the detection and avoidance of harmful cues, is a crucial system in all organisms. Animals use nociceptive systems to escape from substances that decrease survival, and can also modulate the threshold for avoidance behaviors to weigh the attractive features of an environment against its harmful features. To allow regulation, the nociception system of mammals incorporates multiple feedback and feedforward loops in its central and peripheral pathways. The nociception system of the roundworm Caenorhabditis elegans shares many features of the mammalian circuit. Both neural circuits feature a direct path from sensory neurons to motor neurons that is connected by a …
Specialized Signals For Spatial Attention In The Ventral And Dorsal Visual Streams, Pablo Polosecki
Specialized Signals For Spatial Attention In The Ventral And Dorsal Visual Streams, Pablo Polosecki
Student Theses and Dissertations
Neuroscientists have traditionally conceived the visual system as having a ventral stream of vision for perception and a dorsal one associated with vision for action. However functional differences between them have become relatively blurred in recent years, not the least by the systematic parallel mapping of functions allowed by functional magnetic resonance imaging (fMRI). Here, using fMRI to simultaneously monitor several brain regions, we first studied a hallmark ventral stream computation: the processing of faces. We did so by probing responses to motion, an attribute whose processing is typically associated with the dorsal stream. In humans, it is known that …
Therapeutic Uses Of Broadly Neutralizing Anti-Hiv-1 Antibodies In Humanized Mice, Ariel Halper-Stromberg
Therapeutic Uses Of Broadly Neutralizing Anti-Hiv-1 Antibodies In Humanized Mice, Ariel Halper-Stromberg
Student Theses and Dissertations
Combination anti-retroviral drug therapy (ART) significantly suppresses HIV-1 viremia in most infected individuals, but is incapable of curing disease. The major barrier to HIV-1 cure is a population of long-lived cells that harbor replication-competent provirus and are refractory to current therapies—termed the latent reservoir. New therapeutic approaches to clear latent HIV-1-infected cells are necessary to achieve cure. In the first part of this thesis, I show that HIV-1 mutates and diversifies at the expected rate within humanized mice (humice) and that hu-mice can sustain HIV-1 viremia for up to 4 months, thus allowing hu-mice to be used as a small …
Development Of Novel Chemical Biology Tools For Probing Structure-Function Relationships In G Protein-Coupled Receptors, Tian He
Student Theses and Dissertations
G protein-coupled receptors (GPCRs) constitute a large family of transmembrane receptors that transduce extracellular signals into intracellular biochemical responses. Understanding with chemical precision how GPCRs function in cellular membranes is an active area of biological research, but despite recent reports of X-ray crystal structures of several GPCRs, some important questions remain unresolved. For example, the kinetics and thermodynamics of ligand-receptor interactions that lead to receptor activation and how allosteric modulators affect receptor signaling need to be addressed. In addition to basic understanding of transmembrane signaling, studies of GPCRs can provide insights that might advance drug discovery since a large proportion …
A Reductionist Approach To Modeling Human Corticogenesis, Mohammad Zeeshan Ozair
A Reductionist Approach To Modeling Human Corticogenesis, Mohammad Zeeshan Ozair
Student Theses and Dissertations
The formation of the mammalian cerebral cortex is a complex multi-tiered process that involves three major milestones: 1) neural induction and folding of the neuroepithelium, 2) areal patterning and generation of various progenitor types, and 3) corticogenesis. Our current understanding of the molecular and cellular basis of cortical development comes largely from mouse studies due to the genetic tractability of this model system. However, as primate studies have shown, the primate brain is unique in terms of its progenitor and neuronal composition, cortical areas, scale, and gene expression. Limitations in the availability of non-human primate and human fetal material, the …
Xenopus Dppa2 Is A Direct Inhibitor Of Microtubule Polymerization Required For Nuclear Assembly, John Zhao Xue
Xenopus Dppa2 Is A Direct Inhibitor Of Microtubule Polymerization Required For Nuclear Assembly, John Zhao Xue
Student Theses and Dissertations
The eukaryotic nucleus mediates the genomic functions of information storage and gene expression, but must be completely rebuilt after every open mitosis as well as during fertilization. Nuclear abnormalities are observed in many tissue malignancies and congenital disorders, but the causes and effects of such pathologies remain poorly understood. Here we use cell-free Xenopus egg extracts to investigate the contribution of the DNA-binding protein Dppa2 to nuclear assembly. In Dppa2-depleted extracts, nuclei are small and deformed, assemble incomplete nuclear envelopes and fail DNA replication. We show that Dppa2 directly depolymerizes microtubules, and must be localized on DNA to tune local …
Hair Bundles Of A Jawless Vertebrate Employ Tetrapod-Like Tuned Mechanical Amplification, Katherine J. Leitch
Hair Bundles Of A Jawless Vertebrate Employ Tetrapod-Like Tuned Mechanical Amplification, Katherine J. Leitch
Student Theses and Dissertations
In the hearing and balance organs of tetrapod vertebrates, mechanical signals are transduced by an elegant organelle called the hair bundle. Deflections of this structure apply forces to mechanically gated ion channels. Hair bundles are not passive receivers of stimuli, but are instead active participants in the process of sensory transduction. They expend chemical energy to exert mechanical work, and can harness this active process to amplify their mechanical response to stimuli. Furthermore, the active process is tuned, allowing a given hair bundle to preferentially amplify a particular frequency; this feature is valuable in the analysis of complex sounds. Hair …
Mechanisms Of Olfactory Plasticity In Caenorhabditis Elegans, Christine Cho
Mechanisms Of Olfactory Plasticity In Caenorhabditis Elegans, Christine Cho
Student Theses and Dissertations
Animals live in constantly changing environments with fluctuating resource availability and hazardous threats. By gathering information from past experiences, individuals modify their behavioral response to adapt to the changing environment, a phenomenon known as “experience-dependent plasticity”. This ability to change is a crucial for survival, and how an organism achieves this adaptive plasticity is a question of much interest. Research in the field has yielded insight into how changes in connectivity within the brain can drive changes in behavior. Understanding the neural mechanisms of plasticity not only satisfies intellectual curiosity, but also provides a basis for understanding pathological conditions that …
Metagenomics-Based Tryptophan Dimer Natural Product Discovery And Development Pipeline, Fang-Yuan Chang
Metagenomics-Based Tryptophan Dimer Natural Product Discovery And Development Pipeline, Fang-Yuan Chang
Student Theses and Dissertations
Most microbial natural product discovery programs rely on the growth of bacteria in the laboratory, yet it is now well established that the vast majority of bacteria in the environment have not been cultured, particularly from the diverse soil microbiota. By extracting DNA directly from soil samples to construct large archived environmental DNA (eDNA) libraries, thousands of genomes from both cultured and as yet uncultured bacteria can be simultaneously screened for gene clusters encoding natural products of interest. Several natural products with pharmaceutically relevant biological activity arise from the dimerization of tryptophans, such as staurosporine, rebeccamycin, and violacein. To discover …
Investigating Mechanisms Of Telomere End-Protection, Shaheen Kabir
Investigating Mechanisms Of Telomere End-Protection, Shaheen Kabir
Student Theses and Dissertations
Shelterin is an essential telomeric protein complex that prevents DNA damage signaling and DNA repair in a compartmentalized manner. We assessed contributions of the conserved shelterin component, Rap1, to telomere endprotection. Rap1 was first discovered in budding yeast as a transcription factor and was later shown to bind directly to telomeres. Two important functions of Rap1 in yeast are: the negative regulation of telomere length, and the inhibition of the double-strand break (DSB) repair pathway non homologous end-joining (NHEJ). Mammalian Rap1 interacts with shelterin factor TRF2, to localize to telomeres, and …
Mechanism Of Action Of Ing4 As A Transcriptional Coactivator Of P53, Jabez Bok
Mechanism Of Action Of Ing4 As A Transcriptional Coactivator Of P53, Jabez Bok
Student Theses and Dissertations
ING4 belongs to a family of proteins that have been implicated in tumor suppression and has been linked to the activation of p53 target genes in a p53- dependent manner. However the mechanism by which it interacts with p53 to activate transcription from these genes is unclear. In this study I use in vitro reconstitutions of cellular processes to biochemically dissect the activity of the ING4 complex, complementing the cell based assays that give a more physiological but less defined window into ING4’s effect on p53 transcriptional activity. Purification of the ING4 complex allowed verification of previously known subunits and …
Studies On The Maturation Of Secreted Quorum Sensing Peptides That Regulates S. Aureus Virulence, Jeffrey Grant Johnson
Studies On The Maturation Of Secreted Quorum Sensing Peptides That Regulates S. Aureus Virulence, Jeffrey Grant Johnson
Student Theses and Dissertations
The accessory gene regulator (agr) locus in the commensal human pathogen, Staphylococcus aureus, is a two-promoter operon with allelic variability that encodes a quorum sensing circuit involved in regulating virulence in the bacterium. Secretion of unique autoinducing peptides (AIPs) and detection of their concentration via AgrC, a transmembrane receptor histidine kinase, coordinates local bacterial population density with global changes in gene expression. In order for S. aureus to produce AIP, three proteolytic transformations involving the proteins AgrB and SpsB are required. However, despite our current understanding of AIP peptide processing, the actual manner in which the AIP crosses the cellular …
Activity Based Profiling: New Insights Into Metabolic Homeostasis, Keith Tan
Activity Based Profiling: New Insights Into Metabolic Homeostasis, Keith Tan
Student Theses and Dissertations
There is mounting evidence that demonstrates that body weight and energy homeostasis is tightly regulated by a physiological system. This system consists of sensing and effector components that primarily reside in the central nervous system and disruption to these components can lead to obesity and metabolic disorders. Although many neural substrates have been identified in the past decades, there is reason to believe that there are numerous unidentified neural populations that play a role in energy balance. Besides regulating caloric consumption and energy expenditure, neural components that control energy homeostasis are also tightly intertwined with circadian rhythmicity but this aspect …
Identification Of Tmem2 As A Sox4 Transcriptional Target Involved In Breast Cancer Metastasis, Hyeseung Lee
Identification Of Tmem2 As A Sox4 Transcriptional Target Involved In Breast Cancer Metastasis, Hyeseung Lee
Student Theses and Dissertations
The transcription factor SRY (sex determining region Y)-box 4 (SOX4) regulates embryonic development and has been shown to drive the progression and metastasis of multiple solid cancer types. A common transcriptional target of SOX4 that mediates its effects in multiple cancer types has yet to be identified. Through a systematic molecular and genomic approach, we identify the transmembrane protein 2 (TMEM2) gene as a direct transcriptional target of SOX4. TMEM2 is transcriptionally activated by SOX4 in both breast cancer and lung adenocarcinoma cells and mediates pro-invasive and pro-migratory effects of SOX4. TMEM2, like SOX4, is sufficient to promote breast cancer …
Why Mosquitoes Bite Some People More Than Others: Metabolic Correlates Of Human Attraction In Aedes Aegypti, Lindsay Lee Bellani
Why Mosquitoes Bite Some People More Than Others: Metabolic Correlates Of Human Attraction In Aedes Aegypti, Lindsay Lee Bellani
Student Theses and Dissertations
Aedes aegypti mosquitoes are the principal vectors of two major infectious diseases that plague the developing world today: dengue fever and chikungunya, with dengue fever alone resulting in ~400 million total yearly infections, and ~24,000 deaths (Bhatt et al., 2013). Understanding the biology behind Ae. aegypti attraction to humans is critical for developing novel strategies to combat these diseases. Yet, even the basic act of how mosquitoes choose one human host over another is poorly understood. Many previous studies on differential attraction have focused on small, homogenous subject populations and addressed a single hypothesis. We took the opposite strategy and …
Components Of The Ubiquitin Proteasome System Are Required For The Nonapoptotic Death Of The C. Elegans Linker Cell, Jennifer Zuckerman Malin
Components Of The Ubiquitin Proteasome System Are Required For The Nonapoptotic Death Of The C. Elegans Linker Cell, Jennifer Zuckerman Malin
Student Theses and Dissertations
Cell death is a major cell fate that promotes tissue sculpting and morphogenesis during animal development. Many developmental cell-culling events cannot be accounted for solely by caspase-dependent apoptosis, yet, alternate pathways are poorly understood. Direct evidence that caspase-independent non-apoptotic cell death pathways operate during animal development is provided by studies of the C. elegans linker cell. Genetic studies of linker cell death have led to the identification of genes that promote this process, including pqn-41, which encodes a glutamine-rich protein, as well as tir-1/TIRdomain and sek-1/MAPKK, which may function in the same pathway as pqn-41. The let- 7 microRNA and …
Synapse Formation In The Zebrafish Lateral Line, Eliot Dow
Synapse Formation In The Zebrafish Lateral Line, Eliot Dow
Student Theses and Dissertations
Although much is known about how axons and dendrites are guided to a target tissue, little is understood regarding how pre- and postsynaptic partners are matched for synapse formation. The zebrafish lateral line offers the opportunity for greater insight into this process. Hair cells in the lateral-line neuromast exist as two intermingled subpopulations, anteriorly and posteriorly polarized cells. Afferent neurons form synapses with hair cells of only one subpopulation, and this polarity-specific innervation arises independently of synaptic activity. The research presented in my thesis deepens the understanding of synapse formation in the zebrafish lateral line. First, I examine the neuronal …
Normalization Among Heterogeneous Population Confers Stimulus Discriminability On The Macaque Face Patch Neurons, Akinori F. Ebihara
Normalization Among Heterogeneous Population Confers Stimulus Discriminability On The Macaque Face Patch Neurons, Akinori F. Ebihara
Student Theses and Dissertations
Primates are capable of recognizing faces even in highly cluttered natural scenes. In order to understand how the primate brain achieves face recognition despite this clutter, it is crucial to study the representation of multiple faces in face selective cortex. However, contrary to the essence of natural scenes, most experiments on face recognition literatures use only few faces at a time on a homogeneous background to study neural response properties. It thus remains unclear how face selective neurons respond to multiple stimuli, some of which might be encompassed by their receptive fields (RFs), others not. How is the neural representation …
Mechanical Control Of Sensory Hair-Bundle Function, Joshua D. Salvi
Mechanical Control Of Sensory Hair-Bundle Function, Joshua D. Salvi
Student Theses and Dissertations
Hair bundles detect sound in the auditory system, head position and rotation in the vestibular system, and fluid flow in the lateral-‐‑line system. To do so, bundles respond to periodic, static, and hydrodynamic forces contingent upon the receptor organs in which they are situated. As the mechanosensory function of a hair bundle varies, so too do the mechanical properties of the bundle and its microenvironment. Hair bundles range in height from 1 μμm to 100 μμm and in stiffness from 100 μμN·∙m-‐‑1 to 10,000 μμN·∙m-‐‑1. They are composed of actin-‐‑filled, hypertrophic microvilli—stereocilia—that number from fewer than 20 through more than …
Functional Dissection Of Brainstem Circuitry, Alexander Ryan Nectow
Functional Dissection Of Brainstem Circuitry, Alexander Ryan Nectow
Student Theses and Dissertations
Eat. Sleep. Breathe. Move. These functions, critical to an individual’s survival, are controlled by highly conserved neurotransmitter and neuromodulatory systems, which are principally located in the brainstem. These different brainstem neural populations, while performing apparently simple life sustaining functions, are remarkably complex. For proper function, survival circuits need to receive information from brain regions responsible for sensing survival needs, and rapidly exert broad control over the brain to generate adaptive behavior like foraging during energy deficit and escape from predation. How can survival circuits generate such autocratic control? Survival circuits principally affect global brain function in two ways: diffuse projection …
Molecular Determinants Of Tumor Re-Initiation In Breast Cancer, Jason Barzel Ross
Molecular Determinants Of Tumor Re-Initiation In Breast Cancer, Jason Barzel Ross
Student Theses and Dissertations
Cancer progression is characterized by the formation of tumors in primary organs and the subsequent re-formation of tumors in distant metastatic sites. The tumorigenic, or tumor-forming, capacity of cancer cells drives cancer along a continuum that includes primary tumor formation, metastatic re-initiation, and macroscopic relapse. As such, a greater understanding of the biological features and molecular determinants that govern tumor-forming capacity in the primary and metastatic site is of great importance to the scientific and biomedical communities. This thesis presents an unbiased approach to systematically select and characterize breast cancer cells with enhanced tumorigenic capacity in order to elucidate genes …
A Genomic Portrait Of Hepatitis C Virus And Microrna-122, Joseph M. Luna
A Genomic Portrait Of Hepatitis C Virus And Microrna-122, Joseph M. Luna
Student Theses and Dissertations
Hepatitis C virus (HCV) uniquely requires the liver specific microRNA-122 (miR- 122) for replication, yet global effects on endogenous microRNA (miRNA) targets during infection are unexplored. In this body of work, we employed highthroughput sequencing and crosslinking immunoprecipitation (HITS-CLIP) experiments of human Argonaute (AGO) during HCV infection. We demonstrate robust AGO binding on the 5' untranslated region of HCV RNA at known and predicted miR-122 sites, thereby establishing conclusive biochemical evidence of endogenous miR-122 action on HCV RNA that firmly agrees with previous genetic evidence. We further characterize novel AGO binding on HCV RNA to determine its dependence on miR-122, …
Characterization Of Bacterial Metabolites Involved In Host Pathogen Resistance, Kavita J. Rangan
Characterization Of Bacterial Metabolites Involved In Host Pathogen Resistance, Kavita J. Rangan
Student Theses and Dissertations
The intestinal microbiome can mediate host resistance to enteric pathogens by modulating host immunity or by directly inhibiting pathogen growth and virulence. Although the abundance and diversity of bacterial metabolites in the intestine is appreciated, the majority of intestinal bacteria and bacterial products have not been characterized in the context of microbiota-mediated pathogen resistance. In this thesis, we describe two projects aimed at developing new methodologies to study how intestinal bacteria, and the metabolites they generate, inhibit bacterial pathogenesis. In Chapters 2 and 3, we use a chemical reporter strategy to analyze fatty acid protein modifications in bacteria. Dietary and …
A Mechanism For Spatial Orientation Based On Sensory Adaptation In Caenorhabditis Elegans, Johannes Larsch
A Mechanism For Spatial Orientation Based On Sensory Adaptation In Caenorhabditis Elegans, Johannes Larsch
Student Theses and Dissertations
During chemotaxis, animals compute spatial information about odor gradients to make navigational choices for finding or avoiding an odor source. The challenge to the neural circuitry is to interpret and respond to odor concentrations that change over time as animals traverse a gradient. In this thesis, I ask how a nervous system regulates spatial navigation by studying the chemotaxis response of Caenorhabditis elegans to diacetyl. A behavioral analysis demonstrated that AWA sensory neurons drive chemotaxis over several orders of magnitude in odor concentration, providing an entry point for dissecting the mechanistic basis of chemotaxis at the level of neural activity. …