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Full-Text Articles in Life Sciences
Deep Brain Stimulation To Increase Generalized Arousal In Intact Mice And A Mouse Model Of Traumatic Brain Injury, Amy Wells Quinkert
Deep Brain Stimulation To Increase Generalized Arousal In Intact Mice And A Mouse Model Of Traumatic Brain Injury, Amy Wells Quinkert
Student Theses and Dissertations
G protein-coupled receptors (GPCRs) are dynamic membrane proteins that bind extracellular molecules to transduce biological signals. Although GPCRs represent the largest class of targets for therapeutic agents, ligand-binding sites have been precisely defined for only a small percentage of the receptors in the human genome. A general cellbased photocrosslinking approach was developed to investigate the binding interfaces necessary for the formation of GPCR signaling complexes. Amber codon suppression was extended to facilitate the incorporation of photoactivatable unnatural amino acids, pbenzoyl- L-phenylalanine and p-azido-L-phenylalanine, into engineered GPCRs expressed in mammalian cells in culture. Proof-of-concept studies were carried out in chemokine receptors …
Novel Molecules From Environmental Dna-Derived Type Ii Polyketide Biosynthetic Gene Clusters, Ryan W. King
Novel Molecules From Environmental Dna-Derived Type Ii Polyketide Biosynthetic Gene Clusters, Ryan W. King
Student Theses and Dissertations
Natural products have been a significant source of new drugs over the past 25 years. In fact, the origins of nearly 70% of antibacterial, antifungal, antiparasitic and antiviral small molecule drugs are in natural products (Newman and Cragg 2007). A significant proportion of natural product drugs and leads have been isolated from microbes (Newman and Cragg 2007). However, the discovery of novel natural products from microbes faces the growing hurdle of rediscovering known metabolites. Streptomyces is a microbe that has been a particularly rich source of natural products; however, it has been predicted that the last easily accessible novel Streptomyces …
Studies Of G Protein-Coupled Receptor Stability And Dimerization Using Novel Fluorescence And Crosslinking Approaches, Adam Knepp
Student Theses and Dissertations
G protein-coupled receptors (GPCRs) comprise a large family of related seventransmembrane- helical membrane proteins that bind to specific extracellular ligands, such as hormones or neuromodulators. The active receptor-ligand complex then engages with a heterotrimeric G protein on the cytoplasmic surface of the plasma membrane to facilitate a change in the concentration of an intracellular second messenger, such as cAMP. A number of non-canonical signaling pathways, such as β-arrestin-mediated signaling, also exist for many, if not all, GPCRs. Receptor signaling is attenuated by phosphorylation and receptor internalization. Recent advances in structural studies of GPCRs have revealed high-resolution structures of both inactive …
Tuning Of Neuronal Excitation By A Brain Specific Microrna Mir-128: From Targets To Behavior, Chan Lek Tan
Tuning Of Neuronal Excitation By A Brain Specific Microrna Mir-128: From Targets To Behavior, Chan Lek Tan
Student Theses and Dissertations
MicroRNAs constitute a vital new component of our evolving understanding of regulatory mechanisms that shape cellular gene expression. As ubiquitous regulators of protein translation, microRNAs have a unique regulatory function that is only beginning to be fully described. In addition, their role in the control of gene expression in neurons, which underpins neuronal identity and information processing, has not been fully addressed. In this thesis, I present studies that demonstrate a potent yet previously unknown regulation of neuronal intrinsic excitability by the microRNA miR-128. I show using genetic models that endogenous miR-128 plays a powerful role in dampening the excitability …
Examining The Regulation Of Cell Division By The Spindle Assembly Checkpoint, Maria Maldonado
Examining The Regulation Of Cell Division By The Spindle Assembly Checkpoint, Maria Maldonado
Student Theses and Dissertations
Accurate chromosome segregation during cell division is essential for the maintenance of a cell’s genomic stability. The molecular surveillance mechanism called the spindle assembly checkpoint (SAC) inhibits chromosome segregation before all chromosomes are correctly attached (bi-oriented) on the microtubule spindle to prevent segregation errors that may lead to chromosomal instability and cell death. In this thesis, I have developed and used tools to examine the roles of different checkpoint proteins in the mechanism of SAC signaling. In the first part of the thesis, I manipulate the localization of the checkpoint protein Mad1 and show that its constitutive presence at the …
Application Of Genetically-Encoded Photoactivatable Crosslinkers To Map Ligand-Binding Sites On G Protein-Coupled Receptors, Amy Grunbeck
Application Of Genetically-Encoded Photoactivatable Crosslinkers To Map Ligand-Binding Sites On G Protein-Coupled Receptors, Amy Grunbeck
Student Theses and Dissertations
G protein-coupled receptors (GPCRs) are dynamic membrane proteins that bind extracellular molecules to transduce biological signals. Although GPCRs represent the largest class of targets for therapeutic agents, ligand-binding sites have been precisely defined for only a small percentage of the receptors in the human genome. A general cellbased photocrosslinking approach was developed to investigate the binding interfaces necessary for the formation of GPCR signaling complexes. Amber codon suppression was extended to facilitate the incorporation of photoactivatable unnatural amino acids, pbenzoyl- L-phenylalanine and p-azido-L-phenylalanine, into engineered GPCRs expressed in mammalian cells in culture. Proof-of-concept studies were carried out in chemokine receptors …
Cannabinoid Cb1r Receptor Mediates Metabolic Syndrome In Models Of Circadian And Glucocorticoid Dysregulation, Nicole Bowles
Cannabinoid Cb1r Receptor Mediates Metabolic Syndrome In Models Of Circadian And Glucocorticoid Dysregulation, Nicole Bowles
Student Theses and Dissertations
The most recent projections in the growing obesity rates across the nation show an increase to 60% by the year 2030. These growing rates of obesity are paralleled by an increased rates of depressive conditions, anxiety, and sleep loss, often with environmental factors at the root of the cause. Stress and the stress response is a dynamic system that reflects one’s ability to cope with events, behaviorally or physiologically, as stressors occur over a lifetime. While many key players mediate the effects of stress exposure on disease outcomes including the sympathetic nervous system, parasympathetic, inflammatory cytokines and metabolic hormones, this …
Top-Down Control Of Lateral Interactions In Visual Cortex, Nirmala Ramalingam
Top-Down Control Of Lateral Interactions In Visual Cortex, Nirmala Ramalingam
Student Theses and Dissertations
V1 neurons are capable of integrating information over a large area of visual field. Their responses to local features are dependent on the global characteristics of contours and surfaces that extend well beyond their receptive fields. These contextual influences in V1 are subject to cognitive influences of attention, perceptual task and expectation. Previously it’s been shown that the response properties of V1 neurons change to carry more information about behaviorally relevant stimulus features (Li et al. 2004). We hypothesized that top-down modulation of effective connectivity within V1 underlies the behaviorally dependent modulations of contextual interactions in V1. To test this …
Decoding 5hmc As An Active Chromatin Mark In The Brain And Its Link To Rett Syndrome, Pinar Ayata
Decoding 5hmc As An Active Chromatin Mark In The Brain And Its Link To Rett Syndrome, Pinar Ayata
Student Theses and Dissertations
Functions of the nervous system are accompanied at the cellular level by changes in gene expression, regulated by transcription factors and epigenetic mechanisms, such as histone modifications and DNA methylation, that are frequently altered in neurological disorders. 5-hydroxymethylcytosine (5hmC), a recently identified DNA base derived from 5-methylcytosine, accounts for ~40% of modified cytosines in the neuronal genomes, suggesting that 5hmC is a stable epigenetic mark and its interpretation in the nervous system may differ from the other tissues. This hypothesis was supported by the recent findings showing that 5hmC is enriched over the bodies of active genes within euchromatin in …
Analysis Of Small Molecule Inhibitors Aimed At Bacterial Virulence, Paul Daniel Dossa
Analysis Of Small Molecule Inhibitors Aimed At Bacterial Virulence, Paul Daniel Dossa
Student Theses and Dissertations
The emergence of antibiotic-resistant bacterial pathogens and the discovery of new bacterial pathogens have motivated the development of novel antibacterials. One recently proposed strategy is to target pathogenic bacteria specifically by inhibiting virulence mechanisms as opposed to killing bacteria indiscriminately, which includes commensal strains. Due to the increased appreciation for the role commensal bacteria play in the immune response and the importance for maintaining a healthy microbiota, specifically targeting pathogenic bacteria is a desirable goal to attain. Genetic and biochemical studies have highlighted type III secretion systems (T3SSs) as essential components for infection of host cells by Gram-negative bacterial pathogens. …
Frequency Selectivity Of Synaptic Exocytosis In Hair Cells Of The Bullfrog's Amphibian Papilla, Suchit H. Patel
Frequency Selectivity Of Synaptic Exocytosis In Hair Cells Of The Bullfrog's Amphibian Papilla, Suchit H. Patel
Student Theses and Dissertations
Auditory organs act as spectral analyzers by decomposing acoustic stimuli into their frequency constituents. Individual auditory afferent neurons of the VIIIth cranial nerve respond best to a particular frequency of stimulation, and are thus frequency-tuned. Much of the tuning in the inner ears of mammals is ascribed to the frequency dependence of the traveling waves on the basilar membrane, the flexible structure that houses hair cells, the auditory receptors. However, in non-mammalian vertebrates, the basilar membrane does not conduct a traveling wave. In some animals, the membrane is absent entirely. Yet auditory fibers from these animals display comparable sharpness of …
Discovery And Characterization Of Methylation Of Arginine 42 On Histone H3: A Novel Histone Modification With Positive Transcriptional Effects, Fabio Casadio
Student Theses and Dissertations
Eukaryotic genomic DNA is packaged in the form of chromatin, which contains repeating nucleosomal units consisting of roughly two super-helical turns of DNA wrapped around an octamer of core histone proteins composed of four histone species: one histone H3/H4 tetramer and two histone H2A/H2B dimers. Histones are basic globular proteins rich in lysine and arginine residues, with unstructured N-terminal “tail” regions protruding outside the nucleosome structure, and structured “core” domains in the DNA-associated portion. Several core residues, and in particular arginines in H3 and H4, mediate key interactions between the histone octamer and DNA in forming the nucleosomal particle. Histone …
An Analysis Of Synaptotagmins In Caenorhabditis Elegans, Laura Winzenread
An Analysis Of Synaptotagmins In Caenorhabditis Elegans, Laura Winzenread
Student Theses and Dissertations
Neurotransmission involves the release of neurotransmitters from a presynapticneuron, followed by the reuptake of the protein components of the synaptic vesicle. The basic steps of synaptic vesicle exocytosis and endocytosis have been elucidated, and a number of components of the neurotransmission machinery have been identified. The exact function of each component, however, has been difficult to ascertain as many components act in multiple steps of neurotransmission. In my thesis, I describe the identification of a mutation in the snt-1 gene, which encodes a member of the synaptotagmin family in Caenorhabditis elegans. Synaptotagmins are best known as the calcium-sensing proteins …
Phenotypic And Genotypic Models Of Streptococcal Colonization Of The Human Tonsil, Dennis J. Spencer
Phenotypic And Genotypic Models Of Streptococcal Colonization Of The Human Tonsil, Dennis J. Spencer
Student Theses and Dissertations
Pharyngitis due to oropharyngeal infection with Streptococcus pyogenes is most commonly treated by using penicillin-derived antibiotics.While treatment failure in the 1950’s was reported in 4-8% of children, more recent studies have alarmingly found antibiotic failure as high as 20-40% providing the impetus to study this important pathogen. The contiguous mucosa along neighboring oropharyngeal surfaces is classically unaffected during Strep ”Throat” suggesting pathogen specificity for palatine tonsil epithelium. While recent studies are advancing the premise of pathogen-host microenvironment effects on streptococcal virulence, the specific interaction between S. pyogenes and the human tonsillar surface relative to neighboring tissues remains insufficiently understood. This …
Mechanism Of Translational Control By The Fragile X Mental Retardation Protein And Creation Of The Fmrp Ctag Mouse, Sarah Van Driesche
Mechanism Of Translational Control By The Fragile X Mental Retardation Protein And Creation Of The Fmrp Ctag Mouse, Sarah Van Driesche
Student Theses and Dissertations
The Fragile X Mental Retardation Protein (FMRP) is a neuronal RNA-binding protein that is predominantly associated with polyribosomes. Loss of FMRP results in Fragile X Syndrome, characterized by mental retardation, autism and epilepsy. FMRP was recently found to be associated with a specific set of mRNAs with key roles in neuronal function and to physically interact with targeted mRNAs along their entire coding sequences (Darnell 2011). Here, we find that FMRP inhibits translation on these target transcripts by stalling ribosomes, both in vivo and in rabbit reticulocyte lysate programmed with endogenous brain polyribosomes. In these systems, loss of FMRP function …
Telomere-Driven Tetraploidy And Its Relevance To Cancer, Teresa Davoli
Telomere-Driven Tetraploidy And Its Relevance To Cancer, Teresa Davoli
Student Theses and Dissertations
Aneuploidy, i.e. the state of having an abnormal chromosome number, is a hallmark of human solid tumors. A fraction of aneuploid tumors is near-diploid and can be explained by individual chromosome gains and losses in mitosis. The remaining fraction is subtetraploid, containing an increased chromosome number, ranging from 60 to 90 chromosomes. Mounting evidence argues that tetraploidization, i.e. whole genome doubling, followed by chromosome loss is likely to represent an early event in the development of subtetraploid tumors. The origin of tetraploidization in cancer is still unclear. Here we de- scribe a new potential mechanism of tetraploidization in cancer, originating …
Rna Dynamics In T Cell Activation, Emily Conn Gantman
Rna Dynamics In T Cell Activation, Emily Conn Gantman
Student Theses and Dissertations
Eukaryotic cells employ multiple posttranscriptional mechanisms to fine tune gene expression programs in response to external signals. Regulation of messenger RNA and microRNA by RNA-binding proteins is critical to the control of this process. Hence, disruptions of RNA regulatory processes result in neurologic diseases, cancer, and immunologic disorders among other complications. Posttranscriptional control of RNA is particularly important for precise cytokine expression in T cells during adaptive immune responses. We have studied human lymphocyte activation as a model for correlating changes in RNA regulation with dynamic cellular state changes and stress responses. We hypothesize that RNA-binding proteins such as Argonaute …