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Full-Text Articles in Life Sciences
Mitochondrial Distribution Of Glycine Receptors In Motor Neuron Cell Lines, Katsiaryna Milashevich
Mitochondrial Distribution Of Glycine Receptors In Motor Neuron Cell Lines, Katsiaryna Milashevich
Student Theses and Dissertations
Although non-essential, glycine plays an important role in major metabolic reactions and is most known for its anti-inflammatory effects. An accumulation of contemporary research has shown that glycine is able to stabilize membrane potential using glycine receptors at the cellular level and to protect mitochondrial function directly, whether it is from inflammation, heavy metal poisoning, or ischemia-induced neuroinflammation. In this research, the existence of a hypothetical mitochondrial glycine receptor is examined. Immunofluorescence imaging was used to examine the presence of the glycine receptor subunits alpha 1 and alpha 2 in both non- differentiated and differentiated neuroblastoma cell lines. The preliminary …
Linker Histone Medicated Regulation Of Mitotic Chromosome Compaction And Individualization, Pavan Choppakatla
Linker Histone Medicated Regulation Of Mitotic Chromosome Compaction And Individualization, Pavan Choppakatla
Student Theses and Dissertations
Mitotic chromosomes are scaled to the cell size to ensure effective chromosome segregation. Recent studies have shown how condensins and DNA topoisomerase II organize the mitotic chromosome. However, the regulation of these factors in maintaining proper chromosome size in different cell types remains a mystery. Here, I investigated the role of the linker histone variant H1.8 in regulating mitotic chromosome structure. I showed that H1.8 suppresses binding of condensins and topo II to mitotic chromatin in Xenopus egg extracts. Using an in vitro reconstitution system, I showed that H1.8 inhibits binding of purified condensins and topo II to nucleosome arrays. …
Unraveling The Interaction Between Beige Adipocytes And The Sympathetic Nervous System, Jingyi Chi
Unraveling The Interaction Between Beige Adipocytes And The Sympathetic Nervous System, Jingyi Chi
Student Theses and Dissertations
Obesity affects more than one in three adults in the United States and is a significant risk factor for a constellation of chronic diseases. The crucial role of adipose tissue in energy balance has driven great interest in investigating this tissue as a target for treatment of obesity and its sequelae. While white adipocytes store excess energy, thermogenic brown and beige adipocytes convert lipids and glucose into heat, thereby increasing energy expenditure. Unlike classical brown adipocytes which are thermogenic under basal conditions, inducible brown adipocytes, commonly known as beige adipocytes, reside in white adipose depots and need to be activated …
Metabolic Coordination Of Stem Cell Fate Controls Tumor Initiation And Tissue Repair, Sanjeethan C. Baksh
Metabolic Coordination Of Stem Cell Fate Controls Tumor Initiation And Tissue Repair, Sanjeethan C. Baksh
Student Theses and Dissertations
Tissue stem cells balance fate decisions of self-renewal and differentiation to maintain homeostasis over the lifetime of an organism, as well as to repair tissues upon injury and wounding. Disrupting the balance between self-renewal and differentiation results in pathology: excessive self-renewal at the expense of differentiation is associated with tumor initiation, whereas failure to properly self-renew leads to stem cell exhaustion and aging. Stem cell fate is under tight regulation by the surrounding microenvironment, or niche, which includes neighboring cell types, signaling molecules, extracellular matrix, and nutrients. While the role of stromal cells and the signals they produce has been …
Not Black And White: Bmp Signaling Drives Melanocyte Differentiation Down Stream Of Stem Cell Activation, Nicole Rai Infarinato
Not Black And White: Bmp Signaling Drives Melanocyte Differentiation Down Stream Of Stem Cell Activation, Nicole Rai Infarinato
Student Theses and Dissertations
Tissue stem cells (SCs) maintain, regenerate, and repair the body over the course of an organism’s lifetime. To preserve their long-term function, SCs must exert precise control over their cell state dynamics as they move from quiescence to activation and commit to full differentiation. My graduate research has been centered on investigating the molecular mechanisms that fuel these transitions in melanocyte stem cells (McSCs), a unique neural crest-derived SC population located in the hair follicle (HF). Through periodic bouts synchronous with HF cycling, quiescent McSCs become activated to proliferate, giving rise to committed proliferative progeny (McCP) that differentiate into mature …
The Taste Of Blood, Veronica Jove
The Taste Of Blood, Veronica Jove
Student Theses and Dissertations
Human blood and floral nectar are both appetizing meals to a hungry female mosquito, yet each meal fulfills a distinct nutritional requirement. While protein obtained from blood is required for females to develop eggs and successfully reproduce, carbohydrates supplied from plant nectar are sufficient for energy metabolism in both females and males. To procure essential nutrients from these distinct food sources, females employ two mutually exclusive feeding programs with unique sensory appendages, meal sizes, digestive tract targets, and metabolic fates. When a female is ready to reproduce, she must selectively seek the taste of blood and ignore the sweet taste …
Mechanisms For The Evolution Of Superorganismality In Ants, Vikram Chandra
Mechanisms For The Evolution Of Superorganismality In Ants, Vikram Chandra
Student Theses and Dissertations
Ant colonies appear to behave as superorganisms; they exhibit very high levels of within-colony cooperation, and very low levels of within-colony conflict. The evolution of such superorganismality has occurred multiple times across the animal phylogeny, and indeed, origins of multicellularity represent the same evolutionary process. Understanding the origin and elaboration of superorganismality is a major focus of research in evolutionary biology. Although much is known about the ultimate factors that permit the evolution and persistence of superorganisms, we know relatively little about how they evolve. One limiting factor to the study of superorganismality is the difficulty of conducting manipulative experiments …
The Role Of Nutrient Availability In Therapeutic Response Of Leukemia, Rohiverth Guarecuco Jr
The Role Of Nutrient Availability In Therapeutic Response Of Leukemia, Rohiverth Guarecuco Jr
Student Theses and Dissertations
Tumor environment influences the response to anti-cancer therapy, but which extracellular nutrients impact drug sensitivity is largely unknown. In this work, we used functional genomics to identify metabolic modifiers of the response to L-asparaginase (ASNase), a therapy that depletes plasma asparagine and targets leukemic cells with insufficient asparagine synthesis. Our approach revealed thiamine pyrophosphate kinase 1 (TPK1), which converts vitamin B1 (thiamine) into the cofactor thiamine pyrophosphate (TPP), as a metabolic dependency under ASNase treatment. In glutamine-anaplerotic leukemia cells, we found that TPP availability enables asparagine synthesis from extracellular glutamine. Mechanistically, TPP is critical for the activity of alpha-ketoglutarate dehydrogenase …
Tension Propagation Along Tip-Link Cadherins: Regulation And Implications For The Auditory System, Daniel M. Firester
Tension Propagation Along Tip-Link Cadherins: Regulation And Implications For The Auditory System, Daniel M. Firester
Student Theses and Dissertations
Hair bundles detect sound by shearing in response to vibrations spanning orders of magnitude in intensity and frequency. Their responsiveness stems from mechanosensitive ion channels that sit atop the stereocilia and are gated by tension in tip links. Experimental evidence and theoretical arguments implicate a soft compliant element, with a stiffness of 1-4 mN/m, as necessary for mechanotransduction. Although the identity of this element remains an open question, direct measurements of a component of the tip link have highlighted entropic elasticity as one relevant characteristic. A tip link comprises a heterotetremer of protocadherin-15 and cadherin-23, arranged in a loose helical …
Non-Canonical Axonal Insulin Receptor Signaling Drives Aversive Olfactory Learning, Du Cheng
Non-Canonical Axonal Insulin Receptor Signaling Drives Aversive Olfactory Learning, Du Cheng
Student Theses and Dissertations
Animals rely on their flexible nervous systems to learn to navigate the changing environment around them. One important function of the nervous system is to form associative memories. A simple model of associative learning is provided by nematode C. elegans, which can form memories of different types of odor stimuli through its simple yet sophisticated nervous system. C. elegans uses its sensory neurons to detect and navigate towards the odors of its food source - edible bacteria. Thus, it is crucial for worms to form memories between odors and availably of food. The volatile chemical butanone is a common product …
Brochemical Studies Of Peptidoglycan Hydrolases From Commensal And Pathogenic Bacteria, Juliel Espinosa
Brochemical Studies Of Peptidoglycan Hydrolases From Commensal And Pathogenic Bacteria, Juliel Espinosa
Student Theses and Dissertations
The intestinal microbiota consists of diverse bacterial species and their effectors that play key roles in regulating human health. Interestingly, cell wall, or peptidoglycan, fragments from commensal and pathogenic bacteria can activate host immunity. The mechanism(s) by which immunologically active peptidoglycan fragments are generated, however, are not well-understood. In this regard, peptidoglycan hydrolases are ubiquitous in bacteria and possess diverse activities to remodel the cell wall during cell growth and division. These peptidoglycan hydrolases can also generate cell wall fragments in this process that are shed or recycled and available for triggering host immunity. In this thesis, we describe methodologies …
Accessory Nucleases Provide Robust Antiparasite Immunity For Type Iii Crispr-Cas Systems, Jakob Træland Rostøl
Accessory Nucleases Provide Robust Antiparasite Immunity For Type Iii Crispr-Cas Systems, Jakob Træland Rostøl
Student Theses and Dissertations
To protect against parasites like bacteriophages and plasmids, bacteria employ diverse and sophisticated defence systems. Clustered, regularly interspaced short palindromic repeats (CRISPR)-Cas systems are adaptive immune systems that can integrate short “spacers” from a parasite into its CRISPR locus as a form of immunological memory. Upon reinfection, short RNAs transcribed from the CRISPR locus can guide Cas proteins to the viral genome through complementary base pairing. Cas nucleases then destroy the invader’s genome. To date, six major types and multiple subtypes of CRISPR systems exist, each with their own signature genes and mechanisms of action. Type III CRISPR systems are …
The Role Of Dna Methylation In Defining The Vocal Learning Transcriptome Of The Zebra Finch, Caitlin Sun Gilbert
The Role Of Dna Methylation In Defining The Vocal Learning Transcriptome Of The Zebra Finch, Caitlin Sun Gilbert
Student Theses and Dissertations
Vocal learning is a rare, complex behavior which is a critical component of human spoken language acquisition. It is convergent across several independent lineages of birds and mammals, including songbirds and humans. The development of speech and song production in humans and songbirds is strikingly similar, though the molecular mechanisms underlying these similarities are not yet understood. Our lab has previously found convergently differentially expressed genes in the vocal learning circuitry of humans and song-learning birds relative to adjacent non-vocal motor circuits. Most notably, the RA song nucleus in the songbird is molecularly convergent with the human laryngeal motor cortex. …
A Proteomic Approach To Elucidating The Function Of Picornavirus 2a Protease, Artem Serganov
A Proteomic Approach To Elucidating The Function Of Picornavirus 2a Protease, Artem Serganov
Student Theses and Dissertations
Human-infecting viruses have evolved diverse strategies to enter cells and hijack the host machinery to promote their self-replication. Viruses deploy their proteins to subvert a number of host functions, such as the cell cycle, cellular metabolism, protein synthesis, nuclear and RNA transport across the nuclear pore complex, apoptosis, and innate immune responses. Picornaviruses are the most dominant human disease-causing viruses and present an excellent clinical target for research studies into their molecular mechanisms. Picornaviruses have an RNA genome that is translated as a single polyprotein, which is processed into individual components by two proteases, termed 2A and 3C. In addition …
A Role For Acsbg1 In Obesity-Accelerated Breast, Olivia Maguire
A Role For Acsbg1 In Obesity-Accelerated Breast, Olivia Maguire
Student Theses and Dissertations
Overweight and obesity affect more than 70% of American adults and are major risk factors for the development of comorbidities, including cancer. Breast cancer is the most commonly diagnosed malignancy in American women: 1 in 8 women will develop breast cancer in their lifetimes, and more than 40,000 women die from breast cancer each year. Obesity is associated with increased incidence and worse prognosis in breast cancer, including aggressive triple-negative breast cancer, which has a particularly poor prognosis with few treatment options. The goal of this thesis was to elucidate the mechanisms by which obesity promotes breast cancer progression. To …
Genome-Wide Human-Specific Rna Regulatory Elements In The Brain, Elisabeth A. Murphy
Genome-Wide Human-Specific Rna Regulatory Elements In The Brain, Elisabeth A. Murphy
Student Theses and Dissertations
Advancements in DNA sequencing technology and the implementation of clinical genome and exome sequencing have allowed for the identification of candidate variants and genes essential in brain development and pathogenesis of neurological diseases, yet there is still much to be learned. It is estimated that the molecular diagnostic rate of whole exome sequencing (WES) of constitutional diseases is between 9-41%; however, it is thought that diagnostic yield could be much improved by gaining a better understanding of individual variation and regulation at the transcript level. Identifying the root cause of diversity between humans and specifically in the human brain has …
Restriction Of Food Intake By Dorsomedial Hypothalamus, Caner Caglar
Restriction Of Food Intake By Dorsomedial Hypothalamus, Caner Caglar
Student Theses and Dissertations
Leptin deficient ob/ob mice eat voraciously and their food intake is markedly reduced by leptin treatment. Leptin acts in part by regulating the activity of AGRP neurons and POMC neurons in the arcuate nucleus and neurons in other brain regions. In these dissertation, I will describe how we identify novel neuronal populations that are regulated by leptin directly or indirectly. In order to identify novel sites of leptin action, we used phosphotrap, to molecularly profile leptin responsive neurons in the hypothalamus and brain stem. In addition to identifying several known leptin responsive populations, we found that neurons in Dorsomedial Hypothalamus …
Interactions Between Microbial, Neuronal, And Immune Cells In The Digestive System, Fanny Matheis
Interactions Between Microbial, Neuronal, And Immune Cells In The Digestive System, Fanny Matheis
Student Theses and Dissertations
The intestine is the largest continuous environmental interface of the body. As such, it exerts homeostatic tissue functions, including digestion, sensing and absorption of nutrients, and excretion of waste products. In performing these roles, the intestine faces the unique challenge of remaining tolerant to harmless or beneficial diet- and microbederived stimuli, while simultaneously protecting against pathogen invasion. To tackle these challenges, the intestine houses both the body’s largest immune compartment, as well as a vast neuronal network, the enteric nervous system (ENS). In concert with the commensal intestinal microbiota, the enteric immune and nervous systems communicate with one another, and …
Finding Common Ground: The Common Marmoset As A Model To Accessing And Providing Insight Into The Social Brain, Margaret Fabiszak
Finding Common Ground: The Common Marmoset As A Model To Accessing And Providing Insight Into The Social Brain, Margaret Fabiszak
Student Theses and Dissertations
Utilizing the immense strengths of the common marmoset (Callithrix jacchus) as a model organism, we executed three efforts with the common goal of revealing key insights into dissecting the social brain. First, we examined the hypothesis that there is a neural, functional architecture underlying face processing. Faces form a unique category of stimuli that bridge visual perception and social cognition. They are processed in dedicated areas of cortex, face patches, which are organized into an interconnected network. While insight into neurons within face patches has been explored through extracellular electrophysiology, the functional architecture of local ensembles of cells has remained …
The Role Of Compartmentalized Metabolism In Cellular Metal Homeostasis, Ross A. Weber
The Role Of Compartmentalized Metabolism In Cellular Metal Homeostasis, Ross A. Weber
Student Theses and Dissertations
The building blocks of cells are usually thought to be DNA, RNA, and proteins. However, life, as we know it, is not possible without iron. While the list of iron’s vital cellular functions is extensive, iron is also quite cytotoxic. Thus, great pains have been taken, at the gene regulation level, to assure that a cell has sufficient iron to copy its genome and power its mitochondria but not too much to damage its membranes with lipid peroxides. Cellular organelles, which accompanied the rise of atmospheric oxygen and an increased need for iron, also play a key role in iron …
Pathogenic Characterization And Therapeutic Development For Fiblrolamellar Hepatocellular Carcinoma, Solomon N. Levin
Pathogenic Characterization And Therapeutic Development For Fiblrolamellar Hepatocellular Carcinoma, Solomon N. Levin
Student Theses and Dissertations
Fibrolamellar hepatocellular carcinoma (FLC) is a rare liver cancer that primarily affects adolescents and young adults. There are no known successful systemic chemotherapies for this disease, and thus, surgery is the only potential path to a cure in patients with FLC. Once the disease has grown or metastasized to a point where surgery is no longer an option, a patient’s chance for survival approaches zero. There is a recurrent genetic deletion in FLC cells, which has been found in almost all FLC tumor samples sequenced to date, but not in normal liver tissue from the same patients. The deletion encompasses …
Single-Molecule Investigation Of Chromatin-Associated Factors In Genome Organization And Epigenetic Maintenance, Rachel Leicher
Single-Molecule Investigation Of Chromatin-Associated Factors In Genome Organization And Epigenetic Maintenance, Rachel Leicher
Student Theses and Dissertations
The central dogma of biology has laid the foundation for understanding gene expression through the mechanisms of transcription and translation. However, another layer of eukaryotic gene regulation lies in the complex structure of chromatin. This scaffold of structural proteins and enzymatic regulators determines what genes are expressed at what times, leading to cell differentiation, cell fate, and often disease. Currently, the field of chromatin biology has relied on basic biochemistry and cellular assays to identify key epigenetic regulators and their role in genomic maintenance. For this thesis work, I have developed a biophysical platform to study chromatin-associated factors at the …
Developmental Dynamics Of 5-Hydroxymethylcytosine And Its Role In The Terminal Differentiation Of Neurons, Elitsa Stoyanova
Developmental Dynamics Of 5-Hydroxymethylcytosine And Its Role In The Terminal Differentiation Of Neurons, Elitsa Stoyanova
Student Theses and Dissertations
While epigenetic dynamics in mitotic differentiating cells have been characterized in depth, little is known about how postmitotic neurons regulate their chromatin state. Modulation of transcription through the regulation of accessibility of transcription factor binding sites is essential for the regulation of migration, synapse formation and terminal differentiation. Although 5-hydroxymethylcytosine (5hmC), the oxidized form of 5-methylcytosine, accumulates to high levels in neuronal lineages and refines the genomic binding of MeCP2, the functional consequences of 5hmC deposition in differentiating neurons have not been determined. We report high resolution characterization of the genomic landscape of developing postmitotic Purkinje neurons, confirm the relationship …
Transcriptional Regulation Of The Metabolic Response To Therapy In Leukemia, Robert Thomas Williams
Transcriptional Regulation Of The Metabolic Response To Therapy In Leukemia, Robert Thomas Williams
Student Theses and Dissertations
Cancer cells are under constant stress due to their uncontrolled growth, oncogenic signaling, and the metabolic insufficiencies of their microenvironments. Under various stresses, cells activate the integrated stress response (ISR), a transcriptional program to restore cellular homeostasis. Activating transcription factor 4 (ATF4) acts as the master transcriptional regulator of the ISR by promoting the transcription of genes that mitigate stress or promote cell death if the stress remains unresolved. Despite being the common mediator of various stress response and metabolic pathways, ATF4 generates tailored transcriptional outputs to distinct cellular stresses by cooperating with other transcriptional machinery. The precise mechanisms by …
Quantifying The Release Of Protein Substrates From Aaa+ Atpase Clpx By Single Molecule Total Internal Reflection Fluorescence Microscopy, Xiao Wang
Student Theses and Dissertations
The safe disposal of proteins is an essential process for maintaining proteostasis in cells. AAA+ proteases, such as proteasomes, play a major role in selective degradation of proteins. Degradation by AAA+ proteases typically requires the substrate to be physically unfolded before proteolysis. The efficiency of the unfolding process is hence a critical parameter for determining the turnover rate of the substrate. However, the mechanism by which force is utilized to unfold the protein substrate is not fully characterized. One parameter regulating the efficiency of the unfolding process is the rate by which a substrate is prematurely released before unfolded. Importantly, …
Chemical Tools For Exploring Metabolite Interactions With Nuclear Receptors And Beyond, Taku Tsukidate
Chemical Tools For Exploring Metabolite Interactions With Nuclear Receptors And Beyond, Taku Tsukidate
Student Theses and Dissertations
The identification and functional characterization of specific metabolite–protein interactions remains a major challenge in chemical biology and drug development. The functionalization of native metabolites and synthetic small molecules with bio-orthogonal detection tags (alkyne, azide, and others) has afforded chemical reporters for the biochemical analysis of metabolically labelled proteins, whereas functionalization with photo-crosslinkers enables non-covalent metabolite–protein interactions to be captured. While we and many others have employed this approach to different metabolites and synthetic ligands, the installation of bio-orthogonal detection tags and photo-crosslinkers to more complex and diverse small molecules can be challenging and limiting. In this regard, activity-based protein profiling …
Structural Study Of Disease Relevant Abc Transporters-Cystic Fibrosis Transmembrane Conductance Regulator And Abca4, Fangyu Liu
Student Theses and Dissertations
ATP-binding cassette (ABC) transporters are primary transporters that utilize the energy from ATP binding and hydrolysis to transport substrates across membrane against their concentration gradients [1]. Structurally, canonical ABC transporters consist of four subunits— two transmembrane domains (TMDs) which form the substrate transport pathway and two nucleotide binding domains (NBDs) which dimerize upon ATP binding to provide energy for substrate transport. Most mammalian ABC transporters are exporters, with three exceptions: SUR—a regulatory protein for the KATP channel, cystic fibrosis transmembrane conductance regulator (CFTR)—an chloride channel and ABCA4 (aka the Rim protein and ABCR)—an retinylidene-PE importer [1-3]. In addition to their …
Cerebral Amyloid Angiopathy-Causing Beta-Amyloid Variants Have Altered Effects On The Clotting System, Steven Cajamarca
Cerebral Amyloid Angiopathy-Causing Beta-Amyloid Variants Have Altered Effects On The Clotting System, Steven Cajamarca
Student Theses and Dissertations
Cerebral amyloid angiopathy (CAA), where beta-amyloid (Aβ) deposits around cerebral blood vessels, is a major contributor of vascular dysfunction in Alzheimer’s disease (AD) patients. However, the molecular mechanism underlying CAA formation and CAA-induced cerebrovascular pathologies, including intracerebral hemorrhage (ICH) is unclear. Hereditary cerebral amyloid angiopathy (HCAA) is a rare familial form of CAA in which mutations within the Aβ peptide cause an increase in vascular deposits. Since the interaction between normal wild-type (WT) Aβ and fibrinogen increases CAA and plays an important role in cerebrovascular damage in AD, I investigated the role of the Aβ-fibrinogen interaction in HCAA pathology. My …
Characterizing Inflammatory Mechanisms In Hidradenitis Suppurativa, Kristina Navrazhina
Characterizing Inflammatory Mechanisms In Hidradenitis Suppurativa, Kristina Navrazhina
Student Theses and Dissertations
Hidradenitis suppurativa (HS) is an inflammatory skin disease manifesting in painful nodules and abscesses, and malodorous draining tunnels in more advanced disease. Effective treatment options remain limited, with Tumor Necrosis Factor inhibitor adalimumab remaining the only approved biologic despite its limited efficacy. The development of novel therapeutics is impeded by our lack of understanding of disease pathogenesis and an absence of standardized approaches to study HS. In this thesis, we establish a translational approach to characterize HS by examining nonlesional, perilesional and lesional HS skin in comparison to site-matched control skin from healthy volunteers. We demonstrate that relatively healthy-appearing perilesional …
The Identification Of A Leptin Dependent Neural Pathway Regulating Adipose Tissue Innervation, Putianqi Wang
The Identification Of A Leptin Dependent Neural Pathway Regulating Adipose Tissue Innervation, Putianqi Wang
Student Theses and Dissertations
Leptin, secreted by the adipose tissue, is an afferent signal of a negative feedback loop that regulates body weight balance through its effects on feeding and energy expenditure. Mutations in the leptin gene or its cognate receptor result in severe obesity in both human and mice. My thesis work revealed a leptin-dependent, plastic pathway spanning the central to peripheral nervous system that is responsible for regulating energy homeostasis in mice. Leptin deficient (ob/ob) mice accumulate excessive fat mass due to increased food intake, and decreased energy expenditure partially as a result of defective fat utilization. Chronic leptin delivery to ob/ob …