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Full-Text Articles in Life Sciences
Small-Molecule Activation Of Yap For Inner-Ear Regeneration And Beyond, Nathaniel Kastan
Small-Molecule Activation Of Yap For Inner-Ear Regeneration And Beyond, Nathaniel Kastan
Student Theses and Dissertations
Hippo signaling is an evolutionarily conserved pathway that restricts organ growth during development and suppresses regeneration in mature organs. Using a highthroughput phenotypic screen, we have identified a potent, non-toxic, and reversible inhibitor of Hippo signaling. An ATP-competitive inhibitor of Lats kinases, the compound causes Yap-dependent proliferation of murine supporting cells in the inner ear, murine cardiomyocytes, and human Müller glia in retinal organoids. The compound promotes the initial stages of the proliferative regeneration of hair cells, a process thought to be permanently suppressed in the adult mammalian inner ear. In conjunction with the Tri- Institutional Therapeutics Discovery Institute, we …
Germline Genetic Determination Of Cancer Outcome, Benjamin N. Ostendorf
Germline Genetic Determination Of Cancer Outcome, Benjamin N. Ostendorf
Student Theses and Dissertations
Immunotherapy has transformed the treatment of melanoma patients. However, despite the enormous promise of immunotherapy, a major fraction of patients with advanced melanoma still succumb to this deadly disease. In addition, systemic immunotherapy can lead to relevant toxicities. Therefore, it is an unmet need to identify the factors that modulate the outcome and response to therapy of melanoma patients. One major factor accounting for individual differences in the host response to cancer is the genetic makeup of the germline. A thorough assessment of the role of germline genetics in melanoma outcome is lacking, partly because of the difficulty in assessing …
Blood-Derived Plasminogen Modulates The Neuroimmune Response In Both Alzheimer's Disease And Systemic Infection Models, Sarah K. Baker
Blood-Derived Plasminogen Modulates The Neuroimmune Response In Both Alzheimer's Disease And Systemic Infection Models, Sarah K. Baker
Student Theses and Dissertations
Alzheimer’s disease (AD) is a progressive neurodegenerative disease that affects 44 million people worldwide. To date, there are no effective treatments that prevent progression or death from the disease. It is clear that AD development is multifactorial and can arise from genetic or lifestyle factors and that vascular dysfunction and inflammation play a role in the progression of the disease. Many cardiovascular factors associated with an increase in systemic infection have been linked to a risk of AD development and progression. However, the link between vascular risk factors, systemic inflammation, and the neuroinflammation characteristic of AD are not fully understood. …
Cas9-Primed Adaptive Immunity During The Crispr-Cas Response, Philip M. Nussenzweig
Cas9-Primed Adaptive Immunity During The Crispr-Cas Response, Philip M. Nussenzweig
Student Theses and Dissertations
Prokaryotes have developed numerous defense strategies to combat the constant threat of viruses (bacteriophages) that endanger them. Clustered, regularly interspaced short palindromic repeats (CRISPR) loci provide archaea and bacteria with adaptive immune systems that allow them to counteract these rapidly evolving genetic parasites. These diverse systems all generally contain two components: a set of CRISPR-associated (cas) genes and a series of repetitive DNA elements intercalated with variable sequences known as spacers. Following viral infection, these sequences are acquired from the viral genome and integrated in the CRISPR array as new spacers. Spacers are then transcribed into CRISPR RNAs (crRNAs) that …
Small Molecule Activation Of Yap For Inner-Ear Regeneration And Beyond, Nathaniel Kastan
Small Molecule Activation Of Yap For Inner-Ear Regeneration And Beyond, Nathaniel Kastan
Student Theses and Dissertations
Hippo signaling is an evolutionarily conserved pathway that restricts organ growth during development and suppresses regeneration in mature organs. Using a highthroughput phenotypic screen, we have identified a potent, non-toxic, and reversible inhibitor of Hippo signaling. An ATP-competitive inhibitor of Lats kinases, the compound causes Yap-dependent proliferation of murine supporting cells in the inner ear, murine cardiomyocytes, and human Müller glia in retinal organoids. The compound promotes the initial stages of the proliferative regeneration of hair cells, a process thought to be permanently suppressed in the adult mammalian inner ear. In conjunction with the Tri- Institutional Therapeutics Discovery Institute, we …
Diverse Kappa Opioid Receptor Agonists: Relationships Between Signaling And Behavior, Amelia Dunn
Diverse Kappa Opioid Receptor Agonists: Relationships Between Signaling And Behavior, Amelia Dunn
Student Theses and Dissertations
The opioid system, comprised mainly of the three opioid receptors (kappa, mu and delta) and their endogenous neuropeptide ligands (dynorphin, endorphin and enkephalin, respectively), mediates mood and reward. Activation of the mu opioid receptor is associated with positive reward and euphoria, while activation of the kappa opioid receptor (KOR) has the opposite effect. Activation of the KOR causes a decrease in dopamine levels in reward-related regions of the brain, and can block the rewarding effects of various drugs of abuse, making it a potential drug target for addictive diseases. KOR agonists are of particular interest for the treatment of cocaine …
Hybridization In Ants, Ian Butler
Hybridization In Ants, Ian Butler
Student Theses and Dissertations
Interspecific hybridization is a relatively common occurrence within all animal groups. Two main factors make hybridization act differently in ants than in other species: eusociality and haplodiploidy. These factors serve to reduce the costs of interspecific hybridization in ants while simultaneously allowing them to take advantage of certain benefits. Eusociality may mitigate the effects of hybridization by allowing hybrids to be shunted into the worker caste, potentially reducing the effects of hybrid sterility. In haplodiploid species, males do not have a father. They instead develop from unfertilized eggs as haploid clones of their mother. This means that interspecifically mated queens …
Identification Of Previously Unknown Interactions Between G Protein-Coupled Receptors And Receptor Activity-Modifying Proteins, Emily Margaretha Lorenzen
Identification Of Previously Unknown Interactions Between G Protein-Coupled Receptors And Receptor Activity-Modifying Proteins, Emily Margaretha Lorenzen
Student Theses and Dissertations
G protein-coupled receptors (GPCRs) are known to interact with several other classes of integral membrane proteins. However, the extent of these interactions and their role in regulating GPCR-mediated transmembrane signaling is not well understood. For example, receptor activitymodifying proteins (RAMPs), a family of single transmembrane proteins with only three members, are ubiquitously expressed and have been shown to interact with several different GPCRs. Most research to date has focused on the ability of RAMPs to modulate the function of several GPCRs in the secretin-like GPCR family. GPCR-RAMP interactions were shown to affect the ligand binding affinity of two different secretin-like …
Structural And Functional Studies Of The Unconventional Proteobacterial Transcription Activator Crl In Complex With The Transcription Machinery, Alexis Jaramillo Cartagena
Structural And Functional Studies Of The Unconventional Proteobacterial Transcription Activator Crl In Complex With The Transcription Machinery, Alexis Jaramillo Cartagena
Student Theses and Dissertations
The σS subunit of RNA polymerase (RNAP) is the master regulator of stress responses in many Gram-negative bacteria. This alternative σ factor assembles with the core RNA polymerase to initiate the transcription of genes needed to survive different environmental changes. Crl is a small protein that activates the transcription of σSdependent genes. In contrast to most transcription activators, Crl does not bind DNA to help recruit RNA polymerase and instead interacts directly with σS. At the outset of my research, little was known about how the binding of Crl to σS leads to transcription activation. It was not clear if …
Monogenic Defects Of The Type 1 Interferon Signaling Pathway In Human: Molecular And Clinical Implications, Nicholas Hernandez
Monogenic Defects Of The Type 1 Interferon Signaling Pathway In Human: Molecular And Clinical Implications, Nicholas Hernandez
Student Theses and Dissertations
The germ theory of disease, which dictates that microorganisms colloquially referred to as “germs” can invade humans or other hosts and cause disease, has remained the dominant conceptualization of infectious disease since the late nineteenth century. Since that time, growing appreciation for the extent of subclinical infections, that is, infections where the germ is detectable in its host without causing overt disease, and the Mendelian inheritance patterns of some infectious diseases have reinvigorated the study of the human genetic basis of infectious disease. This theory, so far demonstrated for a number of bacterial, fungal, and viral infections, holds that germs …
Cell Memory And Fate In Human Development, Anna Kresovich Yoney
Cell Memory And Fate In Human Development, Anna Kresovich Yoney
Student Theses and Dissertations
No abstract provided.
Chemical Biology Of Dynein, Cristina C. Santarossa
Chemical Biology Of Dynein, Cristina C. Santarossa
Student Theses and Dissertations
Cytoplasmic dynein is a AAA (ATPase Associated with various Activities) motor protein that transports cellular cargoes towards the microtubule minus-end. Despite its essential role in intracellular transport, dynein remains the least understood cytoskeletal motor. With speeds >25 μm/min in cells, dynein’s cellular functions are challenging to study using genetic approaches, such as CRISPR and RNA interference, as the perturbation timescales far exceed those of dynein action. Fast-acting small molecule probes can be powerful tools to study dynein’s many cellular mechanisms, but the design of potent and selective inhibitors of dynein remains challenging. Inhibitors of dynein’s motor domain have been reported, …
Time-Restricted Feeding Extends Longevity In Drosophila Melanogaster, Daniel Cabrera
Time-Restricted Feeding Extends Longevity In Drosophila Melanogaster, Daniel Cabrera
Student Theses and Dissertations
Time-restricted feeding (TRF) is a dietary intervention in which daily feeding patterns align with behavioral patterns, synchronizing feeding times with periods of higher activity, e.g. humans eating only during the day or rodents (nocturnal animals) at night. TRF has been shown to improve cardiac health in Drosophila melanogaster, reduce metabolic markers in rodent models, and reduce glycemic indices in prediabetic men. However, the mechanism and long-term effects of this intervention remain elusive. To understand the effect of TRF on longevity we used the fruit fly Drosophila melanogaster, which is a useful model for longevity, sleep and circadian studies because of …
Genetic Functional Dissection Of The Synaptic Output Of A Dual-Function Integrating Neuron, Aylesse Sordillo
Genetic Functional Dissection Of The Synaptic Output Of A Dual-Function Integrating Neuron, Aylesse Sordillo
Student Theses and Dissertations
Animals must vary their behavior in response to changes in their environment, but behavior also remains consistent over time. This thesis focuses on a single interneuron, RIM, and a single behavior, the reversal, to better understand how the circuits driving motor outputs accomplish the seemingly contradictory tasks of generating appropriate and variable behaviors. In the compact and well-defined nervous system of C. elegans, the interneuron RIM is an important part of the reversal behavior circuit that contributes to sensory integration, behavioral variability, generation of behavioral states, and learning. RIM releases both glutamate and the biogenic amine tyramine (~noradrenaline) and forms …
Ddi1/2 And Rtf2-Dependent Regulation Of Rnase H2 At The Replisome Ensures Genome Stability, Brooke A. Conti
Ddi1/2 And Rtf2-Dependent Regulation Of Rnase H2 At The Replisome Ensures Genome Stability, Brooke A. Conti
Student Theses and Dissertations
Proteasome shuttle proteins, DNA Damage Inducible 1 (DDI1) and DNA Damage Inducible 2 (DDI2), are active in the replication stress response (Kottemann et al., 2018). Under conditions of replication stress, DDI1/2 function to remove Replication Termination Factor 2 (RTF2) from the replisome. Persistence of RTF2 at the replisome compromises the replication stress response, resulting in accumulation of single-stranded DNA, inefficient replication fork restart, genome instability, and cell death. During unperturbed replication, RTF2 travels with the replication fork (Kottemann et al., 2018). Here we examine the function of RTF2 and address why RTF2’s removal from the replisome is necessary for recovery …
Molecular Characterization Of Mammalian De Novo Dna Methyltransferase Chromatin Recruitment, Daniel N. Weinberg
Molecular Characterization Of Mammalian De Novo Dna Methyltransferase Chromatin Recruitment, Daniel N. Weinberg
Student Theses and Dissertations
Precise deposition of CpG methylation is critical for mammalian development and tissue homeostasis and is often dysregulated in human diseases. The genomic localization of de novo DNA methyltransferases 3A (DNMT3A) and 3B (DNMT3B) is facilitated in part by chromatin “reader” domains to establish DNA methylation patterns genome-wide. Recent work has highlighted a role for the PWWP reader domain in directing recruitment of DNMT3B to actively transcribed gene bodies. However, our understanding of de novo DNA methyltransferase chromatin recruitment remains incomplete. Here I demonstrate using a variety of biochemical and cellular techniques that DNMT3A genomic localization is regulated by competing chromatin …
Visualizing Protease Activation, Retrochmp3 Activity, And Vpr Recruitment During Hiv-1 Assembly, Kate Bredbenner
Visualizing Protease Activation, Retrochmp3 Activity, And Vpr Recruitment During Hiv-1 Assembly, Kate Bredbenner
Student Theses and Dissertations
This thesis covers my contributions to the field of HIV-1 assembly and the field of science communication. Over the course of my studies, I have determined when the HIV-1 protease becomes active during the assembly of new virions, elucidated the mechanism by which the protein retroCHMP3 has an antiviral function, and examined the kinetics of recruitment of the HIV-1 accessory protein Vpr. I have also added significantly to science communication research through a study which evaluated the effectiveness of science summary methods. HIV-1 virions assemble at the plasma membrane of infected cells. The assembly of new viruses is driven by …
Testing The T-Loop Model Of Telomeric End Protection, Leonid Alexeevich Timashev
Testing The T-Loop Model Of Telomeric End Protection, Leonid Alexeevich Timashev
Student Theses and Dissertations
Telomeres are the key structures that protect the ends of linear chromosomes. Although they are often thought about in the context of cellular aging, their most important role is actually to protect the end of the DNA from being mis-interpreted as a site of DNA damage. Telomeres are thought to accomplish this through the action of shelterin. Shelterin is a multi-protein complex where each subunit is dedicated to a specific role in repressing a form of DNA damage signaling, repair, or recruiting telomerase to extend the telomere end. One of the critical anchor points of shelterin is a protein known …
Monogenic Defects Of The Type I Interferons Signaling Pathway In Humans: Molecular And Clinical Implications, Nicholas Hernandez
Monogenic Defects Of The Type I Interferons Signaling Pathway In Humans: Molecular And Clinical Implications, Nicholas Hernandez
Student Theses and Dissertations
The germ theory of disease, which dictates that microorganisms colloquially referred to as “germs” can invade humans or other hosts and cause disease, has remained the dominant conceptualization of infectious disease since the late nineteenth century. Since that time, growing appreciation for the extent of subclinical infections, that is, infections where the germ is detectable in its host without causing overt disease, and the Mendelian inheritance patterns of some infectious diseases have reinvigorated the study of the human genetic basis of infectious disease. This theory, so far demonstrated for a number of bacterial, fungal, and viral infections, holds that germs …
Cryo-Em Studies Of Bacterial Rna Polymerase, James Chen
Cryo-Em Studies Of Bacterial Rna Polymerase, James Chen
Student Theses and Dissertations
In bacteria, a single RNA polymerase (RNAP) performs all transcription. The overall structure of bacterial RNAP resembles a crab claw with pincers comprising the β’ and β subunits and a large cleft where the active site sits. Structural information about this essential enzyme has mainly been provided by X-ray crystal structures of stable transcription complexes. RNAP crystal structures are difficult to obtain and the captured states may not always represent physiological states of the enzyme due to crystal packing artifacts. Recent advances in electron detectors and software enable near-atomic resolution structures of large biological complexes to be determined by single …
Mechanisms Of Evasion: Anti-Tumor Immune Suppression & Trna-Dependent Growth In Cancer Metastasis, Lisa Brooke Noble
Mechanisms Of Evasion: Anti-Tumor Immune Suppression & Trna-Dependent Growth In Cancer Metastasis, Lisa Brooke Noble
Student Theses and Dissertations
Metastatic disease presents diverse therapeutic challenges for cancer patients, clinicians, and scientists. Cancer cells have developed sophisticated mechanisms of evasion to survive the selective pressures provided by the metastatic cascade. Two themes of success encompass modulating their surrounding microenvironment, or manipulating cell autonomous regulatory programs not intended for differentiated somatic cells. Both challenges are addressed in this body of work which focus on gastrointestinal and breast cancer metastasis. During cancer progression, tumour cells employ mechanisms that suppress both adaptive and innate immune responses. While our understanding of the molecular basis of adaptive immune suppression by cancer cells has led to …
Molecular Mechanisms And Antigen Receptor Requirements For Lymphocyte Adaptation To Intestinal Tissues, Mariya B. London
Molecular Mechanisms And Antigen Receptor Requirements For Lymphocyte Adaptation To Intestinal Tissues, Mariya B. London
Student Theses and Dissertations
The intestine plays a crucial role in food digestion, nutrient absorption, water retention, and waste excretion. It contains the most populous immune cell reservoir in the body and is continuously exposed to a large and diverse number of diet- and microbiota- derived antigens. The highly stimulating luminal environment is separated from the core of the body, the lamina propria (LP), by just a single layer of epithelial cells. The intestinal immune system is thus tasked with being able to tolerate innocuous stimuli while mounting an effective response against potential pathogens in a controlled manner. To ensure appropriate balance between tolerance …
Dissection Of Neurons And Circuits Involved In Regulating Innate Behaviors, Movement And Higher Cognitive Functions In Mice, Luca Parolari
Dissection Of Neurons And Circuits Involved In Regulating Innate Behaviors, Movement And Higher Cognitive Functions In Mice, Luca Parolari
Student Theses and Dissertations
Elucidating the mechanisms through which brain circuits influence behavior is a fundamental tenet of Systems Neuroscience. Advancements in this field are critical to help us understand the inner workings of our brains, and eventually who we are as humans. Describing the physiologic functioning of neural circuits is also necessary to recognize their malfunctions, and to develop strategies to correct them. In many cases, however, alterations in the activity of brainwide circuits can be traced back to specific neuronal populations, and acting selectively upon these cells can restore the normal activity within the system, ultimately correcting the aberrant behavior. Thus, understanding …
Characterizing The Rna Editing Specificityof Adar Isoforms And Deaminase Domains In Vitro, Mariel Therese Bartley
Characterizing The Rna Editing Specificityof Adar Isoforms And Deaminase Domains In Vitro, Mariel Therese Bartley
Student Theses and Dissertations
Adenosine deaminases acting on RNA (ADARs) convert adenosine-to-inosine in double stranded RNA. Selectivity of editing sites depends on the sequence of the RNA as well as the secondary structure. Identification of sites of ADAR editing by editome analysis is skewed due to the different abundance of each adenosine-containing triplet, as well as the presence of complex RNA structures. To determine the editing specificity of each ADAR protein, a high throughput sequencing based assay was developed to measure editing in a synthetic dsRNA substrate with one of each of the 16 different adenosine-containing triplets, so that each possible editing site was …
The Role Of Adipocytes In The Tumor Microenvironment In Obesity-Driven Breast Cancer Progression, Sarah Ackerman
The Role Of Adipocytes In The Tumor Microenvironment In Obesity-Driven Breast Cancer Progression, Sarah Ackerman
Student Theses and Dissertations
Obesity affects more than 1 in 3 adults in the United States and has been shown to increase the relative risk of death for women with breast cancer and to increase the risk of developing breast cancer in post-menopausal women. Breast cancer develops in an environment containing white adipose tissue (WAT) which predominately consists of mature white adipocytes. In obesity, WAT undergoes hypertrophy and hyperplasia and can ultimately develop hypoxia, insulin resistance, inflammation, and dysregulated endocrine function. Since obesity directly affects WAT, we hypothesized that molecular changes in white adipocytes in the tumor microenvironment contribute to breast cancer progression. We …
Crispr/Caste: Functional Genomic Studies Of The Major Evolutionary Innovations Of Ants, Waring Trible
Crispr/Caste: Functional Genomic Studies Of The Major Evolutionary Innovations Of Ants, Waring Trible
Student Theses and Dissertations
Ants are social organisms that live in groups and depend intimately on their nestmates for growth and survival. Ants have evolved a number of highly sophisticated, social phenotypes that allow them to form coherent colonies. This thesis explores two particularly derived features of ant biology: complex chemical communication and caste plasticity. To study these features, I had a particular focus on generating and characterizing germ-line mutants. I believe that the study of mutants, and applying molecular biology methods more generally, can lead to insights in ant biology that would not be possible with more traditional methods. I first describe my …
Analyzing Resistance To Design Chemical Inhibitors Of Aaa Proteins, Rudolf Pisa
Analyzing Resistance To Design Chemical Inhibitors Of Aaa Proteins, Rudolf Pisa
Student Theses and Dissertations
Chemotype-specific resistance is a major factor limiting the efficacy of molecularly targeted therapeutics. Analyses of resistance mechanisms to drugs reveal that mutations conferring resistance often arise in the drug’s binding sites. As selective binding of inhibitors to their protein targets is mediated by specific interactions of the inhibitor with the protein backbone and side chains, mutations that disrupt these interactions can lead to resistance. Identifying resistance-conferring alleles can thus reveal and suggest the biochemical determinants of the drug’s selectivity and potency. In this thesis, I explore how mutations in active sites of proteins can be leveraged to understand inhibitor binding …
A Role For Mindbomb 1 In Adenovirus Genome Delivery, Stephanie Sarbanes
A Role For Mindbomb 1 In Adenovirus Genome Delivery, Stephanie Sarbanes
Student Theses and Dissertations
The journey from plasma membrane to nuclear pore is a critical step in the lifecycle of DNA viruses, many of which must successfully deposit their genomes into the nucleus for replication. Viral capsids strategically navigate this vast distance (and all subsequent lifecycle steps) through the coordinated hijacking of a number of cellular proteins subsequently termed host factors. Given the virus’ dependence on these proteins, host factors therefore represent valuable targets for therapeutic interventions. Still, the identity and function of many of these factors remains unknown. In this body of work, I will detail our own journey from initial identification to …
Identification Of Gene Expression Changes In Sleep Mutants Associated With Reduced Longevity In Drosophila, Zikun Wang
Identification Of Gene Expression Changes In Sleep Mutants Associated With Reduced Longevity In Drosophila, Zikun Wang
Student Theses and Dissertations
Sleep deprivation has become a common problem in modern society, yet the physiological consequences of sleep deprivation remain poorly understood. Sleep disruption has been shown to shorten lifespan in multiple animal species. In my thesis study, I investigated the relationship between sleep and longevity using Drosophila melanogaster. By analyzing the sleep and longevity profiles from a panel of sleep mutants, I discovered a robust positive correlation between daily sleep time and median longevity. This discovery led to my hypothesis that sleep disruption as a result of genetic mutation would elicit certain gene expression changes that ultimately would lead to shortened …
A Network Approach To Understanding Mirna Regulation In Adipose Tissue, Sean O’Connor
A Network Approach To Understanding Mirna Regulation In Adipose Tissue, Sean O’Connor
Student Theses and Dissertations
Adipose tissue is a complex organ that is essential for lipid storage and energy homeostasis in mammals. While transcription factors that govern adipogenesis, inflammation, non-shivering thermogenesis, and endocrine function in fat tissue have been well-described, comparatively less attention has been given to post-transcriptional regulators. Here, we employ two contrasting approaches to identify miRNAs that influence adipocyte phenotype. First, miRNAs were sequenced from 6 fat pads, primary preadipocytes, and primary mature adipocytes. Comparative analyses of abundance across adipose tissue type and stage of differentiation revealed a number of miRNAs that influence key metabolic processes. miR-335 inhibited adipogenesis, miR-192 promoted pro-thermogenic and …