Life Sciences Commons^™

Investigating The Mechanisms Of Surface Sensing Using Motility Appendages By Pseudomonas Aeruginosa Pa14, Christopher James Geiger

Dartmouth College Ph.D Dissertations

Biofilms are surfaced attached communities of cells encased in an extracellular matrix. The transition from free-swimming planktonic cells to a surface attached biofilm begins with cellular changes that occur after surface contact. This process is known as "surface sensing" and the opportunistic pathogen Pseudomonas aeruginosa PA14 uses its two motility appendages, type IV pili (T4P) and a single, polar flagellum to sense and traverse surfaces. The first cellular changes to occur within this organism upon surface contact is an increase in the second messengers cAMP and cdi- GMP. While the genes involved in surface sensing by P. aeruginosa are known, …

Elucidating Neuroinflammation In Multiple Sclerosis By Network Analysis, Nora C. Welsh

Dartmouth College Ph.D Dissertations

Multiple sclerosis (MS) is a heterogeneous disease, differing on many variables, including disease course, sex, and overall activity. Key characteristics of the disease encompass demyelination, axonal damage, neuronal loss, glial cell activation, and the infiltration of peripheral immune cells. Molecular proxies of these functions are secreted proteins, including cytokines and immunoglobulins, which, in the central nervous system (CNS), can be secreted into the cerebrospinal fluid (CSF). A detailed analysis of these secreted proteins can offer insights into the evolving immunological and neurodegenerative features as the disease progresses. To understand the dynamic biological processes involved in MS, I used network analysis …

Estrogen Receptor (Er) Alpha Regulatory Mechanisms And Therapeutic Strategies In Er+ Breast Cancer, Bianca A. Romo

Dartmouth College Ph.D Dissertations

Breast cancer is among the most frequently diagnosed cancers in the U.S. and is one of the leading causes of cancer-related mortalities, second to lung cancer. Estrogen receptor alpha-positive (ER+) breast cancer accounts for 2/3 of diagnosed cases. Patients diagnosed with this subtype of breast cancer typically undergo endocrine therapy that aims to mitigate the growth-promoting effects of estrogen/ER. While therapies are effective, 1/3 of patients will experience recurrence. To begin addressing this drug-resistant patient population, we investigated potential drug targets involved in response to treatment.

Coregulators have been implicated in the regulation of ER transcriptional activity and subsequently affecting …

Target Selection And Enhancement During Attentional Tracking, Marvin R. Maechler

Dartmouth College Ph.D Dissertations

At any waking moment, we are bombarded with more sensory information than we can fully process. Attention is necessary to deal with the dynamic world we live in. One fundamental function of vision and attention is to keep track of moving objects, but what are the targets of attention during tracking?

One of the first theories of attentional tracking predicted that targets would be selected at early processing stages. By employing the double-drift illusion, which dissociates physical and perceived positions of moving objects, we investigated which of these positions is selected for tracking. Contrary to earlier theories and in line …

Dna Methylation-Based Epigenetic Biomarkers In Cell-Type Deconvolution And Tumor Tissue Of Origin Identification, Ze Zhang

Dartmouth College Ph.D Dissertations

DNA methylation is an epigenetic modification that regulates gene expression and is essential to establishing and preserving cellular identity. Genome-wide DNA methylation arrays provide a standardized and cost-effective approach to measuring DNA methylation. When combined with a cell-type reference library, DNA methylation measures allow the assessment of underlying cell-type proportions in heterogeneous mixtures. This approach, known as DNA methylation deconvolution or methylation cytometry, offers a standardized and cost-effective method for evaluating cell-type proportions. While this approach has succeeded in discerning cell types in various human tissues like blood, brain, tumors, skin, breast, and buccal swabs, the existing methods have major …

Tracing Evolution Of Gene Transfer Agents Using Comparative Genomics, Roman Kogay

Dartmouth College Ph.D Dissertations

The accumulating evidence suggest that viruses and their components can be domesticated by their hosts, equipping them with convenient molecular toolkits for various functions. One of such domesticated system is Gene Transfer Agents (GTAs) that are produced by some bacteria and archaea. GTAs morphologically resemble small phage-like particles and contain random fragments of their host genome. They are produced only by a small fraction of the microbial population and are released through a lysis of the host cell. Bioinformatic analyses suggest that GTAs are especially abundant in the taxonomic class of Alphaproteobacteria, where they are vertically inherited and evolve …

Oligodendrocyte 2phatal Reveals Dynamics Of Myelin Degeneration And Repair, Timothy W. Chapman

Dartmouth College Ph.D Dissertations

Oligodendrocytes are responsible for producing myelin in the central nervous system. This lipid-rich coating along axons helps to increase action potential velocity, provide metabolic support to axons, and facilitate fine-tuning of neuronal circuitry. Demyelination and/or myelin dysfunction is widespread in neurodegenerative diseases and aging. Despite this, we know very little about how individual oligodendrocytes, or the myelin sheaths they produce, degenerate. Myelin repair, carried out by resident oligodendrocyte precursor cells (OPCs), is known to occur following myelin damage in certain contexts. We sought to investigate the cellular dynamics of oligodendrocyte degeneration and repair by developing a non-inflammatory demyelination model, combining …

Self-Supervised Pretraining And Transfer Learning On Fmri Data With Transformers, Sean Paulsen

Dartmouth College Ph.D Dissertations

Transfer learning is a machine learning technique founded on the idea that knowledge acquired by a model during “pretraining” on a source task can be transferred to the learning of a target task. Successful transfer learning can result in improved performance, faster convergence, and reduced demand for data. This technique is particularly desirable for the task of brain decoding in the domain of functional magnetic resonance imaging (fMRI), wherein even the most modern machine learning methods can struggle to decode labelled features of brain images. This challenge is due to the highly complex underlying signal, physical and neurological differences between …

Genome-Scale Methylation Analysis In Blood And Tumor Identifies Immune Profile, Age Acceleration, And Dna Methylation Alterations Associated With Bladder Cancer Outcomes, Ji-Qing Chen

Dartmouth College Ph.D Dissertations

Bladder cancer patients receive frequent screening due to the high tumor recurrence rate (more than 60%). Nowadays, the conventional monitoring method relies on cystoscopy which is highly invasive and increases patient morbidity and burden to the health care system with frequent follow-up. As a result, it is urgent to explore novel markers related to the outcomes of bladder cancer. Immune profiles have been associated with cancer outcomes and may have the potential to be biomarkers for outcomes management. However, little work has been conducted to investigate the associations of immune cell profiles with bladder cancer outcomes. Here, I utilized the …

Proteomic Approaches To Identify Unique And Shared Substrates Among Kinase Family Members, Charles Lincoln Howarth

Dartmouth College Ph.D Dissertations

Protein phosphorylation is a reversible post-translational modification that is a critical component of almost all signaling pathways. Kinases regulate substrate proteins through phosphorylation, and nearly all proteins are phosphorylated to some extent. Crucially, breakdown in phosphorylation signaling is an underlying factor in many diseases, including cancer. Understanding how phosphorylation signaling mediates cellular pathways is crucial for understanding cell biology and human disease.

Targeted protein degradation (TPD) is a strategy to rapidly deplete a protein of interest (POI) and is applicable to any gene that is amenable to CRISPR-Cas9 editing. One TPD approach is the auxin-inducible degron (AID) system, which relies …

Regulation Of The Wnt/Wingless Receptor Lrp6/Arrow By The Deubiquitylating Complex Usp46, Zachary T. Spencer

Dartmouth College Ph.D Dissertations

The evolutionarily conserved Wnt/Wingless signal transduction pathway is critical for the proper development of all animals and implicated in numerous diseases in adulthood. Upon binding of the Wnt/Wingless ligand, a cascade of events culminates in inactivation of the destruction complex, a negative regulator of the pathway, and the subsequent formation of singalosomes which mediate pathway activation. A critical component of signalosome formation is the Wnt/Wingless receptor LRP6/Arrow. Upon canonical pathway activation, LRP6/Arrow undergoes activation via phosphorylation by several kinases and complexes with another Wnt/Wingless receptor Frizzled, along with several cytoplasmic components. While many studies have investigated the regulatory mechanisms of …

Complement System In Multiple Sclerosis: Its Role In Disease Course And Potential As A Therapeutic Target, Michael R. Linzey

Dartmouth College Ph.D Dissertations

Multiple sclerosis (MS) is a clinically heterogeneous neurological condition characterized by neuroinflammation and neurodegeneration. Relapsing-remitting MS, defined by inflammatory attacks, is the most common initial form of MS and there are currently 23 FDA-approved treatments for these patients. These therapies work primarily by reducing inflammation in the CNS; they do not work well in progressive disease. Therefore, an unmet medical need exists for effective therapeutic options to treat progressive MS (PMS).

In MS, intrathecal immunoglobulins synthesis (IIgS) correlates with disease progression. My goals for this dissertation were to establish the pathological role of IIgS and identify new potential therapeutic …

Soil Respiration Measurements Reveal High Retention Of Organic Carbon From Corn Residue Derived High-Lignin Fermentation Byproduct Enabling Sustainable Lignocellulosic Biofuel Production, Michelle Sun Wang

Dartmouth College Master’s Theses

While 2G biofuel production can utilize non-edible, lignocellulosic feedstocks such as agricultural residues to produce liquid fuel, harvesting crop residues is unsustainable without careful management of the soil underneath. By harvesting a fraction of the crop residues left in the field after harvest, soil health can diminish and critically, the soil organic carbon (SOC) stored in agricultural fields can decrease. Currently, in the most popular 2G process models published, the issue of soil degradation remains unresolved with residue harvest strategies receiving considerable attention in the literature and other SOC management strategies receiving far less. Specifically, the strategy of returning the …

Behavioral And Neural Mechanisms Of Serotonin Modulation Of Impulsivity And Reward, Stephanie S. Desrochers

Dartmouth College Ph.D Dissertations

Despite its prevalence in many psychiatric disorders, such as attention deficit hyperactivity disorder, suicidal depression, schizophrenia, and aggression and motivational disorders, impulsivity and its biological bases remain poorly understood. Subdivisions of impulsivity, including impulsive action (reduced response inhibition) and impulsive choice (reduced delay of gratification), sometimes present in an uncorrelated manner. This complexity renders pathological impulsivity difficult to treat, as different underlying causes likely result in different phenotypic presentations, despite being placed under one umbrella term. In order to study the behavior and biology of one particular facet of impulsivity, this dissertation utilizes the serotonin 1B receptor (5-HT1BR; an inhibitory …

Understanding The Implications Of Lineage Plasticity In Breast Cancer Evolution And Chemotherapy Response, Gadisti Aisha Mohamed

Dartmouth College Ph.D Dissertations

Intra-tumoral heterogeneity and the presence of a phenotypically diverse cell population within a single tumor represents a major hurdle in the understanding of tumor progression and dynamics, and complicates the effective diagnosis and management of this disease. One of the ways by which tumors gain intra-tumoral variation is through the acquisition of phenotypic or lineage plasticity, whereby tumor cells evolve away from the lineage of origin and gain altered profiles. These alterations may impart specific survival benefits to different subpopulations of cells, enabling them to proliferate faster, migrate away from the site of the primary tumor or evade drug-induced elimination, …

Cell-Typing And Interaction Analysis Of The Immune Compartment Of The Tumor Microenvironment Using High-Resolution Omics Modalities, Courtney Taylor Schiebout

Dartmouth College Ph.D Dissertations

Single-cell RNA-sequencing (scRNA-seq) has provided a new frontier for the investigation of complex tissues. One ideal candidate for the utilization of this method is the tumor microenvironment (TME). The TME is often host to a complex set of cell populations and behaviors that can be highly influential for cancer inhibition or progression. This is especially true of the immune compartment of the TME: the presence of certain types of immune cells in the TME and their expression profiles can significantly affect cancer prognosis in some cases. By providing individual cell-level gene expression data, scRNA-seq can be highly informative for characterizing …

Gabaergic Interneurons And Prenatal Ethanol Exposure: From Development To Aging, Adelaide R. Tousley

Dartmouth College Ph.D Dissertations

Fetal Alcohol Spectrum Disorders are the most common non-genetic cause of neurodevelopmental disability worldwide. Individuals with Fetal Alcohol Spectrum Disorder experience clinical symptoms including differences in physical, cognitive and behavioral development beginning in early childhood, but continue to face challenges into adulthood. There is a critical need to examine the effects of prenatal ethanol exposure across early development, and to establish how the developmental effects of prenatal ethanol exposure may or may not progress in aging individuals. To contribute to these two areas, I asked how a binge-type prenatal ethanol exposure might affect: (1) early postnatal development of striatal neurons …

Deep Learning Methods For Prediction Of And Escape From Protein Recognition, Bowen Dai

Dartmouth College Ph.D Dissertations

Protein interactions drive diverse processes essential to living organisms, and thus numerous biomedical applications center on understanding, predicting, and designing how proteins recognize their partners. While unfortunately the number of interactions of interest still vastly exceeds the capabilities of experimental determination methods, computational methods promise to fill the gap. My thesis pursues the development and application of computational methods for several protein interaction prediction and design tasks. First, to improve protein-glycan interaction specificity prediction, I developed GlyBERT, which learns biologically relevant glycan representations encapsulating the components most important for glycan recognition within their structures. GlyBERT encodes glycans with a branched …

Encoding Permanent Records Of Transcription In The Genome, Francesco Ettore Emiliani

Dartmouth College Ph.D Dissertations

Current approaches to study cellular transcriptional states offer only a single frame in the life of a cell, often in a destructive fashion. This means that our state snapshot neither has the context of the past, nor the ability to be traced into the future. To overcome this, we present a technology that can permanently encode gene expression for later recovery. Our technology uses transcriptional responses to guide CRISPR/AsCas12a to ‘write’ information into the cell’s own genome, creating a permanent and heritable record of this response. By placing a set of AsCas12a guides under the control of a Wnt-responsive TCF/LEF …

The Immune Modulation On Innate Immunity, From Pathogen Recognition To Fungal Clearance., Ko-Wei Liu

Dartmouth College Ph.D Dissertations

The human lung is not sterile but a complex environment with various microorganisms. Besides commensals in the lung, hundreds to thousands of individual microbiomes enter the lung every day but without causing the symptom. Host innate immunity plays an important role in maintaining homeostasis of the lung environment and as the first defense line against pathogens. Aspergillus fumigatus (A. fumigatus) is a saprophytic filamentous fungus that can cause human disease in immune compromised patients. However, with functional innate immunity, immune cells can quickly recognize pathogen associated molecular patterns (PAMPs) from A. fumigatus through pattern recognition receptors (PRRs). The activation of …

Mitochondrial Division: Synergizing In Mitochondrial Divisome, Ao Liu

Dartmouth College Ph.D Dissertations

Mitochondria are the energy factories of the cell. The dynamic nature of cells demands routine changes in mitochondrial morphology by fusion and division. The dynamin GTPase Drp1 is a central mitochondrial division protein, driving constriction of the outer mitochondrial membrane via oligomerization. At least four regulatory factors control Drp1 activity on the outer mitochondrial membrane (OMM): 1) receptor proteins (Mff, MiD49, MiD51, and Fis1); 2) actin filaments; 3) the mitochondrial phospholipid cardiolipin (CL); and 4) Drp1 post-translational modifications, of which two phosphorylation sites (S579 and S600) are the most well studied. However, the molecular mechanism of how these factors work …

Measuring How Kinetochore-Microtubule Detachment Contributes To Chromosome Movement And The Correction Of Attachment Errors, Melissa K. Parks

Dartmouth College Ph.D Dissertations

The goal of mitosis is to achieve faithful chromosome segregation; ensuring that the daughter cells inherit equal numbers of chromosomes. This is vital to cell health and viability and if mis-regulated can result in birth defects and disease such as cancer. There are many intricately regulated processes that occur throughout mitosis to achieve proper chromosome segregation, and one such example is the dynamic attachments formed between cytoskeletal structures, known as microtubules, and chromosomes, the carriers of genetic material. These attachments occur at structures called kinetochores, and the microtubules attached here are referred to as kinetochore-microtubules (k-MTs). These k-MTs are inherently …

Airborne Sound And Substrate-Borne Vibration In Orthopteran Communication, Ciara E. Kernan

Dartmouth College Ph.D Dissertations

The challenge of attracting and locating potential mates has driven the evolution of diverse mate-finding signaling systems. These systems can be complex, with multiple signals or signal components spread across different sensory modalities. When multiple modalities are combined in one communication system, features of each can be important to individual fitness; over evolutionary time, these can shape investment in different parts of a signal repertoire. One group of animals that commonly uses multiple signal modalities is Orthoptera. Cricket and katydid species within this order often produce airborne sound calls to advertise to potential mates. Many also produce substrate-borne vibrational signals. …

Accelerated Forgetting In People With Epilepsy: Pathologic Memory Loss, Its Neural Basis, And Potential Therapies, Sarah Ashley Steimel Phd

Dartmouth College Ph.D Dissertations

While forgetting is vital to human functioning, delineating between normative and disordered forgetting can become incredibly complex. This thesis characterizes a pathologic form of forgetting in epilepsy, identifies a neural basis, and investigates the potential of stimulation as a therapeutic tool. Chapter 2 presents a behavioral characterization of the time course of Accelerated Long-Term Forgetting (ALF) in people with epilepsy (PWE). This chapter shows evidence of ALF on a shorter time scale than previous studies, with a differential impact on recall and recognition. Chapter 3 builds upon the work in Chapter 2 by extending ALF time points and investigating the …

Mapping The Malleable Self: How Self-Views Are Represented And Learned Within The Social Brain, Sasha Carmela Brietzke

Dartmouth College Ph.D Dissertations

Humans possess a unique and wide-ranging ability to self-reflect that takes center stage in our everyday cognition. While many people believe their own self to be immutable, different contexts may warp how we perceive the self. The goal of this dissertation is to investigate two lenses through which we may view the self: (1) across time in the past and future, and (2) through the eyes of others via evaluative feedback. In Studies 1-3, I demonstrate that people’s ratings of their own personality become increasingly less differentiated as they consider more distant past and future selves. This effect was preferential …

Novel Mechanistic Insight Into Ciliary Regulation: Old Pathways Yield New Mechanisms, Larissa L. Dougherty

Dartmouth College Ph.D Dissertations

Cilia are structures present on most eukaryotic cells which provide important signaling and motile components to cells from early development to fully differentiated and matured cells. Regulation of these structures is critical to proper functioning of the cell and is known to be tied to the cell cycle. Preparation for ciliary assembly following cell cycle exit and ciliary disassembly following cell cycle reentry requires components throughout the cell body and within the cilium to facilitate this process. Here I identify how the cell adapts to ensure modifications to cilia occur for assembly or disassembly using the model organism Chlamydomonas reinhardtii. …

Structural Files For The Etr1 Ethylene-Receptor Dimer Based On Computational Modeling, Beenish J. Azhar, Safdar Abbas, Sitwat Aman, Maria V. Yamburenko, Wei Chen, Lena Muller, Buket Uzun, David A. Jewell, Jian Dong, Samina N. Shakeel, Georg Groth, Brad M. Binder, Gevorg Grigoryan, G. Eric Schaller

Dartmouth Scholarship

Structural models for the ETR1 homodimer were generated with AlphaFold-Multimer. Coppers were modeled under two potential coordinations involving Cys65 and His69 of the ETR1 homodimer, one in which the two coppers are bound independently and do not share an interaction with each other, and another where they are closely bonded.

See the following publication for details: Azhar, B.J., Abbas, S., Aman, S., Yamburenko, M.V., Chen, W., Müller, L., Uzun, B., Jewell, D.A., Dong, J., Shakeel, S.N., Groth, G., Binder, B.M., Grigoryan, G., Schaller, G.E. (2023) Basis for high-affinity ethylene binding by the ethylene receptor ETR1 of Arabidopsis. Proc. Natl. Acad. …

Identifying Spatial Heterogeneity In And Potential Biological Consequences Of River Thermal Environments, Keith Jeffrey Fritschie

Dartmouth College Ph.D Dissertations

Temperature is a nearly ubiquitous driver of ecological and evolutionary processes, especially for organisms whose body temperature changes with the environment. The overarching biological importance of environmental temperature and increased availability of temperature datasets have led to its inclusion in spatially continuous models of species’ performance, abundance, and distribution. However, variation in both environmental temperature and animal behavior at finer scales than captured by these models may reduce the accuracy of their scientific conclusions and conservation recommendations. Here I contribute to an improved understanding of thermal variability in river systems and its potential biological consequences for an iconic coldwater species, …

Interactomics And Targeted Protein Degradation For Kinase Substrate Discovery, Juan C. Mercado Del Valle

Dartmouth College Ph.D Dissertations

Reversible phosphorylation is one of the most important post translational modifications that has allowed us as a species to quickly adapt to changing molecular environments due to external stimulation. This process is only capable through the activity of kinases to carry out the targeting of specific substrates defined by their recognition motif allowing for selective phosphorylation and activation and inactivation of distinct pathways as well as other changes that permit cell survival. By being so important for the maintenance of the cells disruption often leads to worsening of the cells, leading to various diseases like cancer, immunological and neurodegenerative disorders. …

Characterization Of Cell Type-Specific Molecular Heterogeneity In Cancer Using Multi-Omic Approaches, Min Kyung Lee

Dartmouth College Ph.D Dissertations

Tumors are composed of heterogeneous cell types each with its own unique molecular profiles. Recent advances in single cell genomics technologies have begun to increase our understanding of the molecular heterogeneity that exists in tumors with particular focus on gene expression and chromatin accessibility profiles. However, due to limitations in methods for certain sample types and high cost for single cell genomics, bulk tumor molecular profiling has been and remains widely used. In addition, other facets of single cell epigenomic profiling, particularly methylation and hydroxymethylation, remains underexplored. Thus, investigations to understand the cell type specific epigenetic heterogeneity and the cooperation …