Cell and Developmental Biology Commons^™

Carbon Monoxide Releasing Polymeric Micelles, Riya Joshi

Electronic Theses and Dissertations

Carbon monoxide (CO), traditionally known as a toxic gas, has emerged as a potential therapeutic agent due to its cytoprotective, anti-inflammatory, and vasodilatory properties. This study explores the development of CO-releasing polymeric micelles as a controlled delivery system for biomedical applications. Using ring-opening metathesis polymerization (ROMP), we synthesized diblock copolymers incorporating CO-releasing moiety diphenylcyclopropenone (DPCP) with hydrophilic polyethylene glycol (PEG) to enhance solubility and stability of the overall CO releasing system. Dynamic light scattering (DLS) and electron microscopy (EM) confirmed the formation of well-defined micelles, while fluorescence assays demonstrated efficient CO release with the use of Iridium photocatalyst under 470 …

The Anticancer Activity Of Novel Chromene Derivatives Against Colorectal Cancer Cells, Rym Magramane

Thesis/ Dissertation Defenses

Colorectal cancer (CRC) stands as the third most common cancer globally, accounting for nearly 10% of all newly diagnosed cancer cases. In the UAE, CRC was ranked as the third most frequently diagnosed malignancy, and the leading cause of cancer-associated deaths in 2023. Standard CRC treatment strategies include surgical resection, chemotherapy, immunotherapy, targeted therapy, or a combination of all, depending on the cancer stage and molecular profile. Despite these interventions, disease recurrence is experienced by a considerable number of cancer patients. Hence, there is an urgent need to develop novel alternative treatments to overcome poor prognosis. Recently, cancer research has …

Ensemble-Based Binding Free Energy Profiling And Network Analysis Of The Kras Interactions With Darpin Proteins Targeting Distinct Binding Sites: Revealing Molecular Determinants And Universal Architecture Of Regulatory Hotspots And Allosteric Binding, Mohammed Alshahrani, Vedant Parikh, Brandon Foley, Gennady M. Verkhivker

Mathematics, Physics, and Computer Science Faculty Articles and Research

KRAS is a pivotal oncoprotein that regulates cell proliferation and survival through interactions with downstream effectors such as RAF1. Despite significant advances in understanding KRAS biology, the structural and dynamic mechanisms of KRAS allostery remain poorly understood. In this study, we employ microsecond molecular dynamics simulations, mutational scanning, and binding free energy calculations together with dynamic network modeling to dissect how engineered DARPin proteins K27, K55, K13, and K19 engage KRAS through diverse molecular mechanisms ranging from effector mimicry to conformational restriction and allosteric modulation. Mutational scanning across all four DARPin systems identifies a core set of evolutionarily constrained residues …

Breaking The Rules: Post-Translational Modifications And Proteome Dynamics During Anoxia, Chelsea Jordan Hughes

Dissertations and Theses

Most organisms are ill-equipped to survive anoxia, but some organisms have developed molecular strategies to mitigate the cellular stressors associated with a lack of oxygen. While it is established that anoxic survival is contingent on metabolic suppression, it is unclear what mechanisms support this change in gene expression. Gene expression is regulated by a variety of mechanisms within the cell, including alteration of chromatin structure through histone modifications and protein modifications which contribute to the ever-changing proteomic landscape of the cell. Protein modifications such as ubiquitylation can lead to the degradation of proteins, while modifications to transcription factors can change …

Basal Autophagy Promotes Accurate Chromosome Segregation In Drosophila Oocytes And Declines During Oocyte Aging, Diana C. Hilpert

Dartmouth College Ph.D Dissertations

The frequency of trisomic pregnancies exponentially increases with advanced maternal age, a phenomenon known as the maternal age effect. The majority of these aneuploid pregnancies arise from meiotic segregation errors in the oocyte and premature loss of sister chromatid cohesion is a contributing factor. However, the mechanisms that lead to premature cohesion loss during oocyte aging are not fully understood.

Using Drosophila melanogaster as a model organism, work described in this dissertation demonstrates that basal levels of autophagy, a degradation process for damaged organelles and protein aggregates, are required during meiotic prophase for arm cohesion maintenance and accurate meiotic segregation …

Topodino: Self-Supervised Topological Representation Learning For Neuronal Morphologies, Yasser Binbisher

Master's Theses

Neuronal cell types are categorized by transcriptomic identity, yet their morphological heterogeneity defies this classification. In response, researchers have adopted unsupervised graph representation learning as a tool to reveal morphological variation within single-class transcriptomic types. However, the complex geometry of neuronal morphology—especially long axons and dense dendrites—challenges graph neural networks, which struggle with message propagation across extended structures. To mitigate this, current approaches enforce sub-sampling on neuronal graphs and omit axons entirely, sacrificing critical biological features for computational efficiency. To overcome this trade-off, this thesis introduces TopoDINO, a self-supervised, topology-aware representation learning model designed to preserve the full hierarchical organization …

Elucidating The Roles Of Eukaryotic Initiation Factors Involved In Dap5 Mediated Translation, Jacob Nk Quartey

Dissertations, Theses, and Capstone Projects

Translation initiation in eukaryotes is a highly regulated process essential for accurate protein synthesis. It is a dynamic process that involves a complex interplay between messenger RNAs (mRNAs), ribosomal subunits, and a host of initiation factors, ensuring precise start codon selection and the subsequent assembly of the translation machinery. This process has well been known to be mediated by the eukaryotic Initiation Factor (eIF4F), which consists of the cap binding protein eIF4E, the scaffolding protein eIF4GI, and the helicase factor eIF4A.The recognition and binding of eIF4E to the m⁷G cap structure of the mRNA is essential for the …

Understanding How Genetic Mutations Induce Oligodendrocyte Progenitors To Become Cancer Cells, Dennis Huang

Dissertations, Theses, and Capstone Projects

Gliomas are the most devastating adult brain tumors characterized by poor survival rate and limited options for treatment. Previous studies have shown that they are very heterogeneous and can be further sub-classified based on their transcriptional signature and the presence of specific mutations. One such subtype, is the “proneural glioma”, which is characterized by the enrichment in oligodendrocyte progenitor cell (OPC) transcripts and mutations in genes encoding for the tumor suppressor P53 (Trp53) and for Platelet Derived Grow Factor (PDGF) signaling. Since OPCs are the most abundant proliferative population in the adult brain, in this …

Investigating A Link Between Dna Repair And Dna Replication In Escherichia Coli Using A Bacterial Two-Hybrid System, Lo Cooper

University Honors Theses

Cells rely on nucleotide excision repair (NER) to remove bulky DNA lesions, such as those caused by UV light. In Escherichia coli, NER involves the UvrABC complex, and includes two main pathways, global genomic repair and transcription-coupled repair (TCR). While TCR, which preferentially removes lesions that block RNA polymerase on the transcribed strand of active genes, is well studied, less is known about whether a similar coupling between repair proteins and replisomes blocked by damaged DNA exists. Such a process has been suggested by a high throughput interactome study, using the replisome subunit HolC as bait and the damage …

Neovascular Pruning By Ido1 Inhibitors Can Potentiate Immunogenic Cytotoxicity Of Ischemia-Targeted Agents To Synergistically Enhance Anti-Pd-1 Responsiveness, Shih-Chun Shen, Souvik Dey, James B. Duhadaway, Erika Sutanto-Ward, Maurice T. Hampton, Serguei V. Kozlov, George C. Prendergast, Alexander J. Muller

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

BACKGROUND: Strategies for deploying indoleamine 2,3-dioxygenase 1 (IDO1)-targeted therapies for use against cancer have focused on IDO1's role in promoting peripheral immune tolerance that shields tumors from effector T cells. However, preclinical investigation of both primary and metastatic tumor development in the lungs has uncovered a previously unappreciated role for IDO1 in directing a counterregulatory response to interferon (IFN)-γ that realigns the local inflammatory environment to promote tumor neovascularization. Understanding how to therapeutically leverage the ability of IDO1 inhibitors to subvert inflammatory neovascularization within the tumor microenvironment has potential ramifications for future clinical development of these compounds.

METHODS: Pulmonary metastases …

Mechanisms Of Placental Impairment And The Upregulation Of Fetuin-B During Maternal Undernourishment, Mia Camilliere

NYMC Student Theses and Dissertations

Proper nutrition is crucial during pregnancy to support fetal and placental development. Failure to meet these nutritional needs can result in adverse health outcomes for both mother and baby. Despite its high prevalence in underdeveloped countries, maternal undernourishment is a public health issue worldwide. There are several possible causes of maternal undernourishment, and these can occur alone or in combination, such as poor access to nutrition, hyperemesis gravidarum, and drug use. This condition can adversely affect placental development and function to the extent of placental insufficiency, perturbing the entire pregnancy. The placenta is responsible not only for hormonally and physically …

Investigating Genes Associated With Oncogenic Pka Activity In Fibrolamellar Carcinoma, Ananya Singh

Undergraduate Honors Theses

Fibrolamellar Carcinoma (FLC) is a rare liver cancer, predominantly affecting younger individuals with no history of primary liver disease. As FLC comprises only < 1% of all liver tumors, our understanding of its development and treatment are extremely limited. All clinical cases of FLC contain a specific DNAJB1-PRKACA fusion. The mutation produces an oncogenic form of Protein Kinase A (PKA), known as DNAJ-PKAc, with enhanced binding activity compared to wild-type PKA. Specifically, DNAJ-PKAc interacts with different substrates than wild type PKA, affecting downstream signaling pathways to promote cancer development. However, the genetic dependencies that result from oncogenic DNAJ-PKAc signaling are not known. In this paper, I will show the process of performing a genome-wide CRISPRi screen in AML12DNAJ-PKAc cells to identify genes associated with oncogenic DNAJ-PKAc signaling. I will detail the preliminary benchmarking experiments, the screening process, the preparation of genomic DNA for sequencing, and the ongoing validation of screen results. I anticipate that this project will discover genes whose knockdown inhibits oncogenic DNAJ-PKAc signaling and reduces cell growth exclusively in the presence of PKA. The identified genes could represent potential therapeutic targets for cancer drugs that inhibit FLC progression. However, additional research is necessary to characterize their interactions with DNAJ-PKAc and their specific role in FLC development.

The Impact Of Growth Hormone-Releasing Hormone Antagonist On Human Adipose-Derived Stem Cells, Jeanne Michelle Dugas

Master's Theses

Obesity is a condition that affects over 40% of American adults and contributes to numerous preventable health issues. This condition is caused by increased adipose tissue, which forms when stem cells transform into adipocytes. Mesenchymal stem cells, including human adipose-derived stem cells (hASC), are multipotent with the ability to differentiate into adipocytes, osteocytes, or chondrocytes. Many factors affect this transformation, including the peptide growth hormone-releasing hormone (GHRH). The main role of GHRH is to trigger the release of growth hormone, but it has also been found to play an important role in adipocyte metabolism. We expect that if the differentiation …

Targeting Neuronal Nitric Oxide Synthase (Nnos) As A Novel Approach To Enhancing The Anti-Melanoma Activity Of Immune Checkpoint Inhibitors, Anika R. Patel, Shirley Tong, Kate Alison Lozada, Amardeep Awasthi, Richard B. Silverman, Jennifer Totonchy, Sun Yang

Pharmacy Faculty Articles and Research

Background and Objectives: Neuronal nitric oxide synthase (nNOS) overexpressed in melanoma plays a critical role in disease progression. Our previous studies demonstrated that nNOS inhibitors exhibited potent anti-melanoma activity and regulated PD-L1 expressions in the presence of interferon-gamma (IFN-γ). However, the role of nNOS in the melanoma immune response has not been well defined. Methods: Changes in gene expression profiles after nNOS inhibitor treatment were determined by transcriptomic analysis. A melanoma mouse model was used to determine the effects of nNOS inhibition on peripheral T cells and the in vivo anti-tumor activity of combining nNOS inhibitors with immune …

Network Analysis Of Antimicrobial Resistance In Staphylococcus Aureus: Characterization Of Hub Genes And Their Functional Implications, Md Imran Hasan, Davida Smyth, Jeong Yang, Ashley Teufel

Masters Theses (Archived)

Antimicrobial resistance is a major cause of morbidity and mortality in patients with S. aureus infections. In this study, we analyzed genes, molecular mechanisms, and pathways driving drug resistance in S. aureus using network analysis. Using whole-genome sequencing (WGS) data and systems biology approaches, we identified 229 AMR-associated genes and constructed a protein-protein interaction network among these genes. Through network topology and functional enrichment analyses, we not only confirmed their association with resistance, but also highlighted the central roles of these genes in resistance pathways, such as efflux, target replacement, and target protection, which are directly linked to multiple drug …

Myocardin Effector Proteins Affect Tgf-Beta-Induced Myofibroblast Differentiation In Ipf Cells, Allison Gonzalez

Biotechnology Theses

Idiopathic pulmonary fibrosis (IPF) is an incurable interstitial lung disease defined by the progressive, irreversible scarring of the tissues between the lung’s alveoli. To date, only two drugs have received approval for treatment. However, these medications are not considered cures since they do not stop the progression of the disease. A deeper understanding of the mechanisms underlying IPF could aid in discovering a cure. We recently found that myocardin (MyoCD) regulates SMAD2/3 transcription factors in the TGF-β signaling pathway and governs the genes involved in pleural fibrosis. However, it is unclear whether MyoCD plays a critical role in IPF by …

Assessing The Efficiency Of Methotrexate (Mtx) As An Antiviral Drug Against Gammaherpes Virus Replication, Yennifer A. Gaspar Garcia

Honors Projects

It is estimated that ~15% of all cancers are caused by oncogenic virus infections. Two of the top seven cancer-causing human viruses are members of the gammaherpesvirus family: Epstein Barr Virus (EBV) and Kaposi’s Sarcoma Herpesvirus (KSHV). Our lab uses Murine Herpesvirus 68 (MHV-68), a mouse gammaherpesvirus with shares significant genetic homology to KSHV and EBV, as a model system to understand how gammaherpesviruses alter the metabolism of their host during lytic infection to promote their replication. We recently metabolically profiled MHV-68 infected host cells at various time points during the lytic infectious cycle. Our data showed nucleotide metabolism is …

Targeting The Beiging Of Muscle-Associated Adipose Tissue To Promote Muscle Regeneration, Jacob C. Parson

WUSM Theses and Dissertations – All Programs

The expansion of intra-muscular adipose tissue (IMAT) between myofibers and epi-muscular adipose tissue (EMAT) outside of the muscle boundary accompanies numerous pathologies including diabetes, muscular dystrophy, and aging. IMAT and EMAT are anatomically juxtaposed to myofibers. Some evidence supports that IMAT and EMAT impede muscle function. This is potentially due to paracrine factors that are secreted by IMAT/EMAT. Different adipose depots can be classified in numerous ways including where they are located anatomically as well as the factors in which they secrete. Unlike classical white fat, adipose depots classified as brown or beige, noted by the marker uncoupling protein-1 (UCP-1) …

Mechanisms That Contribute To Age-Dependent Segregation Errors In Drosophila Oocytes, Zihan Meng

Dartmouth College Ph.D Dissertations

Meiotic chromosome segregation errors in human oocytes are the leading cause of miscarriages and aneuploid pregnancies, and these errors increase dramatically as women age. Using Drosophila oocytes as a model system, this dissertation identifies the NAD⁺-dependent deacetylase Sirt1 as a key regulator of chromosome segregation and meiotic arm cohesion. Loss of Sirt1 activity during meiotic prophase leads to premature loss of arm cohesion and increased segregation errors in Drosophila oocytes. In addition, elevated acetylation of its substrate, histone H4K16, indicates that Sirt1 activity declines in oocytes during aging. Strikingly, dietary administration of the Sirt1 activator SRT1720 preserves Sirt1 deacetylase activity …

Peripheral Neuroimmune Mechanisms Of Chronic Back Pain, Aleyah Esther Goins

Biomedical Sciences ETDs

Chronic back pain (CBP) affects 1 in 10 people worldwide, reducing mobility, productivity, and quality of life. Despite its prevalence, non-addictive treatments remain limited due to an incomplete understanding of chronic pain mechanisms. This dissertation examines peripheral neuroimmune interactions in CBP using a urokinase-type plasminogen activator (uPA)-induced mouse model (uPA-CBP). uPA, a pro-inflammatory serine protease, was injected into the L2/L3 lumbar spinous ligament, inducing prolonged mechanical and cold hypersensitivity. Flow cytometry of dorsal root ganglia (DRG) showed increased CD45+CD11b+ myeloid cells in males and CD45+CD3+CD4+ lymphocytes in females. DRG neurons from male uPA-CBP mice exhibited heightened action potential firing. Pharmacological …