Biochemistry, Biophysics, and Structural Biology Commons^™

The Role Of Myosin L In The Survival Of Toxoplasma Gondii And The Importance Of Mlc1 For In Vitro And In Vivo Myosin F Motility, Victoria K. Yi

Honors Scholar Theses

My thesis discusses the work that I have conducted on two myosins in Toxoplasma gondii, which is an obligate intracellular parasite that has chronically infected around 10% of the American population. It causes toxoplasmosis and severe health consequences for individuals with compromised immune systems or when infections occur in utero. However, immunocompetent individuals are asymptomatic or present with subclinical symptoms. In the Heaslip lab, I investigated two myosins in the parasite: Myosin L and Myosin F. MyoL is an uncharacterized motor that localizes at the apical end of the parasite. It was shown to be important for parasite …

Effects Of Cholesterol Concentration On Liposome And Proteoliposome Behavior, Ehsaneh Khodadadi

Graduate Theses and Dissertations

Cholesterol is crucial in modulating the behavior and characteristics of biological membranes, liposomes, and proteoliposomes, for instance in drug delivery applications. Cholesterol regulates membrane stability by influencing lipid density, phase separation, and protein-membrane interactions. In planar bilayers, cholesterol enhances membrane thickness, reduces permeability, and promotes lipid ordering, adding rigidity and fluidity. Cholesterol also modulates membrane curvature in curved bilayers and vesicles, stabilizing low-curvature regions. In this work, all-atom molecular dynamics (MD) simulations were employed to examine how varying cholesterol concentrations influence the structure and dynamics of membranes, focusing on planar and curved geometries. Bilayers with cholesterol molar ratios of 0%, …

Implications Of Type Iv Pilus Retraction For Dna Uptake By Acinetobacter Baumannii, Yafan Yu

Dissertations and Doctoral Documents, University of Nebraska-Lincoln, 2023–

Horizontal gene transfer (HGT) via natural competence allows bacteria to incorporate extracellular DNA (eDNA) into their genomes, facilitating genetic diversity and adaptation. In Acinetobacter species, natural competence depends on DNA binding and uptake mediated by type IV pili (T4P). T4P are dynamic extracellular filaments composed primarily of the major pilin subunit PilA, along with a few minor subunits. T4P drive a range of cellular functions including twitching motility, biofilm formation, and DNA uptake, with some functions dependent on pilus retraction and others not. However, how Acinetobacter T4P bind DNA and how T4P/eDNA interactions impact biofilm formation remain unclear. Here, I …

Screening For Chloroplast Inner Envelope-Thylakoid Membrane Contact Site Proteins, Evan W. Labrant

Dissertations and Doctoral Documents, University of Nebraska-Lincoln, 2023–

Most life on Earth is dependent upon the capture of solar energy and subsequent fixation of carbon. In members of the Archaeplastida lineage these biological processes take place in semi-autonomous organelles called chloroplasts. Chloroplasts are bounded by a double membrane envelope and contain the photosynthetic membrane system, thylakoid membranes, where light capture takes place. While a great deal is known about how thylakoid lipids are synthesized and protein complexes therein are properly maintained, very little is known regarding the processes by which lipids are transported to thylakoids which lack de novo glycerolipid synthesis. We have worked to identify candidate proteins …

Treating The Black Fever: Evaluating Combination Chemotherapy For Leishmania Donovani, Robert Frank Mickatavage

Biochemistry and Molecular Biology

Visceral leishmaniasis (VL) is a neglected tropical disease (NTD) endemic to Africa, Asia, and the Americas, caused by the parasite L. donovani and spread by the Phlebotomine sandfly. If left untreated, VL is almost always fatal, bearing a mortality rate of over 95%. Many individuals within endemic regions are often too poor to afford treatment, and the financial burden of current treatments may only exacerbate their poverty. Antimonials and more modern treatments display varying effectiveness, but are nonetheless toxic to the host, commonly inducing hepatotoxicity, nephrotoxicity, and renal failure. The development of more effective and safer treatments is crucial, particularly …

Sodium And Potassium In Health And Cellular Function, Jordyn Branz

Honors Program: Senior Projects (Public)

Sodium (Na⁺) and potassium (K⁺) are essential electrolytes that regulate numerous physiological processes. These include cell function, nerve transmission, and muscle contraction. The Na+/K+-ATPase plays a critical role in maintaining the balance of these ions by actively transporting three sodium ions out of the cell and two potassium ions into the cell against their concentration gradients. This process is vital for maintaining the resting membrane potential and supporting the function of excitable cells. The Na+/K+-ATPase consists of two main subunits, with the alpha-subunit being primarily responsible for ion transport activity. Isoforms alpha1, alpha2, and alpha3 are tissue-specific and contribute to …

Understanding The Properties Of Repair Protein P26 For Dry-State Preservation Of Biological Materials., Hannah Skaggs

College of Arts & Sciences Senior Theses

The preservation of complex biological materials in the frozen state has been well established and plays a critical role in the advancement of clinical applications and the pharmaceutical industry. Cryopreservation of complex biological materials has several clinical applications, including vaccine preservation, bone marrow transplants, cell therapeutics, and increasing the shelf life of red blood cells (RBCs) for transfusion. However, many challenges are present, including the use of toxic protective agents and the financial burden of maintaining extremely low temperatures between 193.15 and – 77.6 K (Parihar, Kumar et al. 2023). Lyophilization, or freeze-drying, presents an opportunity to mitigate such challenges. …

Towards The Design Of A Super Fgf1-Fgf10 Chimera, Megan Brown, Suresh Thallapuranam

Biological Sciences Undergraduate Honors Theses

The Fibroblast Growth Factor family consists of 23 different fibroblast growth factors (FGFs) that are each involved in various cellular processes, including cell proliferation and tissue repair. Fibroblast growth factor receptors (FGFR) are different tyrosine kinase receptors. There are four FGFRs in the human body, each binding to different combinations of FGFs. Fibroblast growth factor 1 (FGF1) is the only FGF that can bind with all four types of fibroblast growth factor receptors. Therefore, it is the most powerful mitogen. However, FGF1 has low thermodynamic stability under the physiological conditions. Prior work in the Kumar lab has constructed several points …

The Expression Of Intestinal Tight Junction Proteins Induced By 1,25-Dihydroxyvitamin D3-Glycosides Supplementation To Reduce Bacterial Chondronecrosis With Osteomyelitis Lameness In Broilers, Kennedy M. Hicks

Biological Sciences Undergraduate Honors Theses

Bacterial Chondronecrosis with Osteomyelitis (BCO) is a leading cause of lameness in broiler chickens, impacting animal welfare and commercial poultry production. Supplementation using organic trace minerals, vitamin D, probiotics, and prebiotics has been studied to mitigate BCO lameness incidences in broiler chickens. Our previous study demonstrated that feeding Panbonis®-G-1,25(OH)₂D₃ from Solanum glaucophyllum, containing 1 µg/kg G-1,25(OH)₂D₃, to broilers for the first 28 days of their production cycle reduced BCO lameness by approximately 50%. In this study, we investigated the impact of 1,25-dihydroxy vitamin D₃ supplementation on the expression of tight junction …

Bpa Adsorption On Microplastics In Different Chemical Conditions, Addison Zehren

University Honors Program Senior Projects

Microplastics (plastic particles < 5 mm in size) are increasingly seen as a health and environmental issue, both for their direct effects when ingested by living organisms and for their ability to adsorb and concentrate other pollutants. Current water treatment processes do not adequately remove microplastics from municipal water supplies, so a thorough understanding of how microplastics affect water quality is needed. The objective of this study is to evaluate the effects of certain water quality parameters on the ability of polystyrene microplastics (PS MPs) to adsorb Bisphenol A (BPA). BPA is an endocrine disruptor (chemically like estrogen) used in plastics which can be released into the environment and act as a water pollutant. Water quality chemical parameters investigated were chloride, nitrate, phosphate, and copper ions. Concentrations of each solute were selected based upon Environmental Protection Agency (EPA) guidelines and previous results obtained from testing Chicago River water samples. A constant amount of PS MPs and BPA were added to each sample and the mixtures were shaken for 5 days to allow time for the BPA to adsorb. The samples were then filtered and the amount of BPA left in the water was determined by measuring its UV absorbance on a UV-vis spectrophotometer. BPA concentrations decreased in the water indicating that it had been adsorbed onto the microplastic surface, with the highest adsorption present with copper, which reduced BPA concentrations from 6.7 mg/L to 3.9 mg/L. Statistical analyses showed differences between copper, phosphate, nitrate, and chloride (df = 9, p = 0.002). Future work can apply these results to investigate the implications of pollutant transportation in urban waterways like the Chicago River.

The Regulatory Role Of Collagen Α1(Xi) Amino-Terminal Domain Isoforms In Collagen Fibrillogenesis, Abu Sayeed Chowdhury

Boise State University Theses and Dissertations

Collagen α1(XI) is a minor fibrillar collagen involved in the critical regulation of collagen fibrils, such as nucleation, assembly, and regulation of fibril diameter. The amino-terminal domain consists of an amino-propeptide (Npp) domain and a variable region, which is the result of alternative splicing from exon 6A, 6B, 7, and 9. The spliced variants involving Npp, with the combinations of exon 6A, 6B, 7, and 9 gives rise to different isoforms with very distinctive chemical nature. The Npp of collagen α1(XI) chain is retained on the surface of the collagen fibril for an extended period of time and may play …

Bang!: Real-Time Measurements And Transcriptomics Of Metabolic Reprogramming In Activated Macrophages At Fever Temperature, Kenneth Howard Taylor

Graduate Theses and Dissertations

We investigated the real-time metabolic rates of activated macrophage cell lines derived from mouse, chicken and rainbow trout. Each species showed a different kinetic signature with metabolic rates accelerating under fever conditions specific to each organism. Upon activation mouse macrophages increased their rate of glycolysis early and then a later reprogramming phase occurred with a dramatic decrease in oxidative phosphorylation (OXPHOS) accompanied by a reciprocal second increase in glycolytic rates. Chicken macrophages showed an initial increase in both glycolytic and OXPHOS rates. The late drop OXPHOS rates also occurred in chicken however there was no reprogramming that occurred as glycolytic …

3d Printing Protein-Rrna Mutations In The Ribosome, Abigail Wilson

Senior Honors Projects

Sometimes conveying research can be difficult through two-dimension models. In my project, I aimed to highlight the significance of three-dimensional visualization in science, thereby enhancing the understanding of complex biomedical concepts. Through my work in Dr. Steven Gregory’s lab, I have been studying the ribosome – the macromolecular machine that utilizes messenger RNA and transfer RNA to link together amino acids thereby synthesizing proteins. Proteins are critical for most processes that occur within every cell. I specifically focus on the interactions between ribosomal proteins and ribosomal RNA (rRNA) at the peptidyl transferase center – the active site where amino acids …

Understanding The Role Of Sabp2-Interacting Proteins Sip432: A Premnaspirodiene Oxygenase Enzyme In Stress Signaling, Cristiana F. Martinez

Undergraduate Honors Theses

This study focuses on the characterization of a SABP2-interacting protein (SIP)-432. SIP432 is a putative premnaspirodiene oxygenase-like P450 enzyme. Premnaspirodiene is a 15-carbon compound that can be converted into antimicrobial compounds by a hydroxylation reaction. The interaction of SIP432 with SABP2, a critical component of salicylic acid-mediated plant immunity, implies a role for SIP432 in plant stress signaling. This study uses the T-DNA knockout mutant of Arabidopsis thaliana SIP432 (homolog of NtSIP432) to help understand its role in abiotic and biotic stress responses. Plants were subjected to abiotic and biotic stress to understand their role in stress response pathways. Gene …

Fc Gamma Receptors Facilitate Antigenic Modulation Of Lilrb4 And Function As Predictive Biomarkers In Acute Monocytic Leukemia, Joshua Morse

Dissertations and Theses (Open Access)

Acute monocytic leukemia (monocytic AML) is a subtype of AML marked by a proliferation of abnormal monoblasts. This subtype represents approximately 10% of AML cases. The prognosis of monocytic AML is poor, with a 5-year survival of ~30%. Most patients are diagnosed at an age when they are unlikely to survive first-line non-targeted cytotoxic chemotherapy as a bridge to hematopoietic stem cell transplant (HSCT). Even patients who achieve remission commonly relapse. This population of patients would greatly benefit from precision-targeted therapies but currently there are none approved for monocytic AML.

Leukocyte immunoglobulin-like receptor B4 (LILRB4) is an immune checkpoint expressed …

Expanding Inducible Epithelial Resistance Against Pneumonia: Novel Virus, Novel Receptor, Michael Longmire

Dissertations and Theses (Open Access)

Pneumonia is the leading infectious cause of death worldwide and presents a continuing risk among immunocompromised patients. Our work has been focused for many years on the phenomenon of inducible epithelial resistance, where activation of the innate immune response in the airway epithelium is necessary and sufficient to produce a pathogen-killing but self-protective environment to prevent severe disease. Inducible resistance is pathogen-agnostic and has been demonstrated against an array of respiratory infections. We achieve this using a combination of pattern recognition receptor agonists – Pam2CSK4 and ODN M362 being the current formulation – which produce synergistic levels of pathogen reduction …

Effect Of Glycation On The Binding Interactions Of Serum Albumin And Silver Nanoparticles, Megan Kirk

Celebrating Scholarship and Creativity Day (2018-)

Nanoparticles are particles ranging from 1-100 nanometers in size. Most nanoparticles, upon contact with biological matrices, are immediately coated with proteins, forming the protein corona, which can alter the structure and function of proteins. Despite the tremendous advancement of nanotechnology over the last decade, the interactions of nanoparticles with proteins are not well characterized. This project investigates the effect of glycation on the binding interactions of HSA, the most abundant protein in human blood, with silver nanoparticles using various spectroscopic techniques. This is important because in diabetic patients, HSA is exposed to high concentrations of glucose over extended periods of …

Identification Of Cadmium As A Structural And Functional Modulator Of Psd-95 Regulating Nmdars At Postsynaptic Membranes, Claudia Garza

Theses and Dissertations

Postsynaptic density-95 (PSD-95) is an essential scaffolding protein in excitatory neurons. PSD-95’s N-terminal palmitoylation region elicits synaptic plasticity by targeting, anchoring, and trafficking glutamate receptors, such as N-methyl-d-aspartate receptors (NMDAR), to the postsynaptic membrane. The molecular interactions of PSD-95 and its dysregulation in excitatory synapses are currently being explored as primary causes of neurodegenerative diseases and disorders, such as Alzheimer’s disease, Schizophrenia, and Parkinson’s disease. Recent studies demonstrate an overaccumulation of zinc at two cysteines (C3 and C5) and two histidines (H24 and H28) of PSD-95 blocks palmitoylation, causing a loss of NMDAR at the postsynaptic membrane. In addition, exposure …

Cloning And Heterologous Expression Of Human Nachrs And A Unique Spider Venom Toxin, Christine M. Vega

Theses and Dissertations

Drug development research has long focused on synthesizing novel therapeutics while overlooking isolation from naturally available sources. Recently, the discovery of the therapeutic effects of highly bioavailable animal venom caused the field of venom research to soar in popularity. Animal venom serves as a natural, sophisticated tool optimized over millions of years by evolution with the ability to bind to ion channels such as nAChRs, non-specific ligand-gated ion channels distributed throughout the human nervous system, with high selectivity and specificity. However, purifying individual venom toxins from crude venom is challenging due to its availability. Therefore, synthesizing large quantities of venom …

Activity-Based Protein Profiling On Nucleophilic Amino Acid Residues With Pyrocarbonates, James Van Horn

Chemistry & Biochemistry Undergraduate Honors Theses

The complexity of the proteome requires strategies that efficiently characterize protein functions. Activity-Based Protein Profiling (ABPP) is a method that identifies enzyme activity by targeting key catalytic residues. This study focused on histidine, a residue involved in enzymatic catalysis, metal coordination, and protein-protein interactions. Despite its importance, histidine-specific chemical probes are limited due to its variable reactivity. This work developed and characterized a histidine-specific probe using a pyrocarbonate-based mechanism. Singleresidue assays confirmed selective reactivity of the probe with histidine over other nucleophilic amino acids. Further testing on enzymatic proteins and lysed cell proteomes showed that the probe modified histidine residues …

Eepd1 Evolved A Unique Dna Clamping Dimer Protecting Reversed Replication Forks, Runze Shen

Dissertations and Theses (Open Access)

Exonuclease/endonuclease/phosphatase (EEP)-fold hydrolases are canonically monomeric phosphodiesterases exemplified by APE1, DNase I, and TDP2 nucleases. While EEP superfamily domain-containing protein 1 (EEPD1) acts in DNA stress responses, its proposed nuclease activities are enigmatic. Here, we integrate hybrid structural methods, evolution, biochemistry, cancer genomics, molecular and cell biology to define EEPD1’s structure, assembly, and function at stalled DNA replication fork intermediates. Combined results show that EEPD1 surprisingly requires both the unique EEP domain dimer and distinctive tandem Helix-hairpin-Helix [(HhH)₂] domains to clamp double-stranded(ds) DNA at reversed DNA replication forks for fork protection. X-ray scattering, crystal, and cryo-EM structures unveil …

Impact Of Tumor Cell Expressed Cd38 On Metastasis And Immune Evasion In Breast Cancer, Tanvi Visal

Dissertations and Theses (Open Access)

Triple-negative breast cancer (TNBC) is a highly metastatic breast cancer subtype. The epithelial-to-mesenchymal transition (EMT) of cancer cells is a key feature of the metastatic cascade and is not a binary process but often generates malignant cells with both epithelial (E) and mesenchymal (M) traits known as hybrid EM cells. Recent studies highlight the enhanced metastatic potential of the hybrid EM cells. However, molecular insights and targetable vulnerabilities within hybrid EM remain elusive. We discovered that hybrid EM murine tumors are enriched in CD38, an immunesuppressive molecule associated with worse clinical outcomes in liquid malignancies but relatively understudied in solid …

The Extracellular Domains Of The Ampa, Kainate, And Orphan Delta Receptor Regulate Channel Gating In Distinct Ways, Cuauhtemoc Ulises Gonzalez

Dissertations and Theses (Open Access)

The ionotropic glutamate receptors are ligand-gated cationic channels essential for neuroplasticity and neurological functions such as learning, memory, behavior, cognition, and motor coordination. Mutations in these channels are linked to various disorders including autism, ataxia, and epilepsy, making them compelling pharmacological targets. Within this family, the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and kainate receptor mediate their function through fast glutamate-gated ionotropic activity, which needs precise structural changes to perform properly. While Cryo-EM structures have provided snap shots of these proteins, questions remain regarding the dynamics across conformations and individual roles of the extracellular amino-terminal and agonist binding domain in dictating function. …

Overcoming Resistance To Cdk4/6-Targeted Therapy Using Jak2/Stat3 Inhibitor In Triple-Negative Breast Cancer, Chuling Zhuang

Dissertations and Theses (Open Access)

Breast cancer is the most common type of cancer diagnosed in women, with nearly 30% of cases becoming metastatic accounting for over 90% of breast cancer-related deaths. Among different breast cancer subtypes, triple-negative breast cancer (TNBC) has the worst prognosis and the highest propensity to metastasize. However, TNBC patients have limited treatment options due to their lack of actionable drug targets while therapeutic resistances result in high rates of recurrence and metastasis. Cyclin-dependent kinase 4 and 6 (CDK4/6) are major cell cycle regulators that control G1 to S phase transition and aberrant hyperactivation of the CDK4/6 pathway results in uncontrolled …

Role Of Mir-4732-3p In Breast Cancer Brain Metastasis And Brain Metastatic Tumor Microenvironment, Munazza Samar Khan

Dissertations and Theses (Open Access)

In this study, we aimed to identify microRNAs (miRNAs) that may play important roles in breast cancer brain metastasis (BCBM). To this end, we conducted miRNA-sequencing of extracellular vesicles isolated from the serum samples of 6 BCBM patients and 8 Stage I/II/III breast cancer patients, and identified 49 circulating miRNAs that were upregulated in BCBM patients compared to Stage I/II/III breast cancer. Upon further analysis, we identified miR-4732-3p to be upregulated in brain-tropic triple-negative breast cancer (TNBC) cell lines, compared to parental lines. MiR-4732-3p overexpression increased metastatic properties of TNBC cells, including proliferation, migration, invasion, and maintenance of a mesenchymal …

Investigating Metabolic And Mitochondrial Adaptations Triggered By Blood Flow During The Endothelial-To-Hematopoietic Transition, Paulina Horton

Dissertations and Theses (Open Access)

Hematopoietic stem cell (HSC) transplant is the standard of care for many hematologic diseases. However, many patients cannot benefit from this potentially curative treatment because they cannot find a suitable donor, contributing to a high level of unmet need. Recently, bona fide HSCs capable of robust engraftment and differentiation have been generated from iPSCs utilizing wall shear stress (WSS) to help promote HSC generation. However, the mechanisms through which WSS regulates hematopoiesis remain poorly understood. Scientists, therefore, continue to look for the mechanotransduction pathways that promote hematopoiesis, and key answers may lie in examining the role of extrinsic factors that …

Transcription Factor Y- Box Binding Protein 1 (Ybx1) Enhances Sorafenib Resistance And Tumorigenic Capacities In Hepatocellular Carcinoma (Hcc), Dennis Kwabiah

Theses and Dissertations

Hepatocellular carcinoma (HCC) is the most common liver cancer, with early-stage cases potentially benefiting from surgical treatments like liver transplantation and hepatectomy. However, advanced HCC stages have poor prognosis due to resistance to therapies, especially sorafenib, a tyrosine kinase inhibitor approved for late-stage HCC. Despite its clinical use, sorafenib has limited efficacy in prolonging survival, and the mechanisms of resistance remain unclear. Analysis of The Cancer Genome Atlas (TCGA) HCC dataset shows elevated Y-box binding protein 1 (YBX1) expression in HCC tumors compared to normal liver tissues. Previous studies have indicated that YBX1 is involved in drug resistance in various …

Structural Stability Of Fgf1-Fgf2 Dimer Established Via Salt Bridges With Mutation K296q, Ashleigh Letterman

Chemistry & Biochemistry Undergraduate Honors Theses

Fibroblast Growth Factors (FGFs) are a family of cell-signaling proteins. FGF, specifically the FGF-1 subfamily, which contains FGF-1 and FGF-2, is important in several biological functions such as wound healing, cell proliferation, and angiogenesis. FGF-1 has cell proliferation properties and FGF-2 has angiogenic properties. These FGFs have great potential for wound-healing therapy medications...

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Regulation Of Ccr7 Signaling Events By G-Protein-Coupled Receptor Kinases 2 And 3, Anahi Sanchez

Open Access Theses & Dissertations

G protein-coupled receptors (GPCR) can bind multiple ligands, leading to differential signaling events termed biased signaling. C-C chemokine receptor 7 (CCR7) is a GPCR known to have biased signaling between the two ligands it binds to, CCL19 and CCL21. Binding of C-C Chemokine Ligand 19 (CCL19) promotes a high level of CCR7 phosphorylation, while CCL21 leads to a much lower level of CCR7 phosphorylation; findings observed in HEK and dendritic cells. GPCR kinases (GRKs), which can control the phosphorylation patterns of a GPCR, are hypothesized to regulate biased signaling of a receptor. GRK expression differs between cell lines and cell …

Developing A Small Molecule To Inhibit Hsf1 Expression In Cancer And Evaluating Natural Genetic Variation In Small Molecule Toxicity., Michaela Kendal Foley

Theses and Dissertations

Each year cancer affects nearly 20 million people worldwide and genetic differences across populations can impact cancer onset and progression. Specifically, tumors with high levels of HSF1, the master regulator of the cytoprotective heat shock response (HSR), are correlated with poor patient outcomes in multiple cancers such as prostate, breast, and melanoma. Subsequently, the development of pharmacological inhibitors of HSF1 represents a promising strategy for anticancer therapeutics. Using a luciferase-based transcriptional reporter, two small molecule libraries were screened for inhibitors of HSF1 expression in human embryonic kidney cells, yielding ten compounds that decrease HSF1 expression. To identify if cancer lines …