Life Sciences Commons^™

Molecular Mechanism Of Rapamycin Resistance In Cancer Cells, Sohag Chakraborty

Dissertations, Theses, and Capstone Projects

The mammalian target of rapamycin (mTOR) acts as the central regulator of multiple cellular processes including cell growth, proliferation, and survival by integrating signals via nutrients, growth factors, hormones, and energy sensing. In cancer cells, the mTOR pathway is highly dysregulated providing survival signals to the cells for their uncontrolled growth. Hence, mTOR has evolved to be a potential therapeutic target for cancer treatment for the past two decades. Application of micro-molar doses of Rapamycin in vitro has been found to successfully inhibit mTOR complex 1 (mTORC1) by blocking the phosphorylation of its downstream substrates- a) ribosomal protein p70 S6 …

Genetic Circadian Mosaics And The Clock Network’S Contributions To Sleep, Lukasz Widziszewski

Dissertations, Theses, and Capstone Projects

Circadian rhythms are physiological and behavioral changes which follow a 24-hour cycle. Drosophila Melanogaster’s circadian clock neuronal network (CCNN) has been identified and several subpopulations have been characterized based on previous studies; the classifications of subpopulations of neurons within the CCNN are based on a return of anticipatory locomotor activity preceding the two daily light transitions (Lights on = dawn/Lights off = dusk). The neurons responsible for the return of anticipatory morning locomotor activity have been referred to as the M-cells, the group of neurons known to rescue evening anticipatory locomotor activity have been termed the E-cells. In this …

The Effects Of Near-Threshold Color Manipulation On Perceptual Decision-Making And Confidence Report, Trevor Caruso

Dissertations, Theses, and Capstone Projects

Confidence measures are sometimes used to index awareness below a participant’s criterion for what counts as being subjectively aware of a stimulus or stimulus property. If confidence ratings index awareness below subjective thresholds, then one might be tempted to use confidence ratings in place of subjective reports of whether a stimulus/stimulus property was “seen” or “unseen”. As such, a dissociation of confidence from performance may be construed as a dissociation of subjective awareness from objective task performance. This methodology has been used as supporting evidence for blindsight in typical observers (Balsdon and Azzopardi 2015; Peters and Lau 2015; Peters et …

Withdrawal From Voluntary Oral Methamphetamine Reveals Female Specific Susceptibilities To Behavioral Deficits And Neurochemical Perpetuators Of Neurotoxicity And Drug Seeking Behavior, Nicoletta K. Memos

Dissertations, Theses, and Capstone Projects

MA is a potent, highly addictive psychomotor stimulant known to produce neurotoxic effects on the brain leading to neurological impairments^1-6 characterized by neurodegeneration of dopaminergic fibers, cell bodies and pathways, as well as brain regions such as the hippocampus, frontal cortex, and midbrain^1,5.

In MA addiction, women are more vulnerable to the behavioral and cognitive effects of MA compared to men. Adult human literature reveals gender differences in usage patterns and women demonstrate increased vulnerability to the neurotoxic effects and health effects of MA use. Women begin drug use at an earlier age, escalate drug use quicker, …

Effects Of Chronic Stress On Safety Processing And Physiology In The Medial Prefrontal-Amygdala-Basal Forebrain Circuit, Itamar S. Grunfeld

Dissertations, Theses, and Capstone Projects

Chronic stress increases generalization of fear to non-threatening cues, a key symptom in numerous psychiatric mood disorders. However, the mechanisms through which stress impacts safety learning remain poorly understood. To probe the relationship between stress and safety learning, this dissertation employed multiple behaviors, in conjunction with in-vivo multisite physiology during explicit safety and fear discrimination learning. In Chapter 1, I outline the role of chronic stress in driving neurological adaptations that result in generalized fear and highlight how this occurs because of impaired safety cue encoding. In Chapter 2, I show that chronic stress in the form of social defeat …

Symmetry-Inspired Analysis Of Biological Networks, Ian Leifer

Dissertations, Theses, and Capstone Projects

The description of a complex system like gene regulation of a cell or a brain of an animal in terms of the dynamics of each individual element is an insurmountable task due to the complexity of interactions and the scores of associated parameters. Recent decades brought about the description of these systems that employs network models. In such models the entire system is represented by a graph encapsulating a set of independently functioning objects and their interactions. This creates a level of abstraction that makes the analysis of such large scale system possible. Common practice is to draw conclusions about …

Approach To Dual Base And Sugar Modification Of Adenosine, Cross-Dehydrogenative Coupling Reactions Of Quinazolinones, And A Novel Entry To Carbazolones And Indolones, Dellamol Sebastian

Dissertations, Theses, and Capstone Projects

Analogues of purine nucleosides are of interest due to their antiviral, antibacterial, and anticancer properties. Although there are large number of reports on C6-modification of 6-chloropurine nucleosides with alkyl amines via the S_NAr reaction pathway, there are fewer reports on comparable reactions with aryl amines. Notably, S_NAr reactions of 6-chloropurine nucleosides with electron-deficient aryl amines is a relatively understudied area. A simple method has been developed for the S_NAr reactions of 6-chloropurine ribonucleosides with electron-deficient-, electron-rich-, and electronically neutral aryl amines. Under the developed conditions, S_NAr reactions of 2’,3’,5’-O-(tert …

The Impact Of Focused Attention And Opening Monitoring Meditation Styles On Attention, Jennifer Wheary

Dissertations, Theses, and Capstone Projects

Mindfulness meditation – often broken down into two distinct types, focused attention (FA) and open monitoring (OM) – has been associated with a range of affective and attentional benefits. Using an attentional blink (AB) paradigm that demonstrated improved attention for novice FA meditators, we explored whether novices who engaged in a single, brief bout of meditation exhibited any differences in alpha or theta power during meditation, and whether these differences were apparent by meditation type. In the AB paradigm, participants are asked to identify two targets, T1 and T2, which are separated by 200-500 ms. Our results showed no significant …

Cdc6 Is Sequentially Regulated By Pp2a-Cdc55, Cdc14, And Sic1 For Origin Licensing In S. Cerevisiae, Jasmin Philip

Dissertations, Theses, and Capstone Projects

Control of DNA replication is critical for progression of the cell cycle and genomic stability. Cyclin-dependent kinases (CDKs) coordinate numerous phosphorylation events to accomplish two biological tasks for all living organisms: DNA replication and cell division. One CDK, Cyclin-Cdc28, is responsible for cell cycle progression in budding yeast. DNA replication requires a stepwise assembly of the pre-replicative complex on DNA, including Orc1-6, Cdc6, Cdt1 and Mcm2-7, during M-G1 phase. Cdc6 contains eight Cdc28 consensus sites, SP or TP motifs. Clb5-Cdc28 phosphorylates Cdc6-T7 to recruit Cks1, the Cdc28 phospho-adaptor, for subsequent multisite phosphorylation during S phase. There are two phospho-degrons at …

Genomic Insights Into Mechanisms Of Microbial Evolution And Evolution-Inspired Strategies To Combat Pathogen Diversity, Saymon Akther

Dissertations, Theses, and Capstone Projects

We live in an era of emerging infectious diseases that are increasingly common, rapidly spreading, and gravely devastating. Lyme disease, caused by bacteria belonging to the genus Borreliella, is rapidly rising in the Northern Hemisphere because of geographic range expansion of both the tick vectors and the pathogens. Evolutionary comparative analysis of Borreliella genomes is a key to understanding the phylogeographic history and mechanisms of their global diversification. Moreover, genomic variations in Borreliella associated with human pathogenicity, e.g., at loci encoding cell-surface antigens interacting with the vertebrate hosts, have not been fully identified. Similarly, the ongoing COVID-19 pandemic, caused …

Elucidating Mechanisms Of Biofluorescence And Bioluminescence In Marine Organisms, Andrew M. Guarnaccia

Dissertations, Theses, and Capstone Projects

Biofluorescence and bioluminescence are two methods of light emission that entail separate mechanisms of action but end at the same process: a colorful display that have tremendous ecological and behavioral benefits, whether it be used to communicate with conspecifics, camouflage into a multicolored background, attract unsuspecting prey, or alert others to a predator. In biofluorescence, higher-energy, shorter wavelength light is absorbed then re-emitted as lower-energy, longer-wavelength light. Bioluminescence on the other hand entails a chemical reaction in which a small molecule is oxidized by an enzyme, creating a high-energy intermediate that sheds the excess energy in the form of visible …

Robert Rosen And Relational System Theory: An Overview, James Lennox

Dissertations, Theses, and Capstone Projects

Relational system theory is the science of organization and function. It is the study of how systems are organized which is based on their functions and the relations between their functions. The science was originally developed by Nicolas Rashevsky, and further developed by Rashevsky’s student Robert Rosen, and continues to be developed by Rosen’s student A. H. Louie amongst others. Due to its revolutionary character, it is often misunderstood, and to some, controversial. We will mainly be focusing on Rosen’s contributions to this science. The formal and conceptual setting for Rosen’s relational system theory is category theory. Rosen was the …

Diet And Nutrition Of Lemurs In The Lean Season, Santiago Cassalett

Dissertations, Theses, and Capstone Projects

Animals must navigate complex food and nutrient environments that are constantly in flux to obtain the macro and micronutrients necessary for their growth, reproduction, and survival. The nutritional needs of animals also vary over the life course, further complicating the search for adequate foods and the nutrients within them. The hypervariable and unpredictable environment of Madagascar creates a complex nutrient landscape for lemurs in particular because they are subject to large fluctuations in food availability. These fluctuations are thought to create extreme periods of nutritional stress during the dry season (known as the lean season) for lemurs. In response, lemurs …

Investigating Steady State Visually Evoked Potentials As A Novel Biosignature For Anxiety-Related Attention Bias, Elizabeth R. Davis

Dissertations, Theses, and Capstone Projects

Anxiety-related attention bias (AB), a type of cognitive bias underlying the development and maintenance of anxiety disorders, is typically defined as exaggerated attention towards threat; however, some individuals also demonstrate AB away from threat and in some instances, no detectable AB at all. Debate about the reliability and validity of AB behavioral measures has prompted examination of additional assessment methods. Neurophysiological methods, such electroencephalography (EEG), have yielded encouraging early findings. The steady-state visually evoked potential (SSVEP), a measure of selective visual attention derived from EEG, holds promise as a biosignature for AB. Research documents heightened SSVEP power to emotionally salient …

Testing An Overtraining Protocol For Fear Learning In Humans, Gordon M. Haskell

Dissertations, Theses, and Capstone Projects

Successful regulation of fear memories is a fundamental tenet to the exposure-based therapies often employed by mental health professionals for individuals with PTSD, phobias, and other anxiety disorders. Consequently, the efficacy of these treatment methodologies is largely dependent on the strength of the fear memory, as stronger memories are often characterized by an increased resistance to extinction and heightened fear recovery. However, there is little consensus within the scientific community regarding how to effectively maximize fear memory strength in human studies, and the literature exploring the impact of variability in acquisition parameters on memory strength is sparse. Here, we tested …

Sik2 Inhibition Enhances Parp Inhibitor Activity Synergistically In Ovarian And Triple-Negative Breast Cancers, Zhen Lu, Weiqun Mao, Hailing Yang, Janice M Santiago-O'Farrill, Philip J Rask, Hu Chen, Xiuping Liu, Chang-Gong Liu, Yuanxin Xi, Kenta Masuda, Eli M Carrami, Meng Chen, Yitao Tang, Lan Pang, David S Lakomy, George A Calin, Han Liang, Ahmed A Ahmed, Hariprasad Vankayalapati, Robert C Bast

Faculty, Staff and Student Publications

Poly(ADP-ribose) polymerase inhibitors (PARP inhibitors) have had an increasing role in the treatment of ovarian and breast cancers. PARP inhibitors are selectively active in cells with homologous recombination DNA repair deficiency caused by mutations in BRCA1/2 and other DNA repair pathway genes. Cancers with homologous recombination DNA repair proficiency respond poorly to PARP inhibitors. Cancers that initially respond to PARP inhibitors eventually develop drug resistance. We have identified salt-inducible kinase 2 (SIK2) inhibitors, ARN3236 and ARN3261, which decreased DNA double-strand break (DSB) repair functions and produced synthetic lethality with multiple PARP inhibitors in both homologous recombination DNA repair deficiency and …

Diversity Of Two-Pore Channels And The Accessory Naadp Receptors In Intracellular Ca2+ Signaling, Kunal R Shah, Xin Guan, Jiusheng Yan

Faculty, Staff and Student Publications

Intracellular Ca2+ signaling via changes or oscillation in cytosolic Ca2+ concentration controls almost every aspect of cellular function and physiological processes, such as gene transcription, cell motility and proliferation, muscle contraction, and learning and memory. Two-pore channels (TPCs) are a class of eukaryotic cation channels involved in intracellular Ca2+ signaling, likely present in a multitude of organisms from unicellular organisms to mammals. Accumulated evidence indicates that TPCs play a critical role in Ca2+ mobilization from intracellular stores mediated by the second messenger molecule, nicotinic acid adenine dinucleotide phosphate (NAADP). In recent years, significant progress has been made regarding our understanding …

Association Of Driver Oncogene Variations With Outcomes In Patients With Locally Advanced Non-Small Cell Lung Cancer Treated With Chemoradiation And Consolidative Durvalumab, Yufei Liu, Zhe Zhang, Waree Rinsurongkawong, Carl M Gay, Xiuning Le, Jeff Lewis, J Jack Lee, Jack Roth, Stephen Swisher, Saumil Gandhi, Percy P Lee, Don L Gibbons, Ara A Vaporciyan, John V Heymach, Jianjun Zhang, Steven H Lin

Faculty, Staff and Student Publications

Importance: Consolidative durvalumab after definitive chemoradiation for unresectable locally advanced non-small cell lung cancer (NSCLC) can significantly improve progression-free survival (PFS) and overall survival (OS), as shown in the PACIFIC trial. However, whether patients with driver variations derive equal benefit from this regimen remains unclear.

Objectives: To compare outcomes of patients with locally advanced NSCLC with and without driver variations treated with the PACIFIC regimen.

Design, setting, and participants: This cohort study examined 104 patients with unresectable locally advanced NSCLC with mutational profiling treated at a tertiary cancer center with definitive chemoradiation and consolidative durvalumab from June 2017 through May …

Outcomes After Definitive Surgery For Mandibular Osteoradionecrosis, Kevin J Contrera, Steven B Chinn, Randal S Weber, Dianna Roberts, Jeffery N Myers, Carol M Lewis, Ann M Gillenwater, Collin F Mulcahy, Peirong Yu, Matthew M Hanasono, Clifton D Fuller, Mark S Chambers, Mark E Zafereo

Faculty, Staff and Student Publications

Objectives: To analyze charges, complications, survival, and functional outcomes for definitive surgery of mandibular osteoradionecrosis (ORN).

Materials and methods: Retrospective analysis of 76 patients who underwent segmental mandibulectomy with reconstruction from 2000 to 2009.

Results: Complications occurred in 49 (65%) patients and were associated with preoperative drainage (odds ratio [OR] 4.40, 95% confidence interval [CI] 1.01-19.27). The adjusted median charge was $343 000, and higher charges were associated with double flap reconstruction (OR 8.15, 95% CI 2.19-30.29) and smoking (OR 5.91, 95% CI 1.69-20.72). Improved swallow was associated with age <67 years (OR 3.76, 95% CI 1.16-12.17) and preoperative swallow (OR 3.42, 95% CI 1.23-9.51). Five-year ORN-recurrence-free survival was 93% while overall survival was 63% and associated with pulmonary disease (HR [hazard ratio] 3.57, 95% CI 1.43-8.94).

Conclusions: Although recurrence of ORN is rare, surgical complications are …

Statins Enhance The Chemosensitivity Of R-Chop In Diffuse Large B-Cell Lymphoma, Sushanth Gouni, Paolo Strati, Gokce Toruner, Akanksha Aradhya, Ralf Landgraf, Francisco Vega

Faculty, Staff and Student Publications

The beneficial effect of statins on the anti-lymphoma activity of the rituximab-based chemotherapy regimen is controversial. Here, we retrospectively reviewed patients with naïve-treated advanced diffuse large B-cell lymphoma (DLBCL) receiving frontline R-CHOP, and for whom data regarding differential statins use was available at the time of initiation of treatment. We observe that patients treated with statins and R-CHOP experienced a significantly higher CR rate as compared to those who received R-CHOP only. We further show that patients receiving medium or high intensity statins and R-CHOP experienced a significantly higher CR as compared to those treated with R-CHOP. Six-year progression free …

A Phase 1 Trial Of 8-Chloro-Adenosine In Relapsed/Refractory Acute Myeloid Leukemia: An Evaluation Of Safety And Pharmacokinetics, Rong Chen, Yuling Chen, Ping Xiong, Daniella Zheleva, David Blake, William G Wierda

Faculty, Staff and Student Publications

Fadraciclib (CYC065) is a second-generation aminopurine CDK2/9 inhibitor with increased potency and selectivity toward CDK2 and CDK9 compared to seliciclib (R-roscovitine). In chronic lymphocytic leukemia (CLL), a disease that depends on the over-expression of anti-apoptotic proteins for its survival, inhibition of CDK9 by fadraciclib reduced phosphorylation of the C-terminal domain of RNA polymerase II and blocked transcription in vitro; these actions depleted the intrinsically short-lived anti-apoptotic protein Mcl-1 and induced apoptosis. While the simulated bone marrow and lymph node microenvironments induced Mcl-1 expression and protected CLL cells from apoptosis, these conditions did not prolong the turnover rate of Mcl-1, and …

Cooking After Cancer: The Structure And Implementation Of A Community-Based Cooking Program For Cancer Survivors, Margaret Raber, Molly Costigan, Joya Chandra, Karen Basen-Engquist

Faculty, Staff and Student Publications

Cancer survivors are a growing population that may particularly benefit from nutrition and lifestyle interventions. Community-based programs teaching healthy cooking skills are increasingly popular and offer an opportunity to support survivors within communities. The objective of this study is to describe the curriculum and implementation of a cooking class program designed for cancer survivors, housed within an established community-based organization. First, we evaluated the class curriculum for specific constructs. An evidence-based measure of healthy cooking constructs, the Healthy Cooking Index (HCI), was used to analyze included recipes and revealed both summative cooking quality scores and individual constructs underlying the overall …

Factors Impacting Adolescent And Young Adult Cancer Patients’ Decision To Pursue Genetic Counseling And Testing, Megan Morand, Michael Roth, Susan K Peterson, Erica M Bednar, Aarti Ramdaney, Angela Yarbrough

Faculty, Staff and Student Publications

Purpose: Adolescent and young adult (AYA) cancer patients face challenges when navigating cancer treatment and survivorship. Many are at risk for cancer predisposition syndromes; however, factors influencing pursuit of genetic counseling and testing have not been reported. We describe AYA cancer patients' decision-making process, including motivational factors and barriers, as it relates to utilization of genetic services.

Methods: Thirty AYAs diagnosed with cancer previously referred for cancer predisposition genetic counseling completed semi-structured interviews via audio-only Zoom calls. Thematic analysis was used to perform qualitative analysis and identify major themes.

Results: The sample comprised 21 AYAs who had genetic counseling and …

A Multi-Task Gaussian Process Self-Attention Neural Network For Real-Time Prediction Of The Need For Mechanical Ventilators In Covid-19 Patients, Xiaoqian Jiang

Faculty, Staff and Student Publications

OBJECTIVE: The Coronavirus Disease 2019 (COVID-19) pandemic has overwhelmed the capacity of healthcare resources and posed a challenge for worldwide hospitals. The ability to distinguish potentially deteriorating patients from the rest helps facilitate reasonable allocation of medical resources, such as ventilators, hospital beds, and human resources. The real-time accurate prediction of a patient's risk scores could also help physicians to provide earlier respiratory support for the patient and reduce the risk of mortality.

METHODS: We propose a robust real-time prediction model for the in-hospital COVID-19 patients' probability of requiring mechanical ventilation (MV). The end-to-end neural network model incorporates the Multi-task …

Gdf5+ Chondroprogenitors Derived From Human Pluripotent Stem Cells Preferentially Form Permanent Chondrocytes, Guangsheng Pei, Qing Yan, Brian R Davis, Johnny Huard, Zhongming Zhao, Naoki Nakayama

Faculty, Staff and Student Publications

It has been established in the mouse model that during embryogenesis joint cartilage is generated from a specialized progenitor cell type, distinct from that responsible for the formation of growth plate cartilage. We recently found that mesodermal progeny of human pluripotent stem cells gave rise to two types of chondrogenic mesenchymal cells in culture: SOX9+ and GDF5+ cells. The fast-growing SOX9+ cells formed in vitro cartilage that expressed chondrocyte hypertrophy markers and readily underwent mineralization after ectopic transplantation. In contrast, the slowly growing GDF5+ cells derived from SOX9+ cells formed cartilage that tended to express low to undetectable levels of …

Comprehensive Characterization Of Tumor Immune Landscape Following Oncolytic Virotherapy By Single-Cell Rna Sequencing

Faculty, Staff and Student Publications

An important mechanism of oncolytic virotherapy in ameliorating cancer immunotherapy is by inducing significant changes in the immune landscape in the tumor microenvironment (TME). Despite this notion and the potential therapeutic implications, a comprehensive analysis of the immune changes in carcinomas induced by virotherapy has not yet been elucidated. We conducted single-cell RNA sequencing analysis on carcinomas treated with an HSV-2-based oncolytic virus to characterize the immunogenic changes in the TME. We specifically analyzed and compared the immune cell composition between viral treated and untreated tumors. We also applied CellChat to analyze the complex interactions among the infiltrated immune cells. …

Peripheral Blood Gene Expression Profiling Shows Predictive Significance For Response To Mycophenolate In Systemic Sclerosis-Related Interstitial Lung Disease, Holly Wilhalme, Marka A Lyons, Michael D Roth, Donald P Tashkin

Faculty, Staff and Student Publications

OBJECTIVES: To characterise the peripheral blood cell (PBC) gene expression changes ensuing from mycophenolate mofetil (MMF) or cyclophosphamide (CYC) treatment and to determine the predictive significance of baseline PBC transcript scores for response to immunosuppression in systemic sclerosis (SSc)-related interstitial lung disease (ILD).

METHODS: PBC RNA samples from baseline and 12-month visits, corresponding to the active treatment period of both arms in Scleroderma Lung Study II, were investigated by global RNA sequencing. Joint models were created to examine the predictive significance of

RESULTS: 134 patients with SSc-ILD (CYC=69 and MMF=65) were investigated. CYC led to an upregulation of erythropoiesis, inflammation …

Distribution Modelling Of Socotra Cormorant Using Maxent, Areej Mustafa Jaradat

Theses

This thesis is concerned with species distribution modeling of the Socotra Cormorant (Phalacrocorax nigrogularis), a regionally endemic seabird to the Arabian Gulf, the Arabian Sea, and the Gulf of Aden. Socotra Cormorants are important for the marine ecosystem as they apply top-down control and maintain the balance between trophic levels. They also contribute to the cycling of nutrients significantly. The bird is categorized as vulnerable by the IUCN. Large portions of their suitable habitat are disturbed or degraded due to oil exploration and coastal development. The seabird is poorly studied in every ecological aspect. The main objective of …

Optimization Of Palmitic Acid Production In Chloroidium Sp. Utex 3007 As A Sustainable Source Of Palm Oil Alternative, Amnah Salem Alzahmi

Theses

The increase in palm oil consumption and production has resulted in removing up to 90% of trees in some tropical forests. The green microalgae Chloroidium sp. UTEX 3007 can be an alternative sustainable source of palm oil due to its high palmitic acid content. The objective of this study was to generate a mutant Chloroidium population that is capable of producing and accumulating elevated levels of palmitic acid and to characterize the obtained populations’ lipid contents. The palmitic acid production optimization in Chloroidium sp. UTEX 3007 was conducted via a workflow of ultraviolet (UV) mutagenesis and sorting of high-lipid producing …

Physicochemical, Techno-Functional And Bioactive Properties Of Camel Whey Protein Concentrate As Affected By Spray-Drying And Ultrasonication Treatment, Alanoud Muhsen Al Thaibani

Theses

Whey protein concentrates (WPCs) are gaining importance as a functional ingredient due to their nutritional, techno-functional and bioactive properties. In this study, WPCs were prepared from skimmed camel milk, then either spray-dried (SD) at 170, 185 and 200°C, or treated by ultrasonication (US) (20 kHz) for 5, 10 and 15 min followed by freeze-drying to obtain powders. The characterization of WPC powders was carried out by Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and Reverse-Phase Ultra Performance Liquid Chromatography (RP-UPLC) which showed that the US treatment degraded the proteins more than SD. The morphology, particle size, and surface charge of WPC …