Life Sciences Commons^™

Membrane-Anchored And Tumor-Targeted Il12 (Attil12)-Pbmc Therapy For Osteosarcoma, Qing Yang, Jiemiao Hu, Zhiliang Jia, Qi Wang, Jing Wang, Wendong Zhang, Xueqing Xia, Richard Gorlick, Shulin Li

Faculty, Staff and Student Publications

Purpose: Chimeric antigen receptor (CAR) T-cell therapy has shown great promise for treating hematologic malignancies but requires a long duration of T-cell expansion, is associated with severe toxicity, and has limited efficacy for treating solid tumors. We designed experiments to address those challenges.

Experimental design: We generated a cell membrane-anchored and tumor-targeted IL12 (attIL12) to arm peripheral blood mononuclear cells (PBMC) instead of T cells to omit the expansion phase for required CAR T cells.

Results: This IL12-based attIL12-PBMC therapy showed significant antitumor efficacy in both heterogeneous osteosarcoma patient-derived xenograft tumors and metastatic osteosarcoma tumors with no observable toxic effects. …

Hic2 Controls Developmental Hemoglobin Switching By Repressing Bcl11a Transcription, Peng Huang, Scott A Peslak, Ren Ren, Eugene Khandros, Kunhua Qin, Belinda Giardine, Xianjiang Lan, Malini Sharma, John R Horton, Osheiza Abdulmalik, Stella T Chou, Junwei Shi, Merlin Crossley, Ross C Hardison, Xiaodong Cheng, Gerd A Blobel

Faculty, Staff and Student Publications

The fetal-to-adult switch in hemoglobin production is a model of developmental gene control with relevance to the treatment of hemoglobinopathies. The expression of transcription factor BCL11A, which represses fetal β-type globin (HBG) genes in adult erythroid cells, is predominantly controlled at the transcriptional level but the underlying mechanism is unclear. We identify HIC2 as a repressor of BCL11A transcription. HIC2 and BCL11A are reciprocally expressed during development. Forced expression of HIC2 in adult erythroid cells inhibits BCL11A transcription and induces HBG expression. HIC2 binds to erythroid BCL11A enhancers to reduce chromatin accessibility and binding of transcription factor GATA1, …

Repurposing Epigenetic Inhibitors To Target The Clostridioides Difficile-Specific Dna Adenine Methyltransferase And Sporulation Regulator Cama, Jujun Zhou, John R Horton, Dan Yu, Ren Ren, Robert M Blumenthal, Xiaodong Cheng

Faculty, Staff and Student Publications

Epigenetically targeted therapeutic development, particularly for SAM-dependent methylations of DNA, mRNA and histones has been proceeding rapidly for cancer treatments over the past few years. However, this approach has barely begun to be exploited for developing new antibiotics, despite an overwhelming global need to counter antimicrobial resistance. Here, we explore whether SAM analogues, some of which are in (pre)clinical studies as inhibitors of human epigenetic enzymes, can also inhibit Clostridioides difficile-specific DNA adenine methyltransferase (CamA), a sporulation regulator present in all C. difficile genomes sequenced to date, but found in almost no other bacteria. We found that SGC0946 (an …

Bintrafusp Alfa, An Anti-Pd-L1:Tgf-Β Trap Fusion Protein, In Patients With Ctdna-Positive, Liver-Limited Metastatic Colorectal Cancer, Van K Morris, Michael J Overman, Michael Lam, Christine M Parseghian, Benny Johnson, Kanwal Raghav, Ryan Huey, Robert A Wolff, John Paul Shen, June Li, Isabel Zorrilla, Ching-Wei D Tzeng, Hop S Tran Cao, Yun Shin Chun, Timothy E Newhook, Nicolas Vauthey, Dzifa Duose, Raja Luthra, Cara Haymaker, Scott Kopetz

Faculty, Staff and Student Publications

Background: Identification of circulating tumor DNA (ctDNA) following curative intent therapies is a surrogate for microscopic residual disease for patients with metastatic colorectal cancer (mCRC). Preclinically, in micrometastatic microsatellite stable (MSS) CRC, increased TGF-β signaling results in exclusion of anti-tumor cytotoxic T cells from the tumor microenvironment. Bintrafusp alfa (BA) is a bifunctional fusion protein composed of the extracellular domain of the TGF-βRII receptor ("TGF-β trap") and anti-PD-L1 antibody.

Methods: Patients with liver-limited, MSS mCRC and with detected ctDNA after complete resection of all known tumors and standard-of-care therapy were treated with 1200 mg of BA intravenously every 14 days …

Game Of Clones: Battles In The Field Of Carcinogenesis, Zahraa Rahal, Ansam Sinjab, Ignacio I Wistuba, Humam Kadara

Faculty, Staff and Student Publications

Recent advances in bulk sequencing approaches as well as genomic decoding at the single-cell level have revealed surprisingly high somatic mutational burdens in normal tissues, as well as increased our understanding of the landscape of "field cancerization", that is, molecular and immune alterations in mutagen-exposed normal-appearing tissues that recapitulated those present in tumors. Charting the somatic mutational landscapes in normal tissues can have strong implications on our understanding of how tumors arise from mutagenized epithelium. Making sense of those mutations to understand the progression along the pathologic continuum of normal epithelia, preneoplasias, up to malignant tissues will help pave way …

The Insulin Receptor Regulates The Persistence Of Mechanical Nociceptive Sensitization In Flies And Mice, Tatiana V Karpinets, Xiaogang Wu, Travis Solley, Molly B El Alam, Travis T Sims, Erica Lynn, Greyson Biegert, Jingyan Yue, Xingzhi Song, Huandong Sun, Joseph F Petrosino, Melissa P Mezzari, Pablo Okhuysen, Patricia J Eifel, Anuja Jhingran, Lilie L Lin, Kathleen M Schmeler, Lois Ramondetta, Nadim Ajami, Robert R Jenq, Andrew Futreal, Jianhua Zhang, Ann H Klopp, Lauren E Colbert

Faculty, Staff and Student Publications

Early phase diabetes is often accompanied by pain sensitization. In Drosophila, the insulin receptor (InR) regulates the persistence of injury-induced thermal nociceptive sensitization. Whether Drosophila InR also regulates the persistence of mechanical nociceptive sensitization remains unclear. Mice with a sensory neuron deletion of the insulin receptor (Insr) show normal nociceptive baselines; however, it is uncertain whether deletion of Insr in nociceptive sensory neurons leads to persistent nociceptive hypersensitivity. In this study, we used fly and mouse nociceptive sensitization models to address these questions. In flies, InR mutants and larvae with sensory neuron-specific expression of RNAi …

Schwann Cells Induce Phenotypic Changes In Oral Cancer Cells, Maria Daniela Santi, Morgan Zhang, Elizabeth Salvo, Kesava Asam, Chi T Viet, Moran Amit, Yi Ye

Faculty, Staff and Student Publications

Head and neck cancer (HNC) is the seventh most common cancer worldwide, the majority being oral squamous cell carcinoma. Despite advances in cancer diagnosis and treatment, the survival rate of patients with HNC remains stagnant. The cancer-nerve interaction has been recognized as an important driver of cancer progression. Schwann cells, a type of peripheral glia, have been implicated in promoting cancer cell growth, migration, dispersion, and invasion into the nerve in many cancers. Here, it is demonstrated that the presence of Schwann cells makes oral cancer cells more aggressive by promoting their proliferation, extracellular matrix breakdown, and altering cell metabolism. …

Impact Of Medicaid Expansion Under The Affordable Care Act On Receipt Of Surgery For Breast Cancer, Leisha C Elmore, Meng Li, Heather Lin, Yu Shen, Simona F Shaitelman, Nina Tamirisa

Faculty, Staff and Student Publications

To determine whether Medicaid expansion under the 2010 Affordable Care Act affected rates of breast cancer surgery.

Background: Data regarding the impact of Medicaid expansion on access to surgical treatment of breast cancer are limited.

Methods: Patients in the National Cancer Database diagnosed with non-metastatic breast cancer between January 1, 2010 and December 31, 2017 and residing in a state that expanded Medicaid in January 2014 or in a state that opted out of expansion were included. A quasi-experimental, difference-in-differences (DID) approach was used to assess rate of omission of surgical treatment.

Results: Of 624,237 patients diagnosed with invasive breast …

Clinical Acceptability Of Fully Automated External Beam Radiotherapy For Cervical Cancer With Three Different Beam Delivery Techniques, Dong Joo Rhee, Anuja Jhingran, Kai Huang, Tucker J Netherton, Nazia Fakie, Alicia Sherriff, Lifei Zhang, Surendra Prajapati, Stephen F Kry, Beth M Beadle, William Shaw, Frederika O'Reilly, Jeannette Parkes, Hester Burger, Chris Trauernicht, Hannah Simonds, Laurence E Court

Faculty, Staff and Student Publications

Purpose: To fully automate CT-based cervical cancer radiotherapy by automating contouring and planning for three different treatment techniques.

Methods: We automated three different radiotherapy planning techniques for locally advanced cervical cancer: 2D 4-field-box (4-field-box), 3D conformal radiotherapy (3D-CRT), and volumetric modulated arc therapy (VMAT). These auto-planning algorithms were combined with a previously developed auto-contouring system. To improve the quality of the 4-field-box and 3D-CRT plans, we used an in-house, field-in-field (FIF) automation program. Thirty-five plans were generated for each technique on CT scans from multiple institutions and evaluated by five experienced radiation oncologists from three different countries. Every plan was …

Fusobacterium Is Enriched In Oral Cancer And Promotes Induction Of Programmed Death-Ligand 1 (Pd-L1), Chieko Michikawa, Vancheswaran Gopalakrishnan, Amani M Harrandah, Tatiana V Karpinets, Rekha Rani Garg, Yuk Pheel Park, Nikhita Yadlapalli, Kelly C Erikson-Carter, Frederico Omar Gleber-Netto, Elias Sayour, Ann Progulske-Fox, Edward K L Chan, Xiaogang Wu, Jianhua Zhang, Christian Jobin, Jennifer A Wargo, Curtis R Pickering, Jeffrey N Myers, Natalie Silver

Faculty, Staff and Student Publications

Recently, increased number of studies have demonstrated a relationship between the oral microbiome and development of head and neck cancer, however, there are few studies to investigate the role of oral bacteria in the context of the tumor microenvironment in a single head and neck subsite. Here, paired tumor and adjacent normal tissues from thirty-seven oral tongue squamous cell carcinoma (SCC) patients were subjected to 16S rRNA gene sequencing and whole exome sequencing (WES), in addition to RNA sequencing for tumor samples. We observed that Fusobacterium was significantly enriched in oral tongue cancer and that Rothia and Streptococcus were enriched …

Severe Radiation-Induced Lymphopenia Attenuates The Benefit Of Durvalumab After Concurrent Chemoradiotherapy For Nsclc, Wang Jing, Ting Xu, Lirong Wu, Pablo B Lopez, Clemens Grassberger, Radhe Mohan, George R Blumenschein, Janet Tu, Mehmet Altan, Percy Lee, Zhongxing Liao, Steven H Lin

Faculty, Staff and Student Publications

Introduction: Durvalumab after concurrent chemoradiation (CCRT) for NSCLC improves survival, but only in a subset of patients. We investigated the effect of severe radiation-induced lymphopenia (sRIL) on survival in these patients.

Methods: Outcomes after CCRT (2010-2019) or CCRT followed by durvalumab (2018-2019) were reviewed. RIL was defined by absolute lymphocyte count (ALC) nadir in samples collected at end of CCRT; sRIL was defined as nadir ALC less than 0.23 × 109/L (the lowest tertile). Progression-free survival (PFS) and overall survival (OS) were calculated by the Kaplan-Meier method. Cox proportional hazard modeling evaluated associations between clinical variables and survival.

Results: Of …

Tumor Immune Microenvironment Changes By Multiplex Immunofluorescence Staining In A Pilot Study Of Neoadjuvant Talazoparib For Early-Stage Breast Cancer Patients With A Hereditary Brca Mutation, Tapsi Kumar, Evie Hobbs, Fei Yang, Jeffrey T Chang, Alejandro Contreras, Haven Garber, Yiling Lu, Marion E Scoggins, Beatriz E Adrada, Gary J Whitman, Banu K Arun, Elizabeth A Mittendorf, Jennifer K Litton

Faculty, Staff and Student Publications

PURPOSE: The immunological profile of early-stage breast cancer treated with neoadjuvant PARP inhibitors has not been described. The aim of this study was to delineate the changes in the tumor immune microenvironment (TiME) induced by talazoparib.

PATIENTS AND METHODS: Patients with operable germline BRCA1/2 pathogenic variant (gBRCA1/2+) breast cancer were enrolled in a feasibility study of neoadjuvant talazoparib. Thirteen patients who received 8 weeks of neoadjuvant talazoparib were available for analysis, including 11 paired pre- and post-talazoparib core biopsies. Treatment-related changes in tumor-infiltrating lymphocytes were examined and immune cell phenotypes and their spatial distribution in the TiME were identified and …

Tumor Immune Contexture Is A Determinant Of Anti-Cd19 Car T Cell Efficacy In Large B Cell Lymphoma, Nathalie Scholler, Regis Perbost, Frederick L Locke, Michael D Jain, Sarah Turcan, Edmund C Chang, David B Miklos, Caron A Jacobson, Lazaros J Lekakis, Yi Lin, Armin Ghobadi, Jenny J Kim, Justin Chou, Vicki Plaks, Zixing Wang, Allen Xue, Mike Mattie, John M Rossi, Adrian Bot, Jérôme Galon

Faculty, Staff and Student Publications

Axicabtagene ciloleucel (axi-cel) is an anti-CD19 chimeric antigen receptor (CAR) T cell therapy approved for relapsed/refractory large B cell lymphoma (LBCL) and has treatment with similar efficacy across conventional LBCL subtypes. Toward patient stratification, we assessed whether tumor immune contexture influenced clinical outcomes after axi-cel. We evaluated the tumor microenvironment (TME) of 135 pre-treatment and post-treatment tumor biopsies taken from 51 patients in the ZUMA-1 phase 2 trial. We uncovered dynamic patterns that occurred within 2 weeks after axi-cel. The biological associations among Immunoscore (quantification of tumor-infiltrating T cell density), Immunosign 21 (expression of pre-defined immune gene panel) and cell …

Swallowing After Primary Tors And Unilateral Or Bilateral Radiation For Low- To Intermediate-Risk Tonsil Cancer, Carly E A Barbon, Christopher M K Yao, Christine B Peterson, Amy C Moreno, Ryan P Goepfert, Gregory M Chronowski, Neil D Gross, Katherine A Hutcheson

Faculty, Staff and Student Publications

Objective: The primary course of treatment for patients with low- to intermediate-risk tonsil cancer has evolved with a shift toward primary transoral robotic surgery (TORS) or radiation therapy (RT). While favorable outcomes have been reported after deintensification via unilateral TORS or RT (uniRT), comparisons of functional outcomes between these treatments are lacking. We compared clinical outcomes (Dynamic Imaging Grade of Swallowing Toxicity [DIGEST] and feeding tube [FT]) and patient-reported swallowing outcomes (MD Anderson Dysphagia Inventory [MDADI]) based on primary treatment strategy: TORS, uniRT, or bilateral RT (biRT).

Study design: Secondary analysis of prospective cohort.

Setting: Single institution.

Methods: The study …

Mass Transport Model Of Radiation Response: Calibration And Application To Chemoradiation For Pancreatic Cancer, Charles X Wang, Dalia Elganainy, Mohamed M Zaid, Joseph D Butner, Anshuman Agrawal, Bruce D Minsky, Cullen M Taniguchi, Grace L Smith, Albert C Koong, Joseph M Herman, Prajnan Das, Anirban Maitra, Huamin Wang, Robert A Wolff, Matthew H G Katz, Christopher H Crane, Vittorio Cristini, Eugene J Koay

Faculty, Staff and Student Publications

PURPOSE: The benefit of radiation therapy for pancreatic ductal adenocarcinoma (PDAC) remains unclear. We hypothesized that a new mechanistic mathematical model of chemotherapy and radiation response could predict clinical outcomes a priori, using a previously described baseline measurement of perfusion from computed tomography scans, normalized area under the enhancement curve (nAUC).

METHODS AND MATERIALS: We simplified an existing mass transport model that predicted cancer cell death by replacing previously unknown variables with averaged direct measurements from randomly selected pathologic sections of untreated PDAC. This allowed using nAUC as the sole model input to approximate tumor perfusion. We then compared the …

Development And Characterization Of A Novel, Genetically- Encoded Sensor To Image Sonic Hedgehog Signaling In Functional Circuits, Sonia Bernal

Dissertations, Theses, and Capstone Projects

Dynamic neurotransmitter and neuromodulator signaling in functional circuits is the neural substrate of animal behavior and cognition. The study of said circuits requires tools with sufficient spatiotemporal dynamics that can probe complex signaling patterns and decode their functional relevance by coupling the signal to behavioral output, ideally in awake, behaving animals. Much is known about the role of classical neurotransmitters such as dopamine in behavior, but a wide variety of peptides and small molecules also regulate neuronal transmission. One of these is Shh, whose presence has been observed in a variety of brain regions known to modulate movement, perception, and …

Role Of The G Protein Beta Gamma Subunits In Serotonin Transporter Dynamics, Nora Awadallah

Dissertations, Theses, and Capstone Projects

Serotonin is a vital neurotransmitter and hormone with significant roles in almost every organ system. In the central nervous system, serotonin mediates physiological functions that in turn guide behavior and mood. Here, serotonin is released from serotonergic neurons and exerts its effects through serotonin receptors. Regulation of serotonin neurotransmission is important for the maintenance of its physiological functions; thus, extracellular serotonin must be sequestered to limit the intensity and duration of serotonin transmission. Disproportionate transmission is strongly linked with neurological and psychiatric ailments.

Extracellular serotonin levels are primarily mediated by the serotonin transporter (SERT), a critically important plasma membrane protein …

Genetic Determinants Of Carotenoid Pigmentation In The Opportunistic Pathogen Mycobacterium Kansasii, Niklas Janisch

Dissertations, Theses, and Capstone Projects

Mycobacterium kansasii (Mk) is an opportunistic pulmonary pathogen causing infections, predominantly in immunocompromised people, with symptoms similar to those caused by its close relative Mycobacterium tuberculosis (Mt). In contrast to the latter, little work has been done on Mk genetics and even less on its defining characteristic of photochromogenicity, the controlled expression of carotenoid pigments in response to light exposure.

This work represents major progress in the investigation of pigmentation-related genetic factors in Mk. We report the creation of a large-scale, random transposon-insertion mutant library of Mk and its subsequent screening for mutants with an aberration in the …

Nutrient Dynamics And Ecosystem Development Of Urban Forests, Gisselle A. Mejía

Dissertations, Theses, and Capstone Projects

Urban growth and expansion are a major component of global environmental change, with impacts on climate, air and water quality, biodiversity, and human well-being. Forests embedded in urban landscapes are critical in mitigating these impacts at local, regional, and continental scales. However, assessing urban forests is difficult because cities are heterogenous in physical, chemical, biological, and social dimensions. This heterogeneity has constrained how urban forests are defined, and therefore, how they are studied. The objective of this dissertation is to determine how these biophysical and social factors drive ecological processes in urban forests and will address three outstanding challenges in …

The Effects Of False Heartbeat Feedback On Moral Judgment, Scott Koenig

Dissertations, Theses, and Capstone Projects

Research on human morality is at a crossroads, with one side claiming that moral judgment is the result of rational inference and the other side claiming that it is the result of emotion-laden intuition. This study investigated whether emotion drives moral judgment by manipulating a core component of the experience of emotion: physiological arousal. The sample consisted of 77 undergraduate students at Brooklyn College (57% women, 43% men; mean age = 20.1). One group of participants was led to believe their heart was beating quickly, and another group slowly, while they read and evaluated a series of text vignettes depicting …

Prenatal Choline Supplementation During Maternal Obesity Alters Offspring Response To Western Diets, Hunter W. Korsmo

Dissertations, Theses, and Capstone Projects

Maternal obesity has led to an increase in adverse offspring developmental outcomes and a greater risk for long-term metabolic diseases. Choline, a semi-essential nutrient, can be incorporated into phosphatidylcholine (PC) as well as sphingomyelin (SM) and donate its labile methyl group for the remethylation of homocysteine after choline is oxidized to betaine. Prenatal choline insufficiency has been related to maternal obesity and metabolic diseases, such as metabolic associated fatty liver disease (MAFLD). Choline may interact with maternal obesity to influence the programming offspring.

Chapter 1 presents an introduction of choline and the various clinical outcomes associated with choline supplementation during …

Isolation And Characterization Of Fluorescent Proteins And Small Molecules From Marine Vertebrates, Sara Rose Krivoshik

Dissertations, Theses, and Capstone Projects

Fluorescence is a phenomenon in which a wavelength of light excites a fluorophore and then emits light at a higher, longer wavelength. This occurs throughout the biological world, in both the terrestrial and marine realms. Encompassing a diverse set of mechanisms from small molecules to large protein complexes; fluorescence has been used as a biological tool with a wide range of applications to study molecular and cellular biology for decades. This dissertation looks to identify and characterize novel fluorescent proteins and small molecules to allow for more efficient translation in developing new biotechnologies. Using a combination of RNA-Seq, Mass-Spec, protein …

Role Of Nuclear Lamins In Oligodendrocyte Lineage Cells, Camila Yattah

Dissertations, Theses, and Capstone Projects

Differentiation of oligodendrocytes from progenitor cells is a highly regulated process characterized by a series of molecular changes, resulting in nuclear and morphological features unique to the mature oligodendrocyte state. Heterochromatin formation starting at the nuclear periphery, as well as increased nuclear rigidity are characteristically observed. The nuclear periphery is characterized by the presence of the nuclear lamina and it has been implicated in higher-order genome organization in cells. Lamins are the protein components of the nuclear lamina, and their expression is dependent upon the cell differentiation stage of the cells. While Lamin B1 (LMNB1) expression is high in progenitors …

Expulsive Greening: A Cross-Sectional Analysis Of Green Gentrification In The Resilience Paradigm, Brooklyn 2010–2020, Rose Jimenez

Dissertations, Theses, and Capstone Projects

Background: This project analyzes the spatial coincidence between gentrification typologies and urban greening in Brooklyn, New York from 2010 to 2020. Assets formed under the NYC Green Infrastructure Program were chosen as a proxy for urban greening to represent the spatial practice specifically within the 21st-century climate change resilience paradigm of development. Methods: First, five indexes measuring variations of economic and demographic conditions related to gentrification were applied to Brooklyn for comparative analysis: NOAA’s Social Vulnerability Indicators of Gentrification Pressure, The NYC Heat Vulnerability Index, The Small Area Index of Gentrification, Typologies of Gentrification and Displacement, and The Housing Risk …

Determining The Roles Of The Oligomerization And C-Terminal Domains In Mutant P53 Gain-Of-Function Activities, George K. Annor

Dissertations, Theses, and Capstone Projects

The tumor suppressor p53 (TP53) gene is often mutated in cancer, with missense mutations found in the central DNA binding domain, and less often in the oligomerization domain (OD) and C-terminal domain (CTD). The OD and CTD have been found to be critical for the tumor suppressor functionality of wild-type p53 (wtp53). Specific missense mutations in the DNA binding domain have been found to confer new gain-of-function (GOF) activities. Mutations that destabilize tetramer formation, or deletion of key lysine residues within the CTD, downregulate the ability of wtp53 to transactivate (increase the rate of transcription of) its target …

Unexpected Arousal Suppresses Memory And Metamemory Predictions During Associative Face-Name Recognition Task, Sameer Sabharwal-Siddiqi

Dissertations, Theses, and Capstone Projects

Successful recognition often depends on probabilistic estimation of memory-signal. Arousal has been shown to offset the influence of heuristic evidence on memory prediction. We conducted three experiments that tested whether arousal also suppresses predictions relevant to memory confidence. Experiments employed associative face-name memory tasks that included retrospective (Experiments 1 and 2) or concurrent (Experiment 3) judgements of confidence. During test, subjects were presented with a masked-affective face on a subset of trials. By timing the masked-affective face to precede a recognition judgement (Experiment 1), we replicated the finding that unexpected arousal offsets the influence of heuristic evidence on expectations of …

Novel Therapeutic Strategies For Alzheimer’S Disease: Prostaglandin D2 Signaling And Its Human Polymorphisms As Well As A Polypharmacological Approach, Charles H. Wallace

Dissertations, Theses, and Capstone Projects

Alzheimer’s disease (AD) is an age related neurodegenerative disease with pathology that includes amyloid plaques, neurofibrillary tangles and non-resolving neuroinflammation. Non-resolving neuroinflammation lasts the entire course of the disease and has deleterious effects and is often thought to accelerate AD pathology. Non-Steroidal Anti-inflammatory Drugs (NSAIDs) have commonly been used as therapeutics to treat pain, inflammation and vascular. NSAIDs work by altering the cyclooxygenase (COX) mediated biosynthesis of prostaglandins which are lipid mediators that have many physiological functions, for example nociception, inflammation and vasodilation. Epidemiological studies support the notion that NSAIDs could be used to treat AD. Yet, clinical trials using …

Competitive And Facilitative Interactions Between Pavlovian Cues In Human Associative Learning: A Behavioral And Neural Analysis, Fahd Alhazmi

Dissertations, Theses, and Capstone Projects

Learning to anticipate significant events accurately is a crucial element of survival for all species. The process by which animals acquire this knowledge has been a central question of psychological research. A fundamental assumption of many learning theories is that the predictive value assigned to cues is not simply determined by their probability of reinforcement but rather by their ability to compete with other cues present during learning. The assumption of cue competition has significantly contributed to the development of behavioral and neuroscience research for decades, as it has opened the door to new empirical and theoretical advances on the …

Biochemical And Biophysical Characterization Of Replicative Helicase Loading By Vibrio Cholerae Dcia, Crystal Structure Of A Monoclonal Antibody Bound To A C-Terminal Fragment Of Ebna-1 From Epstein Barr Virus, Nicholas Gao

Dissertations, Theses, and Capstone Projects

DNA replication initiation is mediated by the binding of an initiator protein to genomic origins of replication to begin the process of loading replicative helicases onto the genome. The loading of the helicase requires the action of an accessory protein, named a “loader”. Studies on well-characterized loaders have outlined how the bacterial DnaB replicative helicase is loaded via mechanisms of “Ring-Breaking” by E. coli DnaC (EcDnaC)/protein P from bacteriophage lambda (LP) and “Ring-Making” by B. subtilis DnaI. Mounting evidence points to a recently discovered candidate loader, named DciA, that shows a more widespread distribution throughout bacteria than DnaC and DnaI …

Gamma Protocadherin Synaptic Localization And Intracellular Trafficking Is Consistent With Distinct Adhesive And Anti-Adhesive Roles In Development, Nicole Lamassa

Dissertations, Theses, and Capstone Projects

Clustered protocadherins (Pcdhs) constitute a family of cell adhesion molecules with approximately 60 Pcdh genes clustered in a 1 MB locus on chromosome 5q31 in humans. The Pcdh gene cluster is subdivided into α, β, and γ subclusters which encode related proteins. Individual neurons activate different subsets of Pcdh-α, Pcdh-β and Pcdh-γ genes by epigenetic mechanisms to generate distinct Pcdh adhesive units expressed by each neuron. This is thought to serve as a “surface barcode” for single-cell identity and synaptic recognition in the nervous system. The actual role for Pcdhs in neural development is still relatively unknown and different roles …