Biochemistry, Biophysics, and Structural Biology Commons^™

Adult Memory T Cell Responses To The Respiratory Syncytial Virus Fusion Protein During A Single Rsv Season (2018-2019), Brittani N Blunck, Laura S Angelo, David Henke, Vasanthi Avadhanula, Matthew Cusick, Laura Ferlic-Stark, Lynn Zechiedrich, Brian E Gilbert, Pedro A Piedra

Faculty, Staff and Students Publications

Respiratory Syncytial Virus (RSV) is ubiquitous and re-infection with both subtypes (RSV/A and RSV/B) is common. The fusion (F) protein of RSV is antigenically conserved, induces neutralizing antibodies, and is a primary target of vaccine development. Insight into the breadth and durability of RSV-specific adaptive immune response, particularly to the F protein, may shed light on susceptibility to re-infection. We prospectively enrolled healthy adult subjects (n = 19) and collected serum and peripheral blood mononuclear cells (PBMCs) during the 2018–2019 RSV season. Previously, we described their RSV-specific antibody responses and identified three distinct antibody kinetic profiles associated with infection …

Clinical Reasoning Education In The Clerkship Years: A Cross-Disciplinary National Needs Assessment, Jonathan G Gold, Christopher L Knight, Jennifer G Christner, Christopher E Mooney, David E Manthey, Valerie J Lang

Faculty, Staff and Students Publications

BACKGROUND: Improving clinical reasoning education has been identified as an important strategy to reduce diagnostic error-an important cause of adverse patient outcomes. Clinical reasoning is fundamental to each specialty, yet the extent to which explicit instruction in clinical reasoning occurs across specialties in the clerkship years remains unclear.

METHOD: The Alliance for Clinical Education (ACE) Clinical Reasoning Workgroup and the Directors of Clinical Skills Courses (DOCS) Clinical Reasoning Workgroup collaborated to develop a clinical reasoning needs assessment survey. The survey questionnaire covered seven common clinical reasoning topics including illness scripts, semantic qualifiers, cognitive biases and dual process theory. Questionnaires were …

Multiplex Hextuple Luciferase Assaying, Alejandro Sarrion-Perdigones, Yezabel Gonzalez, Lyra Chang, Tatiana Gallego-Flores, Damian W Young, Koen J T Venken

Faculty, Staff and Students Publications

We recently expanded the commonly used dual luciferase assaying method toward multiplex hextuple luciferase assaying, allowing monitoring the activity of five experimental pathways against one control at the same time. In doing so, while our expanded assay utilizes a total of six orthogonal luciferases instead of two, this assay, conveniently, still utilizes the well-established reagents and principles of the widely used dual luciferase assay. Three quenchable D-luciferin-consuming luciferases are measured after addition of D-Luciferin substrate, followed by quenching of their bioluminescence (BL) and the measurement of three coelenterazine (CTZ)-consuming luciferases after addition of CTZ substrate, all in the same vessel. …

The Impact Of Plant Secondary Metabolites On Auxin And Cytokinin Signaling, Timothy E. Shull

Theses and Dissertations--Plant and Soil Sciences

Secondary metabolites are a broad class of specialized compounds that mediate plant-environment interactions and mitigate stress. It is increasingly clear that many phenylalanine-derived secondary metabolites are nearly indispensable for plant survival and that plants adjust their growth according to their secondary metabolic outputs. Consequently, many phenylalanine-derived secondary metabolites have influence over hormone activity. For instance, multiple phenylpropanoid intermediates and catecholamines alter the sensitivity of plants to the central hormone auxin, which in concert with cytokinin directs most aspects of plant growth and development. This dissertation reviews previous research on the influence of phenylpropanoid intermediates and catecholamines on plants, with a …

ฤทธิ์การเหนี่ยวนำร่วมระหว่างสารพฤกษเคมีกลุ่มฟลาโวนอยด์และแนพโทควิโนนกับสารสะแมคไมเมติกต่อการตายของเซลล์มะเร็งที่กระตุ้นภูมิคุ้มกันในเซลล์มะเร็งท่อน้ำดี, ภัทธร ใจกล้า

Chulalongkorn University Theses and Dissertations (Chula ETD)

มะเร็งท่อน้ำดีเป็นมะเร็งที่เกิดขึ้นบริเวณท่อทางเดินน้ำดี โดยมีความหลากหลายของเซลล์มะเร็งบริเวณเนื้อเยื่อมะเร็งและมีความรุนแรง มะเร็งท่อน้ำดีจัดเป็นสาเหตุหลักในการเสียชีวิตของผู้ป่วยในประเทศไทย เนื่องจากผู้ป่วยได้รับการวินิจฉัยเมื่อมะเร็งเจริญพัฒนาไปยังระยะท้ายและยังขาดวิธีการรักษาที่มีประสิทธิภาพ การรักษามะเร็งท่อน้ำดีด้วยวิธีมาตรฐานในปัจจุบันในผู้ป่วยที่ไม่สามารถผ่าตัดได้ หรือในผู้ป่วยหลังการผ่าตัด คือ การรักษาด้วยยาเคมีบำบัด ชนิดเจมไซทาบีนหรือยาเจมไซทาบีนร่วมกับยาซิสพลาติน แต่อย่างไรก็ตามผู้ป่วยส่วนใหญ่พบปัญหาการดื้อต่อยาเคมีบำบัดนำไปสู่การพยากรณ์โรคที่ไม่ดี ดังนั้นการพัฒนาการรักษาที่มีประสิทธิภาพมากยิ่งขึ้นถือว่ามีความจำเป็นเร่งด่วน โดยได้มีการศึกษาการตายของเซลล์มะเร็งแบบใหม่ที่ทำให้เซลล์มะเร็งตาย และกระตุ้นการทำงานของระบบภูมิคุ้มกันแบบจำเพาะ เรียกว่า การตายของเซลล์ที่กระตุ้นภูมิคุ้มกัน โดยการตายของเซลล์แบบเนคโครปโทซิส จัดว่าเป็นการตายของเซลล์ที่กระตุ้นภูมิคุ้มกัน โดยได้มีการศึกษาอย่างแพร่หลายในมะเร็งหลายชนิด โดยพบว่าการกระตุ้นให้เซลล์มะเร็งตายแบบเนคโครปโทซิสสามารถกระตุ้นระบบภูมิคุ้มแบบจำเพาะและยับยั้งการเจริญพัฒนาของก้อนมะเร็งในหนูทดลอง การศึกษาภายในห้องปฏิบัติการก่อนหน้าของคณะผู้วิจัยพบว่าการเหนี่ยวนำร่วมกันระหว่างยาเคมีบำบัดเจมไซทาบีนและสารสะแมคไมเมติกสามารถเหนี่ยวนำให้เซลล์มะเร็งท่อน้ำดีตายแบบเนคโครปโทซิสในสภาวะที่มีการยับยั้งการทำงานของเอนไซม์แคสเปส ทั้งนี้จากข้อจำกัดที่ยาเคมีบำบัดมีความเป็นพิษที่สูง การศึกษานี้จึงมีจุดมุ่งหมายเพื่อค้นหาสารที่สามารถนำมาทำการเหนี่ยวนำร่วมกับสารสะแมคไมเมติก โดยมีสมมติฐานของงานวิจัย คือ สารพฤกษเคมีที่มีฤทธิ์ทำให้เกิดการทำลายของดีเอ็นเอและหยุดวัฏจักรของเซลล์จะสามารถเสริมฤทธิ์กับสารสะแมคไมเมติก โดยกระตุ้นการตายของเซลล์แบบในคโครปโทซิสในเซลล์มะเร็งท่อน้ำดี โดยงานวิจัยนี้ได้ทำการศึกษาฤทธิ์ยับยั้งการแบ่งตัวและการตายเซลล์มะเร็งท่อน้ำดีของสารพฤกษเคมี ได้แก่ ชิโคนิน พลัมบาจิน เควอซิติน โดยพบว่าสารเควอซิตินมีค่าความเข้มข้นของสารที่ยับยั้งการรอดชีวิตของเซลล์ได้ 50% (IC50) ที่ต่ำที่สุดเมื่อเปรียบเทียบกับสารพฤกษเคมีชนิดอื่นๆ ในการวิเคราะห์ด้วยวิธีการทางชีวสารสนเทศน์พบว่าสารเควอซิตินมีเป้าหมายไปยังยีนที่มีบทบาทในการควบคุมวัฏจักรเซลล์ระยะ G2/M และยีนเป้าหมายของสารเควอซิตินมีการแสดงออกที่เพิ่มมากขึ้นอย่างมีนัยสำคัญในเนื้อเยื่อมะเร็งท่อน้ำดีเมื่อเปรียบเทียบกับเซลล์ปกติ การทดลองในเซลล์มะเร็งท่อน้ำดี (in vitro) พบว่าสารเควอซิตินสามารถหยุดวัฏจักรเซลล์ที่ระยะ G2/M นอกจากนี้สารเควอซิตินช่วงความเข้มข้นค่าต่ำที่มีความเป็นพิษน้อยในรูปแบบสารเดี่ยว เมื่อนำไปเหนี่ยวนำร่วมกับสารสะแมคไมเมติกชนิด LCL-161 แล้วพบว่าสามารถเสริมฤทธิ์กันกระตุ้นการตายของเซลล์มะเร็งท่อน้ำดี โดยเมื่อทำการวิเคราะห์ชนิดการตายของเซลล์เพิ่มเติมพบว่ามีการแสดงออกที่เพิ่มขึ้นของโปรตีนเอ็มแอลเคแอลที่ถูกเติมหมู่ฟอสเฟต (phosphorylated MLKL; pMLKL) ซึ่งเป็นตัวบ่งชี้ที่จำเพาะต่อการตายแบบเนคโครปโทซิส นอกจากนั้นยังพบว่าการตายของเซลล์ถูกยับยั้งเมื่อมีการเติมตัวยับยั้งที่จำเพาะกับโปรตีนที่สำคัญต่อการเกิดเนคโครปโทซิส แสดงให้เห็นว่าการเหนี่ยวนำเซลล์ด้วยสารเควอซิตินร่วมกับสารสะแมคไมเมติกสามารถกระตุ้นให้เซลล์มะเร็งท่อน้ำดีตายผ่านเนคโครปโทซิส การศึกษาเพิ่มเติมเพื่อศึกษาการตายของเซลล์ที่กระตุ้นภูมิคุ้มกัน โดยการวิเคราะห์การเคลื่อนย้ายของโปรตีนเอชเอ็มจีบีวัน (HMGB-1) จากภายในนิวเคลียสมายังบริเวณไซโตพลาสซึมด้วยวิธีการย้อมแบบอิมมูโนฟลูออเรสเซนส์ พบว่าการเหนี่ยวนำเซลล์มะเร็งท่อน้ำดีด้วยสารเควอซิตินร่วมกับสารสะแมคไมเมติกสามารถกระตุ้นการตายของเซลล์ที่กระตุ้นภูมิคุ้ม กล่าวโดยสรุป การเหนี่ยวนำร่วมกันระหว่างสารเควอซิตินและสารสะแมคไมเมติกในสภาวะที่มีการยับยั้งเอนไซม์แคสเปสสามารถเสริมฤทธิ์กันโดยกระตุ้นการตายของเซลล์มะเร็งท่อน้ำดีแบบเนคโครปโทซิสและการตายของเซลล์ที่กระตุ้นภูมิคุ้มกัน ดังนั้นงานวิจัยนี้อาจนำไปสู่การพัฒนากลยุทธ์การรักษามะเร็งท่อน้ำดีแบบใหม่ที่เพิ่มประสิทธิภาพในการรรักษาในอนาคต อย่างไรก็ตาม งานวิจัยนี้ยังต้องมีการศึกษาเพิ่มเติม เช่น การศึกษากลไกการเสริมฤทธิ์และการกระตุ้นการตายของเซลล์ การศึกษาฤทธิ์ในเซลล์มะเร็งท่อน้ำดีชนิดอื่นๆ และการเมินความเป็นพิษในเซลล์ปกติ เป็นต้น

Structural And Functional Characterization Of Two Poly(Aspartic Acid) Hydrolases, Amanda Jansch

College of Graduate Studies: Theses & Dissertations

Due to the accumulation of polymers in the environment, biodegradable alternatives should be used in place of commonly used polymers like poly(carboxylates). Poly(carboxylates) are water-soluble polymers (WSPs) that make up a variety of consumer products, such as detergents, descaling agents, and superabsorbent materials commonly found in diapers and feminine hygiene products. While the visible accumulation of these products may not be obvious, it is necessary to reduce the amount entering the environment. Poly(aspartic acid) (PAA) is an alternative WSP that is biodegradable through the action of three different enzymes, PahZ1_KT-1, PahZ2_KT-1, and PahZ1_KP-2. Originally …

Development Of Novel Pyridazine Derivatives And Drug Delivery Systems Against Dengue, Janae A. Culmer

College of Graduate Studies: Theses & Dissertations

The lack of approved vaccines, medications and treatment regimens has significantly contributed to the rapid spread of mosquito-borne viruses such as Dengue and Zika virus. The complex immunopathology of these viruses presents limitations for the development and implementation of a definitive, safe and effective approach to combat infections.Previous research has demonstrated that vector control strategies such as the elimination of larval habitats, larviciding with insecticides, the use of biological agents and the application of adulticides have been unsuccessful in the reduction of viral transmission leading to the need for the continued development of antivirals. This research proposes an approach for …

Selective Serotonin Reuptake Inhibitors And Associated Bleeding Risks: A Narrative And Clinical Review., Amber N. Edinoff, Keerthiga Raveendran, Marc A. Colon, Bennett H. Thomas, Katie A. Trettin, Grace W. Hunt, Adam M. Kaye, Elyse M. Cornett, Alan David Kaye

School of Pharmacy Faculty Articles

Major Depressive Disorder (MDD) is a major cause of disability worldwide and is associated with serious lasting impairment. A leading hypothesis of the pathophysiology of MDD is the monoamine deficiency hypothesis which suggests that depression is caused by depletion of serotonin, norepinephrine, or dopamine in the central nervous system. Serotonin is the most widely studied neurotransmitter in the pathophysiology of depression, with studies showing that reduced central serotonin synthesis leads to depressive symptoms in individuals at risk for depression. Selective Serotonin Reuptake Inhibitors (SSRI) inhibit serotonin reuptake and subsequently increase the amount of serotonin available in synapses. Common side effects …

Viloxazine, A Non-Stimulant Norepinephrine Reuptake Inhibitor, For The Treatment Of Attention Deficit Hyperactivity Disorder: A 3 Year Update., Hannah W. Haddad, Paul B. Hankey, Jimin Ko, Zahaan Eswani, Pravjit Bhatti, Amber N. Edinoff, Adam M. Kaye, Alan David Kaye

School of Pharmacy Faculty Articles

Attention deficit hyperactivity disorder (ADHD) is the most common neurodevelopmental disorder in childhood. Current treatment options for ADHD include pharmacological treatment (stimulants, non-stimulants, anti-depressants, anti-psychotics), psychological treatment (behavioral therapy with or without parent training, cognitive training, neurofeedback), and complementary and alternative therapies (vitamin supplementation, exercise). Central nervous system (CNS) stimulants are the primary pharmacological therapy used in treatment; however, these stimulant drugs carry a high potential for abuse and severe psychological/physical dependence. Viloxazine, a non-stimulant medication without evidence of drug dependence, is a selective norepinephrine reuptake inhibitor that has historically been prescribed as an anti-depressant medication. The extended-release (ER) form …

Buprenorphine And Its Formulations: A Comprehensive Review., Salomon Poliwoda, Nazir Noor, Jack S. Jenkins, Cain W. Stark, Mattie Steib, Jamal Hasoon, Giustino Varrassi, Ivan Urits, Omar Viswanath, Adam M. Kaye, Alan David Kaye

School of Pharmacy Faculty Articles

Buprenorphine, a novel long-acting analgesic, was developed with the intention of two purposes: analgesia and opioid use disorder. Regarding its pharmacodynamics, it is a partial agonist at mu receptors, an inverse agonist at kappa receptors, and an antagonist at delta receptors. For the purpose of analgesia, three formulations of buprenorphine were developed: IV/IM injectable formulation (Buprenex®), transdermal patch formulation (Butrans®), and buccal film formulation (Belbuca®). Related to opioid dependence, the formulations developed were subcutaneous extended release (Sublocade®), subdermal implant (Probuphine®), and sublingual tablets (Subutex®). Lastly, in order to avoid misuse of buprenorphine for opioid dependence, two combination formulations paired with …

Midazolam Nasal Spray To Treat Intermittent, Stereotypic Episodes Of Frequent Seizure Activity: Pharmacology And Clinical Role, A Comprehensive Review., Elyse M. Cornett, Meskerem A. Nemomsa, Bailey Turbeville, Matthew A. Busby, Jessica S. Kaye, Aaron J. Kaye, Joohee Choi, Giovanni F. Ramírez, Giustino Varrassi, Adam M. Kaye, Alan David Kaye, James Wilson, Latha Ganti

School of Pharmacy Faculty Articles

An intranasal formulation of midazolam, Nayzilam, has been FDA-approved to treat intermittent, stereotypic episodes of frequent seizure activity. Nayzilam is easy to administer and can quickly treat seizures that occur outside of the hospital. The intra-nasal route of administration allows non-medical personal to administer the drug which makes it more accessible and user-friendly in the event of a seizure. Many studies have indicated quick cessation of seizures with Nayzilam compared to rectal diazepam, which has been the standard of care treatment. Nayzilam has been proven to be safe and effective for acute seizures in children, deeming it a revolutionary alternative …

Phenothiazines And Their Evolving Roles In Clinical Practice: A Narrative Review., Amber N. Edinoff, Grace Armistead, Christina A. Rosa, Alexandra Anderson, Ronan Patil, Elyse M. Cornett, Kevin S. Murnane, Adam M. Kaye, Alan David Kaye

School of Pharmacy Faculty Articles

Phenothiazines, a diverse class of drugs, can be used to treat multiple mental health and physical conditions. Phenothiazines have been used for decades to treat mental illnesses, including schizophrenia, mania in bipolar disorder, and psychosis. Additionally, these drugs offer relief for physical illnesses, including migraines, hiccups, nausea, and vomiting in both adults and children. Further research is needed to prove the efficacy of phenothiazines in treating physical symptoms. Phenothiazines are dopaminergic antagonists that inhibit D2 receptors with varying potency. High potency phenothiazines such as perphenazine are used to treat various psychiatric conditions such as the positive symptoms of schizophrenia, the …

Aduhelm, A Novel Anti-Amyloid Monoclonal Antibody, For The Treatment Of Alzheimer's Disease: A Comprehensive Review., Hannah W. Haddad, Garett W. Malone, Nicholas J. Comardelle, Arielle E. Degueure, Salomon Poliwoda, Rachel J. Kaye, Kevin S. Murnane, Adam M. Kaye, Alan David Kaye

School of Pharmacy Faculty Articles

Alzheimer's disease (AD) is the most common form of dementia affecting millions of individuals, including family members who often take on the role of caregivers. This debilitating disease reportedly consumes 8% of the total United States healthcare expenditure, with medical and nursing outlays accounting for an estimated $290 billion. Cholinesterase inhibitors and N-methyl-D-aspartate receptor antagonists have historically been the most widely used pharmacologic therapies for patients with AD; however, these drugs are not curative. The present investigation describes the epidemiology, pathophysiology, risk factors, presentation, and current treatment of AD followed by the role of the novel monoclonal antibody, Adulhelm, in …

Rimegepant For The Treatment Of Migraine., Amnon A. Berger, Ariel Winnick, Austin H. Carroll, Alexandra Welschmeyer, Nathan Li, Marc Colon, Antonella Paladini, Giovanni F. Ramírez, Jamal Hasoon, Elyse M. Cornett, Jaehong Song, Giustino Varrassi, Adam M. Kaye, Alan David Kaye, Latha Ganti

School of Pharmacy Faculty Articles

Migraine is a common form of primary headache, affecting up to 1 in every 6 Americans. The pathophysiology is an intricate interplay of genetic factors and environmental influence and is still being elucidated in ongoing studies. The trigeminovascular system is now known to have a significant role in the initiation of migraines, including the release of pain mediators such as CGRP and substance P. Traditional treatment of migraine is usually divided into acute and preventive treatment. Acute therapy includes non-specific therapy, such as NSAIDs and other analgesics, which may provide relief in mild to moderate migraines. 5-HT1 agonists may provide …

Tissue And Sex-Specific Rna Editing During Induced Acute Inflammation, Claire E. Nichols

Graduate Theses/Dissertations

A-to-I RNA editing is a process where select adenosine (A) nucleotides are deaminated by an editing enzyme, ADAR, to become inosines (I) in RNA transcripts. RNA editing can affect the sequence of the encoded protein and the regulation of the RNA. ADAR1 also plays a role in regulating innate immunity and its expression is upregulated during inflammation. Current data on the effects of increasing ADAR1 on RNA editing is limited, and most studies are completed only in male animals. We are interested in expanding RNA editing data to include female animals. Lipopolysaccharide (LPS) was used to induce acute inflammation and …

Nonhematopoietic Erythropoietin: A Study Of Signaling, Structure, And Behavior, Nicholas John Pekas

Dissertations and Theses

Erythropoietin (EPO) is a cytokine hormone known for initiating red blood cell proliferation by binding to its homodimer receptor (EPOR)2 in the bone marrow. Recent progress in neurobiology has shown that EPO also exerts robust neurotrophic and neuroprotective activity in the CNS. It is widely thought that EPO’s neurotrophic activity is centrally involved in its antidepressant and cognitive enhancing effects. However, EPO’s potent erythropoietic effects prevent it from being used in the clinic to treat psychiatric disorders. A chemically engineered non-erythropoietic derivative of EPO, carbamoylated EPO (CEPO), produces psychoactive effects without activating hematopoiesis. However, CEPO is expensive to produce and …

Nutrient Scarcity And Cellular Cooperation In A Clonal Hydroid, Weam S. El Rahmany

Graduate Research Theses & Dissertations

Biological complexity forms when lower-level units (e.g., genes, cells, organisms) cooperatively band together. This complexity may be exemplified by multicellularity, the cooperation between the cells of the same species, or symbiosis, cooperation between the cells of different species. This cooperation is under continual threat, as defection, the opposite of cooperation, is favored by default by lower-level units (i.e., cells). Animal cancers may be the most well-known phenomena that exemplify the concept of cellular defection. Cancer cells have been shown to feature morphological and metabolic traits, developed through differential gene expression or mutations, that favor their growth at the cost of …

Copper(Ii) And Silver(I)‑1,10‑Phenanthroline‑5,6‑Dione Complexes Interact With Double‑Stranded Dna: Further Evidence Of Their Apparent Multi‑Modal Activity Towards Pseudomonas Aeruginosa, Anna Clara Milesi Galdino, Lívia Viganor, Matheus Mendonça Pereira, Michael Devereux, Malachy Mccann, Marta Helena Branquinha, Zara Molphy, Sinéad O'Carroll, Conor Bain, Georgia Menounou, Andrew Kellett, André Luis Souza Dos Santos

Articles

Tackling microbial resistance requires continuous efforts for the development of new molecules with novel mechanisms of action and potent antimicrobial activity. Our group has previously identified metal-based compounds, [Ag(1,10-phenanthroline-5,6-dione)2]ClO4 (Ag-phendione) and [Cu(1,10-phenanthroline-5,6-dione)3](ClO4)2.4H2O (Cu-phendione), with efficient antimicrobial action against multidrug-resistant species. Herein, we investigated the ability of Ag-phendione and Cu-phendione to bind with double-stranded DNA using a combination of in silico and in vitro approaches. Molecular docking revealed that both phendione derivatives can interact with the DNA by hydrogen bonding, hydrophobic and electrostatic interactions. Cu-phendione exhibited the highest binding affinity to either major (− 7.9 kcal/mol) or minor (− 7.2 kcal/mol) …

Xrcc4 And Mre11 Roles And Transcriptional Response To Repair Of Talen-Induced Double-Strand Dna Breaks, Ronald Benjamin, Atoshi Banerjee, Xiaogang Wu, Corey Geurink, Lindsay Buczek, Danielle Eames, Sara G. Trimidal, Janice M. Pluth, Martin R. Schiller

Health Physics and Diagnostic Sciences Faculty Research

Double-strand breaks (DSB) are one of the most lethal forms of DNA damage that, if left unrepaired, can lead to genomic instability, cellular transformation, and cell death. In this work, we examined how repair of transcription activator-like effector nuclease (TALEN)-induced DNA damage was altered when knocking out, or inhibiting a function of, two DNA repair proteins, XRCC4 and MRE11, respectively. We developed a fluorescent reporter assay that uses TALENs to introduce DSB and detected repair by the presence of GFP fluorescence. We observed repair of TALEN-induced breaks in the XRCC4 knockout cells treated with mirin (a pharmacological inhibitor of MRE11 …

Ero1Α Promotes Tumorigenesis In Egfr Driven Nsclc, Brennan D. Johnson

Graduate Theses, Dissertations, and Problem Reports (ETD)

Non-Small Cell Lung Cancer (NSCLC) is a pulmonary malignancy most commonly associated with smoking, or exposure to asbestos or Radon. Approximately, 1.6 Million deaths occur each year due to lung cancer. Lung Cancer is categorized by two main types, Small Cell Lung Cancer (SCLC) and NSCLC. NSCLC accounts for approximately 85% of all lung cancer cases and is subdivided into three sub-categories: Adenocarcinoma, the most common and leading cause of death in the United States; Squamous Cell Carcinoma (SCC), and Large Cell Carcinoma. Though NSCLC treatment regimens have shown increasing clinical benefit over the last two decades with targeted therapies. …

An Investigation Into The Mechanism Of Proteasome Dysfunction In Neurodegenerative Disease And The Biological Impact Of Proteasome Hyperactivation In C. Elegans, Raymond T. Anderson

Graduate Theses, Dissertations, and Problem Reports (ETD)

Aging is an inevitable process that occurs as humans grow older. It is characterized by the chronological accumulation of cellular damage over time leading to functional decline as an organism grows older. Several processes are thought to contribute to the aging phenomenon, but one of the most prolific of these is the disruption of protein homeostasis (proteostasis). The collapse of proteostasis can lead to accelerated aging and the development of age-related diseases including devastating neurodegenerative diseases (NDs) like Alzheimer and Parkinson disease. Virtually all NDs are characterized by the buildup of proteins in and around neurons resulting in neuronal death …

Review Of The Effects Of Asphalt Fume Emission (Vocs And Pahs) In Vitro, In Vivo And Human Studies, Omran Taqi, Nastassja Lewinski, Elham Fini, Eran Rozewski, Judith Klein-Seetharaman

Undergraduate Research Posters

Review of the effects of Asphalt fume emission (VOCs and PAHs) in vitro, in vivo and human studies

Omran Taqi, Nastassja Lewinski¹

1) Department of Chemical and Life Science Engineering, Virginia Commonwealth University, Richmond, VA

Background

Asphalt is abundantly available around human operations including road paving and roofing sites. However, their emissions and fumes (specifically volatile organic compounds (VOCs) and polycyclic aromatic hydrocarbons (PAHs)) have been found to have adverse effects on health. Asphalt fumes are a class 2A carcinogen and exposure can increase the risk of lung cancer, asthma, headache, fatigue, and other cardiovascular diseases.

Methods

We used …

Investigation Of A Carbon Monoxide Dehydrogenase From An Uncultured Archaeon, Luke Moore

Dissertations, Master's Theses and Master's Reports

The Nickel based Carbon Monoxide Dehydrogenase (CODH) is an anaerobic metalloenzyme responsible for the reversible conversion of CO and water into CO2 and 2 protons and 2 electrons. This enzyme has importance in the environment as one of Earth’s first carbon fixation pathways, and for human uses as a potential source of biofuels and other commodity chemicals. CODH enzymes are present in a wide array of taxa, many of which are uncultured. In this study we express and purify the catalytic subunit (CooS) of the anaerobic CODH from an uncultured Hydrothermarchaeota JdFR-17 co-expressed with the nickel insertion accessory protein (CooC) …

Synthesis Of 6,6- And 7,7-Difluoro-1-Acetamidopyrrolizidines And Their Oxidation Catalyzed By The Nonheme Fe Oxygenase Lolo, Nabin Panth

Theses and Dissertations--Chemistry

One of the remarkable steps in loline alkaloid biosynthesis is the installation of an ether bridge between two unactivated C atoms in 1-exo-acetamidopyrrolizidine (AcAP). LolO, a 2-oxoglutarate-dependent nonheme Fe oxygenase, catalyzes both the hydroxylation of AcAP and the resulting alcohol's cycloetherification to give N-acetylnornoline (NANL). The mechanism of hydroxylation is well understood, but the mechanism of the oxacyclization is not. I synthesized difluorinated analogs of AcAP in an attempt to further understand the mechanism of the unusual cycloetherification step.

I prepared 6,6-F₂-AcAP in eight steps from N,O-protected 4-oxoproline. The key step was a Dieckmann …

The Role Of Charge On Dna Packaging And Integrity Within Reconstituted Peptide-Dna Assemblies, Ehigbai Oikeh

Theses and Dissertations--Chemistry

In nature, DNA exists primarily in a highly compacted form. The compaction of DNA in vivo is mediated by cationic proteins; histone in somatic nuclei and arginine-rich peptides called protamines in sperm chromatin. The packaging in the sperm nucleus is significantly higher than somatic nuclei resulting in a final volume roughly 1/20^th that of a somatic nucleus. This tight packaging results in a near crystalline packaging of the DNA helices. While the dense packaging of DNA in sperm nuclei is considered essential for both efficient genetic delivery as well as DNA protection against damage by mutagens and oxidative species, …

Development Of Fluorescence Based Approaches To Understand Astrocyte Biology In The Context Of Nicotine And Nicotinic Receptor Activity, Surya P. Aryal

Theses and Dissertations--Chemistry

Smoking and tobacco use (STU) is a major global health problem and worldwide more than six million people die due to tobacco related diseases each year. Although majority of smokers try to quit smoking several times in their life, traditional therapeutic approaches, which focus only on neuronal cells, have a very low success rate. Understanding the effect of nicotine on glial cells, synaptic communication and blood vasculature in the brain can provide further insights on the neurobiology of substance abuse and can potentially help to design better therapeutic approaches. Glial cells are non-excitable cells in the brain which do not …

Getting To The Root Cause: The Genetic Underpinnings Of Root System Architecture And Rhizodeposition In Sorghum, Farren Smith

Graduate Theses, Dissertations, and Problem Reports (ETD)

Plants are some of the most diverse organisms on earth, consisting of more than 350,000 different species. To understand the underlying processes that contributed to plant diversification, it is fundamental to identify the genetic and genomic components that facilitated various adaptations over evolutionary history. Most studies to date have focused on the underlying controls of above-ground traits such as grain and vegetation; however, little is known about the “hidden half” of plants. Root systems comprise half of the total plant structure and provide vital functions such as anchorage, resource acquisition, and storage of energy reserves. The execution of these key …

Structural Basis Of Bacterial Flagellin For Naip5 Binding And Nlrc4 Inflammasome Activation And The Mechanism Of Flagellin Induced Release Of Cytokines In Vivo, Jian Cui

Theses and Dissertations--Chemistry

The bacterial flagellum is a whip-like structure that protrudes from the cell membrane and is one of the most complex and dynamic biological molecular machines that propels bacteria to swim toward beneficial environments and the sites of infection. It is composed of a basal body, a hook, and a long filament. The flagellar filament contains thousands of copies of the protein flagellin (FliC) monomer arranged helically and ending with a filament cap composed of oligomer protein FliD. The overall structure of the filament core is preserved across bacterial species, while the outer domains exhibit high variability, and in some cases …

Mechanism Of Antibiotic Permeability Through The Gram-Negative Bacterial Envelope, Olaniyi Alegun

Theses and Dissertations--Chemistry

The outer membrane of Gram-negative bacteria (GN) makes them distinct among superbugs that are associated with the development of antibiotic resistance. The outer membrane, and inner membrane, separated by the periplasm, form a double-membrane barrier to the entry of antibiotics into the cell. Several studies have been conducted to examine the role of outer membrane modifications such as porins, lipopolysaccharides, and efflux pumps on antibiotic resistance. However, there is a paucity of knowledge on how antibiotics behave in the periplasm, to gain access into their target region. My thesis focuses on understanding the mechanism of antibiotic permeability through the cellular …

Antibiotic Permeation In Gram-Negative Bacteria And Contribution Of Inflammasome Activation And Pyroptosis In Pathogenesis Of Salmonella Systemic Infection, Ankit Pandeya

Theses and Dissertations--Chemistry

Antibiotic resistance is one of the major global issues in the field of public health and medicine. Good antibiotic candidates need to be selectively toxic, inhibit cellular target, and effectively penetrate and accumulate in bacterial cells. The last factor is a formidable barrier in the development of antimicrobials effective in Gram-negative bacteria, due to the presence of two layers of cell envelope. The first half of my thesis focuses on understanding the permeation of small molecules through this formidable cell envelope, distribution inside the cell of Gram-negative bacteria, and design of novel methods to make small molecules effectively cross the …