Pharmacology, Toxicology and Environmental Health Commons^™

Scalable Feature Selection And Extraction With Applications In Kinase Polypharmacology, Derek Jones

Theses and Dissertations--Computer Science

In order to reduce the time associated with and the costs of drug discovery, machine learning is being used to automate much of the work in this process. However the size and complex nature of molecular data makes the application of machine learning especially challenging. Much work must go into the process of engineering features that are then used to train machine learning models, costing considerable amounts of time and requiring the knowledge of domain experts to be most effective. The purpose of this work is to demonstrate data driven approaches to perform the feature selection and extraction steps in …

Carbon Sequestration In The Cloud Forest: A Comparative Evaluation Of Aboveground Biomass Carbon Stock Potential In The Río Guajalito Reserve, Elli Mapstone

Independent Study Project (ISP) Collection

As carbon dioxide levels in the atmosphere continue to rise at a rapid rate, it is necessary to understand how forests can both contribute to CO₂ levels but also stop them from rising. Carbon sequestration levels in tropical montane cloud forests are a relatively understudied topic. Gathering carbon stock levels is the first step necessary to start a REDD+ project. Carbon stock levels can be studied on a global, regional or local level. This study used the University of Oxford/ Global Ecosystems Monitoring Network (GEM) methodology to examine carbon sequestration levels of aboveground biomass, specifically ground litter, large branches …

Expression Profiling Of Non-Coding Rna By Environmental Interactions In Innate Immunity, Jacob R. Longfellow

Electronic Theses and Dissertations

Cystic fibrosis (CF) is a genetic disorder that affects 30,000 people in the United States and currently has no cure. Although CF affects all of the body’s systems, it is largely characterized as a lung disease. CF is caused by a mutation in both copies of the gene for cystic fibrosis transmembrane conductance regulator (CFTR). A mutation in the CFTR gene leads to improper movement of chloride ions and water into the airways, which dysregulates the airway surface liquid volume and composition. Individuals with CF are prone to lung infections due to inefficient bacterial clearance and by the age of …

Microbial Repopulation Following In Situ Star Remediation, Gavin Overbeeke

Electronic Thesis and Dissertation Repository

In situ STAR (Self-sustaining Treatment for Active Remediation) is an emerging remediation technology which uses smouldering combustion to destroy nonaqueous phase liquid (NAPL) contamination in the subsurface. Since STAR smouldering travels through contaminated soils slowly (~0.5 to 5 m/day) and subjects them to high temperatures (400–1000°C), it is expected that this technology will thoroughly dry and sterilize the zones which it treats. Further, soils surrounding the treatment zone which are not smouldered will be heated, although not smouldered, by virtue of their proximity to STAR, impacting microbial communities within them. Therefore, the objectives of this work are to quantify the …

Network Inference Driven Drug Discovery, Gergely Zahoránszky-Kőhalmi, Tudor I. Oprea Md, Phd, Cristian G. Bologa Phd, Subramani Mani Md, Phd, Oleg Ursu Phd

Biomedical Sciences ETDs

The application of rational drug design principles in the era of network-pharmacology requires the investigation of drug-target and target-target interactions in order to design new drugs. The presented research was aimed at developing novel computational methods that enable the efficient analysis of complex biomedical data and to promote the hypothesis generation in the context of translational research. The three chapters of the Dissertation relate to various segments of drug discovery and development process.

The first chapter introduces the integrated predictive drug discovery platform „SmartGraph”. The novel collaborative-filtering based algorithm „Target Based Recommender (TBR)” was developed in the framework of this …

Bringing Toxicology Into The 21st Century: A Global Call To Action, Troy Seidle, Martin Stephens

Martin Stephens, PhD

Conventional toxicological testing methods are often decades old, costly and low-throughput, with questionable relevance to the human condition. Several of these factors have contributed to a backlog of chemicals that have been inadequately assessed for toxicity. Some authorities have responded to this challenge by implementing large-scale testing programmes. Others have concluded that a paradigm shift in toxicology is warranted. One such call came in 2007 from the United States National Research Council (NRC), which articulated a vision of ‘‘21st century toxicology” based predominantly on non-animal techniques. Potential advantages of such an approach include the capacity to examine a far greater …

Exploration Of Chemical And Biological Management Strategies For Diaphorina Citri The Primary Vector Of Candidatus Liberibacter Asiaticus, Gretta Marie Sharp

Biology Theses

Diaphorina citri (Hemipteran: Psyllidae), the Asian citrus psyllid, is a phloem-feeding, invasive species endemic to southern Asia that was first identified in the United States in Florida in 1998. Since introduction, D. citri has spread across the major citrus growing regions of the United States. This is of great concern to the citrus industry because D. citri is the primary vector of Candidatus Liberibacter asiaticus the causal agent of Haunglongbing (HLB). Haunglongbing is the most economically devastating disease of citrus causing an estimated 8.92 billion dollars lost in revenue and 4.62 billion dollars lost in gross domestic product between 2006-2007 …

Tom Curran, Phd, Frs, Named Executive Director Of Children's Research Institute, Children's Mercy Hospital

Our Story Continues

Tom Curran, PhD, FRS, has been named Chief Scientific Officer and Executive Director of the Children’s Mercy Children’s Research Institute (CRI), effective Feb. 1 [2016]

The Children’s Research Institute at Children’s Mercy Kansas City was established last year to build on the hospital’s century-long history in pediatric research and to focus the hospital’s future research efforts in four key areas:

• Pediatric Genomic Medicine
• Clinical Pharmacology
• Health Services and Outcomes
• Health Care Delivery

Neuronal Insult Either By Exposure To Lead Or By Direct Neuronal Damage Cause Genome-Wide Changes In Dna Methylation And Histone 3 Lysine 36 Trimethylation, Arko Sen

Wayne State University Dissertations

Prenatal and postnatal exposure to pervasive neuro-toxicants such as Lead (Pb) has been reported to causes extensive and diverse changes in the epigenetic profile. Among epigenetic modification, DNA methylation (5mC) is perhaps the most widely studied and has been proposed to be potential early biomarkers for Pb toxicity. Several studies have demonstrated the association between Pb-exposure and 5mC. However most of these studies are restricted to looking at a specific set of target genes or repetitive elements. Therefore, one of the main objectives of our study was to use an unbiased genome-wide approach to look at Pb-exposure associated changes in …

Exploration Of The Srx-Prx Axis As A Small-Molecule Target, Murli Mishra

Theses and Dissertations--Toxicology and Cancer Biology

Lung cancer is a leading cause of cancer-related mortality irrespective of gender. The Sulfiredoxin (Srx) and Peroxiredoxin (Prx) are a group of thiol-based antioxidant proteins that plays an essential role in non-small cell lung cancer. Understanding the molecular characteristics of the Srx-Prx interaction may help design the strategies for future development of therapeutic tools. Based on existing literature and preliminary data from our lab, we hypothesized that the Srx plays a critical role in lung carcinogenesis and targeting the Srx-Prx axis or Srx alone may facilitate future development of targeted therapeutics for prevention and treatment of lung cancer. First, …

Satpdb: A Database Of Structurally Annotated Therapeutic Peptides, Sandeep Singh

Sandeep Singh

SATPdb (http://crdd.osdd.net/raghava/satpdb/) is a database of structurally annotated therapeutic peptides, curated from 22 public domain peptide databases/datasets including 9 of our own. The current version holds 19192 unique experimentally validated therapeutic peptide sequences having length between 2 and 50 amino acids. It covers peptides having natural, non-natural and modified residues. These peptides were systematically grouped into 10 categories based on their major function or therapeutic property like 1099 anticancer, 10585 antimicrobial, 1642 drug delivery and 1698 antihypertensive peptides. We assigned or annotated structure of these therapeutic peptides using structural databases (Protein Data Bank) and state-of-the-art structure prediction methods like I-TASSER, …

A Tail Of Two Phages: Genomic And Functional Analysis Of Listeria Monocytogenes Phages Vb_Lmos_188 And Vb_Lmos_293 Reveal The Receptor-Binding Proteins Involved In Host Specificity, Aidan Casey, Kieran Jordan, Horst Neve, Aidan Coffey, Olivia Mcauliffe

Department of Biological Sciences Publications

The physical characteristics of bacteriophages establish them as viable candidates for downstream development of pathogen detection assays and biocontrol measures. To utilize phages for such purposes, a detailed knowledge of their host interaction mechanisms is a prerequisite. There is currently a wealth of knowledge available concerning Gram-negative phage-host interaction, but little by comparison for Gram-positive phages and Listeria phages in particular. In this research, the lytic spectrum of two recently isolated Listeria monocytogenes phages (vB_LmoS_188 and vB_LmoS_293) was determined, and the genomic basis for their observed serotype 4b/4e host-specificity was investigated using comparative genomics. The late tail genes of these …

Bringing Toxicology Into The 21st Century: A Global Call To Action, Troy Seidle, Martin Stephens

Troy Seidle, PhD

Conventional toxicological testing methods are often decades old, costly and low-throughput, with questionable relevance to the human condition. Several of these factors have contributed to a backlog of chemicals that have been inadequately assessed for toxicity. Some authorities have responded to this challenge by implementing large-scale testing programmes. Others have concluded that a paradigm shift in toxicology is warranted. One such call came in 2007 from the United States National Research Council (NRC), which articulated a vision of ‘‘21st century toxicology” based predominantly on non-animal techniques. Potential advantages of such an approach include the capacity to examine a far greater …

Applications And Improvements In The Molecular Modeling Of Protein And Ligand Interactions, Jason Bret Harris

Doctoral Dissertations

Understanding protein and ligand interactions is fundamental to treat disease and avoid toxicity in biological organisms. Molecular modeling is a helpful but imperfect tool used in computer-aided toxicology and drug discovery. In this work, molecular docking and structural informatics have been integrated with other modeling methods and physical experiments to better understand and improve predictions for protein and ligand interactions. Results presented as part of this research include:

1.) an application of single-protein docking for an intermediate state structure, specifically, modeling an intermediate state structure of alpha-1-antitrypsin and using the resulting model to virtually screen for chemical inhibitors that can …

Integrating Phage Therapy Into Western Medicine, Jacob B. Jaminet

Undergraduate Research Posters

The World Health Organization has described the rise of antibiotic use as a “global heath security emergency” (who.int). With the growing concern about antibiotic resistant bacteria, there has been an increased interest in bacteriophages. Bacteriophages are high-specific viruses that only infect bacteria. The use of bacteriophages medicinally to treat bacteria is called phage therapy. Research in phage therapy gained momentum until the introduction of antibiotics. While the USA and other Western countries accepted antibiotics, the Soviet Union and their satellite nations still continued to research phages. Since the funding for research was supplied by the Soviet military, the results of …

Proteomic Analysis Of 17Β-Estradiol Degradation By Stenotrophomonas Maltophilia, Zhongtian Li

Z Li

Microbial degradation plays a critical role in determining the environmental fate of steroid hormones, such as 17β-estradiol (E2). The molecular mechanisms governing the microbial transformation of E2 and its primary degradation intermediate, estrone (E1), are largely unknown. The objective of this study was to identify metabolism pathways that might be involved in microbial estrogen degradation. To achieve the objective, Stenotrophomonas maltophilia strain ZL1 was used as a model estrogen degrading bacterium and its protein expression level during E2/E1 degradation was studied using quantitative proteomics. During an E2 degradation experiment, strain ZL1 first converted E2 to E1 stoichiometrically. At 16 h …

Removing 17Β-Estradiol From Drinking Water In A Biologically Active Carbon (Bac) Reactor Modified From A Granular Activated Carbon (Gac) Reactor, Zhongtian Li

Z Li

Estrogenic compounds in drinking water sources pose potential threats to human health. Treatment technologies are needed to effectively remove these compounds for the production of safe drinking water. In this study, GAC adsorption was first tested for its ability to remove a model estrogenic compound, 17β-estradiol (E2). Although GAC showed a relatively high adsorption capacity for E2 in isotherm experiments, it appeared to have a long mass transfer zone in a GAC column reactor, causing an early leakage of E2 in the effluent. With an influent E2 concentration of 20 μg/L, the GAC reactor was able to bring down effluent …

Acute Toxicity Of Mercury And Chromium To Clarias Batrachus (Linn), Azhaguraj Ramakrishnan

Azhaguraj Ramakrishnan

Pollution of the aquatic ecosystems by heavy metals is a worldwide problem. In the present study, Clarias batrachus was exposed to Mercury and Chromium for 24, 48, 72 and 96 hrs. The median lethal concentration (LC50) of mercury to C. batrachus for 24, 48, 72 and 96 h of exposure were 1.4 ppm, 1.2 ppm, 1.0 ppm and 0.8 ppm respectively. The median lethal concentration (LC50) of chromium to C. batrachus for 24, 48, 72 and 96 h of exposure were 120 ppm, 115 ppm, 110 ppm and 102 ppm respectively. The acute toxicity levels were derived from LC50 concentrations …

In Vitro Expression And Purification Of Class I Mhc Molecules, Loi Cheng

Honors Scholar Theses

The major histocompatibility complex (MHC) is a gene family responsible for many critical functions of the immune system in most vertebrates. The MHC consists of three classes differentiated by their structure and function, and MHC class I encodes antigen binding proteins as well as chaperone and accessory proteins such as tapasin. The purpose of this project is to reconstitute several human MHC class I molecules in their peptide-filled and peptide-deficient forms, and to purify these proteins for biochemical study. The expressed proteins include wild type and mutant variants of the fusion protein human leukocyte antigen HLA-B*0801-fos, and human beta-2-microglobulin (β2m). …

Integronlike Structures In Campylobacter Spp. Of Human And Animal Origin, Brigid Lucey, D. Crowley, P. Moloney, B. Cryan, M. Daly, F. O'Halloran, E. J. Threlfall, S. Fanning

Department of Biological Sciences Publications

Resistance to antimicrobial agents used to treat severe Campylobacter spp. gastroenteritis is increasing worldwide. We assessed the antimicrobial resistance patterns of Campylobacter spp. isolates of human and animal origin. More than half (n = 32) were resistant to sulphonamide, a feature known to be associated with the presence of integrons. Analysis of these integrons will further our understanding of Campylobacter spp. epidemiology.