Genetics and Genomics Commons^™

Interleukin-6 (Il-6) Rs1800796 And Cyclin Dependent Kinase Inhibitor (Cdkn2a/Cdkn2b) Rs2383207 Are Associated With Ischemic Stroke In Indigenous West African Men, Rufus Akinyemi, Donna K. Arnett, Hemant K. Tiwari, Bruce Ovbiagele, Fred Sarfo, Vinodh Srinivasasainagendra, Marguerite Ryan Irvin, Abiodun Adeoye, Rodney T. Perry, Albert Akpalu, Carolyn Jenkins, Lukman Owolabi, Reginald Obiako, Kolawole Wahab, Emmanuel Sanya, Morenikeji Komolafe, Michael Fawale, Philip Adebayo, Godwin Osaigbovo, Taofiki Sunmonu, Paul Olowoyo, Innocent Chukwuonye, Yahaya Obiabo, Onoja Akpa, Sylvia Melikam, Raelle Saulson, Raj Kalaria, Adesola Ogunniyi, Mayowa Owolabi

Epidemiology and Environmental Health Faculty Publications

Background—Inherited genetic variations offer a possible explanation for the observed peculiarities of stroke in sub – Saharan African populations. Interleukin–6 polymorphisms have been previously associated with ischemic stroke in some non-African populations.

Aim—Herein we investigated, for the first time, the association of genetic polymorphisms of IL-6 and CDKN2A- CDKN2B and other genes with ischemic stroke among indigenous West African participants in the Stroke Investigative Research and Education Network (SIREN) Study.

Methods—Twenty-three previously identified single nucleotide polymorphisms (SNPs) in 14 genes of relevance to the neurobiology of ischemic stroke were investigated. Logistic regression models adjusting for known …

Linking Kindling To Increased Glutamate Release In The Dentate Gyrus Of The Hippocampus Through The Stxbp5/Tomosyn-1 Gene, Seth R. Batten, Elena A. Matveeva, Sidney W. Whiteheart, Thomas C. Vanaman, Greg A. Gerhardt, John T. Slevin

Psychology Faculty Publications

Introduction: In kindling, repeated electrical stimulation of certain brain areas causes progressive and permanent intensification of epileptiform activity resulting in generalized seizures. We focused on the role(s) of glutamate and a negative regulator of glutamate release, STXBP5/tomosyn-1, in kindling.

Methods: Stimulating electrodes were implanted in the amygdala and progression to two successive Racine stage 5 seizures was measured in wild-type and STXBP5/tomosyn-1^−/− (Tom^−/−) animals. Glutamate release measurements were performed in distinct brain regions using a glutamate-selective microelectrode array (MEA).

Results: Naïve Tom^−/− mice had significant increases in KCl-evoked glutamate release compared to naïve wild type as …

Accurate Cytogenetic Biodosimetry Through Automated Dicentric Chromosome Curation And Metaphase Cell Selection, Jin Liu, Yanxin Li, Ruth Wilkins, Canadian Nuclear Laboratories, Joan H. Knoll, Peter Rogan

Biochemistry Publications

Accurate digital image analysis of abnormal microscopic structures relies on high quality images and on minimizing the rates of false positive (FP) and negative objects in images. Cytogenetic biodosimetry detects dicentric chromosomes (DCs) that arise from exposure to ionizing radiation, and determines radiation dose received based on DC frequency. Improvements in automated DC recognition increase the accuracy of dose estimates by reclassifying FP DCs as monocentric chromosomes or chromosome fragments. We also present image segmentation methods to rank high quality digital metaphase images and eliminate suboptimal metaphase cells. A set of chromosome morphology segmentation methods selectively filtered out FP DCs …

Relative Contribution Of Porcine Reproductive And Respiratory Syndrome Virus Open Reading Frames 2–4 To The Induction Of Protective Immunity, Katherine Kimpston-Burkgren, Ignacio Correas, Fernando A. Osorio, David Steffen, Asit K. Pattnaik, Ying Fang, Hiep L. X. Vu

Nebraska Center for Virology: Faculty Publications

The minor glycoproteins (GPs) of PRRSV, GP2, GP3, and GP4, form a heterotrimer that is required for viral infectivity, presumably due to its interaction with the key cellular receptor CD163. These 3 GPs are encoded by open reading frames (ORFs) 2a, 3, and 4 (herein referred to as ORFs 2–4), respectively. The goal of this study was to investigate the immunogenicity of the PRRSV-2 minor GPs. Through the use of reverse genetics, a chimeric virus (designated SDFL24) was constructed by replacing ORFs 2–4 of the PRRSV-1 strain SD01-08 with the corresponding genes of the PRRSV-2 strain FL12. While the parental …

Molecular Mechanisms Of Dna Replication Initiation In Hpvs With Genetic Variations Leading To Cellular Carcinogenesis, Gulden Yilmaz

Graduate School of Biomedical Sciences Theses and Dissertations

Human papillomaviruses are a vast family of double-stranded DNA viruses containing non-carcinogenic and carcinogenic types, whose crucial differences remain unknown, except for the difference in the frequency of DNA replication. The human papillomavirus (HPV) E2 protein regulates the initiation of viral DNA replication and transcription. Its recognition and binding to four 12 bp palindromic sequences in the viral origin is essential for its function. Little is known about the DNA binding mechanism of the E2 protein found in HPV types that have low risk for oncogenicity (low-risk) as well as the roles of various elements of the individual binding sites. …

Chaperoning Ef Hands That Shape Calcium Response: Ncald, Hpca And S100b, Jingyi Zhang

Graduate School of Biomedical Sciences Theses and Dissertations

All organisms have an internal clock with a defined period between repetitions of activities. The period for circadian clock in human is 24.5 hours, while in mouse and rat, it is 23.5 hours. However, all organisms are forced to be in synchronization with their environment. A major environmental force that resets the internal clock to 24 hours is light. This phenomenon is defined as “light entrainment” or “phase-setting”. It is unclear how this entrainment process occurs. Studies from this laboratory indicate a role for two neuronal calcium sensor proteins: Neurocalcin  (NCALD) and S100B. For these two genes, mRNA as …

Clinical And Experimental Studies Of A Novel P525r Fus Mutation In Amyotrophic Lateral Sclerosis, Lisha Kuang, Marisa Kamelgarn, Alexandra Arenas, Jozsef Gal, Deborah Taylor, Weiming Gong, Martin Brown, Daret St. Clair, Edward J. Kasarskis, Haining Zhu

Molecular and Cellular Biochemistry Faculty Publications

Objective: To describe the clinical features of a novel fused in sarcoma (FUS) mutation in a young adult female amyotrophic lateral sclerosis (ALS) patient with rapid progression of weakness and to experimentally validate the consequences of the P525R mutation in cellular neuronal models.

Methods: We conducted sequencing of genomic DNA from the index patient and her family members. Immunocytochemistry was performed in various cellular models to determine whether the newly identified P525R mutant FUS protein accumulated in cytoplasmic inclusions. Clinical features of the index patient were compared with 19 other patients with ALS carrying the P525L mutation in the same …

Pro-Angiogenesis Therapy And Aging: A Mini-Review, Charles T. Ambrose

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Apart from major illnesses and chronic afflictions, the elderly experience lesser ailments, such as muscle weakness, cold intolerance, and transient memory lapses. Physical signs in the aged include wrinkled skin and the slow healing of skin abrasions. These ailments and signs are grouped together because they may be due in part to an age-linked, waning microcirculation. A reduced capillary density (CD) throughout the body of aged people and animals has been reported in over 40 papers. The reduced CD is due in turn to declining levels of angiogenic growth factors (AGFs) throughout the body during old age, as documented in …

Wisp1 Is An Overexpressed Driver Of Glioblastoma, Pushan R. Dasgupta

Dissertations and Theses (Open Access)

Despite current multimodal therapies for glioblastoma (GBM) the prognosis remains very grim. There is a tremendous need to identify new genetic drivers which can serve as potential therapeutic targets. In order to find new drivers, we leveraged genomic datasets to conduct a context specific in vivo functional genomic screen of overexpressed and/or amplified genes in GBM. We identified WISP1, a secreted extracellular matrix protein, to be an overexpressed driver in GBM. Overexpression of WISP1 was able to drive tumor growth in various in vivo models. Knockdown of WISP1 with shRNAs resulted in reduced colony formation in vitro and reduced tumor …

Impact Of Home Visit Capacity On Genetic Association Studies Of Late-Onset Alzheimer's Disease, David W. Fardo, Laura E. Gibbons, Shubhabrata Mukherjee, M. Maria Glymour, Wayne Mccormick, Susan M. Mccurry, James D. Bowen, Eric B. Larson, Paul K. Crane

Biostatistics Faculty Publications

INTRODUCTION—Findings for genetic correlates of late-onset Alzheimer's disease (LOAD) in studies that rely solely on clinic visits may differ from those with capacity to follow participants unable to attend clinic visits.

METHODS—We evaluated previously identified LOAD-risk single nucleotide variants in the prospective Adult Changes in Thought study, comparing hazard ratios (HRs) estimated using the full data set of both in-home and clinic visits (n = 1697) to HRs estimated using only data that were obtained from clinic visits (n = 1308). Models were adjusted for age, sex, principal components to account for ancestry, and additional health indicators.

RESULTS …

Reversion Of Epithelial-Mesenchymal Transition By A Novel Agent Dz-50 Via Igf Binding Protein-3 In Prostate Cancer Cells, Zheng Cao, Shahriar Koochekpour, Stephen E. Strup, Natasha Kyprianou

Urology Faculty Publications

Dysregulation of transforming growth factor-β1 (TGF-β1) and insulin-like growth factor (IGF) axis has been linked to reactive stroma dynamics in prostate cancer progression. IGF binding protein-3 (IGFBP3) induction is initiated by stroma remodeling and could represent a potential therapeutic target for prostate cancer. In previous studies a lead quinazoline-based Doxazosin® derivative, DZ-50, impaired prostate tumor growth by targeting proteins involved in focal adhesion, anoikis resistance and epithelial-mesenchymal-transition (EMT). This study demonstrates that DZ-50 increased expression of the epithelial marker E-cadherin, and decreased the mesenchymal marker N-cadherin in human prostate cancer cells. In DU-145 cells, the effect of DZ-50 on EMT …

Developing A 670k Genotyping Array To Tag ~2m Snps Across 24 Horse Breeds, Robert J. Schaefer, Mikkel Schubert, Ernest F. Bailey, Danika L. Bannasch, Eric Barrey, Gila Kahila Bar-Gal, Gottfried Brem, Samantha A. Brooks, Ottmar Distl, Ruedi Fries, Carrie J. Finno, Vinzenz Gerber, Bianca Haase, Vidhya Jagannathan, Ted Kalbfleisch, Tosso Leeb, Gabriella Lindgren, Maria Susana Lopes, Núria Mach, Artur Da Câmara Machado, James N. Macleod, Annette Mccoy, Julia Metzger, Cecilia Penedo, Sagi Polani, Stefan Rieder, Imke Tammen, Jens Tetens, Georg Thaller, Andrea Verini-Supplizi

Gluck Equine Research Center Faculty Publications

Background: To date, genome-scale analyses in the domestic horse have been limited by suboptimal single nucleotide polymorphism (SNP) density and uneven genomic coverage of the current SNP genotyping arrays. The recent availability of whole genome sequences has created the opportunity to develop a next generation, high-density equine SNP array.

Results: Using whole genome sequence from 153 individuals representing 24 distinct breeds collated by the equine genomics community, we cataloged over 23 million de novo discovered genetic variants. Leveraging genotype data from individuals with both whole genome sequence, and genotypes from lower-density, legacy SNP arrays, a subset of ~5 million high-quality, …

Bacterial Communities Associated With Healthy And Diseased Acropora Cervicornis (Staghorn Coral) Using High-Throughput Sequencing, Charles Walton

HCNSO Student Theses and Dissertations

Coral diseases were first noted in the 1960s and 1970s and have had major impacts globally on coral reef community structures. In the Caribbean, a major outbreak of white band disease has been considered responsible for the drastic decline of Caribbean Acroporids since the 1970s. In addition to white band disease, another more recently described condition known as rapid tissue loss (RTL) has had major impacts on Acropora cervicornis populations, specifically offshore Broward County Southeast Florida. While these diseases have contributed to the population decline, determining their etiologies has been elusive.

Coral diseases have been characterized by shifts in their …

The Feoabc Locus Of Yersinia Pestis Likely Has Two Promoters Causing Unique Iron Regulation, Lauren O'Connor, Jacqueline D. Fetherston, Robert D. Perry

Microbiology, Immunology, and Molecular Genetics Faculty Publications

The FeoABC ferrous transporter is a wide-spread bacterial system. While the feoABC locus is regulated by a number of factors in the bacteria studied, we have previously found that regulation of feoABC in Yersinia pestis appears to be unique. None of the non-iron responsive transcriptional regulators that control expression of feoABC in other bacteria do so in Y. pestis. Another unique factor is the iron and Fur regulation of the Y. pestis feoABC locus occurs during microaerobic but not aerobic growth. Here we show that this unique iron-regulation is not due to a unique aspect of the Y. pestis …

Integrin Α6Β4 Upregulates Amphiregulin And Epiregulin Through Base Excision Repair-Mediated Dna Demethylation And Promotes Genome-Wide Dna Hypomethylation, Brittany L. Carpenter, Jinpeng Liu, Lei Qi, Chi Wang, Kathleen L. O'Connor

Markey Cancer Center Faculty Publications

Aberrant DNA methylation patterns are a common theme across all cancer types. Specific DNA demethylation of regulatory sequences can result in upregulation of genes that are critical for tumor development and progression. Integrin α6β4 is highly expressed in pancreatic carcinoma and contributes to cancer progression, in part, through the specific DNA demethylation and upregulation of epidermal growth factor receptor (EGFR) ligands amphiregulin (AREG) and epiregulin (EREG). Whole genome bisulfite sequencing (WGBS) revealed that integrin α6β4 signaling promotes an overall hypomethylated state and site specific DNA demethylation of enhancer elements within the proximal promoters of AREG and EREG. Additionally, we find …

Alzheimer's Disease Genetics And Abca7 Splicing, Jared B. Vasquez, James F. Simpson, Ryan Harpole, Steven Estus

Physiology Faculty Publications

Both common and rare polymorphisms within ABCA7 have been associated with Alzheimer’s disease (AD). In particular, the rare AD associated polymorphism rs200538373 was associated with altered ABCA7 exon 41 splicing and an AD risk odds ratio of ∼1.9. To probe the role of this polymorphism in ABCA7 splicing, we used minigene studies and qPCR of human brain RNA. We report aberrant ABCA7 exon 41 splicing in the brain of a carrier of the rs200538373 minor C allele. Moreover, minigene studies show that rs200538373 acts as a robust functional variant in vitro. Lastly, although the ABCA7 isoform with an extended …

Quaternary Interactions And Supercoiling Modulate The Cooperative Dna Binding Of Agt, Manana Melikishvili, Michael G. Fried

Center for Structural Biology Faculty Publications

Human O⁶-alkylguanine-DNA alkyltransferase (AGT) repairs mutagenic O⁶-alkylguanine and O⁴-alkylthymine adducts in single-stranded and duplex DNAs. The search for these lesions, through a vast excess of competing, unmodified genomic DNA, is a mechanistic challenge that may limit the repair rate in vivo. Here, we examine influences of DNA secondary structure and twist on protein–protein interactions in cooperative AGT complexes formed on lesion-free DNAs that model the unmodified parts of the genome. We used a new approach to resolve nearest neighbor (nn) and long-range (lr) components from the ensemble-average cooperativity, ω_ave. We found …

Consumer Knowledge, Perception And Attitudes Of Unlabeled Genetically Modified Foods Of An Educated Population In The State Of Kentucky, Aldious A. Waite

Masters Theses & Specialist Projects

Genetically modified (GM) foods technology is a novel idea for improving food and crop production, but the supposed health risk of GM foods, such as possible negative long-term health effects to humans, animals and the environment, have provoked the European Union to create assessment protocols to monitor and regulate the safety of GM foods and crops. This research investigates the perception and attitudes of unlabeled GM foods of the WKU faculty and staff. A survey was administered via WKU Qualtrics, and chi-square tests were performed to see how the benefits and disadvantages of GM foods may affect the purchasing decisions …

Praja Is Overexpressed In Glioblastoma And Contributes To Neural Precursor Development, Joshua Shin, Viveka Mishra, Eric Glasgow, Sobia Zaidi, Kazufumi Ohshiro, Lopa Mishra, Shuyun Rao, +Several Additional Authors

Medicine Faculty Publications

PRAJA, a RING-H2 E3 ligase, is abundantly expressed in brain tissues such as the cerebellum and frontal cortex, amongst others, and more specifically in neural progenitor cells as well as in multiple cancers that include glioblastomas. However, the specific role that Praja plays in neural development and gliomas remains unclear. In this investigation, we performed bioinformatic analyses to examine Praja1 and Praja2 expression across 29 cancer types, and observed raised levels of Praja1 and Praja2 in gliomas with an inverse relationship between Praja1 and apoptotic genes and Praja substrates such as Smad3. We analyzed the role of Praja in the …

Meta-Analysis Of Five Genome-Wide Association Studies Identifies Multiple New Loci Associated With Testicular Germ Cell Tumor., Zhaoming Wang, Katherine A Mcglynn, Ewa Rajpert-De Meyts, D Timothy Bishop, Charles C Chung, Marlene D Dalgaard, Mark H Greene, Ramneek Gupta, Tom Grotmol, Trine B Haugen, Robert Karlsson, Kevin Litchfield, Nandita Mitra, Kasper Nielsen, Louise C Pyle, Stephen M Schwartz, Vésteinn Thorsson, Saran Vardhanabhuti, Fredrik Wiklund, Clare Turnbull, Stephen J Chanock, Peter A Kanetsky, Katherine L Nathanson

Articles, Abstracts, and Reports

The international Testicular Cancer Consortium (TECAC) combined five published genome-wide association studies of testicular germ cell tumor (TGCT; 3,558 cases and 13,970 controls) to identify new susceptibility loci. We conducted a fixed-effects meta-analysis, including, to our knowledge, the first analysis of the X chromosome. Eight new loci mapping to 2q14.2, 3q26.2, 4q35.2, 7q36.3, 10q26.13, 15q21.3, 15q22.31, and Xq28 achieved genome-wide significance (P < 5 × 10

Crystal Structure Of Yersinia Pestis Virulence Factor Yfea Reveals Two Polyspecific Metal-Binding Sites, Christopher D. Radka, Lawrence J. Delucas, Landon S. Wilson, Matthew B. Lawrenz, Robert D. Perry, Stephen G. Aller

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Gram-negative bacteria use siderophores, outer membrane receptors, inner membrane transporters and substrate-binding proteins (SBPs) to transport transition metals through the periplasm. The SBPs share a similar protein fold that has undergone significant structural evolution to communicate with a variety of differentially regulated transporters in the cell. In Yersinia pestis, the causative agent of plague, YfeA (YPO2439, y1897), an SBP, is important for full virulence during mammalian infection. To better understand the role of YfeA in infection, crystal structures were determined under several environmental conditions with respect to transition-metal levels. Energy-dispersive X-ray spectroscopy and anomalous X-ray scattering data show that …

Validating Candidate Congenital Heart Disease Genes In Drosophila., Jun-Yi Zhu, Yulong Fu, Adam Richman, Zhe Han

Pediatrics Faculty Publications

Genomic sequencing efforts can implicate large numbers of genes and de novo mutations as potential disease risk factors. A high throughput in vivo model system to validate candidate gene association with pathology is therefore useful. We present such a system employing Drosophila to validate candidate congenital heart disease (CHD) genes. The protocols exploit comprehensive libraries of UAS-GeneX-RNAi fly strains that when crossed into a 4×Hand-Gal4 genetic background afford highly efficient cardiac-specific knockdown of endogenous fly orthologs of human genes. A panel of quantitative assays evaluates phenotypic severity across multiple cardiac parameters. These include developmental lethality, larva and adult heart morphology, …

Genome-Wide Association Study Of Borderline Personality Disorder Reveals Genetic Overlap With Bipolar Disorder, Major Depression And Schizophrenia, S. H. Witt, F. Streit, M. Jungkunz, J. Frank, Ney Alliey Rodriguez

School of Medicine Publications

Borderline personality disorder (BOR) is determined by environmental and genetic factors, and characterized by affective instability and impulsivity, diagnostic symptoms also observed in manic phases of bipolar disorder (BIP). Up to 20% of BIP patients show comorbidity with BOR. This report describes the first case-control genome-wide association study (GWAS) of BOR, performed in one of the largest BOR patient samples worldwide. The focus of our analysis was (i) to detect genes and gene sets involved in BOR and (ii) to investigate the genetic overlap with BIP. As there is considerable genetic overlap between BIP, major depression (MDD) and schizophrenia (SCZ) …

Naturally-Derived Molecular Ensembles In Medicine, Materials Science And Evolutionary Biology: An Interdisciplinary Study, Silvio Panettieri

Dissertations, Theses, and Capstone Projects

The first chapter will introduce the work carried out in collaboration with the Govind laboratory at CCNY. Our quest was set forth to investigate the intimate relationship lying between chronic inflammation and tumor development. For at least the last fifteen years much research has been conducted on this topic; yet, the level of complexity arising from exceedingly interwoven biochemical pathways in mammals has resulted in slow advancements in this field. This is why we resorted to a simple yet powerful immunogenetic model organism, the fruit fly Drosophila melanogaster, in combination with the administration of the most common anti-inflammatory drug, …

Genetic Associations With Lipoprotein Subfraction Measures Differ By Ethnicity In The Multi-Ethnic Study Of Atherosclerosis (Mesa), Zhe Wang, Ani Manichukal, David C. Goff, Samia Mora, Jose M. Ordovas, Nicholas M. Pajewski, Wendy S. Post, Jerome I. Rotter, Michele M. Sale, Stephanie A. Santorico, David Siscovick, Michael Y. Tsai, Donna K. Arnett, Stephen Rich, Alexis C. Frazier-Wood

Epidemiology and Environmental Health Faculty Publications

A recent genome-wide association study associated 62 single nucleotide polymorphisms (SNPs) from 43 genomic loci, with fasting lipoprotein subfractions in European–Americans (EAs) at genome-wide levels of significance across three independent samples. Whether these associations are consistent across ethnicities with a non-European ancestry is unknown. We analyzed 15 lipoprotein subfraction measures, on 1677 African–Americans (AAs), 1450 Hispanic–Americans (HAs), and 775 Chinese–Americans (CHN) participating in the multi-ethnic study of atherosclerosis (MESA). Genome-wide data were obtained using the Affymetrix 6.0 and Illumina HumanOmni chips. Linear regression models between genetic variables and lipoprotein subfractions were adjusted for age, gender, body mass index, smoking, study …

Examination Of The Monoamine Oxidase A Gene Promoter On Motivation To Exercise And Levels Of Voluntary Physical Activity, Erin M. Kinney

Senior Theses

Purpose: The purpose of this study was to examine the genetic basis underlying voluntary exercise. Monoamine oxidase A (MAO-A) is an enzyme that acts on monoamine neurotransmitters, such as dopamine, to cause inactivation. There are several polymorphisms in the promoter region of the MAO-A gene, and these variations change transcriptional activity and the amount of MAO-A produced, leading to alterations in available dopamine levels. Interestingly, polymorphisms in MAO-A have been associated recently with physical activity level. This study sought to determine whether there is an association between motivation to exercise, levels of voluntary physical activity, and MAO-A gene polymorphisms.

Methods: …

Genome- And Cd4+ T-Cell Methylome-Wide Association Study Of Circulating Trimethylamine-N-Oxide In The Genetics Of Lipid Lowering Drugs And Diet Network (Goldn), Stella Aslibekyan, Marguerite R. Irvin, Bertha A. Hidalgo, Rodney T. Perry, Elias J. Jeyarajah, Erwin Garcia, Irina Shalaurova, Paul N. Hopkins, Michael A. Province, Hemant K. Tiwari, Jose M. Ordovas, Devin M. Absher, Donna K. Arnett

Epidemiology and Environmental Health Faculty Publications

Background: Trimethylamine-N-oxide (TMAO), an atherogenic metabolite species, has emerged as a possible new risk factor for cardiovascular disease. Animal studies have shown that circulating TMAO levels are regulated by genetic and environmental factors. However, large-scale human studies have failed to replicate the observed genetic associations, and epigenetic factors such as DNA methylation have never been examined in relation to TMAO levels.

Methods and results: We used data from the family-based Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) to investigate the heritable determinants of plasma TMAO in humans. TMAO was not associated with other plasma markers of cardiovascular disease, …

Modulation Of Bax And Mtor For Cancer Therapeutics., Rui Li, Chunyong Ding, Jun Zhang, Maohua Xie, Dongkyoo Park, Ye Ding, Guo Chen, Guojing Zhang, Melissa Gilbert-Ross, Wei Zhou, Adam I Marcus, Shi-Yong Sun, Zhuo G Chen, Gabriel L Sica, Suresh S Ramalingam, Andrew T Magis, Haian Fu, Fadlo R Khuri, Walter J Curran, Taofeek K Owonikoko, Dong M Shin, Jia Zhou, Xingming Deng

Articles, Abstracts, and Reports

A rationale exists for pharmacologic manipulation of the serine (S)184 phosphorylation site of the proapoptotic Bcl2 family member Bax as an anticancer strategy. Here, we report the refinement of the Bax agonist SMBA1 to generate CYD-2-11, which has characteristics of a suitable clinical lead compound. CYD-2-11 targeted the structural pocket proximal to S184 in the C-terminal region of Bax, directly activating its proapoptotic activity by inducing a conformational change enabling formation of Bax homooligomers in mitochondrial membranes. In murine models of small-cell and non-small cell lung cancers, including patient-derived xenograft and the genetically engineered mutant KRAS-driven lung cancer models, CYD-2-11 …

Swainsonine Biosynthesis Genes In Diverse Symbiotic And Pathogenic Fungi, Daniel Cook, Bruno G. G. Donzelli, Rebecca Creamer, Deana L. Baucom, Dale R. Gardner, Juan Pan, Neil Moore, Stuart B. Krasnoff, Jerzy W. Jaromczyk, Christopher L. Schardl

Plant Pathology Faculty Publications

Swainsonine—a cytotoxic fungal alkaloid and a potential cancer therapy drug—is produced by the insect pathogen and plant symbiont Metarhizium robertsii, the clover pathogen Slafractonia leguminicola, locoweed symbionts belonging to Alternaria sect. Undifilum, and a recently discovered morning glory symbiont belonging to order Chaetothyriales. Genome sequence analyses revealed that these fungi share orthologous gene clusters, designated “SWN,” which included a multifunctional swnKgene comprising predicted adenylylation and acyltransferase domains with their associated thiolation domains, a β-ketoacyl synthase domain, and two reductase domains. The role of swnK was demonstrated by inactivating it in M. robertsii through homologous …

Zinc Transporters Ybtx And Znuabc Are Required For The Virulence Of Yersinia Pestis In Bubonic And Pneumonic Plague In Mice, Alexander G. Bobrov, Olga Kirillina, Marina Y. Fosso, Jacqueline D. Fetherston, M. Clarke Miller, Tiva T. Vancleave, Joseph A. Burlison, William K. Arnold, Matthew B. Lawrenz, Sylvie Garneau-Tsodikova, Robert D. Perry

Microbiology, Immunology, and Molecular Genetics Faculty Publications

A number of bacterial pathogens require the ZnuABC Zinc (Zn²⁺) transporter and/or a second Zn²⁺ transport system to overcome Zn²⁺ sequestration by mammalian hosts. Previously we have shown that in addition to ZnuABC, Yersinia pestis possesses a second Zn²⁺ transporter that involves components of the yersiniabactin (Ybt), siderophore-dependent iron transport system. Synthesis of the Ybt siderophore and YbtX, a member of the major facilitator superfamily, are both critical components of the second Zn²⁺ transport system. Here we demonstrate that a ybtX znu double mutant is essentially avirulent in mouse models of bubonic and pneumonic …