Life Sciences Commons^™

Comprehensive Genetic Testing Identifies Targetable Genomic Alterations In Most Patients With Non-Small Cell Lung Cancer, Specifically Adenocarcinoma, Single Institute Investigation, Janani Vigneswaran, Yi-Hung Carol Tan, Septimiu D. Murgu, Brian M. Won, Kathryn Alexa Patton, Victoria M. Villaflor, Philip C. Hoffman, Thomas Hensing, D. Kyle Hogarth, Renuka Malik

Dartmouth Scholarship

This study reviews extensive genetic analysis in advanced non-small cell lung cancer (NSCLC) patients in order to: describe how targetable mutation genes interrelate with the genes identified as variants of unknown significance; assess the percentage of patients with a potentially targetable genetic alterations; evaluate the percentage of patients who had concurrent alterations, previously considered to be mutually exclusive; and characterize the molecular subset of KRAS. Thoracic Oncology Research Program Databases at the University of Chicago provided patient demographics, pathology, and results of genetic testing. 364 patients including 289 adenocarcinoma underwent genotype testing by various platforms such as FoundationOne, Caris Molecular …

Genomic Characterization Of Patient-Derived Xenograft Models Established From Fine Needle Aspirate Biopsies Of A Primary Pancreatic Ductal Adenocarcinoma And From Patient-Matched Metastatic Sites, Robert J. Allaway, Dawn A. Fischer, Francine B. De Abreu, Timothy B. Gardner, Stuart R. Gordon, Richard J. Barth, Thomas A. Colacchio, Matthew Wood, Balint Z. Kacsoh, Stephanie J. Bouley

Dartmouth Scholarship

N-of-1 trials target actionable mutations, yet such approaches do not test genomically-informed therapies in patient tumor models prior to patient treatment. To address this, we developed patient-derived xenograft (PDX) models from fine needle aspiration (FNA) biopsies (FNA-PDX) obtained from primary pancreatic ductal adenocarcinoma (PDAC) at the time of diagnosis. Here, we characterize PDX models established from one primary and two metastatic sites of one patient. We identified an activating KRAS G12R mutation among other mutations in these models. In explant cells derived from these PDX tumor models with a KRAS G12R mutation, treatment with inhibitors of CDKs (including CDK9) reduced …

Modulating Foveal Representation Can Influence Visual Discrimination In The Periphery, Qing Yu, Won Mok Shim

Dartmouth Scholarship

A previous study by Williams et al. (2008) provided evidence for a novel form of feedback in the visual system, whereby peripheral information is contained in foveal retinotopic cortex. Beyond its possible implication for peripheral object recognition, few studies have examined the effect of a direct behavioral manipulation of the foveal feedback representation. To address this question, we measured participants' peripheral visual discrimination performance while modulating their foveal representation in a series of psychophysical experiments. On each trial, participants discriminated the identities of briefly presented novel, three-dimensional objects or the orientations of gratings in a peripheral location while fixating at …

Role Of Deubiquitinating Enzymes In Dna Repair, Younghoon Kee, Tony T. Huang

Molecular Biosciences Faculty Publications

Both proteolytic and nonproteolytic functions of ubiquitination are essential regulatory mechanisms for promoting DNA repair and the DNA damage response in mammalian cells. Deubiquitinating enzymes (DUBs) have emerged as key players in the maintenance of genome stability. In this minireview, we discuss the recent findings on human DUBs that participate in genome maintenance, with a focus on the role of DUBs in the modulation of DNA repair and DNA damage signaling.

Molecular Evolution And Intraclade Recombination Of Enterovirus D68 During The 2014 Outbreak In The United States., Yi Tan, Ferdaus Hassan, Jennifer E. Schuster, Ari Simenauer, Rangaraj Selvarangan, Rebecca A. Halpin, Xudong Lin, Nadia Fedorova, Timothy B. Stockwell, Tommy Tsan-Yuk Lam, James D. Chappell, Tina V. Hartert, Edward C. Holmes, Suman R. Das

Manuscripts, Articles, Book Chapters and Other Papers

In August 2014, an outbreak of enterovirus D68 (EV-D68) occurred in North America, causing severe respiratory disease in children. Due to a lack of complete genome sequence data, there is only a limited understanding of the molecular evolution and epidemiology of EV-D68 during this outbreak, and it is uncertain whether the differing clinical manifestations of EV-D68 infection are associated with specific viral lineages. We developed a high-throughput complete genome sequencing pipeline for EV-D68 that produced a total of 59 complete genomes from respiratory samples with a 95% success rate, including 57 genomes from Kansas City, MO, collected during the 2014 …

Genome-Wide Annotation, Identification, And Global Transcriptomic Analysis Of Regulatory Or Small Rna Gene Expression In Staphylococcus Aureus, Ronan K. Carroll, Andy Weiss, William H. Broach, Richard E Wiemels, Austin B. Mogen, Kelly C. Rice, Lindsey N. Shaw

Molecular Biosciences Faculty Publications

In Staphylococcus aureus, hundreds of small regulatory or small RNAs (sRNAs) have been identified, yet this class of molecule remains poorly understood and severely understudied. sRNA genes are typically absent from genome annotation files, and as a consequence, their existence is often overlooked, particularly in global transcriptomic studies. To facilitate improved detection and analysis of sRNAs in S. aureus, we generated updated GenBank files for three commonly used S. aureus strains (MRSA252, NCTC 8325, and USA300), in which we added annotations for >260 previously identified sRNAs. These files, the first to include genome-wide annotation of sRNAs in S. aureus, were …

The Two-Component System Cpxra Negatively Regulates The Locus Of Enterocyte Effacement Of Enterohemorrhagic Escherichia Coli Involving Σ32 And Lon Protease, Miguel A. De La Cruz, Jason K. Morgan, Miguel A. Ares, Jorge A. Yáñez-Santos, James T. Riordan, Jorge A. Girón

Molecular Biosciences Faculty Publications

Enterohemorrhagic Escherichia coli (EHEC) is a significant cause of serious human gastrointestinal disease worldwide. EHEC strains contain a pathogenicity island called the locus of enterocyte effacement (LEE), which encodes virulence factors responsible for damaging the gut mucosa. The Cpx envelope stress response of E. coli is controlled by a two-component system (TCS) consisting of a sensor histidine kinase (CpxA) and a cytoplasmic response regulator (CpxR). In this study, we investigated the role of CpxRA in the expression of LEE-encoded virulence factors of EHEC. We found that a mutation in cpxA significantly affected adherence of EHEC to human epithelial cells. Analysis …

Reconstructing Representations Of Dynamic Visual Objects In Early Visual Cortex, Edmund Chong, Ariana M. Familiar, Won Mok Shim

Dartmouth Scholarship

As raw sensory data are partial, our visual system extensively fills in missing details, creating enriched percepts based on incomplete bottom-up information. Despite evidence for internally generated representations at early stages of cortical processing, it is not known whether these representations include missing information of dynamically transforming objects. Long-range apparent motion (AM) provides a unique test case because objects in AM can undergo changes both in position and in features. Using fMRI and encoding methods, we found that the “intermediate” orientation of an apparently rotating grating, never presented in the retinal input but interpolated during AM, is reconstructed in population-level, …

Global Regulator Of Virulence A (Grva) Coordinates Expression Of Discrete Pathogenic Mechanisms In Enterohemorrhagic Escherichia Coli Through Interactions With Gadw-Gade, Jason K. Morgan, Ronan K. Carroll, Carly M. Harro, Khoury W Vendura, Lindsey N. Shaw, James T. Riordan

Molecular Biosciences Faculty Publications

UNLABELLED: Global regulator of virulence A (GrvA) is a ToxR-family transcriptional regulator that activates locus of enterocyte effacement (LEE)-dependent adherence in enterohemorrhagic Escherichia coli (EHEC). LEE activation by GrvA requires the Rcs phosphorelay response regulator RcsB and is sensitive to physiologically relevant concentrations of bicarbonate, a known stimulant of virulence systems in intestinal pathogens. This study determines the genomic scale of GrvA-dependent regulation and uncovers details of the molecular mechanism underlying GrvA-dependent regulation of pathogenic mechanisms in EHEC. In a grvA-null background of EHEC strain TW14359, RNA sequencing analysis revealed the altered expression of over 700 genes, including the downregulation …

Pharmacogenetic Allele Nomenclature: International Workgroup Recommendations For Test Result Reporting., L V. Kalman, Jag Agúndez, M Lindqvist Appell, J L. Black, G C. Bell, S Boukouvala, C Bruckner, E Bruford, K Caudle, S A. Coulthard, A K. Daly, Al Del Tredici, J T. Den Dunnen, K Drozda, R E. Everts, D Flockhart, R R. Freimuth, Andrea Gaedigk, H Hachad, T Hartshorne, M Ingelman-Sundberg, T E. Klein, V M. Lauschke, D R. Maglott, H L. Mcleod, G A. Mcmillin, U A. Meyer, D J. Müller, D A. Nickerson, W S. Oetting, M Pacanowski, V M. Pratt, M V. Relling, A Roberts, W S. Rubinstein, K Sangkuhl, M Schwab, S A. Scott, S C. Sim, R K. Thirumaran, L H. Toji, R F. Tyndale, Rhn Van Schaik, M Whirl-Carrillo, Ktj Yeo, U M. Zanger

Manuscripts, Articles, Book Chapters and Other Papers

This article provides nomenclature recommendations developed by an international workgroup to increase transparency and standardization of pharmacogenetic (PGx) result reporting. Presently, sequence variants identified by PGx tests are described using different nomenclature systems. In addition, PGx analysis may detect different sets of variants for each gene, which can affect interpretation of results. This practice has caused confusion and may thereby impede the adoption of clinical PGx testing. Standardization is critical to move PGx forward.

Role Of Pharmacogenetics In Improving The Safety Of Psychiatric Care By Predicting The Potential Risks Of Mania In Cyp2d6 Poor Metabolizers Diagnosed With Bipolar Disorder., Santiago Sánchez-Iglesias, Virginia García-Solaesa, Belén García-Berrocal, Almudena Sanchez-Martín, Carolina Lorenzo-Romo, Tomás Martín-Pinto, Andrea Gaedigk, José Manuel González-Buitrago, María Isidoro-García

Manuscripts, Articles, Book Chapters and Other Papers

One of the main concerns in psychiatric care is safety related to drug management. Pharmacogenetics provides an important tool to assess causes that may have contributed the adverse events during psychiatric therapy. This study illustrates the potential of pharmacogenetics to identify those patients for which pharmacogenetic-guided therapy could be appropriate. It aimed to investigate CYP2D6 genotype in our psychiatric population to assess the value of introducing pharmacogenetics as a primary improvement for predicting side effects.A broad series of 224 psychiatric patients comprising psychotic disorders, depressive disturbances, bipolar disorders, and anxiety disorders was included. The patients were genotyped with the AmpliChip …

A Targeted Genetic Association Study Of Epithelial Ovarian Cancer Susceptibility, Madalene Earp, Stacey J. Winham, Nicholas Larson, Jennifer B. Permuth, Hugues Sicotte, Jeremy Chien, Hoda Anton-Culver, Elisa V. Bandera, Andrew Berchuck, Linda S. Cook, Daniel Cramer, Jennifer A. Doherty

Dartmouth Scholarship

BACKGROUND:

Genome-wide association studies have identified several common susceptibility alleles for epithelial ovarian cancer (EOC). To further understand EOC susceptibility, we examined previously ungenotyped candidate variants, including uncommon variants and those residing within known susceptibility loci.

RESULTS:

At nine of eleven previously published EOC susceptibility regions (2q31, 3q25, 5p15, 8q21, 8q24, 10p12, 17q12, 17q21.31, and 19p13), novel variants were identified that were more strongly associated with risk than previously reported variants. Beyond known susceptibility regions, no variants were found to be associated with EOC risk at genome-wide statistical significance (p <5x10(-8)), nor were any significant after Bonferroni correction for 17,000 variants (p< 3x10-6).

METHODS:

A customized genotyping array was used to assess over …

Genetic Loci Associated With Renal Function Measures And Chronic Kidney Disease In Children: The Pediatric Investigation For Genetic Factors Linked With Renal Progression Consortium., Matthias Wuttke, Craig S. Wong, Elke Wühl, Daniel Epting, Li Luo, Anselm Hoppmann, Anke Doyon, Yong Li, Gkdgen Consortium, Betül Sözeri, Daniela Thurn, Martin Helmstädter, Tobias B. Huber, Tom D. Blydt-Hansen, Albrecht Kramer-Zucker, Otto Mehls, Anette Melk, Uwe Querfeld, Susan L. Furth, Bradley A. Warady, Franz Schaefer, Anna Köttgen

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Chronic kidney disease (CKD) in children is characterized by rapid progression and a high incidence of end-stage renal disease and therefore constitutes an important health problem. While unbiased genetic screens have identified common risk variants influencing renal function and CKD in adults, the presence and identity of such variants in pediatric CKD are unknown.

METHODS: The international Pediatric Investigation for Genetic Factors Linked with Renal Progression (PediGFR) Consortium comprises three pediatric CKD cohorts: Chronic Kidney Disease in Children (CKiD), Effect of Strict Blood Pressure Control and ACE Inhibition on the Progression of CRF in Pediatric Patients (ESCAPE) and Cardiovascular …

Assessing Knowledge Of, And Attitudes To, Hiv/Aids Among University Students In The United Arab Emirates, Dalia Haroun, Ola El Saleh, Lesley Wood, Rola Mechli, Nada Al Marzouqi, Samir Anouti

All Works

© 2016 Haroun et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Background: The Middle East and North Africa (MENA) region is among the top two regions in the world with the fastest growing HIV epidemic. In this context, risks and vulnerability are high as the epidemic is on the rise with evidence indicating significantly increasing HIV prevalence, new HIV infections and AIDS-related deaths. Objective: The aim of the survey was to assess …

Predator Diet And Trophic Position Modified With Altered Habitat Morphology, Alexander Tewfik, Susan S. Bell, Kevin S. Mccann, Kristina Morrow

Integrative Biology Faculty and Staff Publications

Empirical patterns that emerge from an examination of food webs over gradients of environmental variation can help to predict the implications of anthropogenic disturbance on ecosystems. This “dynamic food web approach” is rarely applied at the coastal margin where aquatic and terrestrial systems are coupled and human development activities are often concentrated. We propose a simple model of ghost crab (Ocypode quadrata) feeding that predicts changing dominant prey (Emerita talpoida, Talorchestia sp., Donax variablis) along a gradient of beach morphology and test this model using a suite of 16 beaches along the Florida, USA coast. …

Identification Of Novel Cyclic Lipopeptides From A Positional Scanning Combinatorial Library With Enhanced Antibacterial And Antibiofilm Activities, Nina Bionda, Renee M. Fleeman, César De La Fuente-Núñez, Maria C. Rodriguez, Fany Reffuveille, Lindsey N. Shaw, Irena Pastar, Stephen C Davis, Robert E W Hancock, Predrag Cudic

Molecular Biosciences Faculty Publications

Treating bacterial infections can be difficult due to innate or acquired resistance mechanisms, and the formation of biofilms. Cyclic lipopeptides derived from fusaricidin/LI-F natural products represent particularly attractive candidates for the development of new antibacterial and antibiofilm agents, with the potential to meet the challenge of bacterial resistance to antibiotics. A positional-scanning combinatorial approach was used to identify the amino acid residues responsible for driving antibacterial activity, and increase the potency of these cyclic lipopeptides. Screening against the antibiotic resistant ESKAPE pathogens revealed the importance of hydrophobic as well as positively charged amino acid residues for activity of this class …

Gap Junction Mediated Mirna Intercellular Transfer And Gene Regulation: A Novel Mechanism For Intercellular Genetic Communication, Liang Zong, Yan Zhu, Ruqiang Liang, Hong-Bo Zhao

Otolaryngology--Head & Neck Surgery Faculty Publications

Intercellular genetic communication is an essential requirement for coordination of cell proliferation and differentiation and has an important role in many cellular processes. Gap junction channels possess large pore allowing passage of ions and small molecules between cells. MicroRNAs (miRNAs) are small regulatory RNAs that can regulate gene expression broadly. Here, we report that miRNAs can pass through gap junction channels in a connexin-dependent manner. Connexin43 (Cx43) had higher permeability, whereas Cx30 showed little permeability to miRNAs. In the tested connexin cell lines, the permeability to miRNAs demonstrated: Cx43 > Cx26/30 > Cx26 > Cx31 > Cx30 = Cx-null. However, consistent with a uniform …

Gender Representation In The Vision Sciences: A Longitudinal Study, Emily A. Cooper, Ana Radonjic

Dartmouth Scholarship

Understanding the current status and historical trends of gender representation within a research field is an important component of fostering a diverse and inclusive scientific community. Here, we report on the gender representation of a large sample of the vision science research community—the attendees of the Annual Meeting of the Vision Sciences Society (VSS). Our analysis shows that the majority of scientists at all career levels in our sample are male. This imbalance is most pronounced for the senior scientists, whereas predoctoral students are nearly balanced between the genders. Historically, the gender imbalance was larger than it is at present, …

Post-Prandial Glucose And Insulin Responses Of Hummus Alone Or Combined With A Carbohydrate Food: A Dose-Response Study, Livia S. Augustin, Laura Chiavaroli, Janice Campbell, Adish Ezatagha, Alexandra L. Jenkins, Amin Esfahani, Cyril Kendall

NYMC Faculty Publications

OBJECTIVES: Pulses are low glycemic index (GI) foods and have been associated with reduced risk of heart disease, diabetes and some cancers. However the blood glucose and insulin responses of hummus, a food containing chickpea, have not been thoroughly tested.

METHODS: Ten healthy subjects each consumed 11 breakfast study meals in randomized order over a period of 15 weeks. Hummus was consumed alone at three doses (2.7 g, 10.8 g and 25 g available carbohydrate [avCHO] portions) and with 50 g avCHO from white bread at three doses (2.7 g, 5.4 g and 10.8 g avCHO portions). The responses elicited …

Imaging Tumour Cell Heterogeneity Following Cell Transplantation Into Optically Clear Immune-Deficient Zebrafish, Qin Tang, John C. Moore, Myron S. Ignatius, Inês M. Tenente, Madeline N. Hayes, Elaine G. Garcia, Nora Torres Yordán, Caitlin Bourque, Shuning He, Jessica S. Blackburn, A. Thomas Look, Yariv Houvras, David M. Langenau

Molecular and Cellular Biochemistry Faculty Publications

Cancers contain a wide diversity of cell types that are defined by differentiation states, genetic mutations and altered epigenetic programmes that impart functional diversity to individual cells. Elevated tumour cell heterogeneity is linked with progression, therapy resistance and relapse. Yet, imaging of tumour cell heterogeneity and the hallmarks of cancer has been a technical and biological challenge. Here we develop optically clear immune-compromised rag2^E450fs (casper) zebrafish for optimized cell transplantation and direct visualization of fluorescently labelled cancer cells at single-cell resolution. Tumour engraftment permits dynamic imaging of neovascularization, niche partitioning of tumour-propagating cells in embryonal rhabdomyosarcoma, emergence of clonal …

Mir494 Reduces Renal Cancer Cell Survival Coinciding With Increased Lipid Droplets And Mitochondrial Changes, Punashi Dutta, Edward Haller, Arielle Sharp, Meera Nanjundan

Molecular Biosciences Faculty Publications

Background: miRNAs can regulate cellular survival in various cancer cell types. Recent evidence implicates the formation of lipid droplets as a hallmark event during apoptotic cell death response. It is presently unknown whether MIR494, located at 14q32 which is deleted in renal cancers, reduces cell survival in renal cancer cells and if this process is accompanied by changes in the number of lipid droplets.

Methods: 769-P renal carcinoma cells were utilized for this study. Control or MIR494 mimic was expressed in these cells following which cell viability (via crystal violet) and apoptotic cell numbers (via Annexin V/PI staining) were …

H2ax Deficiency Is Associated With Erythroid Dysplasia And Compromised Haematopoietic Stem Cell Function, Baobing Zhao, Timothy L. Tan, Yang Mei, Jing Yang, Yiting Yu, Amit Verma, Ying Liang, Juehua Gao, Peng Ji

Toxicology and Cancer Biology Faculty Publications

Myelodysplastic syndromes (MDS) are clonal disorders of haematopoiesis characterised by dysplastic changes of major myeloid cell lines. However, the mechanisms underlying these dysplastic changes are poorly understood. Here, we used a genetically modified mouse model and human patient data to examine the physiological roles of H2AX in haematopoiesis and how the loss of H2AX contributes to dyserythropoiesis in MDS. H2AX knockout mice showed cell-autonomous anaemia and erythroid dysplasia, mimicking dyserythropoiesis in MDS. Also, dyserythropoiesis was increased in MDS patients with the deletion of chromosome 11q23, where H2AX is located. Although loss of H2AX did not affect the early stage of …

Effect Of Hydroxychloroquine And Characterization Of Autophagy In A Mouse Model Of Endometriosis, A. Ruiz, S. Rockfield, N. Taran, E. Haller, Robert Engelman, I Flores, P Panina-Bordignon, Meera Nanjundan

Molecular Biosciences Faculty Publications

In endometriosis, the increased survival potential of shed endometrial cells (which normally undergo anoikis) is suggested to promote lesion development. One mechanism that may alter anoikis is autophagy. Using an autophagic flux inhibitor hydroxychloroquine (HCQ), we identified that it reduces the in vitro survival capacity of human endometriotic and endometrial T-HESC cells. We also identified that HCQ could decrease lesion numbers and disrupt lesion histopathology, as well as increase the levels of peritoneal macrophages and the IP-10 (10 kDa interferon-γ-induced protein) chemokine in a mouse model of endometriosis. We noted that RNA levels of a subset of autophagic …

Targeting Wnt/Β-Catenin Pathway In Hepatocellular Carcinoma Treatment, Valery Vilchez, Lilia M. Turcios, Francesc Marti, Roberto Gedaly

Surgery Faculty Publications

Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related death worldwide. Liver cancer is generally related to hepatitis B or C infection and cirrhosis. Usually, patients with HCC are asymptomatic and are diagnosed at late stages when surgical treatment is no longer suitable. Limited treatment options for patients with advanced HCC are a major concern. Therefore, there is an urge for finding novel therapies to treat HCC. Liver cancer is highly heterogeneous and involved deregulation of several signaling pathways. Wnt/β-catenin pathway is frequently upregulated in HCC and it is implicated in maintenance of tumor initiating cells, drug …

Human Gut Bacteria Are Sensitive To Melatonin And Express Endogenous Circadian Rhythmicity, Jiffin K. Paulose, John M. Wright, Akruti G. Patel, Vincent M. Cassone

Biology Faculty Publications

Circadian rhythms are fundamental properties of most eukaryotes, but evidence of biological clocks that drive these rhythms in prokaryotes has been restricted to Cyanobacteria. In vertebrates, the gastrointestinal system expresses circadian patterns of gene expression, motility and secretion in vivo and in vitro, and recent studies suggest that the enteric microbiome is regulated by the host’s circadian clock. However, it is not clear how the host’s clock regulates the microbiome. Here, we demonstrate at least one species of commensal bacterium from the human gastrointestinal system, Enterobacter aerogenes, is sensitive to the neurohormone melatonin, which is secreted into the …

Phlpp Negatively Regulates Cell Motility Through Inhibition Of Akt Activity And Integrin Expression In Pancreatic Cancer Cells, Alena J. Smith, Yang-An Wen, Payton D. Stevens, Jingpeng Liu, Chi Wang, Tianyan Gao

Markey Cancer Center Faculty Publications

Pancreatic adenocarcinoma is currently the fourth leading cause for cancer-related mortality. Malignant progression of pancreatic cancer depends not only on rapid proliferation of tumor cells but also on increased cell motility. In this study, we showed that increased PHLPP expression significantly reduced the rate of migration in pancreatic ductal adenocarcinoma (PDAC) cells whereas knockdown of PHLPP had the opposite effect. In addition, cell motility at the individual cell level was negatively regulated by PHLPP as determined using time-lapse imaging. Interestingly, the expression of β1 and β4 integrin proteins were decreased in PHLPP overexpressing cells and increased in PHLPP knockdown cells …

Serum Amyloid A Impairs The Antiinflammatory Properties Of Hdl, Chang Yeop Han, Chongren Tang, Myriam E. Guevara, Hao Wei, Tomasz Wietecha, Baohai Shao, Savitha Subramanian, Mohamed Omer, Shari Wang, Kevin D. O'Brien, Santica M. Marcovina, Thomas N. Wight, Tomas Vaisar, Maria C. De Beer, Frederick C. De Beer, William R. Osborne, Keith B. Elkon, Alan Chait

Physiology Faculty Publications

HDL from healthy humans and lean mice inhibits palmitate-induced adipocyte inflammation; however, the effect of the inflammatory state on the functional properties of HDL on adipocytes is unknown. Here, we found that HDL from mice injected with AgNO₃ fails to inhibit palmitate-induced inflammation and reduces cholesterol efflux from 3T3-L1 adipocytes. Moreover, HDL isolated from obese mice with moderate inflammation and humans with systemic lupus erythematosus had similar effects. Since serum amyloid A (SAA) concentrations in HDL increase with inflammation, we investigated whether elevated SAA is a causal factor in HDL dysfunction. HDL from AgNO₃-injected mice lacking Saa1.1 …

High Throughput Genomic Sequencing Of Bioaerosols In Broiler Chicken Production Facilities, Kate M. O’Brien, Michael S. Chimenti, Morgan Farnell, Tom Tabler, Thomas Bair, Joey Lynn Bray, Matthew W. Nonnenmann

Faculty Publications

Chronic inhalation exposure to agricultural dust promotes the development of chronic respiratory diseases among poultry workers. Poultry dust is composed of dander, chicken feed, litter bedding and microbes. However, the microbial composition and abundance has not been fully elucidated. Genomic DNA was extracted from settled dust and personal inhalable dust collected while performing litter sampling or mortality collection tasks. DNA libraries were sequenced using a paired-end sequencing-by-synthesis approach on an Illumina HiSeq 2500. Sequencing data showed that poultry dust is predominantly composed of bacteria (64–67%) with a small quantity of avian, human and feed DNA (< 2% of total reads). Staphylococcus sp. AL1, Salinicoccus carnicancri and Lactobacillus crispatus were the most abundant bacterial species in personal exposure samples of inhalable dust. Settled dust had a moderate relative abundance of these species as well as Staphylococcus lentus and Lactobacillus salivarius. There was a statistical difference between the microbial composition of aerosolized and settled dust. Unlike settled dust composition, aerosolized dust composition had little variance between samples. These data provide an extensive analysis of the microbial composition and relative abundance in personal inhalable poultry dust and settled poultry dust.

The Pros And Cons Of Ecological Risk Assessment Based On Data From Different Levels Of Biological Organization, Jason R. Rohr, Christopher J. Salice, Roger M. Nisbet

Integrative Biology Faculty and Staff Publications

Ecological risk assessment (ERA) is the process used to evaluate the safety of manufactured chemicals to the environment. Here we review the pros and cons of ERA across levels of biological organization, including suborganismal (e.g., biomarkers), individual, population, community, ecosystem and landscapes levels. Our review revealed that level of biological organization is often related negatively with ease at assessing cause-effect relationships, ease of high-throughput screening of large numbers of chemicals (it is especially easier for suborganismal endpoints), and uncertainty of the ERA because low levels of biological organization tend to have a large distance between their measurement (what is quantified) …

It Is All About (U)Biquitin: Role Of Altered Ubiquitin-Proteasome System And Uchl1 In Alzheimer Disease, Antonella Tramutola, Fabio Di Domenico, Eugenio Barone, Marzia Perluigi, D. Allan Butterfield

Chemistry Faculty Publications

Free radical-mediated damage to macromolecules and the resulting oxidative modification of different cellular components are a common feature of aging, and this process becomes much more pronounced in age-associated pathologies, including Alzheimer disease (AD). In particular, proteins are particularly sensitive to oxidative stress-induced damage and these irreversible modifications lead to the alteration of protein structure and function. In order to maintain cell homeostasis, these oxidized/damaged proteins have to be removed in order to prevent their toxic accumulation. It is generally accepted that the age-related accumulation of “aberrant” proteins results from both the increased occurrence of damage and the decreased efficiency …