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1.  The Identification of Proteoglycans and Glycosaminoglycans in Archaeological Human Bones and Teeth 
PLoS ONE  2015;10(6):e0131105.
Bone tissue is mineralized dense connective tissue consisting mainly of a mineral component (hydroxyapatite) and an organic matrix comprised of collagens, non-collagenous proteins and proteoglycans (PGs). Extracellular matrix proteins and PGs bind tightly to hydroxyapatite which would protect these molecules from the destructive effects of temperature and chemical agents after death. DNA and proteins have been successfully extracted from archaeological skeletons from which valuable information has been obtained; however, to date neither PGs nor glycosaminoglycan (GAG) chains have been studied in archaeological skeletons. PGs and GAGs play a major role in bone morphogenesis, homeostasis and degenerative bone disease. The ability to isolate and characterize PG and GAG content from archaeological skeletons would unveil valuable paleontological information. We therefore optimized methods for the extraction of both PGs and GAGs from archaeological human skeletons. PGs and GAGs were successfully extracted from both archaeological human bones and teeth, and characterized by their electrophoretic mobility in agarose gel, degradation by specific enzymes and HPLC. The GAG populations isolated were chondroitin sulfate (CS) and hyaluronic acid (HA). In addition, a CSPG was detected. The localization of CS, HA, three small leucine rich PGs (biglycan, decorin and fibromodulin) and glypican was analyzed in archaeological human bone slices. Staining patterns were different for juvenile and adult bones, whilst adolescent bones had a similar staining pattern to adult bones. The finding that significant quantities of PGs and GAGs persist in archaeological bones and teeth opens novel venues for the field of Paleontology.
PMCID: PMC4481269  PMID: 26107959
2.  Lumican expression, localization and antitumor activity in prostate cancer 
Experimental cell research  2013;319(7):967-981.
The stromal reaction surrounding tumors leads to the formation of a tumor-specific microenvironment, which may play either a restrictive role or a supportive role in the growth and progression of the tumors. Lumican, a small leucine-rich proteoglycan (SLRP) of the extracellular matrix (ECM), regulates collagen fibrillogenesis. Recently, lumican has also been shown to regulate cell behavior during embryonic development, tissue repair and tumor progression. The role of lumican in cancer varies according to the type of tumor. In this study we analyze the role of lumican in the pathogenesis of prostate cancer both in vivo and in vitro. Overall lumican up-regulation was observed in the primary tumors analyzed through both real-time PCR and immunostaining. The increase in lumican expression was observed in the reactive stroma surrounding prostate primary tumors with fibrotic deposition surrounding the acinar glands. In vitro analysis demonstrated that lumican inhibited both the migration and invasion of metastatic prostate cancer cells isolated from lymph node, bone and brain. Moreover, prostate cancer cells seeded on lumican presented a decrease in the formation of cellular projections, lamellipodia detected by a decreased rearrangement in ZO-1, keratin 8/18, integrin β1 and MT1-MMP, and invadopodia detected by disruption of α-smooth muscle actin, cortactin and N-WASP. Moreover, a significant increase in prostate cancer cell invasion was observed through the peritoneum of lumican knockout mice, further demonstrating the restrictive role lumican present in the ECM has on prostate cancer invasion. In conclusion, lumican present in the reactive stroma surrounding prostate primary tumors plays a restrictive role on cancer progression, and we therefore postulate that lumican could be a valuable marker in prostate cancer staging.
PMCID: PMC3633477  PMID: 23399832
Lumican; desmoplasia; tumor markers; prostate cancer; cytoskeleton; cell migration
3.  Annexin A1 expression in a pooled breast cancer series: association with tumor subtypes and prognosis 
BMC Medicine  2015;13:156.
Annexin A1 (ANXA1) is a protein related with the carcinogenesis process and metastasis formation in many tumors. However, little is known about the prognostic value of ANXA1 in breast cancer. The purpose of this study is to evaluate the association between ANXA1 expression, BRCA1/2 germline carriership, specific tumor subtypes and survival in breast cancer patients.
Clinical-pathological information and follow-up data were collected from nine breast cancer studies from the Breast Cancer Association Consortium (BCAC) (n = 5,752) and from one study of familial breast cancer patients with BRCA1/2 mutations (n = 107). ANXA1 expression was scored based on the percentage of immunohistochemical staining in tumor cells. Survival analyses were performed using a multivariable Cox model.
The frequency of ANXA1 positive tumors was higher in familial breast cancer patients with BRCA1/2 mutations than in BCAC patients, with 48.6 % versus 12.4 %, respectively; P <0.0001. ANXA1 was also highly expressed in BCAC tumors that were poorly differentiated, triple negative, EGFR-CK5/6 positive or had developed in patients at a young age. In the first 5 years of follow-up, patients with ANXA1 positive tumors had a worse breast cancer-specific survival (BCSS) than ANXA1 negative (HRadj = 1.35; 95 % CI = 1.05–1.73), but the association weakened after 10 years (HRadj = 1.13; 95 % CI = 0.91–1.40). ANXA1 was a significant independent predictor of survival in HER2+ patients (10-years BCSS: HRadj = 1.70; 95 % CI = 1.17–2.45).
ANXA1 is overexpressed in familial breast cancer patients with BRCA1/2 mutations and correlated with poor prognosis features: triple negative and poorly differentiated tumors. ANXA1 might be a biomarker candidate for breast cancer survival prediction in high risk groups such as HER2+ cases.
Electronic supplementary material
The online version of this article (doi:10.1186/s12916-015-0392-6) contains supplementary material, which is available to authorized users.
PMCID: PMC4489114  PMID: 26137966
Breast cancer; Annexin A1; BRCA1 and BRCA2 mutations
4.  A Type I Interferon Transcriptional Signature Precedes Autoimmunity in Children Genetically at Risk for Type 1 Diabetes 
Diabetes  2014;63(7):2538-2550.
Diagnosis of the autoimmune disease type 1 diabetes (T1D) is preceded by the appearance of circulating autoantibodies to pancreatic islets. However, almost nothing is known about events leading to this islet autoimmunity. Previous epidemiological and genetic data have associated viral infections and antiviral type I interferon (IFN) immune response genes with T1D. Here, we first used DNA microarray analysis to identify IFN-β–inducible genes in vitro and then used this set of genes to define an IFN-inducible transcriptional signature in peripheral blood mononuclear cells from a group of active systemic lupus erythematosus patients (n = 25). Using this predefined set of 225 IFN signature genes, we investigated the expression of the signature in cohorts of healthy controls (n = 87), patients with T1D (n = 64), and a large longitudinal birth cohort of children genetically predisposed to T1D (n = 109; 454 microarrayed samples). Expression of the IFN signature was increased in genetically predisposed children before the development of autoantibodies (P = 0.0012) but not in patients with established T1D. Upregulation of IFN-inducible genes was transient, temporally associated with a recent history of upper respiratory tract infections (P = 0.0064), and marked by increased expression of SIGLEC-1 (CD169), a lectin-like receptor expressed on CD14+ monocytes. DNA variation in IFN-inducible genes altered T1D risk (P = 0.007), as exemplified by IFIH1, one of the genes in our IFN signature for which increased expression is a known risk factor for disease. These findings identify transient increased expression of type I IFN genes in preclinical diabetes as a risk factor for autoimmunity in children with a genetic predisposition to T1D.
PMCID: PMC4066333  PMID: 24561305
6.  Characterizing human vestibular sensory epithelia for experimental studies: new hair bundles on old tissue and implications for therapeutic interventions in ageing 
Neurobiology of Aging  2015;36(6):2068-2084.
Balance disequilibrium is a significant contributor to falls in the elderly. The most common cause of balance dysfunction is loss of sensory cells from the vestibular sensory epithelia of the inner ear. However, inaccessibility of inner ear tissue in humans severely restricts possibilities for experimental manipulation to develop therapies to ameliorate this loss. We provide a structural and functional analysis of human vestibular sensory epithelia harvested at trans-labyrinthine surgery. We demonstrate the viability of the tissue and labeling with specific markers of hair cell function and of ion homeostasis in the epithelium. Samples obtained from the oldest patients revealed a significant loss of hair cells across the tissue surface, but we found immature hair bundles present in epithelia harvested from patients >60 years of age. These results suggest that the environment of the human vestibular sensory epithelium could be responsive to stimulation of developmental pathways to enhance hair cell regeneration, as has been demonstrated successfully in the vestibular organs of adult mice.
PMCID: PMC4436436  PMID: 25818177
Human vestibular; Utricle; Hair cells; Supporting cells; Stereocilia; Aging pathologies
8.  Adoption in Eastern Grey Kangaroos: A Consequence of Misdirected Care? 
PLoS ONE  2015;10(5):e0125182.
Adoption is rare in animals and is usually attributed to kin selection. In a 6-year study of eastern grey kangaroos (Macropus giganteus), 11 of 326 juveniles were adopted. We detected eight adoptions by observing behavioural associations and nursing between marked mothers and young and three more by analysing the relatedness of mothers and young using microsatellite DNA. Four adoptions involved reciprocal switches and three were by mothers whose own pouch young were known to subsequently disappear. Adoptive mothers were not closely related to each other or to adoptees but adoptive mothers and young associated as closely as did biological pairs, as measured by half-weight indices. Switch mothers did not associate closely. Maternal age and body condition did not influence the likelihood of adoption but females were more likely to adopt in years with high densities of females with large pouch young. Adoption did not improve juvenile survival. We conclude that adoptions in this wild population were potentially costly and likely caused by misdirected care, suggesting that eastern grey kangaroos may have poorly developed mother-offspring recognition mechanisms.
PMCID: PMC4430339  PMID: 25970624
9.  Random versus Game Trail-Based Camera Trap Placement Strategy for Monitoring Terrestrial Mammal Communities 
PLoS ONE  2015;10(5):e0126373.
Camera trap surveys exclusively targeting features of the landscape that increase the probability of photographing one or several focal species are commonly used to draw inferences on the richness, composition and structure of entire mammal communities. However, these studies ignore expected biases in species detection arising from sampling only a limited set of potential habitat features. In this study, we test the influence of camera trap placement strategy on community-level inferences by carrying out two spatially and temporally concurrent surveys of medium to large terrestrial mammal species within Tanzania’s Ruaha National Park, employing either strictly game trail-based or strictly random camera placements. We compared the richness, composition and structure of the two observed communities, and evaluated what makes a species significantly more likely to be caught at trail placements. Observed communities differed marginally in their richness and composition, although differences were more noticeable during the wet season and for low levels of sampling effort. Lognormal models provided the best fit to rank abundance distributions describing the structure of all observed communities, regardless of survey type or season. Despite this, carnivore species were more likely to be detected at trail placements relative to random ones during the dry season, as were larger bodied species during the wet season. Our findings suggest that, given adequate sampling effort (> 1400 camera trap nights), placement strategy is unlikely to affect inferences made at the community level. However, surveys should consider more carefully their choice of placement strategy when targeting specific taxonomic or trophic groups.
PMCID: PMC4423779  PMID: 25950183
10.  The TyrR Transcription Factor Regulates the Divergent akr-ipdC Operons of Enterobacter cloacae UW5 
PLoS ONE  2015;10(3):e0121241.
The TyrR transcription factor regulates genes involved in the uptake and biosynthesis of aromatic amino acids in Enterobacteriaceae. Genes may be positively or negatively regulated depending on the presence or absence of each aromatic amino acid, all three of which function as cofactors for TyrR. In this report we detail the transcriptional control of two divergently transcribed genes, akr and ipdC, by TyrR, elucidated by promoter fusion expression assays and electrophoretic mobility shift assays to assess protein-DNA interactions. Expression of both genes was shown to be controlled by TyrR via interactions with two TyrR boxes located within the akr-ipdC intergenic region. Expression of ipdC required TyrR bound to the proximal strong box, and is strongly induced by phenylalanine, and to a lesser extent by tryptophan and tyrosine. Down-regulation of akr was reliant on interactions with the weak box, and may also require a second, as yet unidentified protein for further repression. Tyrosine enhanced repression of akr. Electrophoretic mobility shift assays demonstrated that TyrR interacts with both the strong and weak boxes, and that binding of the weak box in vitro requires an intact adjacent strong box. While the strong box shows a high degree of conservation with the TyrR binding site consensus sequence, the weak box has atypical spacing of the two half sites comprising the palindromic arms. Site-directed mutagenesis demonstrated sequence-specific interaction between TyrR and the weak box. This is the first report of TyrR-controlled expression of two divergent protein-coding genes, transcribed from independent promoters. Moreover, the identification of a predicted aldo-keto reductase as a member of the TyrR regulon further extends the function of the TyrR regulon.
PMCID: PMC4374768  PMID: 25811953
11.  Growth of a deep-water, predatory fish is influenced by the productivity of a boundary current system 
Scientific Reports  2015;5:9044.
The effects of climate change on predatory fishes in deep shelf areas are difficult to predict because complex processes may govern food availability and temperature at depth. We characterised the net impact of recent environmental changes on hapuku (Polyprion oxygeneios), an apex predator found in continental slope habitats (>200 m depth) by using dendrochronology techniques to develop a multi-decadal record of growth from otoliths. Fish were sampled off temperate south-western Australia, a region strongly influenced by the Leeuwin Current, a poleward-flowing, eastern boundary current. The common variance among individual growth records was relatively low (3.4%), but the otolith chronology was positively correlated (r = 0.61, p < 0.02) with sea level at Fremantle, a proxy for the strength of the Leeuwin Current. The Leeuwin Current influences the primary productivity of shelf ecosystems, with a strong current favouring growth in hapuku. Leeuwin Current strength is predicted to decline under climate change models and this study provides evidence that associated productivity changes may flow through to higher trophic levels even in deep water habitats.
PMCID: PMC4356959  PMID: 25761975
12.  The deubiquitylase Ataxin-3 restricts PTEN transcription in lung cancer cells 
Oncogene  2013;33(33):4265-4272.
The phosphatidylinositol-3-kinase (PI3K) pathway is commonly hyperactivated in cancer. One mechanism by which this occurs is by silencing of the phosphatase and tensin homolog (PTEN), a tumor suppressor and major antagonist of the pathway, through genetic, epigenetic or posttranscriptional mechanisms. Here, we used an unbiased siRNA screen in non-small-cell lung cancer cells to identify deubiquitylases (DUBs) that have an impact on PI3K signaling by regulating the abundance of PTEN. We found that PTEN expression was induced by depleting any of three members of the Josephin family DUBs: ataxin 3 (ATXN3), ataxin 3-like (ATXN3L) and Josephin domain containing 1 (JOSD1). However, this effect is not mediated through altered PTEN protein stability. Instead, depletion of each DUB increases expression of both the PTEN transcript and its competing endogenous RNA, PTENP1. In ATXN3-depleted cells, under conditions of transcriptional inhibition, PTEN and PTENP1 mRNAs rapidly decay, suggesting that ATXN3 acts primarily by repressing their transcription. Importantly, the PTEN induction observed in response to ATXN3 siRNA is sufficient to downregulate Akt phosphorylation and hence PI3K signaling. Histone deacetylase inhibitors (HDACi) have been suggested as potential mediators of PTEN transcriptional reactivation in non-small-cell lung cancer. Although PTEN exhibits a very limited response to the broad-spectrum HDACi Vorinostat (SAHA) in A549 cells, we find that combination with ATXN3 depletion enhances PTEN induction in an additive manner. Similarly, these interventions additively decrease cell viability. Thus, ATXN3 provides an autonomous, complementary therapeutic target in cancers with epigenetic downregulation of PTEN.
PMCID: PMC4351423  PMID: 24292675
deubiquitinase; ATXN3; phosphatase and tensin homolog; PTENP1; ceRNA; MJD
13.  Drosophila Muller F Elements Maintain a Distinct Set of Genomic Properties Over 40 Million Years of Evolution 
Leung, Wilson | Shaffer, Christopher D. | Reed, Laura K. | Smith, Sheryl T. | Barshop, William | Dirkes, William | Dothager, Matthew | Lee, Paul | Wong, Jeannette | Xiong, David | Yuan, Han | Bedard, James E. J. | Machone, Joshua F. | Patterson, Seantay D. | Price, Amber L. | Turner, Bryce A. | Robic, Srebrenka | Luippold, Erin K. | McCartha, Shannon R. | Walji, Tezin A. | Walker, Chelsea A. | Saville, Kenneth | Abrams, Marita K. | Armstrong, Andrew R. | Armstrong, William | Bailey, Robert J. | Barberi, Chelsea R. | Beck, Lauren R. | Blaker, Amanda L. | Blunden, Christopher E. | Brand, Jordan P. | Brock, Ethan J. | Brooks, Dana W. | Brown, Marie | Butzler, Sarah C. | Clark, Eric M. | Clark, Nicole B. | Collins, Ashley A. | Cotteleer, Rebecca J. | Cullimore, Peterson R. | Dawson, Seth G. | Docking, Carter T. | Dorsett, Sasha L. | Dougherty, Grace A. | Downey, Kaitlyn A. | Drake, Andrew P. | Earl, Erica K. | Floyd, Trevor G. | Forsyth, Joshua D. | Foust, Jonathan D. | Franchi, Spencer L. | Geary, James F. | Hanson, Cynthia K. | Harding, Taylor S. | Harris, Cameron B. | Heckman, Jonathan M. | Holderness, Heather L. | Howey, Nicole A. | Jacobs, Dontae A. | Jewell, Elizabeth S. | Kaisler, Maria | Karaska, Elizabeth A. | Kehoe, James L. | Koaches, Hannah C. | Koehler, Jessica | Koenig, Dana | Kujawski, Alexander J. | Kus, Jordan E. | Lammers, Jennifer A. | Leads, Rachel R. | Leatherman, Emily C. | Lippert, Rachel N. | Messenger, Gregory S. | Morrow, Adam T. | Newcomb, Victoria | Plasman, Haley J. | Potocny, Stephanie J. | Powers, Michelle K. | Reem, Rachel M. | Rennhack, Jonathan P. | Reynolds, Katherine R. | Reynolds, Lyndsey A. | Rhee, Dong K. | Rivard, Allyson B. | Ronk, Adam J. | Rooney, Meghan B. | Rubin, Lainey S. | Salbert, Luke R. | Saluja, Rasleen K. | Schauder, Taylor | Schneiter, Allison R. | Schulz, Robert W. | Smith, Karl E. | Spencer, Sarah | Swanson, Bryant R. | Tache, Melissa A. | Tewilliager, Ashley A. | Tilot, Amanda K. | VanEck, Eve | Villerot, Matthew M. | Vylonis, Megan B. | Watson, David T. | Wurzler, Juliana A. | Wysocki, Lauren M. | Yalamanchili, Monica | Zaborowicz, Matthew A. | Emerson, Julia A. | Ortiz, Carlos | Deuschle, Frederic J. | DiLorenzo, Lauren A. | Goeller, Katie L. | Macchi, Christopher R. | Muller, Sarah E. | Pasierb, Brittany D. | Sable, Joseph E. | Tucci, Jessica M. | Tynon, Marykathryn | Dunbar, David A. | Beken, Levent H. | Conturso, Alaina C. | Danner, Benjamin L. | DeMichele, Gabriella A. | Gonzales, Justin A. | Hammond, Maureen S. | Kelley, Colleen V. | Kelly, Elisabeth A. | Kulich, Danielle | Mageeney, Catherine M. | McCabe, Nikie L. | Newman, Alyssa M. | Spaeder, Lindsay A. | Tumminello, Richard A. | Revie, Dennis | Benson, Jonathon M. | Cristostomo, Michael C. | DaSilva, Paolo A. | Harker, Katherine S. | Jarrell, Jenifer N. | Jimenez, Luis A. | Katz, Brandon M. | Kennedy, William R. | Kolibas, Kimberly S. | LeBlanc, Mark T. | Nguyen, Trung T. | Nicolas, Daniel S. | Patao, Melissa D. | Patao, Shane M. | Rupley, Bryan J. | Sessions, Bridget J. | Weaver, Jennifer A. | Goodman, Anya L. | Alvendia, Erica L. | Baldassari, Shana M. | Brown, Ashley S. | Chase, Ian O. | Chen, Maida | Chiang, Scott | Cromwell, Avery B. | Custer, Ashley F. | DiTommaso, Tia M. | El-Adaimi, Jad | Goscinski, Nora C. | Grove, Ryan A. | Gutierrez, Nestor | Harnoto, Raechel S. | Hedeen, Heather | Hong, Emily L. | Hopkins, Barbara L. | Huerta, Vilma F. | Khoshabian, Colin | LaForge, Kristin M. | Lee, Cassidy T. | Lewis, Benjamin M. | Lydon, Anniken M. | Maniaci, Brian J. | Mitchell, Ryan D. | Morlock, Elaine V. | Morris, William M. | Naik, Priyanka | Olson, Nicole C. | Osterloh, Jeannette M. | Perez, Marcos A. | Presley, Jonathan D. | Randazzo, Matt J. | Regan, Melanie K. | Rossi, Franca G. | Smith, Melanie A. | Soliterman, Eugenia A. | Sparks, Ciani J. | Tran, Danny L. | Wan, Tiffany | Welker, Anne A. | Wong, Jeremy N. | Sreenivasan, Aparna | Youngblom, Jim | Adams, Andrew | Alldredge, Justin | Bryant, Ashley | Carranza, David | Cifelli, Alyssa | Coulson, Kevin | Debow, Calise | Delacruz, Noelle | Emerson, Charlene | Farrar, Cassandra | Foret, Don | Garibay, Edgar | Gooch, John | Heslop, Michelle | Kaur, Sukhjit | Khan, Ambreen | Kim, Van | Lamb, Travis | Lindbeck, Peter | Lucas, Gabi | Macias, Elizabeth | Martiniuc, Daniela | Mayorga, Lissett | Medina, Joseph | Membreno, Nelson | Messiah, Shady | Neufeld, Lacey | Nguyen, San Francisco | Nichols, Zachary | Odisho, George | Peterson, Daymon | Rodela, Laura | Rodriguez, Priscilla | Rodriguez, Vanessa | Ruiz, Jorge | Sherrill, Will | Silva, Valeria | Sparks, Jeri | Statton, Geeta | Townsend, Ashley | Valdez, Isabel | Waters, Mary | Westphal, Kyle | Winkler, Stacey | Zumkehr, Joannee | DeJong, Randall J. | Hoogewerf, Arlene J. | Ackerman, Cheri M. | Armistead, Isaac O. | Baatenburg, Lara | Borr, Matthew J. | Brouwer, Lindsay K. | Burkhart, Brandon J. | Bushhouse, Kelsey T. | Cesko, Lejla | Choi, Tiffany Y. Y. | Cohen, Heather | Damsteegt, Amanda M. | Darusz, Jess M. | Dauphin, Cory M. | Davis, Yelena P. | Diekema, Emily J. | Drewry, Melissa | Eisen, Michelle E. M. | Faber, Hayley M. | Faber, Katherine J. | Feenstra, Elizabeth | Felzer-Kim, Isabella T. | Hammond, Brandy L. | Hendriksma, Jesse | Herrold, Milton R. | Hilbrands, Julia A. | Howell, Emily J. | Jelgerhuis, Sarah A. | Jelsema, Timothy R. | Johnson, Benjamin K. | Jones, Kelly K. | Kim, Anna | Kooienga, Ross D. | Menyes, Erika E. | Nollet, Eric A. | Plescher, Brittany E. | Rios, Lindsay | Rose, Jenny L. | Schepers, Allison J. | Scott, Geoff | Smith, Joshua R. | Sterling, Allison M. | Tenney, Jenna C. | Uitvlugt, Chris | VanDyken, Rachel E. | VanderVennen, Marielle | Vue, Samantha | Kokan, Nighat P. | Agbley, Kwabea | Boham, Sampson K. | Broomfield, Daniel | Chapman, Kayla | Dobbe, Ali | Dobbe, Ian | Harrington, William | Ibrahem, Marwan | Kennedy, Andre | Koplinsky, Chad A. | Kubricky, Cassandra | Ladzekpo, Danielle | Pattison, Claire | Ramirez, Roman E. | Wande, Lucia | Woehlke, Sarah | Wawersik, Matthew | Kiernan, Elizabeth | Thompson, Jeffrey S. | Banker, Roxanne | Bartling, Justina R. | Bhatiya, Chinmoy I. | Boudoures, Anna L. | Christiansen, Lena | Fosselman, Daniel S. | French, Kristin M. | Gill, Ishwar S. | Havill, Jessen T. | Johnson, Jaelyn L. | Keny, Lauren J. | Kerber, John M. | Klett, Bethany M. | Kufel, Christina N. | May, Francis J. | Mecoli, Jonathan P. | Merry, Callie R. | Meyer, Lauren R. | Miller, Emily G. | Mullen, Gregory J. | Palozola, Katherine C. | Pfeil, Jacob J. | Thomas, Jessica G. | Verbofsky, Evan M. | Spana, Eric P. | Agarwalla, Anant | Chapman, Julia | Chlebina, Ben | Chong, Insun | Falk, I.N. | Fitzgibbons, John D. | Friedman, Harrison | Ighile, Osagie | Kim, Andrew J. | Knouse, Kristin A. | Kung, Faith | Mammo, Danny | Ng, Chun Leung | Nikam, Vinayak S. | Norton, Diana | Pham, Philip | Polk, Jessica W. | Prasad, Shreya | Rankin, Helen | Ratliff, Camille D. | Scala, Victoria | Schwartz, Nicholas U. | Shuen, Jessica A. | Xu, Amy | Xu, Thomas Q. | Zhang, Yi | Rosenwald, Anne G. | Burg, Martin G. | Adams, Stephanie J. | Baker, Morgan | Botsford, Bobbi | Brinkley, Briana | Brown, Carter | Emiah, Shadie | Enoch, Erica | Gier, Chad | Greenwell, Alyson | Hoogenboom, Lindsay | Matthews, Jordan E. | McDonald, Mitchell | Mercer, Amanda | Monsma, Nicholaus | Ostby, Kristine | Ramic, Alen | Shallman, Devon | Simon, Matthew | Spencer, Eric | Tomkins, Trisha | Wendland, Pete | Wylie, Anna | Wolyniak, Michael J. | Robertson, Gregory M. | Smith, Samuel I. | DiAngelo, Justin R. | Sassu, Eric D. | Bhalla, Satish C. | Sharif, Karim A. | Choeying, Tenzin | Macias, Jason S. | Sanusi, Fareed | Torchon, Karvyn | Bednarski, April E. | Alvarez, Consuelo J. | Davis, Kristen C. | Dunham, Carrie A. | Grantham, Alaina J. | Hare, Amber N. | Schottler, Jennifer | Scott, Zackary W. | Kuleck, Gary A. | Yu, Nicole S. | Kaehler, Marian M. | Jipp, Jacob | Overvoorde, Paul J. | Shoop, Elizabeth | Cyrankowski, Olivia | Hoover, Betsy | Kusner, Matt | Lin, Devry | Martinov, Tijana | Misch, Jonathan | Salzman, Garrett | Schiedermayer, Holly | Snavely, Michael | Zarrasola, Stephanie | Parrish, Susan | Baker, Atlee | Beckett, Alissa | Belella, Carissa | Bryant, Julie | Conrad, Turner | Fearnow, Adam | Gomez, Carolina | Herbstsomer, Robert A. | Hirsch, Sarah | Johnson, Christen | Jones, Melissa | Kabaso, Rita | Lemmon, Eric | Vieira, Carolina Marques dos Santos | McFarland, Darryl | McLaughlin, Christopher | Morgan, Abbie | Musokotwane, Sepo | Neutzling, William | Nietmann, Jana | Paluskievicz, Christina | Penn, Jessica | Peoples, Emily | Pozmanter, Caitlin | Reed, Emily | Rigby, Nichole | Schmidt, Lasse | Shelton, Micah | Shuford, Rebecca | Tirasawasdichai, Tiara | Undem, Blair | Urick, Damian | Vondy, Kayla | Yarrington, Bryan | Eckdahl, Todd T. | Poet, Jeffrey L. | Allen, Alica B. | Anderson, John E. | Barnett, Jason M. | Baumgardner, Jordan S. | Brown, Adam D. | Carney, Jordan E. | Chavez, Ramiro A. | Christgen, Shelbi L. | Christie, Jordan S. | Clary, Andrea N. | Conn, Michel A. | Cooper, Kristen M. | Crowley, Matt J. | Crowley, Samuel T. | Doty, Jennifer S. | Dow, Brian A. | Edwards, Curtis R. | Elder, Darcie D. | Fanning, John P. | Janssen, Bridget M. | Lambright, Anthony K. | Lane, Curtiss E. | Limle, Austin B. | Mazur, Tammy | McCracken, Marly R. | McDonough, Alexa M. | Melton, Amy D. | Minnick, Phillip J. | Musick, Adam E. | Newhart, William H. | Noynaert, Joseph W. | Ogden, Bradley J. | Sandusky, Michael W. | Schmuecker, Samantha M. | Shipman, Anna L. | Smith, Anna L. | Thomsen, Kristen M. | Unzicker, Matthew R. | Vernon, William B. | Winn, Wesley W. | Woyski, Dustin S. | Zhu, Xiao | Du, Chunguang | Ament, Caitlin | Aso, Soham | Bisogno, Laura Simone | Caronna, Jason | Fefelova, Nadezhda | Lopez, Lenin | Malkowitz, Lorraine | Marra, Jonathan | Menillo, Daniella | Obiorah, Ifeanyi | Onsarigo, Eric Nyabeta | Primus, Shekerah | Soos, Mahdi | Tare, Archana | Zidan, Ameer | Jones, Christopher J. | Aronhalt, Todd | Bellush, James M. | Burke, Christa | DeFazio, Steve | Does, Benjamin R. | Johnson, Todd D. | Keysock, Nicholas | Knudsen, Nelson H. | Messler, James | Myirski, Kevin | Rekai, Jade Lea | Rempe, Ryan Michael | Salgado, Michael S. | Stagaard, Erica | Starcher, Justin R. | Waggoner, Andrew W. | Yemelyanova, Anastasia K. | Hark, Amy T. | Bertolet, Anne | Kuschner, Cyrus E. | Parry, Kesley | Quach, Michael | Shantzer, Lindsey | Shaw, Mary E. | Smith, Mary A. | Glenn, Omolara | Mason, Portia | Williams, Charlotte | Key, S. Catherine Silver | Henry, Tyneshia C. P. | Johnson, Ashlee G. | White, Jackie X. | Haberman, Adam | Asinof, Sam | Drumm, Kelly | Freeburg, Trip | Safa, Nadia | Schultz, Darrin | Shevin, Yakov | Svoronos, Petros | Vuong, Tam | Wellinghoff, Jules | Hoopes, Laura L. M. | Chau, Kim M. | Ward, Alyssa | Regisford, E. 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Devin | Stemler, Kristina M. | Throm, Allison A. | Van Camp, Matt | Weihbrecht, Katie | Wiles, T. Aaron | Williams, Mallory A. | Williams, Matthew | Zoll, Kyle | Bailey, Cheryl | Zhou, Leming | Balthaser, Darla M. | Bashiri, Azita | Bower, Mindy E. | Florian, Kayla A. | Ghavam, Nazanin | Greiner-Sosanko, Elizabeth S. | Karim, Helmet | Mullen, Victor W. | Pelchen, Carly E. | Yenerall, Paul M. | Zhang, Jiayu | Rubin, Michael R. | Arias-Mejias, Suzette M. | Bermudez-Capo, Armando G. | Bernal-Vega, Gabriela V. | Colon-Vazquez, Mariela | Flores-Vazquez, Arelys | Gines-Rosario, Mariela | Llavona-Cartagena, Ivan G. | Martinez-Rodriguez, Javier O. | Ortiz-Fuentes, Lionel | Perez-Colomba, Eliezer O. | Perez-Otero, Joseph | Rivera, Elisandra | Rodriguez-Giron, Luke J. | Santiago-Sanabria, Arnaldo J. | Senquiz-Gonzalez, Andrea M. | delValle, Frank R. Soto | Vargas-Franco, Dorianmarie | Velázquez-Soto, Karla I. | Zambrana-Burgos, Joan D. | Martinez-Cruzado, Juan Carlos | Asencio-Zayas, Lillyann | Babilonia-Figueroa, Kevin | Beauchamp-Pérez, Francis D. | Belén-Rodríguez, Juliana | Bracero-Quiñones, Luciann | Burgos-Bula, Andrea P. | Collado-Méndez, Xavier A. | Colón-Cruz, Luis R. | Correa-Muller, Ana I. | Crooke-Rosado, Jonathan L. | Cruz-García, José M. | Defendini-Ávila, Marianna | Delgado-Peraza, Francheska M. | Feliciano-Cancela, Alex J. | Gónzalez-Pérez, Valerie M. | Guiblet, Wilfried | Heredia-Negrón, Aldo | Hernández-Muñiz, Jennifer | Irizarry-González, Lourdes N. | Laboy-Corales, Ángel L. | Llaurador-Caraballo, Gabriela A. | Marín-Maldonado, Frances | Marrero-Llerena, Ulises | Martell-Martínez, Héctor A. | Martínez-Traverso, Idaliz M. | Medina-Ortega, Kiara N. | Méndez-Castellanos, Sonya G. | Menéndez-Serrano, Krizia C. | Morales-Caraballo, Carol I. | Ortiz-DeChoudens, Saryleine | Ortiz-Ortiz, Patricia | Pagán-Torres, Hendrick | Pérez-Afanador, Diana | Quintana-Torres, Enid M. | Ramírez-Aponte, Edwin G. | Riascos-Cuero, Carolina | Rivera-Llovet, Michelle S. | Rivera-Pagán, Ingrid T. | Rivera-Vicéns, Ramón E. | Robles-Juarbe, Fabiola | Rodríguez-Bonilla, Lorraine | Rodríguez-Echevarría, Brian O. | Rodríguez-García, Priscila M. | Rodríguez-Laboy, Abneris E. | Rodríguez-Santiago, Susana | Rojas-Vargas, Michael L. | Rubio-Marrero, Eva N. | Santiago-Colón, Albeliz | Santiago-Ortiz, Jorge L. | Santos-Ramos, Carlos E. | Serrano-González, Joseline | Tamayo-Figueroa, Alina M. | Tascón-Peñaranda, Edna P. | Torres-Castillo, José L. | Valentín-Feliciano, Nelson A. | Valentín-Feliciano, Yashira M. | Vargas-Barreto, Nadyan M. | Vélez-Vázquez, Miguel | Vilanova-Vélez, Luis R. | Zambrana-Echevarría, Cristina | MacKinnon, Christy | Chung, Hui-Min | Kay, Chris | Pinto, Anthony | Kopp, Olga R. | Burkhardt, Joshua | Harward, Chris | Allen, Robert | Bhat, Pavan | Chang, Jimmy Hsiang-Chun | Chen, York | Chesley, Christopher | Cohn, Dara | DuPuis, David | Fasano, Michael | Fazzio, Nicholas | Gavinski, Katherine | Gebreyesus, Heran | Giarla, Thomas | Gostelow, Marcus | Greenstein, Rachel | Gunasinghe, Hashini | Hanson, Casey | Hay, Amanda | He, Tao Jian | Homa, Katie | Howe, Ruth | Howenstein, Jeff | Huang, Henry | Khatri, Aaditya | Kim, Young Lu | Knowles, Olivia | Kong, Sarah | Krock, Rebecca | Kroll, Matt | Kuhn, Julia | Kwong, Matthew | Lee, Brandon | Lee, Ryan | Levine, Kevin | Li, Yedda | Liu, Bo | Liu, Lucy | Liu, Max | Lousararian, Adam | Ma, Jimmy | Mallya, Allyson | Manchee, Charlie | Marcus, Joseph | McDaniel, Stephen | Miller, Michelle L. | Molleston, Jerome M. | Diez, Cristina Montero | Ng, Patrick | Ngai, Natalie | Nguyen, Hien | Nylander, Andrew | Pollack, Jason | Rastogi, Suchita | Reddy, Himabindu | Regenold, Nathaniel | Sarezky, Jon | Schultz, Michael | Shim, Jien | Skorupa, Tara | Smith, Kenneth | Spencer, Sarah J. | Srikanth, Priya | Stancu, Gabriel | Stein, Andrew P. | Strother, Marshall | Sudmeier, Lisa | Sun, Mengyang | Sundaram, Varun | Tazudeen, Noor | Tseng, Alan | Tzeng, Albert | Venkat, Rohit | Venkataram, Sandeep | Waldman, Leah | Wang, Tracy | Yang, Hao | Yu, Jack Y. | Zheng, Yin | Preuss, Mary L. | Garcia, Angelica | Juergens, Matt | Morris, Robert W. | Nagengast, Alexis A. | Azarewicz, Julie | Carr, Thomas J. | Chichearo, Nicole | Colgan, Mike | Donegan, Megan | Gardner, Bob | Kolba, Nik | Krumm, Janice L. | Lytle, Stacey | MacMillian, Laurell | Miller, Mary | Montgomery, Andrew | Moretti, Alysha | Offenbacker, Brittney | Polen, Mike | Toth, John | Woytanowski, John | Kadlec, Lisa | Crawford, Justin | Spratt, Mary L. | Adams, Ashley L. | Barnard, Brianna K. | Cheramie, Martin N. | Eime, Anne M. | Golden, Kathryn L. | Hawkins, Allyson P. | Hill, Jessica E. | Kampmeier, Jessica A. | Kern, Cody D. | Magnuson, Emily E. | Miller, Ashley R. | Morrow, Cody M. | Peairs, Julia C. | Pickett, Gentry L. | Popelka, Sarah A. | Scott, Alexis J. | Teepe, Emily J. | TerMeer, Katie A. | Watchinski, Carmen A. | Watson, Lucas A. | Weber, Rachel E. | Woodard, Kate A. | Barnard, Daron C. | Appiah, Isaac | Giddens, Michelle M. | McNeil, Gerard P. | Adebayo, Adeola | Bagaeva, Kate
G3: Genes|Genomes|Genetics  2015;5(5):719-740.
The Muller F element (4.2 Mb, ~80 protein-coding genes) is an unusual autosome of Drosophila melanogaster; it is mostly heterochromatic with a low recombination rate. To investigate how these properties impact the evolution of repeats and genes, we manually improved the sequence and annotated the genes on the D. erecta, D. mojavensis, and D. grimshawi F elements and euchromatic domains from the Muller D element. We find that F elements have greater transposon density (25–50%) than euchromatic reference regions (3–11%). Among the F elements, D. grimshawi has the lowest transposon density (particularly DINE-1: 2% vs. 11–27%). F element genes have larger coding spans, more coding exons, larger introns, and lower codon bias. Comparison of the Effective Number of Codons with the Codon Adaptation Index shows that, in contrast to the other species, codon bias in D. grimshawi F element genes can be attributed primarily to selection instead of mutational biases, suggesting that density and types of transposons affect the degree of local heterochromatin formation. F element genes have lower estimated DNA melting temperatures than D element genes, potentially facilitating transcription through heterochromatin. Most F element genes (~90%) have remained on that element, but the F element has smaller syntenic blocks than genome averages (3.4–3.6 vs. 8.4–8.8 genes per block), indicating greater rates of inversion despite lower rates of recombination. Overall, the F element has maintained characteristics that are distinct from other autosomes in the Drosophila lineage, illuminating the constraints imposed by a heterochromatic milieu.
PMCID: PMC4426361  PMID: 25740935
codon bias; evolution of heterochromatin; gene size; melting characteristics; transposons
14.  Resveratrol Prevents Cardiovascular Complications in the SHR/STZ Rat by Reductions in Oxidative Stress and Inflammation 
BioMed Research International  2015;2015:918123.
The cardioprotective effects of resveratrol are well established in animal models of metabolic disease but are yet to be investigated in a combined model of hypertension and diabetes. This study investigated the ability of resveratrol's antioxidant and anti-inflammatory effects to prevent cardiovascular complications in the spontaneously hypertensive streptozotocin-induced diabetic rat. Diabetes was induced in eight-week-old male spontaneously hypertensive rats via a single intravenous injection of streptozotocin. Following this, resveratrol was administered orally for an eight-week period until the animals were sixteen weeks of age. Upon completion of the treatment regime assessments of oxidative stress, lipid peroxidation, inflammation, and cardiovascular function were made. Resveratrol administration to hypertensive-diabetic animals did not impact upon blood glucose or haemodynamics but significantly reduced oxidative stress, lipid peroxidation, and inflammatory cytokines. Reductions in systemic levels of oxidative stress and inflammation conferred improvements in vascular reactivity and left ventricular pump function and electrophysiology. This study demonstrates that resveratrol administration to hypertensive diabetic animals can elicit cardioprotective properties via antioxidant and anti-inflammatory effects. The observed preservation of cardiovascular function was independent of changes in blood glucose concentration and haemodynamics, suggesting that oxidative stress and inflammation are key components within the pathological cascade associated with hypertension and diabetes.
PMCID: PMC4352727  PMID: 25802871
15.  The Effect of Life History on Retroviral Genome Invasions 
PLoS ONE  2015;10(2):e0117442.
Endogenous retroviruses (ERV), or the remnants of past retroviral infections that are no longer active, are found in the genomes of most vertebrates, typically constituting approximately 10% of the genome. In some vertebrates, particularly in shorter-lived species like rodents, it is not unusual to find active endogenous retroviruses. In longer-lived species, including humans where substantial effort has been invested in searching for active ERVs, it is unusual to find them; to date none have been found in humans. Presumably the chance of detecting an active ERV infection is a function of the length of an ERV epidemic. Intuitively, given that ERVs or signatures of past ERV infections are passed from parents to offspring, we might expect to detect more active ERVs in species with longer generation times, as it should take more years for an infection to run its course in longer than in shorter lived species. This means the observation of more active ERV infections in shorter compared to longer-lived species is paradoxical. We explore this paradox using a modeling approach to investigate factors that influence ERV epidemic length. Our simple epidemiological model may explain why we find evidence of active ERV infections in shorter rather than longer-lived species.
PMCID: PMC4333357  PMID: 25692467
16.  A type I interferon transcriptional signature precedes autoimmunity in children genetically at-risk of type 1 diabetes 
Diabetes  2014;63(7):2538-2550.
Diagnosis of the autoimmune disease type 1 diabetes (T1D) is preceded by the appearance of circulating autoantibodies to pancreatic islets. However, almost nothing is known about events leading to this islet autoimmunity. Previous epidemiological and genetic data have associated viral infections and anti-viral type I interferon (IFN) immune response genes with T1D. Here, we first used DNA microarray analysis to identify IFN-β inducible genes in vitro and then used this set of genes to define an IFN-inducible transcriptional signature in peripheral blood mononuclear cells from a group of active systemic lupus erythematosus patients (N=25). Using this predefined set of 225 IFN signature genes, we investigated expression of the signature in cohorts of healthy controls (N=87), T1D patients (N=64) and a large longitudinal birth cohort of children genetically predisposed to T1D (N=109; 454 microarrayed samples). Expression of the IFN signature was increased in genetically-predisposed children prior to the development of autoantibodies (P=0.0012), but not in established T1D patients. Upregulation of IFN-inducible genes was transient, temporally associated with a recent history of upper respiratory tract infections (P=0.0064) and marked by increased expression of SIGLEC-1 (CD169), a lectin-like receptor expressed on CD14+ monocytes. DNA variation in IFN-inducible genes altered T1D risk (P=0.007), as exemplified by IFIH1, one of the genes in our IFN signature and for which increased expression is a known disease risk factor. These findings identify transient increased expression of type I IFN genes in pre-clinical diabetes as a risk factor for autoimmunity in children with a genetic predisposition to T1D.
PMCID: PMC4066333  PMID: 24561305
17.  SOT Symposium Highlight: Translatable Indicators of Testicular Toxicity: Inhibin B, MicroRNAs, and Sperm Signatures 
Toxicological Sciences  2013;136(2):265-273.
Testicular toxicity is an important safety endpoint in drug development and risk assessment, but reliable and translatable biomarkers for predicting injury have eluded researchers. However, this area shows great potential for improvement, with several avenues currently being pursued. This was the topic of a symposium session during the 2013 Society of Toxicology Annual Meeting in San Antonio, TX, entitled “Translatable Indicators of Testicular Toxicity: Inhibin B, MicroRNAs, and Sperm Signatures.” This symposium brought together stakeholders from academia, government, and industry to present the limitations and drawbacks of currently used indicators of injury and discussed the ongoing efforts in developing more predictive biomarkers of injury. The presentations highlighted the early challenges of using circulating inhibin B and microRNA levels, and sperm messenger RNA transcript abundance and DNA methylation profiles, as novel biomarkers of testicular toxicity.
PMCID: PMC3858194  PMID: 24052563
biomarkers; testicular toxicity; inhibin B; microRNA; sperm.
18.  Basal forebrain atrophy correlates with amyloid β burden in Alzheimer's disease 
NeuroImage : Clinical  2014;7:105-113.
The brains of patients suffering from Alzheimer's disease (AD) have three classical pathological hallmarks: amyloid-beta (Aβ) plaques, tau tangles, and neurodegeneration, including that of cholinergic neurons of the basal forebrain. However the relationship between Aβ burden and basal forebrain degeneration has not been extensively studied. To investigate this association, basal forebrain volumes were determined from magnetic resonance images of controls, subjects with amnestic mild cognitive impairment (aMCI) and AD patients enrolled in the longitudinal Alzheimer's Disease Neuroimaging Initiative (ADNI) and Australian Imaging, Biomarkers and Lifestyle (AIBL) studies. In the AIBL cohort, these volumes were correlated within groups to neocortical gray matter retention of Pittsburgh compound B (PiB) from positron emission tomography images as a measure of Aβ load. The basal forebrain volumes of AD and aMCI subjects were significantly reduced compared to those of control subjects. Anterior basal forebrain volume was significantly correlated to neocortical PiB retention in AD subjects and aMCI subjects with high Aβ burden, whereas posterior basal forebrain volume was significantly correlated to neocortical PiB retention in control subjects with high Aβ burden. Therefore this study provides new evidence for a correlation between neocortical Aβ accumulation and basal forebrain degeneration. In addition, cluster analysis showed that subjects with a whole basal forebrain volume below a determined cut-off value had a 7 times higher risk of having a worse diagnosis within ~18 months.
•The link between amyloid (Aβ) and basal forebrain degeneration in AD is unclear.•We find that basal forebrain volumes are correlated with neocortical Aβ burden.•Basal forebrain volume correlates with Aβ burden in at-risk control subjects.•Basal forebrain atrophy delineates subjects at increased risk of progressing to AD.
PMCID: PMC4299972  PMID: 25610772
3D, 3-dimensional; Aβ, amyloid-beta; AD, Alzheimer's disease; ADNI, Alzheimer's Disease Neuroimaging Initiative; AIBL, Australian Imaging, Biomarkers and Lifestyle Flagship Study of Aging; aMCI, amnestic mild cognitive impairment; CSF, cerebrospinal fluid; GM, gray matter; HC, healthy control; MCI, mild cognitive impairment; MNI, Montreal Neurological Institute; MPM, maximum probability maps; MPRAGE, magnetization prepared rapid gradient echo; MRI, magnetic resonance imaging; OR, odds ratio; PET, positron emission tomography; PiB, Pittsburgh compound B; SPSS, statistics software package for the social sciences; SUVR, standard uptake value ratio; SyN, symmetric normalization; T1W, T1-weighted; TG-ROC, two-graph receiver operating characteristic; WM, white matter; Basal forebrain; Amyloid; Alzheimer's disease; Magnetic resonance imaging; PET
19.  Objectively assessed physical activity and lower limb function and prospective associations with mortality and newly diagnosed disease in UK older adults: an OPAL four-year follow-up study 
Age and Ageing  2014;44(2):261-268.
Background: objective measures of physical activity and function with a diverse cohort of UK adults in their 70s and 80s were used to investigate relative risk of all-cause mortality and diagnoses of new diseases over a 4-year period.
Participants: two hundred and forty older adults were randomly recruited from 12 general practices in urban and suburban areas of a city in the United Kingdom. Follow-up included 213 of the baseline sample.
Methods: socio-demographic variables, height and weight, and self-reported diagnosed diseases were recorded at baseline. Seven-day accelerometry was used to assess total physical activity, moderate-to-vigorous activity and sedentary time. A log recorded trips from home. Lower limb function was assessed using the Short Physical Performance Battery. Medical records were accessed on average 50 months post baseline, when new diseases and deaths were recorded.
Analyses: ANOVAs were used to assess socio-demographic, physical activity and lower limb function group differences in diseases at baseline and new diseases during follow-up. Regression models were constructed to assess the prospective associations between physical activity and function with mortality and new disease.
Results: for every 1,000 steps walked per day, the risk of mortality was 36% lower (hazard ratios 0.64, 95% confidence interval (CI) 0.44–0.91, P = 0.013). Low levels of moderate-to-vigorous physical activity (incident rate ratio (IRR) 1.67, 95% CI 1.04–2.68, P = 0.030) and low frequency of trips from home (IRR 1.41, 95% CI 0.98–2.05, P = 0.045) were associated with diagnoses of more new diseases.
Conclusion: physical activity should be supported for adults in their 70s and 80s, as it is associated with reduced risk of mortality and new disease development.
PMCID: PMC4339727  PMID: 25377744
older adults; physical activity; physical function; mortality; newly diagnosed disease
20.  IcgA Is a Virulence Factor of Rhodococcus equi That Modulates Intracellular Growth 
Infection and Immunity  2014;82(5):1793-1800.
Virulence of the intracellular pathogen Rhodococcus equi depends on a 21.3-kb pathogenicity island located on a conjugative plasmid. To date, the only nonregulatory pathogenicity island-encoded virulence factor identified is the cell envelope-associated VapA protein. Although the pathogenicity islands from porcine and equine R. equi isolates have undergone major rearrangements, the virR operon (virR-icgA-vapH-orf7-virS) is highly conserved in both, suggesting these genes play an important role in pathogenicity. VirR and VirS are transcriptional regulators controlling expression of pathogenicity island genes, including vapA. Here, we show that while vapH and orf7 are dispensable for intracellular growth of R. equi, deletion of icgA, formerly known as orf5, encoding a major facilitator superfamily transport protein, elicited an enhanced growth phenotype in macrophages and a significant reduction in macrophage viability, while extracellular growth in broth remained unaffected. Transcription of virS, located downstream of icgA, and vapA was not affected by the icgA deletion during growth in broth or in macrophages, showing that the enhanced growth phenotype caused by deletion of icgA was not mediated through abnormal transcription of these genes. Transcription of icgA increased 6-fold within 2 h following infection of macrophages and remained significantly higher 48 h postinfection compared to levels at the start of the infection. The major facilitator superfamily transport protein IcgA is the first factor identified in R. equi that negatively affects intracellular replication. Aside from VapA, it is only the second pathogenicity island-encoded structural protein shown to play a direct role in intracellular growth of this pathogenic actinomycete.
PMCID: PMC3993432  PMID: 24549327
21.  Differences in speciation progress in feather mites (Analgoidea) inhabiting the same host: the case of Zachvatkinia and Alloptes living on arctic and long-tailed skuas 
Recent molecular phylogenetic analyses have revealed that some apparently oligoxenous feather mite species are in fact monoxenous cryptic species with little morphological differentiation. In this study we analyzed two species, Zachvatkinia isolata (Avenzoariidae) and Alloptes (Sternalloptes) stercorarii (Alloptidae) which prefer different parts of the plumage of two sister species of birds: arctic skua (Stercorarius parasiticus) and long-tailed skua (S. longicaudus) breeding on tundra in the High Arctic archipelago of Svalbard. Given that there are no reports about hybridization events between the host species, we expected that both skuas would have a species-specific acarofauna. The genetic distances among DNA-barcode sequences (COI and 28S rDNA), phylogenetic tree topologies, and haplotype networks of the COI sequences of mites suggested extensive gene flow in Z. isolata between and within populations inhabiting both skua species, whereas the Alloptes populations were host specific and sufficiently genetically separated as to warrant species-level status. The discrepancy in the genetic structure of Alloptes and Zachvatkinia populations suggests frequent but transient contacts between the two skua species in which the probability of mite exchange is much higher for Zachvatkinia, which is present in high numbers and inhabits exposed parts of primary flight feathers, than for the less abundant Alloptes that lives primarily in more protected and inaccessible parts of the plumage. We discuss the possible nature of these contacts between host species and the area(s) where they might take place. The star-like structures in the haplotype network as well as high haplotype diversity and low nucleotide diversity observed in Z. isolata are concordant with the known dispersal strategy of feather mites: vertical colonization of new host individuals followed by rapid growth of founder populations.
Electronic supplementary material
The online version of this article (doi:10.1007/s10493-014-9856-1) contains supplementary material, which is available to authorized users.
PMCID: PMC4274374  PMID: 25342243
DNA barcoding; Haplotype network; Coalescence; Species delimitation; Spitsbergen; Ectocommensal dispersion; Stercorarius
22.  Relative Roles of GM1 Ganglioside, N-Acylneuraminic Acids, and α2β1 Integrin in Mediating Rotavirus Infection 
Journal of Virology  2014;88(8):4558-4571.
N-acetyl- and N-glycolylneuraminic acids (Sia) and α2β1 integrin are frequently used by rotaviruses as cellular receptors through recognition by virion spike protein VP4. The VP4 subunit VP8*, derived from Wa rotavirus, binds the internal N-acetylneuraminic acid on ganglioside GM1. Wa infection is increased by enhanced internal Sia access following terminal Sia removal from main glycan chains with sialidase. The GM1 ligand cholera toxin B (CTB) reduces Wa infectivity. Here, we found sialidase treatment increased cellular GM1 availability and the infectivity of several other human (including RV-3) and animal rotaviruses, typically rendering them susceptible to methyl α-d-N-acetylneuraminide treatment, but did not alter α2β1 usage. CTB reduced the infectivity of these viruses. Aceramido-GM1 inhibited Wa and RV-3 infectivity in untreated and sialidase-treated cells, and GM1 supplementation increased their infectivity, demonstrating the importance of GM1 for infection. Wa recognition of α2β1 and internal Sia were at least partially independent. Rotavirus usage of GM1 was mapped to VP4 using virus reassortants, and RV-3 VP8* bound aceramido-GM1 by saturation transfer difference nuclear magnetic resonance (STD NMR). Most rotaviruses recognizing terminal Sia did not use GM1, including RRV. RRV VP8* interacted minimally with aceramido-GM1 by STD NMR. Unusually, TFR-41 rotavirus infectivity depended upon terminal Sia and GM1. Competition of CTB, Sia, and/or aceramido-GM1 with cell binding by VP8* from representative rotaviruses showed that rotavirus Sia and GM1 preferences resulted from VP8*-cell binding. Our major finding is that infection by human rotaviruses of commonly occurring VP4 serotypes involves VP8* binding to cell surface GM1 glycan, typically including the internal N-acetylneuraminic acid.
IMPORTANCE Rotaviruses, the major cause of severe infantile gastroenteritis, recognize cell surface receptors through virus spike protein VP4. Several animal rotaviruses are known to bind sialic acids at the termini of main carbohydrate chains. Conversely, only a single human rotavirus is known to bind sialic acid. Interestingly, VP4 of this rotavirus bound to sialic acid that forms a branch on the main carbohydrate chain of the GM1 ganglioside. Here, we use several techniques to demonstrate that other human rotaviruses exhibit similar GM1 usage properties. Furthermore, binding by VP4 to cell surface GM1, involving branched sialic acid recognition, is shown to facilitate infection. In contrast, most animal rotaviruses that bind terminal sialic acids did not utilize GM1 for VP4 cell binding or infection. These studies support a significant role for GM1 in mediating host cell invasion by human rotaviruses.
PMCID: PMC3993774  PMID: 24501414
23.  Transplantation of human umbilical mesenchymal stem cells cures the corneal defects of Mucopolysaccharidosis VII mice 
Stem cells (Dayton, Ohio)  2013;31(10):10.1002/stem.1481.
Mucopolysaccharidosis (MPS) are a family of related disorders caused by a mutation in one of the lysosomal exoglycosidases which leads to the accumulation of glycosaminoglycans (GAGs). MPS VII, caused by a mutation in β-glucuronidase, manifests hepatomegaly, skeletal dysplasia, short stature, corneal clouding and developmental delay. Current treatment regimens for MPS are not effective for treating corneal clouding and impaired mental development. We hypothesized that human umbilical mesenchymal stem cells (UMSC) transplanted into the corneal stroma could participate in the catabolism of GAGs providing a means of cell therapy for MPS. For such treatment, human UMSC were intrastromally transplanted into corneas of MPS VII mice. UMSC transplantation restored the dendritic and hexagonal morphology of host keratocytes and endothelial cells, respectively, and in vivo confocal microscopy (HRTII) revealed reduced corneal haze. Immunohistochemistry using antibodies against HS and CS chains as well as LAMP2 revealed a decrease in GAG content and both lysosomal number and size in the treated corneas. Labeling UMSC intracellular compartments prior to transplantation revealed the distribution of UMSC vesicles throughout the corneal stroma and endothelium. An in vitro co-culture assay between skin fibroblasts isolated from MPSVII mice and UMSC demonstrated that neutral vesicles released by the UMSC are taken up by the fibroblasts and proceed to fuse with the acidic lysosomes. Therefore, transplanted UMSC participate both in extracellular GAG turnover and enable host keratocytes to catabolize accumulated GAG products, suggesting that UMSC could be a novel alternative for treating corneal defects associated with MPS and other congenital metabolic disorders.
PMCID: PMC3812352  PMID: 23897660
Mucopolysaccharidosis; umbilical cord mesenchymal stem cells; cornea; glycosaminoglycans; exosomes
24.  Exploring the effects of immunity and life history on the dynamics of an endogenous retrovirus 
Mammalian DNA is littered with the signatures of past retroviral infections. For example, at least 8% of the human genome can be attributed to endogenous retroviruses (ERVs). We take a single-locus approach to develop a simple susceptible–infected–recovered model to investigate the circumstances under which a disease-causing retrovirus can become incorporated into the host genome and spread through the host population if it were to confer an immunological advantage. In the absence of any fitness benefit provided by the long terminal repeat (LTR), we conclude that signatures of ERVs are likely to go to fixation within a population when the probability of evolving cellular/humoral immunity to a related exogenous version of the virus is extremely small. We extend this model to examine whether changing the speed of the host life history influences the likelihood that an exogenous retrovirus will incorporate and spread to fixation. Our results reveal the parameter space under which incorporation of exogenous retroviruses into a host genome may be beneficial to the host. In our final model, we find that the likelihood of an LTR reaching fixation in a host population is not strongly affected by host life history.
PMCID: PMC3758189  PMID: 23938754
endogenous retrovirus; endogenous viral element derived immunity; immunity; susceptible–infected–recovered model; life history
25.  Melatonin Signaling Modulates Clock Genes Expression in the Mouse Retina 
PLoS ONE  2014;9(9):e106819.
Previous studies have shown that retinal melatonin plays an important role in the regulation of retinal daily and circadian rhythms. Melatonin exerts its influence by binding to G-protein coupled receptors named melatonin receptor type 1 and type 2 and both receptors are present in the mouse retina. Earlier studies have shown that clock genes are rhythmically expressed in the mouse retina and melatonin signaling may be implicated in the modulation of clock gene expression in this tissue. In this study we determined the daily and circadian expression patterns of Per1, Per2, Bmal1, Dbp, Nampt and c-fos in the retina and in the photoreceptor layer (using laser capture microdissection) in C3H-f+/+ and in melatonin receptors of knockout (MT1 and MT2) of the same genetic background using real-time quantitative RT-PCR. Our data indicated that clock and clock-controlled genes are rhythmically expressed in the retina and in the photoreceptor layer. Removal of melatonin signaling significantly affected the pattern of expression in the retina whereas in the photoreceptor layer only the Bmal1 circadian pattern of expression was affected by melatonin signaling removal. In conclusion, our data further support the notion that melatonin signaling may be important for the regulation of clock gene expression in the inner or ganglion cells layer, but not in photoreceptors.
PMCID: PMC4159264  PMID: 25203735

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