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JOURNAL ARTICLE
Jenny C Taylor, Hilary C Martin, Stefano Lise, John Broxholme, Jean-Baptiste Cazier, Andy Rimmer, Alexander Kanapin, Gerton Lunter, Simon Fiddy, Chris Allan, A Radu Aricescu, Moustafa Attar, Christian Babbs, Jennifer Becq, David Beeson, Celeste Bento, Patricia Bignell, Edward Blair, Veronica J Buckle, Katherine Bull, Ondrej Cais, Holger Cario, Helen Chapel, Richard R Copley, Richard Cornall, Jude Craft, Karin Dahan, Emma E Davenport, Calliope Dendrou, Olivier Devuyst, Aimée L Fenwick, Jonathan Flint, Lars Fugger, Rodney D Gilbert, Anne Goriely, Angie Green, Ingo H Greger, Russell Grocock, Anja V Gruszczyk, Robert Hastings, Edouard Hatton, Doug Higgs, Adrian Hill, Chris Holmes, Malcolm Howard, Linda Hughes, Peter Humburg, David Johnson, Fredrik Karpe, Zoya Kingsbury, Usha Kini, Julian C Knight, Jonathan Krohn, Sarah Lamble, Craig Langman, Lorne Lonie, Joshua Luck, Davis McCarthy, Simon J McGowan, Mary Frances McMullin, Kerry A Miller, Lisa Murray, Andrea H Németh, M Andrew Nesbit, David Nutt, Elizabeth Ormondroyd, Annette Bang Oturai, Alistair Pagnamenta, Smita Y Patel, Melanie Percy, Nayia Petousi, Paolo Piazza, Sian E Piret, Guadalupe Polanco-Echeverry, Niko Popitsch, Fiona Powrie, Chris Pugh, Lynn Quek, Peter A Robbins, Kathryn Robson, Alexandra Russo, Natasha Sahgal, Pauline A van Schouwenburg, Anna Schuh, Earl Silverman, Alison Simmons, Per Soelberg Sørensen, Elizabeth Sweeney, John Taylor, Rajesh V Thakker, Ian Tomlinson, Amy Trebes, Stephen Rf Twigg, Holm H Uhlig, Paresh Vyas, Tim Vyse, Steven A Wall, Hugh Watkins, Michael P Whyte, Lorna Witty, Ben Wright, Chris Yau, David Buck, Sean Humphray, Peter J Ratcliffe, John I Bell, Andrew Om Wilkie, David Bentley, Peter Donnelly, Gilean McVean
To assess factors influencing the success of whole-genome sequencing for mainstream clinical diagnosis, we sequenced 217 individuals from 156 independent cases or families across a broad spectrum of disorders in whom previous screening had identified no pathogenic variants. We quantified the number of candidate variants identified using different strategies for variant calling, filtering, annotation and prioritization. We found that jointly calling variants across samples, filtering against both local and external databases, deploying multiple annotation tools and using familial transmission above biological plausibility contributed to accuracy...
July 2015: Nature Genetics
#22
JOURNAL ARTICLE
Daniel M Reed, Gabor Foldes, Timothy Gatheral, Koralia E Paschalaki, Zsuzsanna Lendvai, Zsolt Bagyura, Tamas Nemeth, Judit Skopal, Bela Merkely, Aurica G Telcian, Leila Gogsadze, Michael R Edwards, Peter J Gough, John Bertin, Sebastian L Johnston, Sian E Harding, Jane A Mitchell
Human embryonic stem cell-derived endothelial cells (hESC-EC), as well as other stem cell derived endothelial cells, have a range of applications in cardiovascular research and disease treatment. Endothelial cells sense Gram-negative bacteria via the pattern recognition receptors (PRR) Toll-like receptor (TLR)-4 and nucleotide-binding oligomerisation domain-containing protein (NOD)-1. These pathways are important in terms of sensing infection, but TLR4 is also associated with vascular inflammation and atherosclerosis...
2014: PloS One
#23
JOURNAL ARTICLE
Andrew B Allison, M Kevin Keel, Jamie E Philips, Andrew N Cartoceti, Brandon A Munk, Nicole M Nemeth, Trista I Welsh, Jesse M Thomas, James M Crum, Anne B Lichtenwalner, Aly M Fadly, Guillermo Zavala, Edward C Holmes, Justin D Brown
Lymphoproliferative disease virus (LPDV) is an exogenous oncogenic retrovirus that induces lymphoid tumors in some galliform species of birds. Historically, outbreaks of LPDV have been reported from Europe and Israel. Although the virus has previously never been detected in North America, herein we describe the widespread distribution, genetic diversity, pathogenesis, and evolution of LPDV in the United States. Characterization of the provirus genome of the index LPDV case from North America demonstrated an 88% nucleotide identity to the Israeli prototype strain...
February 2014: Virology
#24
REVIEW
Edward F Nemeth, Dolores Shoback
The calcium-sensing receptor (CaSR) plays a pivotal role in regulating systemic Ca(2+) homeostasis and is a target for drugs designed to treat certain disorders of bone and mineral metabolism. Calcimimetics are agonists or positive allosteric modulators of the CaSR; they inhibit parathyroid hormone (PTH) secretion and stimulate renal Ca(2+) excretion. The first calcimimetic drug is cinacalcet, a positive allosteric modulator of the CaSR that is approved for treating secondary hyperparathyroidism (HPT) in patients on renal replacement therapy and for some forms of primary HPT characterized by clinically significant hypercalcemia...
June 2013: Best Practice & Research. Clinical Endocrinology & Metabolism
#25
JOURNAL ARTICLE
Sujeenthar Tharmalingam, Avais M Daulat, Jordan E Antflick, Syed M Ahmed, Edward F Nemeth, Stephane Angers, Arthur D Conigrave, David R Hampson
The calcium-sensing receptor (CaSR) is a family C G protein-coupled receptor that is activated by elevated levels of extracellular divalent cations. The CaSR couples to members of the G(q) family of G proteins, and in the endocrine system this receptor is instrumental in regulating the release of parathyroid hormone from the parathyroid gland and calcitonin from thyroid cells. Here, we demonstrate that in medullary thyroid carcinoma cells, the CaSR promotes cellular adhesion and migration via coupling to members of the integrin family of extracellular matrix-binding proteins...
November 25, 2011: Journal of Biological Chemistry
#26
JOURNAL ARTICLE
Stephen Bent, Kiah Bertoglio, Paul Ashwood, Edward Nemeth, Robert L Hendren
We sought to determine whether HBOT leads to parental reported behavioral changes and alterations in cytokines in children with ASD. Ten children completed 80 sessions of HBOT and all improved by 2 points on the clinician-rated CGI-I scale (much improved) as well as several parent-completed measures of behavior. The lack of a control group limits the ability to determine if improvements were related to HBOT. Enrolled children did not exhibit abnormal cytokine levels at baseline and no significant changes in mean cytokine levels were observed...
June 2012: Journal of Autism and Developmental Disorders
#27
JOURNAL ARTICLE
Robert W Marquis, Amparo M Lago, James F Callahan, Attiq Rahman, Xiaoyang Dong, George B Stroup, Sandra Hoffman, Maxine Gowen, Eric G DelMar, Bradford C Van Wagenen, Sarah Logan, Scott Shimizu, John Fox, Edward F Nemeth, Theresa Roethke, Brian R Smith, Keith W Ward, Pradip Bhatnagar
When administered as a single agent to rats, the previously reported calcium receptor antagonist 3 elicited a sustained elevation of plasma PTH resulting in no increase in overall bone mineral density. The lack of a bone building effect for analogue 3 was attributed to the large volume of distribution (V(dss)(rat) = 11 L/kg), producing a protracted plasma PTH profile. Incorporation of a carboxylic acid functionality into the amino alcohol template led to the identification of 12 with a lower volume of distribution (V(dss)(12) = 1...
November 12, 2009: Journal of Medicinal Chemistry
#28
RANDOMIZED CONTROLLED TRIAL
Sanjay Kumar, Christopher J Matheny, Sandra J Hoffman, Robert W Marquis, Maggie Schultz, Xiaoguang Liang, Janice A Vasko, George B Stroup, Vernal R Vaden, Hyking Haley, John Fox, Eric G DelMar, Edward F Nemeth, Amparo M Lago, James F Callahan, Pradip Bhatnagar, William F Huffman, Maxine Gowen, Bingming Yi, Theodore M Danoff, Lorraine A Fitzpatrick
Daily subcutaneous administration of exogenous parathyroid hormone (PTH) promotes bone formation in patients with osteoporosis. Here we describe two novel, short-acting calcium-sensing receptor antagonists (SB-423562 and its orally bioavailable precursor, SB-423557) that elicit transient PTH release from the parathyroid gland in several preclinical species and in humans. In an ovariectomized rat model of bone loss, daily oral administration of SB-423557 promoted bone formation and improved parameters of bone strength at lumbar spine, proximal tibia and midshaft femur...
February 2010: Bone
#29
JOURNAL ARTICLE
Robert W Marquis, Amparo M Lago, James F Callahan, Robert E Lee Trout, Maxine Gowen, Eric G DelMar, Bradford C Van Wagenen, Sarah Logan, Scott Shimizu, John Fox, Edward F Nemeth, Zheng Yang, Theresa Roethke, Brian R Smith, Keith W Ward, John Lee, Richard M Keenan, Pradip Bhatnagar
Functional screening of the former SmithKline Beecham compound collection against the human calcium receptor (CaR) resulted in the identification of the amino alcohol-based hit 2 (IC(50) = 11 microM). Structure-activity studies of 2 focused on the optimization of the right- and left-hand side aromatic moieties as well as the amino alcohol linker region. Critical to the optimization of this antagonist template was the discovery that the chirality of the C-2 secondary alcohol played a key role in enhancing both CaR potency as well as selectivity over the beta-adrenergic receptor subtypes...
July 9, 2009: Journal of Medicinal Chemistry
#30
JOURNAL ARTICLE
Michelle J Paddack, John D Reynolds, Consuelo Aguilar, Richard S Appeldoorn, Jim Beets, Edward W Burkett, Paul M Chittaro, Kristen Clarke, Rene Esteves, Ana C Fonseca, Graham E Forrester, Alan M Friedlander, Jorge García-Sais, Gaspar González-Sansón, Lance K B Jordan, David B McClellan, Margaret W Miller, Philip P Molloy, Peter J Mumby, Ivan Nagelkerken, Michael Nemeth, Raúl Navas-Camacho, Joanna Pitt, Nicholas V C Polunin, Maria Catalina Reyes-Nivia, D Ross Robertson, Alberto Rodríguez-Ramírez, Eva Salas, Struan R Smith, Richard E Spieler, Mark A Steele, Ivor D Williams, Clare L Wormald, Andrew R Watkinson, Isabelle M Côté
Profound ecological changes are occurring on coral reefs throughout the tropics, with marked coral cover losses and concomitant algal increases, particularly in the Caribbean region. Historical declines in the abundance of large Caribbean reef fishes likely reflect centuries of overexploitation. However, effects of drastic recent degradation of reef habitats on reef fish assemblages have yet to be established. By using meta-analysis, we analyzed time series of reef fish density obtained from 48 studies that include 318 reefs across the Caribbean and span the time period 1955-2007...
April 14, 2009: Current Biology: CB
#31
JOURNAL ARTICLE
Edward F Nemeth
ZT-031 is a cyclic 31-amino acid analog of parathyroid hormone (PTH) that is in development by Zelos Therapeutics Inc for the treatment of osteoporosis and other bone-related disorders. ZT-031 activates the PTH type 1 receptor - the molecular target of the currently marketed osteogenic peptides PTH and PTH(1-34). Daily subcutaneous injections of ZT-031 prevented bone loss and replaced bone that had already been lost in an ovariectomized rat model of osteoporosis. Daily subcutaneous injections of ZT-031 in gonad-intact monkeys increased bone mineral density (BMD) at cortical and cancellous bone sites and increased serum levels of bone formation markers...
November 2008: IDrugs: the Investigational Drugs Journal
#32
JOURNAL ARTICLE
Nicole Nemeth, Gail Kratz, Eric Edwards, Judy Scherpelz, Richard Bowen, Nicholas Komar
In 2005, 13.5% of clinic-admitted raptors in northern Colorado tested positive for West Nile virus (WNV). Clinic-admitted-raptor surveillance detected WNV activity nearly 14 weeks earlier than other surveillance systems. WNV surveillance using live raptor admissions to rehabilitation clinics may offer a novel surveillance method and should be considered along with other techniques already in use.
February 2007: Emerging Infectious Diseases
#33
JOURNAL ARTICLE
Nicole M Nemeth, Susan Beckett, Eric Edwards, Kaci Klenk, Nicholas Komar
We tested 1,549 avian carcasses of 104 species to identify targets for West Nile virus (WNV) surveillance in Colorado, determine species affected by WNV, compare virus isolation versus RNA detection applied to hearts and oral swabs from carcasses, and compare the VecTest WNV Antigen Assay (VecTest) to standard assays. Forty-two species tested positive. From June to September 2003, 86% of corvids, 34% of non-corvid passerines, and 37% of raptors tested positive. We developed the Target Species Index, which identified American crows as the most important avian indicator species...
March 2007: American Journal of Tropical Medicine and Hygiene
#34
JOURNAL ARTICLE
D C Hahn, Nicole M Nemeth, Eric Edwards, Patricia R Bright, Nicholas Komar
Transovarial antibody transfer in owls has not been demonstrated for West Nile virus (WNV). We sampled chicks from captive adult WNV-antibody-positive Eastern Screech-Owls (Megascops asio) to evaluate the prevalence of transovarial maternal antibody transfer, as well as titers and duration of maternal antibodies. Twenty-four owlets aged 1 to 27 days old circulated detectable antibodies with neutralizing antibody titers ranging from 20 to 1600 (median 1:40). Demonstrating that WNV antibodies are passively transferred transovarially is important for accurate interpretation of serologic data from young birds...
September 2006: Avian Diseases
#35
JOURNAL ARTICLE
M Anandan, Neroli J Porter, Andrea H Nemeth, Edward Blair, Susan M Downes
PURPOSE: To report a case of Kabuki make-up syndrome (KMS) or Niikawa-Kuroki syndrome with Coats-type retinal telangiectasia, which has not been previously reported. METHODS: Observational case report. CONCLUSIONS: There have been only two reports of retinal pigmentation abnormalities and a single case of bilateral macular deposits in KMS, but this is the first report of a Coats type retinal telangiectasia. This case highlights the importance of thorough posterior segment examination in cases of KMS...
December 2005: Ophthalmic Genetics
#36
JOURNAL ARTICLE
Ilaria Dal Pra, Anna Chiarini, Edward F Nemeth, Ubaldo Armato, James F Whitfield
Since NO production by NOS-2 made by astrocytes activated by proinflammatory cytokines contributes to the killing of neurons in variously damaged human brains, knowing the mechanisms responsible for NOS-2 expression should contribute to developing effective therapeutics. The expression and activation of NOS-2 in normal adult human cerebral cortical astrocytes treated with three proinflammatory cytokines, IL-1beta, TNF-alpha, and IFN-gamma, are driven by two separable mechanisms. NOS-2 expression requires a burst of p38 MAPK activity, while the activation of the resulting enzyme protein requires MEK/ERK-dependent BH4 (tetrahydrobiopterin) synthesis between 24 and 24...
October 1, 2005: Journal of Cellular Biochemistry
#37
REVIEW
Nobuo Nagano, Edward F Nemeth
Circulating levels of calcium ion (Ca(2+)) are maintained within a narrow physiological range mainly by the action of parathyroid hormone (PTH) secreted from parathyroid cells. Parathyroid cells can sense small fluctuations in plasma Ca(2+) levels by virtue of a cell surface Ca(2+) receptor (CaR) that belongs to the superfamily of G-protein-coupled receptors. Calcimimetics are positive allosteric modulators that activate the CaR on parathyroid cells and thereby immediately suppress PTH secretion. Pre-clinical studies with NPS R-568, a first generation calcimimetic compound, have demonstrated that daily oral administration inhibits the elevation of plasma PTH levels and parathyroid gland hyperplasia and ameliorates impaired bone qualities in rats with chronic renal insufficiency...
March 2005: Journal of Pharmacological Sciences
#38
JOURNAL ARTICLE
Hee-Chang Mun, Alison H Franks, Emma L Culverston, Karen Krapcho, Edward F Nemeth, Arthur D Conigrave
We previously demonstrated that the human calcium-sensing receptor (CaR) is allosterically activated by L-amino acids (Conigrave, A. D., Quinn, S. J., and Brown, E. M. (2000) Proc. Natl. Acad. Sci. U. S. A. 97, 4814-4819). However, the domain-based location of amino acid binding has been uncertain. We now show that the Venus Fly Trap (VFT) domain of CaR, but none of its other major domains, is required for amino acid sensing. Several constructs were informative when expressed in HEK293 cells. First, the wild-type CaR exhibited allosteric activation by L-amino acids as previously observed...
December 10, 2004: Journal of Biological Chemistry
#39
REVIEW
Mariano Rodriguez, Edward Nemeth, David Martin
Serum calcium levels are regulated by the action of parathyroid hormone (PTH). Major drivers of PTH hypersecretion and parathyroid cell proliferation are the hypocalcemia and hyperphosphatemia that develop in chronic kidney disease patients with secondary hyperparathyroidism (SHPT) as a result of low calcitriol levels and decreased kidney function. Increased PTH production in response to systemic hypocalcemia is mediated by the calcium-sensing receptor (CaR). Furthermore, as SHPT progresses, reduced expression of CaRs and vitamin D receptors (VDRs) in hyperplastic parathyroid glands may limit the ability of calcium and calcitriol to regulate PTH secretion...
February 2005: American Journal of Physiology. Renal Physiology
#40
JOURNAL ARTICLE
Norbert Hájos, János Pálhalmi, Edward O Mann, Beáta Németh, Ole Paulsen, Tamas F Freund
Gamma frequency (30-100 Hz) network oscillations occur in the intact hippocampus during awake, attentive behavior. Here, we explored the underlying cellular mechanisms in an in vitro model of persistent gamma-frequency oscillations, induced by bath application of 20 microm carbachol in submerged hippocampal slices at 30 +/- 1 degrees C. Current-source density analysis of the field oscillation revealed a prominent alternating sink-source pair in the perisomatic and apical dendritic regions of CA3. To elucidate the active events generating these extracellular dipoles, we examined the firing properties of distinct neuron types...
October 13, 2004: Journal of Neuroscience
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