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    TERT structural rearrangements in metastatic pheochromocytomas
    Dwight, T ; Flynn, A ; Amarasinghe, K ; Benn, DE ; Lupat, R ; Li, J ; Cameron, DL ; Hogg, A ; Balachander, S ; Candiloro, ILM ; Wong, SQ ; Robinson, BG ; Papenfuss, AT ; Gill, AJ ; Dobrovic, A ; Hicks, RJ ; Clifton-Bligh, RJ ; Tothill, RW (BIOSCIENTIFICA LTD, 2018-01-01)
    Pheochromocytomas (PC) and paragangliomas (PGL) are endocrine tumors for which the genetic and clinicopathological features of metastatic progression remain incompletely understood. As a result, the risk of metastasis from a primary tumor cannot be predicted. Early diagnosis of individuals at high risk of developing metastases is clinically important and the identification of new biomarkers that are predictive of metastatic potential is of high value. Activation of TERT has been associated with a number of malignant tumors, including PC/PGL. However, the mechanism of TERT activation in the majority of PC/PGL remains unclear. As TERT promoter mutations occur rarely in PC/PGL, we hypothesized that other mechanisms - such as structural variations - may underlie TERT activation in these tumors. From 35 PC and four PGL, we identified three primary PCs that developed metastases with elevated TERT expression, each of which lacked TERT promoter mutations and promoter DNA methylation. Using whole genome sequencing, we identified somatic structural alterations proximal to the TERT locus in two of these tumors. In both tumors, the genomic rearrangements led to the positioning of super-enhancers proximal to the TERT promoter, that are likely responsible for the activation of the normally tightly repressed TERT expression in chromaffin cells.
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    Genetic effects on gene expression across human tissues
    Aguet, F ; Brown, AA ; Castel, SE ; Davis, JR ; He, Y ; Jo, B ; Mohammadi, P ; Park, Y ; Parsana, P ; Segre, AV ; Strober, BJ ; Zappala, Z ; Cummings, BB ; Gelfand, ET ; Hadley, K ; Huang, KH ; Lek, M ; Li, X ; Nedzel, JL ; Nguyen, DY ; Noble, MS ; Sullivan, TJ ; Tukiainen, T ; MacArthur, DG ; Getz, G ; Management, NP ; Addington, A ; Guan, P ; Koester, S ; Little, AR ; Lockhart, NC ; Moore, HM ; Rao, A ; Struewing, JP ; Volpi, S ; Collection, B ; Brigham, LE ; Hasz, R ; Hunter, M ; Johns, C ; Johnson, M ; Kopen, G ; Leinweber, WF ; Lonsdale, JT ; McDonald, A ; Mestichelli, B ; Myer, K ; Roe, B ; Salvatore, M ; Shad, S ; Thomas, JA ; Walters, G ; Washington, M ; Wheeler, J ; Bridge, J ; Foster, BA ; Gillard, BM ; Karasik, E ; Kumar, R ; Miklos, M ; Moser, MT ; Jewell, SD ; Montroy, RG ; Rohrer, DC ; Valley, D ; Mash, DC ; Davis, DA ; Sobin, L ; Barcus, ME ; Branton, PA ; Grp, EMW ; Abell, NS ; Balliu, B ; Delaneau, O ; Fresard, L ; Gamazon, ER ; Garrido-Martin, D ; Gewirtz, ADH ; Gliner, G ; Gloudemans, MJ ; Han, B ; He, AZ ; Hormozdiari, F ; Li, X ; Liu, B ; Kang, EY ; McDowell, IC ; Ongen, H ; Palowitch, JJ ; Peterson, CB ; Quon, G ; Ripke, S ; Saha, A ; Shabalin, AA ; Shimko, TC ; Sul, JH ; Teran, NA ; Tsang, EK ; Zhang, H ; Zhou, Y-H ; Bustamante, CD ; Cox, NJ ; Guigo, R ; Kellis, M ; McCarthy, MI ; Conrad, DF ; Eskin, E ; Li, G ; Nobel, AB ; Sabatti, C ; Stranger, BE ; Wen, X ; Wright, FA ; Ardlie, KG ; Dermitzakis, ET ; Lappalainen, T ; Battle, A ; Brown, CD ; Engelhardt, BE ; Montgomery, SB ; Aguet, F ; Ardlie, KG ; Cummings, BB ; Gelfand, ET ; Getz, G ; Hadley, K ; Handsaker, RE ; Huang, KH ; Kashin, S ; Karczewski, KJ ; Lek, M ; Li, X ; MacArthur, DG ; Nedzel, JL ; Nguyen, DT ; Noble, MS ; Segre, AV ; Trowbridge, CA ; Tukiainen, T ; Abell, NS ; Balliu, B ; Barshir, R ; Basha, O ; Battle, A ; Bogu, GK ; Brown, A ; Brown, CD ; Castel, SE ; Chen, LS ; Chiang, C ; Conrad, DF ; Cox, NJ ; Damani, FN ; Davis, JR ; Delaneau, O ; Dermitzakis, ET ; Engelhardt, BE ; Eskin, E ; Ferreira, PG ; Fresard, L ; Gamazon, ER ; Garrido-Martin, D ; Gewirtz, ADH ; Gliner, G ; Gloudemans, MJ ; Guigo, R ; Hall, IM ; Han, B ; He, Y ; Hormozdiari, F ; Howald, C ; Im, HK ; Jo, B ; Kang, EY ; Kim, Y ; Kim-Hellmuth, S ; Lappalainen, T ; Li, G ; Li, X ; Liu, B ; Mangul, S ; McCarthy, MI ; McDowell, IC ; Mohammadi, P ; Monlong, J ; Montgomery, SB ; Munoz-Aguirre, M ; Ndungu, AW ; Nicolae, DL ; Nobel, AB ; Oliva, M ; Ongen, H ; Palowitch, JJ ; Panousis, N ; Papasaikas, P ; Park, Y ; Parsana, P ; Payne, AJ ; Peterson, CB ; Quan, J ; Reverter, F ; Sabatti, C ; Saha, A ; Sammeth, M ; Scott, AJ ; Shabalin, AA ; Sodaei, R ; Stephens, M ; Stranger, BE ; Strober, BJ ; Sul, JH ; Tsang, EK ; Urbut, S ; De Bunt, MV ; Wang, G ; Wen, X ; Wright, FA ; Xi, HS ; Yeger-Lotem, E ; Zappala, Z ; Zaugg, JB ; Zhou, Y-H ; Akey, JM ; Bates, D ; Chan, J ; Chen, LS ; Claussnitzer, M ; Demanelis, K ; Diegel, M ; Doherty, JA ; Feinberg, AP ; Fernando, MS ; Halow, J ; Hansen, KD ; Haugen, E ; Hickey, PF ; Hou, L ; Jasmine, F ; Jian, R ; Jiang, L ; Johnson, A ; Kaul, R ; Kellis, M ; Kibriya, MG ; Lee, K ; Li, JB ; Li, Q ; Li, X ; Lin, J ; Lin, S ; Linder, S ; Linke, C ; Liu, Y ; Maurano, MT ; Molinie, B ; Montgomery, SB ; Nelson, J ; Neri, FJ ; Oliva, M ; Park, Y ; Pierce, BL ; Rinaldi, NJ ; Rizzardi, LF ; Sandstrom, R ; Skol, A ; Smith, KS ; Snyder, MP ; Stamatoyannopoulos, J ; Stranger, BE ; Tang, H ; Tsang, EK ; Wang, L ; Wang, M ; Van Wittenberghe, N ; Wu, F ; Zhang, R ; Fund, NC ; Nierras, CR ; Nci, N ; Branton, PA ; Carithers, LJ ; Guan, P ; Moore, HM ; Rao, A ; Vaught, JB ; Nhgri, N ; Gould, SE ; Lockart, NC ; Martin, C ; Struewing, JP ; Volpi, S ; Nimh, N ; Addington, AM ; Koester, SE ; Nida, N ; Little, AR ; Brigham, LE ; Hasz, R ; Hunter, M ; Johns, C ; Johnson, M ; Kopen, G ; Leinweber, WF ; Lonsdale, JT ; McDonald, A ; Mestichelli, B ; Myer, K ; Roe, B ; Salvatore, M ; Shad, S ; Thomas, JA ; Walters, G ; Washington, M ; Wheeler, J ; Bridge, J ; Foster, BA ; Gillard, BM ; Karasik, E ; Kumar, R ; Miklos, M ; Moser, MT ; Jewell, SD ; Montroy, RG ; Rohrer, DC ; Valley, DR ; Davis, DA ; Mash, DC ; Undale, AH ; Smith, AM ; Tabor, DE ; Roche, NV ; McLean, JA ; Vatanian, N ; Robinson, KL ; Sobin, L ; Barcus, ME ; Valentino, KM ; Qi, L ; Hunter, S ; Hariharan, P ; Singh, S ; Um, KS ; Matose, T ; Tomaszewski, MM ; Study, E ; Barker, LK ; Mosavel, M ; Siminoff, LA ; Traino, HM ; Flicek, P ; Juettemann, T ; Ruffier, M ; Sheppard, D ; Taylor, K ; Trevanion, SJ ; Zerbino, DR ; Craft, B ; Goldman, M ; Haeussler, M ; Kent, WJ ; Lee, CM ; Paten, B ; Rosenbloom, KR ; Vivian, J ; Zhu, J (NATURE PUBLISHING GROUP, 2017-10-12)
    Characterization of the molecular function of the human genome and its variation across individuals is essential for identifying the cellular mechanisms that underlie human genetic traits and diseases. The Genotype-Tissue Expression (GTEx) project aims to characterize variation in gene expression levels across individuals and diverse tissues of the human body, many of which are not easily accessible. Here we describe genetic effects on gene expression levels across 44 human tissues. We find that local genetic variation affects gene expression levels for the majority of genes, and we further identify inter-chromosomal genetic effects for 93 genes and 112 loci. On the basis of the identified genetic effects, we characterize patterns of tissue specificity, compare local and distal effects, and evaluate the functional properties of the genetic effects. We also demonstrate that multi-tissue, multi-individual data can be used to identify genes and pathways affected by human disease-associated variation, enabling a mechanistic interpretation of gene regulation and the genetic basis of disease.
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    Transcriptome analysis of embryonic mammary cells reveals insights into mammary lineage establishment.
    Wansbury, O ; Mackay, A ; Kogata, N ; Mitsopoulos, C ; Kendrick, H ; Davidson, K ; Ruhrberg, C ; Reis-Filho, JS ; Smalley, MJ ; Zvelebil, M ; Howard, BA (Springer Science and Business Media LLC, 2011-08-11)
    INTRODUCTION: The mammary primordium forms during embryogenesis as a result of inductive interactions between its constitutive tissues, the mesenchyme and epithelium, and represents the earliest evidence of commitment to the mammary lineage. Previous studies of embryonic mouse mammary epithelium indicated that, by mid-gestation, these cells are determined to a mammary cell fate and that a stem cell population has been delimited. Mammary mesenchyme can induce mammary development from simple epithelium even across species and classes, and can partially restore features of differentiated tissue to mouse mammary tumours in co-culture experiments. Despite these exciting properties, the molecular identity of embryonic mammary cells remains to be fully characterised. METHODS: Here, we define the transcriptome of the mammary primordium and the two distinct cellular compartments that comprise it, the mammary primordial bud epithelium and mammary mesenchyme. Pathway and network analysis was performed and comparisons of embryonic mammary gene expression profiles to those of both postnatal mouse and human mammary epithelial cell sub-populations and stroma were made. RESULTS: Several of the genes we have detected in our embryonic mammary cell signatures were previously shown to regulate mammary cell fate and development, but we also identified a large number of novel candidates. Additionally, we determined genes that were expressed by both embryonic and postnatal mammary cells, which represent candidate regulators of mammary cell fate, differentiation and progenitor cell function that could signal from mammary lineage inception during embryogenesis through postnatal development. Comparison of embryonic mammary cell signatures with those of human breast cells identified potential regulators of mammary progenitor cell functions conserved across species. CONCLUSIONS: These results provide new insights into genetic regulatory mechanisms of mammary development, particularly identification of novel potential regulators of mammary fate and mesenchymal-epithelial cross-talk. Since cancers may represent diseases of mesenchymal-epithelial communications, we anticipate these results will provide foundations for further studies into the fundamental links between developmental, stem cell and breast cancer biology.
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    Altered proliferative ability of neuronal progenitors in PlexinA1 mutant mice.
    Andrews, WD ; Davidson, K ; Tamamaki, N ; Ruhrberg, C ; Parnavelas, JG (Wiley, 2016-02-15)
    Cortical interneurons are generated predominantly in the medial ganglionic eminence (MGE) and migrate through the ventral and dorsal telencephalon before taking their final positions within the developing cortical plate. Previously we demonstrated that interneurons from Robo1 knockout (Robo1(-/-)) mice contain reduced levels of neuropilin 1 (Nrp1) and PlexinA1 receptors, rendering them less responsive to the chemorepulsive actions of semaphorin ligands expressed in the striatum and affecting their course of migration (Hernandez-Miranda et al. [2011] J. Neurosci. 31:6174-6187). Earlier studies have highlighted the importance of Nrp1 and Nrp2 in interneuron migration, and here we assess the role of PlexinA1 in this process. We observed significantly fewer cells expressing the interneuron markers Gad67 and Lhx6 in the cortex of PlexinA1(-/-) mice compared with wild-type littermates at E14.5 and E18.5. Although the level of apoptosis was similar in the mutant and control forebrain, proliferation was significantly reduced in the former. Furthermore, progenitor cells in the MGE of PlexinA1(-/-) mice appeared to be poorly anchored to the ventricular surface and showed reduced adhesive properties, which may account for the observed reduction in proliferation. Together our data uncover a novel role for PlexinA1 in forebrain development.
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    The molecular control of GnRH neuron development.
    Cariboni, A ; Valentina, A ; Davidson, K ; Parnavelas, J (Springer Science and Business Media LLC, 2015)
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    The Subtilisin-Like Protease AprV2 Is Required for Virulence and Uses a Novel Disulphide-Tethered Exosite to Bind Substrates
    Kennan, RM ; Wong, W ; Dhungyel, OP ; Han, X ; Wong, D ; Parker, D ; Rosado, CJ ; Law, RHP ; McGowan, S ; Reeve, SB ; Levina, V ; Powers, GA ; Pike, RN ; Bottomley, SP ; Smith, AI ; Marsh, I ; Whittington, RJ ; Whisstock, JC ; Porter, CJ ; Rood, JI ; Stebbins, CE (PUBLIC LIBRARY SCIENCE, 2010-11-01)
    Many bacterial pathogens produce extracellular proteases that degrade the extracellular matrix of the host and therefore are involved in disease pathogenesis. Dichelobacter nodosus is the causative agent of ovine footrot, a highly contagious disease that is characterized by the separation of the hoof from the underlying tissue. D. nodosus secretes three subtilisin-like proteases whose analysis forms the basis of diagnostic tests that differentiate between virulent and benign strains and have been postulated to play a role in virulence. We have constructed protease mutants of D. nodosus; their analysis in a sheep virulence model revealed that one of these enzymes, AprV2, was required for virulence. These studies challenge the previous hypothesis that the elastase activity of AprV2 is important for disease progression, since aprV2 mutants were virulent when complemented with aprB2, which encodes a variant that has impaired elastase activity. We have determined the crystal structures of both AprV2 and AprB2 and characterized the biological activity of these enzymes. These data reveal that an unusual extended disulphide-tethered loop functions as an exosite, mediating effective enzyme-substrate interactions. The disulphide bond and Tyr92, which was located at the exposed end of the loop, were functionally important. Bioinformatic analyses suggested that other pathogenic bacteria may have proteases that utilize a similar mechanism. In conclusion, we have used an integrated multidisciplinary combination of bacterial genetics, whole animal virulence trials in the original host, biochemical studies, and comprehensive analysis of crystal structures to provide the first definitive evidence that the extracellular secreted proteases produced by D. nodosus are required for virulence and to elucidate the molecular mechanism by which these proteases bind to their natural substrates. We postulate that this exosite mechanism may be used by proteases produced by other bacterial pathogens of both humans and animals.
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    Programming a serial killer: CAR T cells form non-classical immune synapses.
    Davenport, AJ ; Jenkins, MR (Impact Journals, LLC, 2018-03)
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    Novel Salmonella enterica Serovar Typhimurium Genotype Levels as Herald of Seasonal Salmonellosis Epidemics.
    Sotomayor, C ; Wang, Q ; Arnott, A ; Howard, P ; Hope, K ; Lan, R ; Sintchenko, V (Centers for Disease Control and Prevention (CDC), 2018-06)
    We examined the population dynamics of Salmonella enterica serovar Typhimurium during seasonal salmonellosis epidemics in New South Wales, Australia, during 2009-2016. Of 15,626 isolates, 5%-20% consisted of novel genotypes. Seasons with salmonellosis epidemics were associated with a reduction in novel genotypes in the preceding winter and spring.
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    Multidrug-Resistant Salmonella enterica 4,[5], 12: i:-Sequence Type 34, New South Wales, Australia, 2016-2017
    Arnott, A ; Wang, Q ; Bachmann, N ; Sadsad, R ; Biswas, C ; Sotomayor, C ; Howard, P ; Rockett, R ; Wiklendt, A ; Iredell, JR ; Sintchenko, V (CENTERS DISEASE CONTROL & PREVENTION, 2018-04-01)
    Multidrug- and colistin-resistant Salmonella enterica serotype 4,[5],12:i:- sequence type 34 is present in Europe and Asia. Using genomic surveillance, we determined that this sequence type is also endemic to Australia. Our findings highlight the public health benefits of genome sequencing-guided surveillance for monitoring the spread of multidrug-resistant mobile genes and isolates.
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    The Drosophila melanogaster Phospholipid Flippase dATP8B Is Required for Odorant Receptor Function
    Liu, Y-C ; Pearce, MW ; Honda, T ; Johnson, TK ; Charlu, S ; Sharma, KR ; Imad, M ; Burke, RE ; Zinsmaier, KE ; Ray, A ; Dahanukar, A ; de Bruyne, M ; Warr, CG ; Anholt, RRH (PUBLIC LIBRARY SCIENCE, 2014-03-01)
    The olfactory systems of insects are fundamental to all aspects of their behaviour, and insect olfactory receptor neurons (ORNs) exhibit exquisite specificity and sensitivity to a wide range of environmental cues. In Drosophila melanogaster, ORN responses are determined by three different receptor families, the odorant (Or), ionotropic-like (IR) and gustatory (Gr) receptors. However, the precise mechanisms of signalling by these different receptor families are not fully understood. Here we report the unexpected finding that the type 4 P-type ATPase phospholipid transporter dATP8B, the homologue of a protein associated with intrahepatic cholestasis and hearing loss in humans, is crucial for Drosophila olfactory responses. Mutations in dATP8B severely attenuate sensitivity of odorant detection specifically in Or-expressing ORNs, but do not affect responses mediated by IR or Gr receptors. Accordingly, we find dATP8B to be expressed in ORNs and localised to the dendritic membrane of the olfactory neurons where signal transduction occurs. Localisation of Or proteins to the dendrites is unaffected in dATP8B mutants, as is dendrite morphology, suggesting instead that dATP8B is critical for Or signalling. As dATP8B is a member of the phospholipid flippase family of ATPases, which function to determine asymmetry in phospholipid composition between the outer and inner leaflets of plasma membranes, our findings suggest a requirement for phospholipid asymmetry in the signalling of a specific family of chemoreceptor proteins.