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Search Results: 1 - 10 of 195857 matches for " Graham G. Giles equal contributor "
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Fine-Mapping the HOXB Region Detects Common Variants Tagging a Rare Coding Allele: Evidence for Synthetic Association in Prostate Cancer
Edward J. Saunders,Tokhir Dadaev,Daniel A. Leongamornlert,Sarah Jugurnauth-Little,Malgorzata Tymrakiewicz,Fredrik Wiklund,Ali Amin Al Olama,Sara Benlloch,David E. Neal equal contributor,Freddie C. Hamdy equal contributor,Jenny L. Donovan equal contributor,Graham G. Giles equal contributor,Gianluca Severi equal contributor,Henrik Gronberg equal contributor,Markus Aly equal contributor,Christopher A. Haiman equal contributor,Fredrick Schumacher equal contributor,Brian E. Henderson equal contributor,Sara Lindstrom equal contributor,Peter Kraft equal contributor,David J. Hunter equal contributor,Susan Gapstur equal contributor,Stephen Chanock equal contributor,Sonja I. Berndt equal contributor,Demetrius Albanes equal contributor,Gerald Andriole equal contributor,Johanna Schleutker equal contributor,Maren Weischer equal contributor,B?rge G. Nordestgaard equal contributor,Federico Canzian equal contributor,Daniele Campa equal contributor,Elio Riboli equal contributor,Tim J. Key equal contributor,Ruth C. Travis equal contributor,Sue A. Ingles equal contributor,Esther M. John equal contributor,Richard B. Hayes equal contributor,Paul Pharoah equal contributor,Kay-Tee Khaw equal contributor,Janet L. Stanford equal contributor,Elaine A. Ostrander equal contributor,Lisa B. Signorello equal contributor,Stephen N. Thibodeau equal contributor,Daniel Schaid equal contributor,Christiane Maier equal contributor,Adam S. Kibel equal contributor,Cezary Cybulski equal contributor
PLOS Genetics , 2014, DOI: doi/10.1371/journal.pgen.1004129
Abstract: The HOXB13 gene has been implicated in prostate cancer (PrCa) susceptibility. We performed a high resolution fine-mapping analysis to comprehensively evaluate the association between common genetic variation across the HOXB genetic locus at 17q21 and PrCa risk. This involved genotyping 700 SNPs using a custom Illumina iSelect array (iCOGS) followed by imputation of 3195 SNPs in 20,440 PrCa cases and 21,469 controls in The PRACTICAL consortium. We identified a cluster of highly correlated common variants situated within or closely upstream of HOXB13 that were significantly associated with PrCa risk, described by rs117576373 (OR 1.30, P = 2.62×10?14). Additional genotyping, conditional regression and haplotype analyses indicated that the newly identified common variants tag a rare, partially correlated coding variant in the HOXB13 gene (G84E, rs138213197), which has been identified recently as a moderate penetrance PrCa susceptibility allele. The potential for GWAS associations detected through common SNPs to be driven by rare causal variants with higher relative risks has long been proposed; however, to our knowledge this is the first experimental evidence for this phenomenon of synthetic association contributing to cancer susceptibility.
Phosphoenolpyruvate Carboxylase Identified as a Key Enzyme in Erythrocytic Plasmodium falciparum Carbon Metabolism
Janet Storm equal contributor,Sonal Sethia equal contributor,Gavin J. Blackburn equal contributor,Achuthanunni Chokkathukalam,David G. Watson,Rainer Breitling,Graham H. Coombs,Sylke Müller
PLOS Pathogens , 2014, DOI: doi/10.1371/journal.ppat.1003876
Abstract: Phospoenolpyruvate carboxylase (PEPC) is absent from humans but encoded in the Plasmodium falciparum genome, suggesting that PEPC has a parasite-specific function. To investigate its importance in P. falciparum, we generated a pepc null mutant (D10Δpepc), which was only achievable when malate, a reduction product of oxaloacetate, was added to the growth medium. D10Δpepc had a severe growth defect in vitro, which was partially reversed by addition of malate or fumarate, suggesting that pepc may be essential in vivo. Targeted metabolomics using 13C-U-D-glucose and 13C-bicarbonate showed that the conversion of glycolytically-derived PEP into malate, fumarate, aspartate and citrate was abolished in D10Δpepc and that pentose phosphate pathway metabolites and glycerol 3-phosphate were present at increased levels. In contrast, metabolism of the carbon skeleton of 13C,15N-U-glutamine was similar in both parasite lines, although the flux was lower in D10Δpepc; it also confirmed the operation of a complete forward TCA cycle in the wild type parasite. Overall, these data confirm the CO2 fixing activity of PEPC and suggest that it provides metabolites essential for TCA cycle anaplerosis and the maintenance of cytosolic and mitochondrial redox balance. Moreover, these findings imply that PEPC may be an exploitable target for future drug discovery.
Subtyping of Breast Cancer by Immunohistochemistry to Investigate a Relationship between Subtype and Short and Long Term Survival: A Collaborative Analysis of Data for 10,159 Cases from 12 Studies
Fiona M. Blows equal contributor,Kristy E. Driver equal contributor,Marjanka K. Schmidt,Annegien Broeks,Flora E. van Leeuwen,Jelle Wesseling,Maggie C. Cheang,Karen Gelmon,Torsten O. Nielsen,Carl Blomqvist,P?ivi Heikkil?,Tuomas Heikkinen,Heli Nevanlinna,Lars A. Akslen,Louis R. Bégin,William D. Foulkes,Fergus J. Couch,Xianshu Wang,Vicky Cafourek,Janet E. Olson,Laura Baglietto,Graham G. Giles,Gianluca Severi,Catriona A. McLean,Melissa C. Southey,Emad Rakha,Andrew R. Green,Ian O. Ellis,Mark E. Sherman,Jolanta Lissowska,William F. Anderson,Angela Cox,Simon S. Cross,Malcolm W. R. Reed,Elena Provenzano,Sarah-Jane Dawson,Alison M. Dunning,Manjeet Humphreys,Douglas F. Easton,Montserrat García-Closas,Carlos Caldas,Paul D. Pharoah ,David Huntsman
PLOS Medicine , 2010, DOI: 10.1371/journal.pmed.1000279
Abstract: Background Immunohistochemical markers are often used to classify breast cancer into subtypes that are biologically distinct and behave differently. The aim of this study was to estimate mortality for patients with the major subtypes of breast cancer as classified using five immunohistochemical markers, to investigate patterns of mortality over time, and to test for heterogeneity by subtype. Methods and Findings We pooled data from more than 10,000 cases of invasive breast cancer from 12 studies that had collected information on hormone receptor status, human epidermal growth factor receptor-2 (HER2) status, and at least one basal marker (cytokeratin [CK]5/6 or epidermal growth factor receptor [EGFR]) together with survival time data. Tumours were classified as luminal and nonluminal tumours according to hormone receptor expression. These two groups were further subdivided according to expression of HER2, and finally, the luminal and nonluminal HER2-negative tumours were categorised according to expression of basal markers. Changes in mortality rates over time differed by subtype. In women with luminal HER2-negative subtypes, mortality rates were constant over time, whereas mortality rates associated with the luminal HER2-positive and nonluminal subtypes tended to peak within 5 y of diagnosis and then decline over time. In the first 5 y after diagnosis the nonluminal tumours were associated with a poorer prognosis, but over longer follow-up times the prognosis was poorer in the luminal subtypes, with the worst prognosis at 15 y being in the luminal HER2-positive tumours. Basal marker expression distinguished the HER2-negative luminal and nonluminal tumours into different subtypes. These patterns were independent of any systemic adjuvant therapy. Conclusions The six subtypes of breast cancer defined by expression of five markers show distinct behaviours with important differences in short term and long term prognosis. Application of these markers in the clinical setting could have the potential to improve the targeting of adjuvant chemotherapy to those most likely to benefit. The different patterns of mortality over time also suggest important biological differences between the subtypes that may result in differences in response to specific therapies, and that stratification of breast cancers by clinically relevant subtypes in clinical trials is urgently required. Please see later in the article for the Editors' Summary
Neonatal CD8 T-cell Hierarchy Is Distinct from Adults and Is Influenced by Intrinsic T cell Properties in Respiratory Syncytial Virus Infected Mice
Tracy J. Ruckwardt equal contributor,Allison M. W. Malloy equal contributor,Emma Gostick,David A. Price,Pradyot Dash,Jennifer L. McClaren,Paul G. Thomas,Barney S. Graham
PLOS Pathogens , 2011, DOI: 10.1371/journal.ppat.1002377
Abstract: Following respiratory syncytial virus infection of adult CB6F1 hybrid mice, a predictable CD8+ T cell epitope hierarchy is established with a strongly dominant response to a Kd-restricted peptide (SYIGSINNI) from the M2 protein. The response to KdM282-90 is ~5-fold higher than the response to a subdominant epitope from the M protein (NAITNAKII, DbM187-195). After infection of neonatal mice, a distinctly different epitope hierarchy emerges with codominant responses to KdM282-90 and DbM187-195. Adoptive transfer of na?ve CD8+ T cells from adults into congenic neonates prior to infection indicates that intrinsic CD8+ T cell factors contribute to age-related differences in hierarchy. Epitope-specific precursor frequency differs between adults and neonates and influences, but does not predict the hierarchy following infection. Additionally, dominance of KdM282-90 –specific cells does not correlate with TdT activity. Epitope-specific Vβ repertoire usage is more restricted and functional avidity is lower in neonatal mice. The neonatal pattern of codominance changes after infection at 10 days of age, and rapidly shifts to the adult pattern of extreme KdM282- 90 -dominance. Thus, the functional properties of T cells are selectively modified by developmental factors in an epitope-specific and age-dependent manner.
In Vivo Time-Resolved Microtomography Reveals the Mechanics of the Blowfly Flight Motor
Simon M. Walker equal contributor,Daniel A. Schwyn equal contributor,Rajmund Mokso,Martina Wicklein,Tonya Müller,Michael Doube,Marco Stampanoni,Holger G. Krapp,Graham K. Taylor
PLOS Biology , 2014, DOI: 10.1371/journal.pbio.1001823
Abstract: Dipteran flies are amongst the smallest and most agile of flying animals. Their wings are driven indirectly by large power muscles, which cause cyclical deformations of the thorax that are amplified through the intricate wing hinge. Asymmetric flight manoeuvres are controlled by 13 pairs of steering muscles acting directly on the wing articulations. Collectively the steering muscles account for <3% of total flight muscle mass, raising the question of how they can modulate the vastly greater output of the power muscles during manoeuvres. Here we present the results of a synchrotron-based study performing micrometre-resolution, time-resolved microtomography on the 145 Hz wingbeat of blowflies. These data represent the first four-dimensional visualizations of an organism's internal movements on sub-millisecond and micrometre scales. This technique allows us to visualize and measure the three-dimensional movements of five of the largest steering muscles, and to place these in the context of the deforming thoracic mechanism that the muscles actuate. Our visualizations show that the steering muscles operate through a diverse range of nonlinear mechanisms, revealing several unexpected features that could not have been identified using any other technique. The tendons of some steering muscles buckle on every wingbeat to accommodate high amplitude movements of the wing hinge. Other steering muscles absorb kinetic energy from an oscillating control linkage, which rotates at low wingbeat amplitude but translates at high wingbeat amplitude. Kinetic energy is distributed differently in these two modes of oscillation, which may play a role in asymmetric power management during flight control. Structural flexibility is known to be important to the aerodynamic efficiency of insect wings, and to the function of their indirect power muscles. We show that it is integral also to the operation of the steering muscles, and so to the functional flexibility of the insect flight motor.
Vaccinia Virus Proteins A52 and B14 Share a Bcl-2–Like Fold but Have Evolved to Inhibit NF-κB rather than Apoptosis
Stephen C. Graham equal contributor,Mohammad W. Bahar equal contributor,Samantha Cooray equal contributor,Ron A.-J. Chen,Daniel M. Whalen,Nicola G. A. Abrescia,David Alderton,Raymond J. Owens,David I. Stuart,Geoffrey L. Smith ,Jonathan M. Grimes
PLOS Pathogens , 2008, DOI: 10.1371/journal.ppat.1000128
Abstract: Vaccinia virus (VACV), the prototype poxvirus, encodes numerous proteins that modulate the host response to infection. Two such proteins, B14 and A52, act inside infected cells to inhibit activation of NF-κB, thereby blocking the production of pro-inflammatory cytokines. We have solved the crystal structures of A52 and B14 at 1.9 ? and 2.7 ? resolution, respectively. Strikingly, both these proteins adopt a Bcl-2–like fold despite sharing no significant sequence similarity with other viral or cellular Bcl-2–like proteins. Unlike cellular and viral Bcl-2–like proteins described previously, A52 and B14 lack a surface groove for binding BH3 peptides from pro-apoptotic Bcl-2–like proteins and they do not modulate apoptosis. Structure-based phylogenetic analysis of 32 cellular and viral Bcl-2–like protein structures reveals that A52 and B14 are more closely related to each other and to VACV N1 and myxoma virus M11 than they are to other viral or cellular Bcl-2–like proteins. This suggests that a progenitor poxvirus acquired a gene encoding a Bcl-2–like protein and, over the course of evolution, gene duplication events have allowed the virus to exploit this Bcl-2 scaffold for interfering with distinct host signalling pathways.
SAS-1 Is a C2 Domain Protein Critical for Centriole Integrity in C. elegans
Lukas von Tobel equal contributor,Tamara Mikeladze-Dvali equal contributor,Marie Delattre,Fernando R. Balestra,Simon Blanchoud,Susanne Finger,Graham Knott,Thomas Müller-Reichert,Pierre G?nczy
PLOS Genetics , 2014, DOI: doi/10.1371/journal.pgen.1004777
Abstract: Centrioles are microtubule-based organelles important for the formation of cilia, flagella and centrosomes. Despite progress in understanding the underlying assembly mechanisms, how centriole integrity is ensured is incompletely understood, including in sperm cells, where such integrity is particularly critical. We identified C. elegans sas-1 in a genetic screen as a locus required for bipolar spindle assembly in the early embryo. Our analysis reveals that sperm-derived sas-1 mutant centrioles lose their integrity shortly after fertilization, and that a related defect occurs when maternal sas-1 function is lacking. We establish that sas-1 encodes a C2 domain containing protein that localizes to centrioles in C. elegans, and which can bind and stabilize microtubules when expressed in human cells. Moreover, we uncover that SAS-1 is related to C2CD3, a protein required for complete centriole formation in human cells and affected in a type of oral-facial-digital (OFD) syndrome.
Live Hot, Die Young: Transmission Distortion in Recombination Hotspots
Graham Coop equal contributor,Simon R Myers equal contributor
PLOS Genetics , 2007, DOI: 10.1371/journal.pgen.0030035
Abstract: There is strong evidence that hotspots of meiotic recombination in humans are transient features of the genome. For example, hotspot locations are not shared between human and chimpanzee. Biased gene conversion in favor of alleles that locally disrupt hotspots is a possible explanation of the short lifespan of hotspots. We investigate the implications of such a bias on human hotspots and their evolution. Our results demonstrate that gene conversion bias is a sufficiently strong force to produce the observed lack of sharing of intense hotspots between species, although sharing may be much more common for weaker hotspots. We investigate models of how hotspots arise, and find that only models in which hotspot alleles do not initially experience drive are consistent with observations of rather hot hotspots in the human genome. Mutations acting against drive cannot successfully introduce such hotspots into the population, even if there is direct selection for higher recombination rates, such as to ensure correct segregation during meiosis. We explore the impact of hotspot alleles on patterns of haplotype variation, and show that such alleles mask their presence in population genetic data, making them difficult to detect.
Mutations in LRRC50 Predispose Zebrafish and Humans to Seminomas
Sander G. Basten,Erica E. Davis equal contributor,Ad J. M. Gillis equal contributor,Ellen van Rooijen,Hans Stoop,Nikolina Babala,Ive Logister,Zachary G. Heath,Trudy N. Jonges,Nicholas Katsanis,Emile E. Voest,Freek J. van Eeden,Rene H. Medema,René F. Ketting,Stefan Schulte-Merker,Leendert H. J. Looijenga,Rachel H. Giles
PLOS Genetics , 2013, DOI: 10.1371/journal.pgen.1003384
Abstract: Seminoma is a subclass of human testicular germ cell tumors (TGCT), the most frequently observed cancer in young men with a rising incidence. Here we describe the identification of a novel gene predisposing specifically to seminoma formation in a vertebrate model organism. Zebrafish carrying a heterozygous nonsense mutation in Leucine-Rich Repeat Containing protein 50 (lrrc50 also called dnaaf1), associated previously with ciliary function, are found to be highly susceptible to the formation of seminomas. Genotyping of these zebrafish tumors shows loss of heterozygosity (LOH) of the wild-type lrrc50 allele in 44.4% of tumor samples, correlating with tumor progression. In humans we identified heterozygous germline LRRC50 mutations in two different pedigrees with a family history of seminomas, resulting in a nonsense Arg488* change and a missense Thr590Met change, which show reduced expression of the wild-type allele in seminomas. Zebrafish in vivo complementation studies indicate the Thr590Met to be a loss-of-function mutation. Moreover, we show that a pathogenic Gln307Glu change is significantly enriched in individuals with seminoma tumors (13% of our cohort). Together, our study introduces an animal model for seminoma and suggests LRRC50 to be a novel tumor suppressor implicated in human seminoma pathogenesis.
Nephronophthisis-Associated CEP164 Regulates Cell Cycle Progression, Apoptosis and Epithelial-to-Mesenchymal Transition
Gisela G. Slaats,Amiya K. Ghosh equal contributor,Lucas L. Falke equal contributor,Stéphanie Le Corre,Indra A. Shaltiel,Glenn van de Hoek,Timothy D. Klasson,Marijn F. Stokman,Ive Logister,Marianne C. Verhaar,Roel Goldschmeding,Tri Q. Nguyen,Iain A. Drummond,Friedhelm Hildebrandt,Rachel H. Giles
PLOS Genetics , 2014, DOI: doi/10.1371/journal.pgen.1004594
Abstract: We recently reported that centrosomal protein 164 (CEP164) regulates both cilia and the DNA damage response in the autosomal recessive polycystic kidney disease nephronophthisis. Here we examine the functional role of CEP164 in nephronophthisis-related ciliopathies and concomitant fibrosis. Live cell imaging of RPE-FUCCI (fluorescent, ubiquitination-based cell cycle indicator) cells after siRNA knockdown of CEP164 revealed an overall quicker cell cycle than control cells, although early S-phase was significantly longer. Follow-up FACS experiments with renal IMCD3 cells confirm that Cep164 siRNA knockdown promotes cells to accumulate in S-phase. We demonstrate that this effect can be rescued by human wild-type CEP164, but not disease-associated mutants. siRNA of CEP164 revealed a proliferation defect over time, as measured by CyQuant assays. The discrepancy between accelerated cell cycle and inhibited overall proliferation could be explained by induction of apoptosis and epithelial-to-mesenchymal transition. Reduction of CEP164 levels induces apoptosis in immunofluorescence, FACS and RT-QPCR experiments. Furthermore, knockdown of Cep164 or overexpression of dominant negative mutant allele CEP164 Q525X induces epithelial-to-mesenchymal transition, and concomitant upregulation of genes associated with fibrosis. Zebrafish injected with cep164 morpholinos likewise manifest developmental abnormalities, impaired DNA damage signaling, apoptosis and a pro-fibrotic response in vivo. This study reveals a novel role for CEP164 in the pathogenesis of nephronophthisis, in which mutations cause ciliary defects coupled with DNA damage induced replicative stress, cell death, and epithelial-to-mesenchymal transition, and suggests that these events drive the characteristic fibrosis observed in nephronophthisis kidneys.
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