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Search Results: 1 - 10 of 90834 matches for " Alex W. Hewitt "
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Association of Genetic Variants with Primary Angle Closure Glaucoma in Two Different Populations
Mona S. Awadalla, Suman S. Thapa, Alex W. Hewitt, Kathryn P. Burdon, Jamie E. Craig
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0067903
Abstract: Purpose A recent large genome-wide association study (GWAS) identified multiple variants associated with primary angle-closure glaucoma (PACG). The present study investigated the role of these variants in two cohorts with PACG recruited from Australia and Nepal. Method Patients with PACG and appropriate controls were recruited from eye clinics in Australia (n = 232 cases and n = 288 controls) and Nepal (n = 106 cases and 204 controls). Single nucleotide polymorphisms (SNPs) rs3753841 (COL11A1), rs1015213 (located between PCMTD1 and ST18), rs11024102 (PLEKHA7), and rs3788317 (TXNRD2) were selected and genotyped on the Sequenom. Analyses were conducted using PLINK and METAL. Results After adjustment for age and sex, SNP rs3753841 was found to be significantly associated with PACG in the Australian cohort (p = 0.017; OR = 1.34). SNPs rs1015213 (p = 0.014; OR 2.35) and rs11024102 (p = 0.039; OR 1.43) were significantly associated with the disease development in the Nepalese cohort. None of these SNPs survived Bonferroni correction (p = 0.05/4 = 0.013). However, in the combined analysis, of both cohorts, rs3753841 and rs1015213 showed significant association with p-values of 0.009 and 0.004, respectively both surviving Bonferroni correction. SNP rs11024102 showed suggestive association with PACG (p-value 0.035) and no association was found with rs3788317. Conclusion The present results support the initial GWAS findings, and confirm the SNP’s contribution to PACG. This is the first study to investigate these loci in both Australian Caucasian and Nepalese populations.
No Association between FCγR3B Copy Number Variation and Susceptibility to Biopsy-Proven Giant Cell Arteritis
Emma Dunstan,Sue Lester,Rachel Black,Maureen Rischmueller,Helen Chan,Alex W. Hewitt,Catherine L. Hill
Arthritis , 2013, DOI: 10.1155/2013/514914
Abstract: Objective. To determine the relationship between FCGR3B gene copy number variation (CNV) and biopsy proven giant cell arteritis (GCA). Methods. FCGR3B CNV was determined in 139 Australian biopsy proven GCA patients and 162 population matched controls, using a duplex qPCR assay and RNase P as the reference gene. Copy number was determined using Copy Caller software (v.1.0, Applied Biosystems, USA). CNV genotypes were classified into 3 groups (<2, 2, 3+) for analysis purposes, and analysis was performed using logistic regression. Results. All GCA patients had a positive temporal artery biopsy, and the most common presenting symptoms were visual disturbance and temporal headache. The mean age of patients at biopsy was 74 years (range 51–94) and 88/139 (63%) were female. The frequency of low (<2) FCGR3B copy number was comparable between GCA patients ( %) and controls ( %), as was the frequency of high (3+) FCGR3B copy number (15/130 (10.8%) in GCA patients versus 13/162 (8.0%) in controls). Overall there was no evidence that FCGR3B CNV frequencies differed between GCA patients and controls ( , , ). Conclusion. FCGR3B CNV is not associated with GCA; however, replicate studies are required. 1. Introduction Giant cell arteritis (GCA), also known as temporal arteritis, is a systemic inflammatory vasculitis which primarily affects medium to large extracranial arteries of the head and neck and can result in stroke and blindness. GCA typically affects people aged over 50 years and incidence rates increase with advancing age, peaking around 80 years of age [1]. GCA is 2-3 times more likely to affect females and is more commonly diagnosed in Caucasians than in any other ethnic background with the highest incidence observed in populations of Scandinavian descent [2]. The pathogenesis of GCA is not understood, although environmental, infectious, and genetic risk factors have been implicated. Familial aggregation and established associations with HLA-DR4 provide evidence for a genetic component to GCA [3–5]. Multiple genetic association studies have been performed on a number of immune response genes. However, the majority of these studies have been performed on a single GCA cohort from north-western Spain and, to date, have failed to confirm any additional genetic associations. One gene of interest is Fc gamma receptor 3B (FCGR3B) which exhibits gene copy number variation (CNV), an important source of quantitative genetic variation. Copy number variation is a departure from the normal diploid number of genes ( ) which may arise through gene duplication and deletion
Searching for Dark Matter Annihilation in the Smith High-Velocity Cloud
Alex Drlica-Wagner,German A. Gomez-Vargas,John W. Hewitt,Tim Linden,Luigi Tibaldo
Physics , 2014, DOI: 10.1088/0004-637X/790/1/24
Abstract: Recent observations suggest that some high-velocity clouds may be confined by massive dark matter halos. In particular, the proximity and proposed dark matter content of the Smith Cloud make it a tempting target for the indirect detection of dark matter annihilation. We argue that the Smith Cloud may be a better target than some Milky Way dwarf spheroidal satellite galaxies and use gamma-ray observations from the Fermi Large Area Telescope to search for a dark matter annihilation signal. No significant gamma-ray excess is found coincident with the Smith Cloud, and we set strong limits on the dark matter annihilation cross section assuming a spatially-extended dark matter profile consistent with dynamical modeling of the Smith Cloud. Notably, these limits exclude the canonical thermal relic cross section ($\sim 3\times10^{-26}{\rm cm}^{3}{\rm s}^{-1}$) for dark matter masses $\lesssim 30$ GeV annihilating via the $b \bar b$ or $\tau^{+}\tau^{-}$ channels for certain assumptions of the dark matter density profile; however, uncertainties in the dark matter content of the Smith Cloud may significantly weaken these constraints.
Ethnic and Mouse Strain Differences in Central Corneal Thickness and Association with Pigmentation Phenotype
David P. Dimasi,Alex W. Hewitt,Kenneth Kagame,Sam Ruvama,Ludovica Tindyebwa,Bastien Llamas,Kirsty A. Kirk,Paul Mitchell,Kathryn P. Burdon,Jamie E. Craig
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0022103
Abstract: The cornea is a transparent structure that permits the refraction of light into the eye. Evidence from a range of studies indicates that central corneal thickness (CCT) is strongly genetically determined. Support for a genetic component comes from data showing significant variation in CCT between different human ethnic groups. Interestingly, these studies also appear to show that skin pigmentation may influence CCT. To validate these observations, we undertook the first analysis of CCT in an oculocutaneous albinism (OCA) and Ugandan cohort, populations with distinct skin pigmentation phenotypes. There was a significant difference in the mean CCT of the OCA, Ugandan and Australian-Caucasian cohorts (Ugandan: 517.3±37 μm; Caucasian: 539.7±32.8 μm, OCA: 563.3±37.2 μm; p<0.001). A meta-analysis of 53 studies investigating the CCT of different ethnic groups was then performed and demonstrated that darker skin pigmentation is associated with a thinner CCT (p<0.001). To further verify these observations, we measured CCT in 13 different inbred mouse strains and found a significant difference between the albino and pigmented strains (p = 0.008). Specific mutations within the melanin synthesis pathway were then investigated in mice for an association with CCT. Significant differences between mutant and wild type strains were seen with the nonagouti (p<0.001), myosin VA (p<0.001), tyrosinase (p = 0.025) and tyrosinase related protein (p = 0.001) genes. These findings provide support for our hypothesis that pigmentation is associated with CCT and identifies pigment-related genes as candidates for developmental determination of a non-pigmented structure.
Mitochondrial Oxidative Phosphorylation Compensation May Preserve Vision in Patients with OPA1-Linked Autosomal Dominant Optic Atrophy
Nicole J. Van Bergen, Jonathan G. Crowston, Lisa S. Kearns, Sandra E. Staffieri, Alex W. Hewitt, Amy C. Cohn, David A. Mackey, Ian A. Trounce
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0021347
Abstract: Autosomal Dominant Optic Atrophy (ADOA) is the most common inherited optic atrophy where vision impairment results from specific loss of retinal ganglion cells of the optic nerve. Around 60% of ADOA cases are linked to mutations in the OPA1 gene. OPA1 is a fission-fusion protein involved in mitochondrial inner membrane remodelling. ADOA presents with marked variation in clinical phenotype and varying degrees of vision loss, even among siblings carrying identical mutations in OPA1. To determine whether the degree of vision loss is associated with the level of mitochondrial impairment, we examined mitochondrial function in lymphoblast cell lines obtained from six large Australian OPA1-linked ADOA pedigrees. Comparing patients with severe vision loss (visual acuity [VA]<6/36) and patients with relatively preserved vision (VA>6/9) a clear defect in mitochondrial ATP synthesis and reduced respiration rates were observed in patients with poor vision. In addition, oxidative phosphorylation (OXPHOS) enzymology in ADOA patients with normal vision revealed increased complex II+III activity and levels of complex IV protein. These data suggest that OPA1 deficiency impairs OXPHOS efficiency, but compensation through increases in the distal complexes of the respiratory chain may preserve mitochondrial ATP production in patients who maintain normal vision. Identification of genetic variants that enable this response may provide novel therapeutic insights into OXPHOS compensation for preventing vision loss in optic neuropathies.
The p53 Codon 72 PRO/PRO Genotype May Be Associated with Initial Central Visual Field Defects in Caucasians with Primary Open Angle Glaucoma
Janey L. Wiggs, Alex W. Hewitt, Bao Jian Fan, Dan Yi Wang, Dayse R. Figueiredo Sena, Colm O’Brien, Anthony Realini, Jamie E. Craig, David P. Dimasi, David A. Mackey, Jonathan L. Haines, Louis R. Pasquale
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0045613
Abstract: Background Loss of vision in glaucoma is due to apoptotic retinal ganglion cell loss. While p53 modulates apoptosis, gene association studies between p53 variants and glaucoma have been inconsistent. In this study we evaluate the association between a p53 variant functionally known to influence apoptosis (codon 72 Pro/Arg) and the subset of primary open angle glaucoma (POAG) patients with early loss of central visual field. Methods Genotypes for the p53 codon 72 polymorphism (Pro/Arg) were obtained for 264 POAG patients and 400 controls from the U.S. and in replication studies for 308 POAG patients and 178 controls from Australia (GIST). The glaucoma patients were divided into two groups according to location of initial visual field defect (either paracentral or peripheral). All cases and controls were Caucasian with European ancestry. Results The p53-PRO/PRO genotype was more frequent in the U.S. POAG patients with early visual field defects in the paracentral regions compared with those in the peripheral regions or control group (p = 2.7×10?5). We replicated this finding in the GIST cohort (p = 7.3×10?3, and in the pooled sample (p = 6.6×10?7) and in a meta-analysis of both the US and GIST datasets (1.3×10?6, OR 2.17 (1.58–2.98 for the PRO allele). Conclusions These results suggest that the p53 codon 72 PRO/PRO genotype is potentially associated with early paracentral visual field defects in primary open-angle glaucoma patients.
Discovery of New Interacting Supernova Remnants in the Inner Galaxy
John W. Hewitt,Farhad Yusef-Zadeh
Physics , 2009, DOI: 10.1088/0004-637X/694/1/L16
Abstract: OH(1720 MHz) masers are excellent signposts of interaction between supernova remnants(SNRs) and molecular clouds. Using the GBT and VLA we have surveyed 75 SNRs and six candidates for maser emission. Four new interacting SNRs are detected with OH masers: G5.4-1.2, G5.7-0.0, G8.7-0.1 and G9.7-0.0. The newly detected interacting SNRs G5.7-0.0 and G8.7-0.1 have TeV gamma-ray counterparts which may indicate a local cosmic ray enhancement. It has been noted that maser-emitting SNRs are preferentially distributed in the Molecular Ring and Nuclear Disk. We use the present and existing surveys to demonstrate that masers are strongly confined to within 50 degrees Galactic longitude at a rate of 15 percent of the total SNR population. All new detections are within 10 degrees Galactic longitude emphasizing this trend. Additionally, a substantial number of SNR masers have peak fluxes at or below the detection threshold of existing surveys. This calls into question whether maser surveys of Galactic SNRs can be considered complete and how many maser-emitting remnants remain to be detected in the Galaxy.
Observations of supernova remnants and pulsar wind nebulae at gamma-ray energies
John W. Hewitt,Marianne Lemoine-Goumard
Physics , 2015,
Abstract: In the past few years, gamma-ray astronomy has entered a golden age thanks to two major breakthroughs: Cherenkov telescopes on the ground and the Large Area Telescope (LAT) onboard the Fermi satellite. The sample of supernova remnants (SNRs) detected at gamma-ray energies is now much larger: it goes from evolved supernova remnants interacting with molecular clouds up to young shell-type supernova remnants and historical supernova remnants. Studies of SNRs are of great interest, as these analyses are directly linked to the long standing issue of the origin of the Galactic cosmic rays. In this context, pulsar wind nebulae (PWNe) need also to be considered since they evolve in conjunction with SNRs. As a result, they frequently complicate interpretation of the gamma-ray emission seen from SNRs and they could also contribute directly to the local cosmic ray spectrum, particularly the leptonic component. This paper reviews the current results and thinking on SNRs and PWNe and their connection to cosmic ray production.
Common Genetic Variants near the Brittle Cornea Syndrome Locus ZNF469 Influence the Blinding Disease Risk Factor Central Corneal Thickness
Yi Lu equal contributor,David P. Dimasi equal contributor,Pirro G. Hysi,Alex W. Hewitt,Kathryn P. Burdon,Tze'Yo Toh,Jonathan B. Ruddle,Yi Ju Li,Paul Mitchell,Paul R. Healey,Grant W. Montgomery,Narelle Hansell,Timothy D. Spector,Nicholas G. Martin,Terri L. Young,Christopher J. Hammond,Stuart Macgregor ?,Jamie E. Craig ? ,David A. Mackey ?
PLOS Genetics , 2010, DOI: 10.1371/journal.pgen.1000947
Abstract: Central corneal thickness (CCT), one of the most highly heritable human traits (h2 typically>0.9), is important for the diagnosis of glaucoma and a potential risk factor for glaucoma susceptibility. We conducted genome-wide association studies in five cohorts from Australia and the United Kingdom (total N = 5058). Three cohorts were based on individually genotyped twin collections, with the remaining two cohorts genotyped on pooled samples from singletons with extreme trait values. The pooled sample findings were validated by individual genotyping the pooled samples together with additional samples also within extreme quantiles. We describe methods for efficient combined analysis of the results from these different study designs. We have identified and replicated quantitative trait loci on chromosomes 13 and 16 for association with CCT. The locus on chromosome 13 (nearest gene FOXO1) had an overall meta-analysis p-value for all the individually genotyped samples of 4.6×10?10. The locus on chromosome 16 was associated with CCT with p = 8.95×10?11. The nearest gene to the associated chromosome 16 SNPs was ZNF469, a locus recently implicated in Brittle Cornea Syndrome (BCS), a very rare disorder characterized by abnormal thin corneas. Our findings suggest that in addition to rare variants in ZNF469 underlying CCT variation in BCS patients, more common variants near this gene may contribute to CCT variation in the general population.
Flow boiling of water in a vertical tube at sub-atmospheric pressures
Barbosa Jr., Jader R.;Cheah, Leong W.;Hewitt, Geoffrey F.;
Journal of the Brazilian Society of Mechanical Sciences and Engineering , 2007, DOI: 10.1590/S1678-58782007000400009
Abstract: this paper describes some of the key experimental results and features obtained from a study on upward flow boiling of water in a vertical tube at sub-atmospheric pressures. the experiments were conducted at 250, 500 and 1000 mbar (abs) exit pressures. from the experimental results, several interesting features and effects were observed, namely, heat transfer coefficient maxima at around zero thermodynamic quality were observed for high inlet liquid subcoolings at low sub-atmospheric pressures, which were attributed to local thermal non-equilibrium instability (jeglic and grace, 1965). such effects were also observed in boiling of pure hydrocarbons in vertical tubes (kandlbinder, 1997; urso et al., 2002) and were explained and explored quantitatively with a thermal non-equilibrium slug flow model (barbosa and hewitt, 2005) that associates vigorous bubble growth at sub-atmospheric pressures to the formation of large taylor bubbles separated by subcooled liquid slugs.
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