| 1. |
- Schael, S, et al.
(författare)
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Precision electroweak measurements on the Z resonance
- 2006
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Ingår i: Physics Reports. - : Elsevier BV. - 0370-1573 .- 1873-6270. ; 427:5-6, s. 257-454
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Forskningsöversikt (refereegranskat)abstract
- We report on the final electroweak measurements performed with data taken at the Z resonance by the experiments operating at the electron-positron colliders SLC and LEP. The data consist of 17 million Z decays accumulated by the ALEPH, DELPHI, L3 and OPAL experiments at LEP, and 600 thousand Z decays by the SLID experiment using a polarised beam at SLC. The measurements include cross-sections, forward-backward asymmetries and polarised asymmetries. The mass and width of the Z boson, m(Z) and Gamma(Z), and its couplings to fermions, for example the p parameter and the effective electroweak mixing angle for leptons, are precisely measured: m(Z) = 91.1875 +/- 0.0021 GeV, Gamma(Z) = 2.4952 +/- 0.0023 GeV, rho(l) = 1.0050 +/- 0.0010, sin(2)theta(eff)(lept) = 0.23153 +/- 0.00016. The number of light neutrino species is determined to be 2.9840 +/- 0.0082, in agreement with the three observed generations of fundamental fermions. The results are compared to the predictions of the Standard Model (SM). At the Z-pole, electroweak radiative corrections beyond the running of the QED and QCD coupling constants are observed with a significance of five standard deviations, and in agreement with the Standard Model. Of the many Z-pole measurements, the forward-backward asymmetry in b-quark production shows the largest difference with respect to its SM expectation, at the level of 2.8 standard deviations. Through radiative corrections evaluated in the framework of the Standard Model, the Z-pole data are also used to predict the mass of the top quark, m(t) = 173(+10)(+13) GeV, and the mass of the W boson, m(W) = 80.363 +/- 0.032 GeV. These indirect constraints are compared to the direct measurements, providing a stringent test of the SM. Using in addition the direct measurements of m(t) and m(W), the mass of the as yet unobserved SM Higgs boson is predicted with a relative uncertainty of about 50% and found to be less than 285 GeV at 95% confidence level. (c) 2006 Elsevier B.V. All rights reserved.
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| 2. |
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| 3. |
- Yao, W-M, et al.
(författare)
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Review of Particle Physics
- 2006
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Ingår i: Journal of Physics G: Nuclear and Particle Physics. - : IOP Publishing. - 0954-3899 .- 1361-6471. ; 33:1, s. 1-1
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Tidskriftsartikel (refereegranskat)
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| 4. |
- Amsler, C., et al.
(författare)
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Review of particle physics
- 2008
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Ingår i: Physics Letters. Section B: Nuclear, Elementary Particle and High-Energy Physics. - : Elsevier BV. - 0370-2693 .- 1873-2445. ; 667:1-5, s. 1-1
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Forskningsöversikt (refereegranskat)abstract
- This biennial Review summarizes much of particle physics. Using data from previous editions., plus 2778 new measurements from 645 papers, we list, evaluate, and average measured properties of gauge bosons, leptons, quarks, mesons, and baryons. We also summarize searches for hypothetical particles such as Higgs bosons, heavy neutrinos, and supersymmetric particles. All the particle properties and search limits are listed in Summary Tables. We also give numerous tables, figures, formulae, and reviews of topics such as the Standard Model, particle detectors., probability, and statistics. Among the 108 reviews are many that are new or heavily revised including those on CKM quark-mixing matrix, V-ud & V-us, V-cb & V-ub, top quark, muon anomalous magnetic moment, extra dimensions, particle detectors, cosmic background radiation, dark matter, cosmological parameters, and big bang cosmology.
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| 5. |
- Clark, Andrew G., et al.
(författare)
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Evolution of genes and genomes on the Drosophila phylogeny
- 2007
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 450:7167, s. 203-218
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Tidskriftsartikel (refereegranskat)abstract
- Comparative analysis of multiple genomes in a phylogenetic framework dramatically improves the precision and sensitivity of evolutionary inference, producing more robust results than single-genome analyses can provide. The genomes of 12 Drosophila species, ten of which are presented here for the first time (sechellia, simulans, yakuba, erecta, ananassae, persimilis, willistoni, mojavensis, virilis and grimshawi), illustrate how rates and patterns of sequence divergence across taxa can illuminate evolutionary processes on a genomic scale. These genome sequences augment the formidable genetic tools that have made Drosophila melanogaster a pre-eminent model for animal genetics, and will further catalyse fundamental research on mechanisms of development, cell biology, genetics, disease, neurobiology, behaviour, physiology and evolution. Despite remarkable similarities among these Drosophila species, we identified many putatively non-neutral changes in protein-coding genes, non-coding RNA genes, and cis-regulatory regions. These may prove to underlie differences in the ecology and behaviour of these diverse species.
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| 6. |
- Birney, Ewan, et al.
(författare)
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Prepublication data sharing
- 2009
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 461:7261, s. 168-170
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Tidskriftsartikel (refereegranskat)abstract
- Rapid release of prepublication data has served the field of genomics well. Attendees at a workshop in Toronto recommend extending the practice to other biological data sets.
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| 7. |
- Moortgat-Pick, G., et al.
(författare)
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Polarized positrons and electrons at the linear collider
- 2008
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Ingår i: Physics reports. - : Elsevier BV. - 0370-1573 .- 1873-6270. ; 460:4-5, s. 131-243
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Forskningsöversikt (refereegranskat)abstract
- The proposed International Linear Collider (ILC) is well-suited for discovering physics beyond the Standard Model and for precisely unraveling the structure of the underlying physics. The physics return can be maximized by the use of polarized beams. This report shows the paramount role of polarized beams and summarizes the benefits obtained from polarizing the positron beam, as well as the electron beam. The physics case for this option is illustrated explicitly by analyzing reference reactions in different physics scenarios. The results show that positron polarization, combined with the clean experimental environment provided by the linear collider, allows to improve strongly the potential of searches for new particles and the identification of their dynamics, which opens the road to resolve shortcomings of the Standard Model. The report also presents an overview of possible designs for polarizing both beams at the ILC, as well as for measuring their polarization.
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| 8. |
- Newton-Cheh, Christopher, et al.
(författare)
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Genome-wide association study identifies eight loci associated with blood pressure
- 2009
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 41:6, s. 666-676
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Tidskriftsartikel (refereegranskat)abstract
- Elevated blood pressure is a common, heritable cause of cardiovascular disease worldwide. To date, identification of common genetic variants influencing blood pressure has proven challenging. We tested 2.5 million genotyped and imputed SNPs for association with systolic and diastolic blood pressure in 34,433 subjects of European ancestry from the Global BPgen consortium and followed up findings with direct genotyping (N <= 71,225 European ancestry, N <= 12,889 Indian Asian ancestry) and in silico comparison (CHARGE consortium, N 29,136). We identified association between systolic or diastolic blood pressure and common variants in eight regions near the CYP17A1 (P = 7 x 10(-24)), CYP1A2 (P = 1 x 10(-23)), FGF5 (P = 1 x 10(-21)), SH2B3 (P = 3 x 10(-18)), MTHFR (P = 2 x 10(-13)), c10orf107 (P = 1 x 10(-9)), ZNF652 (P = 5 x 10(-9)) and PLCD3 (P = 1 x 10(-8)) genes. All variants associated with continuous blood pressure were associated with dichotomous hypertension. These associations between common variants and blood pressure and hypertension offer mechanistic insights into the regulation of blood pressure and may point to novel targets for interventions to prevent cardiovascular disease.
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| 9. |
- Smith, A., et al.
(författare)
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LunarEX-a proposal to cosmic vision
- 2009
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Ingår i: Experimental Astronomy. - : Springer Science and Business Media LLC. - 0922-6435 .- 1572-9508. ; 23:3, s. 711-740
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Tidskriftsartikel (refereegranskat)
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| 10. |
- Willer, Cristen J., et al.
(författare)
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Six new loci associated with body mass index highlight a neuronal influence on body weight regulation
- 2009
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 41:1, s. 25-34
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Tidskriftsartikel (refereegranskat)abstract
- Common variants at only two loci, FTO and MC4R, have been reproducibly associated with body mass index (BMI) in humans. To identify additional loci, we conducted meta-analysis of 15 genome-wide association studies for BMI (n > 32,000) and followed up top signals in 14 additional cohorts (n > 59,000). We strongly confirm FTO and MC4R and identify six additional loci (P < 5 x 10(-8)): TMEM18, KCTD15, GNPDA2, SH2B1, MTCH2 and NEGR1 (where a 45-kb deletion polymorphism is a candidate causal variant). Several of the likely causal genes are highly expressed or known to act in the central nervous system (CNS), emphasizing, as in rare monogenic forms of obesity, the role of the CNS in predisposition to obesity.
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| 11. |
- Lindgren, Cecilia M, et al.
(författare)
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Genome-wide association scan meta-analysis identifies three Loci influencing adiposity and fat distribution.
- 2009
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Ingår i: PLoS genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 5:6, s. e1000508-
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Tidskriftsartikel (refereegranskat)abstract
- To identify genetic loci influencing central obesity and fat distribution, we performed a meta-analysis of 16 genome-wide association studies (GWAS, N = 38,580) informative for adult waist circumference (WC) and waist-hip ratio (WHR). We selected 26 SNPs for follow-up, for which the evidence of association with measures of central adiposity (WC and/or WHR) was strong and disproportionate to that for overall adiposity or height. Follow-up studies in a maximum of 70,689 individuals identified two loci strongly associated with measures of central adiposity; these map near TFAP2B (WC, P = 1.9x10(-11)) and MSRA (WC, P = 8.9x10(-9)). A third locus, near LYPLAL1, was associated with WHR in women only (P = 2.6x10(-8)). The variants near TFAP2B appear to influence central adiposity through an effect on overall obesity/fat-mass, whereas LYPLAL1 displays a strong female-only association with fat distribution. By focusing on anthropometric measures of central obesity and fat distribution, we have identified three loci implicated in the regulation of human adiposity.
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| 12. |
- Morrison, Hilary G., et al.
(författare)
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Genomic minimalism in the early diverging intestinal parasite Giardia lamblia
- 2007
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 317:5846, s. 1921-1926
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Tidskriftsartikel (refereegranskat)abstract
- The genome of the eukaryotic protist Giardia lamblia, an important human intestinal parasite, is compact in structure and content, contains few introns or mitochondrial relics, and has simplified machinery for DNA replication, transcription, RNA processing, and most metabolic pathways. Protein kinases comprise the single largest protein class and reflect Giardia's requirement for a complex signal transduction network for coordinating differentiation. Lateral gene transfer from bacterial and archaeal donors has shaped Giardia's genome, and previously unknown gene families, for example, cysteine-rich structural proteins, have been discovered. Unexpectedly, the genome shows little evidence of heterozygosity, supporting recent speculations that this organism is sexual. This genome sequence will not only be valuable for investigating the evolution of eukaryotes, but will also be applied to the search for new therapeutics for this parasite.
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| 13. |
- Mukhtyar, C., et al.
(författare)
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EULAR recommendations for the management of large vessel vasculitis
- 2009
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 68:3, s. 318-323
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: To develop European League Against Rheumatism (EULAR) recommendations for the management of large vessel vasculitis. Methods: An expert group (10 rheumatologists, 3 nephrologists, 2 immunolgists, 2 internists representing 8 European countries and the USA, a clinical epidemiologist and a representative from a drug regulatory agency) identified 10 topics for a systematic literature search through a modified Delphi technique. In accordance with standardised EULAR operating procedures, recommendations were derived for the management of large vessel vasculitis. In the absence of evidence, recommendations were formulated on the basis of a consensus opinion. Results: Seven recommendations were made relating to the assessment, investigation and treatment of patients with large vessel vasculitis. The strength of recommendations was restricted by the low level of evidence and EULAR standardised operating procedures. Conclusions: On the basis of evidence and expert consensus, management recommendations for large vessel vasculitis have been formulated and are commended for use in everyday clinical practice.
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| 14. |
- Mukhtyar, C., et al.
(författare)
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EULAR recommendations for the management of primary small and medium vessel vasculitis
- 2009
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 68:3, s. 310-317
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: To develop European League Against Rheumatism (EULAR) recommendations for the management of small and medium vessel vasculitis. Methods: An expert group ( consisting of 10 rheumatologists, 3 nephrologists, 2 immunologists, 2 internists representing 8 European countries and the USA, a clinical epidemiologist and a representative from a drug regulatory agency) identified 10 topics for a systematic literature search using a modified Delphi technique. In accordance with standardised EULAR operating procedures, recommendations were derived for the management of small and medium vessel vasculitis. In the absence of evidence, recommendations were formulated on the basis of a consensus opinion. Results: In all, 15 recommendations were made for the management of small and medium vessel vasculitis. The strength of recommendations was restricted by low quality of evidence and by EULAR standardised operating procedures. Conclusions: On the basis of evidence and expert consensus, recommendations have been made for the evaluation, investigation, treatment and monitoring of patients with small and medium vessel vasculitis for use in everyday clinical practice.
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| 15. |
- Tala, T., et al.
(författare)
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Toroidal and poloidal momentum transport studies in tokamaks
- 2007
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Ingår i: Plasma Physics and Controlled Fusion. - : IOP Publishing. - 1361-6587 .- 0741-3335. ; 49:12B, s. B291-B302
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Tidskriftsartikel (refereegranskat)abstract
- The present status of understanding of toroidal and poloidal momentum transport in tokamaks is presented in this paper. Similar energy confinement and momentum confinement times, i.e. tau(E)/tau(phi)approximate to 1 have been reported on several tokamaks. It is more important though, to study the local transport both in the core and edge plasma separately as, for example, in the core plasma, a large scatter in the ratio of the local effective momentum diffusivity to the ion heat diffusivity chi(phi eff)/chi(i.eff) among different tokamaks can be found. For example, the value of effective Prandtl number is typically around chi(phi eff)/chi(i.eff)approximate to 0.2 on JET while still tau(E)/tau(phi)approximate to 1 holds. Perturbative NBI modulation experiments on JET have shown, however, that a Prandtl number chi(phi)/chi(i) of around 1 is valid if there is an additional, significant inward momentum pinch which is required to explain the amplitude and phase behaviour of the momentum perturbation. The experimental results, i.e. the high Prandtl number and pinch, are in good qualitative and to some extent also in quantitative agreement with linear gyro-kinetic simulations. In contrast to the toroidal momentum transport which is clearly anomalous, the poloidal velocity is usually believed to be neo-classical. However, experimental measurements on JET show that the carbon poloidal velocity can be an order of magnitude above the predicted value by the neo-classical theory within the ITB. These large measured poloidal velocities, employed for example in transport simulations, significantly affect the calculated radial electric field and therefore the E x B flow shear and hence modify and can significantly improve the simulation predictions. Several fluid turbulence codes have been used to identify the mechanism driving the poloidal velocity to such high values. CUTIE and TRB turbulence codes and also the Weiland model predict the existence of an anomalous poloidal velocity, peaking in the vicinity of the ITB and driven dominantly by the flow due to the Reynold's stress. It is worth noting that these codes and models treat the equilibrium in a simplified way and this affects the geodesic curvature effects and geodesic acoustic modes. The neo-classical equilibrium is calculated more accurately in the GEM code and the simulations suggest that the spin-up of poloidal velocity is a consequence of the plasma profiles steepening when the ITB grows, following in particular the growth of the toroidal velocity within the ITB.
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| 16. |
- Champion, Mia D, et al.
(författare)
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Comparative genomic characterization of Francisella tularensis strains belonging to low and high virulence subspecies
- 2009
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Ingår i: PLoS pathogens. - : Public Library of Science (PLoS). - 1553-7374. ; 5:5, s. e1000459-
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Tidskriftsartikel (refereegranskat)abstract
- Tularemia is a geographically widespread, severely debilitating, and occasionally lethal disease in humans. It is caused by infection by a gram-negative bacterium, Francisella tularensis. In order to better understand its potency as an etiological agent as well as its potential as a biological weapon, we have completed draft assemblies and report the first complete genomic characterization of five strains belonging to the following different Francisella subspecies (subsp.): the F. tularensis subsp. tularensis FSC033, F. tularensis subsp. holarctica FSC257 and FSC022, and F. tularensis subsp. novicida GA99-3548 and GA99-3549 strains. Here, we report the sequencing of these strains and comparative genomic analysis with recently available public Francisella sequences, including the rare F. tularensis subsp. mediasiatica FSC147 strain isolate from the Central Asian Region. We report evidence for the occurrence of large-scale rearrangement events in strains of the holarctica subspecies, supporting previous proposals that further phylogenetic subdivisions of the Type B clade are likely. We also find a significant enrichment of disrupted or absent ORFs proximal to predicted breakpoints in the FSC022 strain, including a genetic component of the Type I restriction-modification defense system. Many of the pseudogenes identified are also disrupted in the closely related rarely human pathogenic F. tularensis subsp. mediasiatica FSC147 strain, including modulator of drug activity B (mdaB) (FTT0961), which encodes a known NADPH quinone reductase involved in oxidative stress resistance. We have also identified genes exhibiting sequence similarity to effectors of the Type III (T3SS) and components of the Type IV secretion systems (T4SS). One of the genes, msrA2 (FTT1797c), is disrupted in F. tularensis subsp. mediasiatica and has recently been shown to mediate bacterial pathogen survival in host organisms. Our findings suggest that in addition to the duplication of the Francisella Pathogenicity Island, and acquisition of individual loci, adaptation by gene loss in the more recently emerged tularensis, holarctica, and mediasiatica subspecies occurred and was distinct from evolutionary events that differentiated these subspecies, and the novicida subspecies, from a common ancestor. Our findings are applicable to future studies focused on variations in Francisella subspecies pathogenesis, and of broader interest to studies of genomic pathoadaptation in bacteria.
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| 17. |
- Liu, Wennuan, et al.
(författare)
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Association of a germ-line copy number variation at 2p24.3 and risk for aggressive prostate cancer.
- 2009
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Ingår i: Cancer research. - 1538-7445. ; 69:6, s. 2176-9
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Tidskriftsartikel (refereegranskat)abstract
- We searched for deletions in the germ-line genome among 498 aggressive prostate cancer cases and 494 controls from a population-based study in Sweden [CAncer of the Prostate in Sweden (CAPS)] using Affymetrix SNP arrays. By comparing allele intensities of approximately 500,000 SNP probes across the genome, a germ-line deletion at 2p24.3 was observed to be significantly more common in cases (12.63%) than in controls (8.28%); P = 0.028. To confirm the association, we genotyped this germ-line copy number variation (CNV) in additional subjects from CAPS and from Johns Hopkins Hospital (JHH). Overall, among 4,314 cases and 2,176 controls examined, the CNV was significantly associated with prostate cancer risk [odds ratio (OR), 1.25; 95% confidence interval (95% CI), 1.06-1.48; P = 0.009]. More importantly, the association was stronger for aggressive prostate cancer (OR, 1.31; 95% CI, 1.08-1.58; P = 0.006) than for nonaggressive prostate cancer (OR, 1.19; 95% CI, 0.98-1.45; P = 0.08). The biological effect of this germ-line CNV is unknown because no known gene resides in the deletion. Results from this study represent the first novel germ-line CNV that was identified from a genome-wide search and was significantly, but moderately, associated with prostate cancer risk. Additional confirmation of this association and functional studies are warranted.
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| 18. |
- Prokopenko, Inga, et al.
(författare)
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Variants in MTNR1B influence fasting glucose levels
- 2009
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 41:1, s. 77-81
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Tidskriftsartikel (refereegranskat)abstract
- To identify previously unknown genetic loci associated with fasting glucose concentrations, we examined the leading association signals in ten genome-wide association scans involving a total of 36,610 individuals of European descent. Variants in the gene encoding melatonin receptor 1B (MTNR1B) were consistently associated with fasting glucose across all ten studies. The strongest signal was observed at rs10830963, where each G allele (frequency 0.30 in HapMap CEU) was associated with an increase of 0.07 (95% CI = 0.06-0.08) mmol/l in fasting glucose levels (P = 3.2 x 10(-50)) and reduced beta-cell function as measured by homeostasis model assessment (HOMA-B, P = 1.1 x 10(-15)). The same allele was associated with an increased risk of type 2 diabetes (odds ratio = 1.09 (1.05-1.12), per G allele P = 3.3 x 10(-7)) in a meta-analysis of 13 case-control studies totaling 18,236 cases and 64,453 controls. Our analyses also confirm previous associations of fasting glucose with variants at the G6PC2 (rs560887, P = 1.1 x 10(-57)) and GCK (rs4607517, P = 1.0 x 10(-25)) loci.
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| 19. |
- Richards, Stephen, et al.
(författare)
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The genome of the model beetle and pest Tribolium castaneum.
- 2008
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Ingår i: Nature. - 1476-4687. ; 452:7190, s. 949-55
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Tidskriftsartikel (refereegranskat)abstract
- Tribolium castaneum is a representative of earth’s most numerous eukaryotic order, a powerful model organism for the study of generalized insect development, and also an important pest of stored agricultural products. We describe its genome sequence here. This omnivorous beetle has evolved an ability to interact with a diverse chemical environment as evidenced by large expansions in odorant and gustatory receptors, as well as p450 and other detoxification enzymes. Developmental patterns in Tribolium are more representative of other arthropods than those found in Drosophila, a fact represented in gene content and function. For one, Tribolium has retained more ancestral genes involved in cell-cell communication than Drosophila, and some are expressed in the growth zone crucial for axial elongation in short germ development. Systemic RNAi in T. castaneum appears to use mechanisms distinct from those found in C. elegans, but nevertheless offers similar power for the elucidation of gene function and identification of targets for selective insect control.
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| 20. |
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| 21. |
- Wiklund, Fredrik, et al.
(författare)
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Association of Reported Prostate Cancer Risk Alleles With PSA Levels Among Men Without a Diagnosis of Prostate Cancer
- 2009
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Ingår i: The Prostate. - : Wiley. - 0270-4137 .- 1097-0045. ; 69:4, s. 419-427
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND. Prostate specific antigen (PSA) is widely used for prostate cancer screening but its levels are influenced by many non cancer-related factors. The goal of the study is to estimate the effect of genetic variants on PSA levels. METHODS. We evaluated the association of SNPs that were reported to be associated with prostate cancer risk in recent genome-wide association studies with plasma PSA levels in a Swedish study population, including 1,722 control subjects without a diagnosis of prostate cancer. RESULTS. Of the 16 SNPs analyzed in control subjects, significant associations with PSA levels (P <= 0.05) were found for six SNPs. These six SNP's had a cumulative effect on PSA levels; the mean PSA levels in men were almost twofold increased across increasing quintile of number of PSA associated alleles, P-trend = 3.4 x 10(-14). In this Swedish study population risk allele frequencies were similar among T1c case patients (cancer detected by elevated PSA levels alone) as compared to T2 and above prostate cancer case patients. CONCLUSIONS. Results from this study may have two important clinical implications. The cumulative effect of six SNPs on PSA levels suggests genetic-specific PSA cutoff values may be used to improve the discriminatory performance of this test for prostate cancer; and the dual associations of these SNPs with PSA levels and prostate cancer risk raise a concern that some of reported prostate cancer risk-associated SNPs may be confounded by the prevalent use of PSA screening. Prostate 69: 419-427, 2009. (C) 2008 Wiley-Liss, Inc.
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| 22. |
- Zeggini, Eleftheria, et al.
(författare)
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Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes
- 2008
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 40:5, s. 638-645
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association (GWA) studies have identified multiple loci at which common variants modestly but reproducibly influence risk of type 2 diabetes (T2D)(1-11). Established associations to common and rare variants explain only a small proportion of the heritability of T2D. As previously published analyses had limited power to identify variants with modest effects, we carried out meta-analysis of three T2D GWA scans comprising 10,128 individuals of European descent and similar to 2.2 million SNPs (directly genotyped and imputed), followed by replication testing in an independent sample with an effective sample size of up to 53,975. We detected at least six previously unknown loci with robust evidence for association, including the JAZF1 (P=5.0 x 10(-14)), CDC123-CAMK1D (P=1.2 x 10(-10)), TSPAN8-LGR5 (P=1.1 x 10(-9)), THADA (P=1.1 x 10(-9)), ADAMTS9 (P=1.2 x 10(-8)) and NOTCH2 (P=4.1 x 10(-8)) gene regions. Our results illustrate the value of large discovery and follow-up samples for gaining further insights into the inherited basis of T2D.
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| 23. |
- Carducci, Michael A., et al.
(författare)
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A phase 3 randomized controlled trial of the efficacy and safety of atrasentan in men with metastatic hormone-refractory prostate cancer
- 2007
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Ingår i: Cancer. - : Wiley. - 1097-0142 .- 0008-543X. ; 110:9, s. 1959-1966
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND. The objective of this study was to evaluate the efficacy and safety of atrasentan (Xinlay), a selective endothelin-A receptor antagonist, in patients with metastatic hormone- refractory prostate cancer (HRPC). METHODS. This multinational, double-blind, placebo-controlled trial enrolled 809 men with metastatic HRPC. Patients were randomized 1:1 to receive either atrasentan 10 mg per day or placebo. The primary endpoint was time to disease progression (TTP), which was determined according to radiographic and clinical measures. Analyses of overall survival and changes in biomarkers also were performed. RESULTS. Atrasentan did not reduce the risk of disease progression relative to placebo (hazards ratio, 0.89; 95% confidence interval, 0.76-1.04; P =.136). Most patients progressed radiographically at the first 12-week bone scan without concomitant clinical progression. In exploratory analyses, increases from baseline to final bone alkaline phosphatase (BAP) and prostate-specific antigen (PSA) levels were significantly lower with atrasentan treatment (P <.05 for each). The median time to BAP progression (> 50% increase from nadir) was twice as long with atrasentan treatment (505 days vs 254 days; P <.01). The delay in time to PSA progression did not reach statistical significance. Atrasentan generally was tolerated well, and the most common adverse events associated with treatment were headache, rhinitis, and peripheral edema, reflecting the vasodilatory and fluid-retention properties of endothelin-A receptor antagonism. CONCLUSIONS. Atrasentan did not delay disease progression in men with metastatic HRPC despite evidence of biologic effects on PSA and BAP as markers of disease burden.
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| 24. |
- Carvalho, Marcelo, et al.
(författare)
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Analysis of a set of missense, frameshift, and in-frame deletion variants of BRCA1
- 2009
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Ingår i: Mutation research. - : Elsevier BV. - 0027-5107 .- 1873-135X .- 1879-2871. ; 660:1-2, s. 1-11
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Tidskriftsartikel (refereegranskat)abstract
- Germline mutations that inactivate BRCA1 are responsible for breast and ovarian cancer susceptibility. One possible outcome of genetic testing for BRCA1 is the finding of a genetic variant of uncertain significance for which there is no information regarding its cancer association. This outcome leads to problems in risk assessment, counseling and preventive care. The purpose of the present study was to functionally evaluate seven unclassified variants of BRCA1 including a genomic deletion that leads to the in-frame loss of exons 16/17 (Delta exons 16/17) in the mRNA, an insertion that leads to a frameshift and an extended carboxy-terminus (5673insC), and five missense variants (K1487R, S1613C, M1652I, Q1826H and V1833M). We analyzed the variants using a functional assay based on the transcription activation property of BRCA1 combined with supervised learning computational models. Functional analysis indicated that variants S1613C, Q1826H, and M1652I are likely to be neutral, whereas variants V1833M, Delta exons 16/17, and 5673insC are likely to represent deleterious variants. In agreement with the functional analysis, the results of the computational analysis also indicated that the latter three variants are likely to be deleterious. Taken together, a combined approach of functional and bioinformatics analysis, plus structural modeling, can be utilized to obtain valuable information pertaining to the effect of a rare variant on the structure and function of BRCA1. Such information can, in turn, aid in the classification of BRCA1 variants for which there is a lack of genetic information needed to provide reliable risk assessment.
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| 25. |
- Hajjar, Adeline M, et al.
(författare)
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Lack of in vitro and in vivo recognition of Francisella tularensis subspecies lipopolysaccharide by Toll-like receptors.
- 2006
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Ingår i: Infection and Immunity. - 0019-9567 .- 1098-5522. ; 74:12, s. 6730-8
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Tidskriftsartikel (refereegranskat)abstract
- Francisella tularensis is an intracellular gram-negative bacterium that is highly infectious and potentially lethal. Several subspecies exist of varying pathogenicity. Infection by only a few organisms is sufficient to cause disease depending on the model system. Lipopolysaccharide (LPS) of gram-negative bacteria is generally recognized by Toll-like receptor 4 (TLR4)/MD-2 and induces a strong proinflammatory response. Examination of human clinical F. tularensis isolates revealed that human virulent type A and type B strains produced lipid A of similar structure to the nonhuman model pathogen of mice, Francisella novicida. F. novicida LPS or lipid A is neither stimulatory nor an antagonist for human and murine cells through TLR4 or TLR2. It does not appear to interact with TLR4 or MD-2, as it is not an antagonist to other stimulatory LPS. Consistent with these observations, aerosolization of F. novicida LPS or whole bacteria induced no inflammatory response in mice. These results suggest that poor innate recognition of F. tularensis allows the bacterium to evade early recognition by the host innate immune system to promote its pathogenesis for mammals.
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| 26. |
- Jones, B, et al.
(författare)
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Lakes & streams
- 2005
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Ingår i: Tourism and Global Environmental Change. Ecological, social, economic and political interrelationships. ; , s. 76-94
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Bokkapitel (övrigt vetenskapligt/konstnärligt)
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| 27. |
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| 28. |
- Salanti, Georgia, et al.
(författare)
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Underlying Genetic Models of Inheritance in Established Type 2 Diabetes Associations
- 2009
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Ingår i: American Journal of Epidemiology. - : Oxford University Press (OUP). - 0002-9262 .- 1476-6256. ; 170:5, s. 537-545
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Forskningsöversikt (refereegranskat)abstract
- For most associations of common single nucleotide polymorphisms (SNPs) with common diseases, the genetic model of inheritance is unknown. The authors extended and applied a Bayesian meta-analysis approach to data from 19 studies on 17 replicated associations with type 2 diabetes. For 13 SNPs, the data fitted very well to an additive model of inheritance for the diabetes risk allele; for 4 SNPs, the data were consistent with either an additive model or a dominant model; and for 2 SNPs, the data were consistent with an additive or recessive model. Results were robust to the use of different priors and after exclusion of data for which index SNPs had been examined indirectly through proxy markers. The Bayesian meta-analysis model yielded point estimates for the genetic effects that were very similar to those previously reported based on fixed- or random-effects models, but uncertainty about several of the effects was substantially larger. The authors also examined the extent of between-study heterogeneity in the genetic model and found generally small between-study deviation values for the genetic model parameter. Heterosis could not be excluded for 4 SNPs. Information on the genetic model of robustly replicated association signals derived from genome-wide association studies may be useful for predictive modeling and for designing biologic and functional experiments.
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| 29. |
- Schwitter, Juerg, et al.
(författare)
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MR-IMPACT : comparison of perfusion-cardiac magnetic resonance with single-photon emission computed tomography for the detection of coronary artery disease in a multicentre, multivendor, randomized trial
- 2008
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Ingår i: European Heart Journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 29:4, s. 480-9
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: To determine in a multicentre, multivendor trial the diagnostic performance for perfusion-cardiac magnetic resonance (perfusion-CMR) in comparison with coronary X-ray angiography (CXA) and single-photon emission computed tomography (SPECT). METHODS AND RESULTS: Of 241 eligible patients from 18 centres, 234 were randomly dosed with 0.01, 0.025, 0.05, 0.075, or 0.1 mmol/kg Gd-DTPA-BMA (Omniscantrade mark, GE-Healthcare) per stress (0.42 mg/kg adenosine) and rest perfusion study. Coronary artery disease (CAD) was defined as diameter stenosis > or =50% on quantitative CXA. Five CMR and eight SPECT studies (of 225 complete studies) were excluded from analyses due to inadequate quality (three blinded readers scored per modality). The comparison of CMR vs. SPECT was based on receiver operating characteristic (ROC) analysis. Perfusion-CMR at the optimal CM dose (0.1 mmol/kg) had similar performance as SPECT, if only the SPECT studies of the 42 patients with this dose were considered [area under ROC curve (AUC): 0.86 +/- 0.06 vs. 0.75 +/- 0.09 for SPECT, P = 0.12]; however, diagnostic performance of perfusion-CMR was better vs. the entire SPECT population (AUC: 0.67 +/- 0.05, n = 212, P = 0.013). CONCLUSIONS: In this multicentre, multivendor trial, ROC analyses suggest perfusion-CMR as a valuable alternative to SPECT for CAD detection showing equal performance in the head-to-head comparison. Comparing perfusion-CMR with the entire SPECT population suggests CMR superiority over SPECT, which warrants further evaluation in larger trials.
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| 30. |
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| 31. |
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| 32. |
- Wenink, Mark H., et al.
(författare)
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The inhibitory Fc gamma IIb receptor dampens TLR4-mediated immune responses and is selectively up-regulated on dendritic cells from rheumatoid arthritis patients with quiescent disease
- 2009
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Ingår i: Journal of Immunology. - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 183:7, s. 4509-4520
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Tidskriftsartikel (refereegranskat)abstract
- Rheumatoid arthritis (RA) is a common autoimmune disease leading to profound disability and premature death. Although a role for FcgammaRs and TLRs is accepted, their precise involvement remains to be elucidated. FcgammaRIIb is an inhibitory FcR important in the maintenance of tolerance. We hypothesized that the inhibitory FcgammaRIIb inhibits TLR responses on monocyte-derived dendritic cells (DC) and serves as a counterregulatory mechanism to dampen inflammation, and we surmised that this mechanism might be defective in RA. The expression of the inhibitory FcgammaRIIb was found to be significantly higher on DCs from RA patients having low RA disease activity in the absence of treatment with antirheumatic drugs. The expression of activating FcgammaRs was similarly distributed among all RA patients and healthy controls. Intriguingly, only DCs with a high expression of FcgammaRIIb were able to inhibit TLR4-mediated secretion of proinflammatory cytokines when stimulated with immune complexes. In addition, when these DCs were coincubated with the combination of a TLR4 agonist and immune complexes, a markedly inhibited T cell proliferation was apparent, regulatory T cell development was promoted, and T cells were primed to produce high levels of IL-13 compared with stimulation of the DCs with the TLR4 agonist alone. Blocking FcgammaRIIb with specific Abs fully abrogated these effects demonstrating the full dependence on the inhibitory FcgammaRIIb in the induction of these phenomena. This TLR4-FcgammaRIIb interaction was shown to dependent on the PI3K and Akt pathway.
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| 33. |
- Wiholm, Clairy, et al.
(författare)
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Mobile phone exposure and spatial memory.
- 2009
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Ingår i: Bioelectromagnetics. - : Wiley. - 1521-186X .- 0197-8462. ; 30:1, s. 59-65
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Tidskriftsartikel (refereegranskat)abstract
- Radiofrequency (RF) emission during mobile phone use has been suggested to impair cognitive functions, that is, working memory. This study investigated the effects of a 2 1/2 h RF exposure (884 MHz) on spatial memory and learning, using a double-blind repeated measures design. The exposure was designed to mimic that experienced during a real-life mobile phone conversation. The design maximized the exposure to the left hemisphere. The average exposure was peak spatial specific absorption rate (psSAR10g) of 1.4 W/kg. The primary outcome measure was a "virtual" spatial navigation task modeled after the commonly used and validated Morris Water Maze. The distance traveled on each trial and the amount of improvement across trials (i.e., learning) were used as dependent variables. The participants were daily mobile phone users, with and without symptoms attributed to regular mobile phone use. Results revealed a main effect of RF exposure and a significant RF exposure by group effect on distance traveled during the trials. The symptomatic group improved their performance during RF exposure while there was no such effect in the non-symptomatic group. Until this new finding is further investigated, we can only speculate about the cause.
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