| 1. |
- Acciari, V. A., et al.
(author)
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Radio Imaging of the Very-High-Energy gamma-Ray Emission Region in the Central Engine of a Radio Galaxy
- 2009
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In: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 325:5939, s. 444-448
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Journal article (peer-reviewed)abstract
- The accretion of matter onto a massive black hole is believed to feed the relativistic plasma jets found in many active galactic nuclei (AGN). Although some AGN accelerate particles to energies exceeding 10(12) electron volts and are bright sources of very-high-energy (VHE) gamma-ray emission, it is not yet known where the VHE emission originates. Here we report on radio and VHE observations of the radio galaxy Messier 87, revealing a period of extremely strong VHE gamma-ray flares accompanied by a strong increase of the radio flux from its nucleus. These results imply that charged particles are accelerated to very high energies in the immediate vicinity of the black hole.
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| 2. |
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| 3. |
- Abe, O, et al.
(author)
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Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials
- 2005
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In: The Lancet. - 1474-547X. ; 365:9472, s. 1687-1717
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Journal article (peer-reviewed)abstract
- Background Quinquennial overviews (1985-2000) of the randomised trials in early breast cancer have assessed the 5-year and 10-year effects of various systemic adjuvant therapies on breast cancer recurrence and survival. Here, we report the 10-year and 15-year effects. Methods Collaborative meta-analyses were undertaken of 194 unconfounded randomised trials of adjuvant chemotherapy or hormonal therapy that began by 1995. Many trials involved CMF (cyclophosphamide, methotrexate, fluorouracil), anthracycline-based combinations such as FAC (fluorouracil, doxombicin, cyclophosphamide) or FEC (fluorouracil, epirubicin, cyclophosphamide), tamoxifen, or ovarian suppression: none involved taxanes, trastuzumab, raloxifene, or modem aromatase inhibitors. Findings Allocation to about 6 months of anthracycline-based polychemotherapy (eg, with FAC or FEC) reduces the annual breast cancer death rate by about 38% (SE 5) for women younger than 50 years of age when diagnosed and by about 20% (SE 4) for those of age 50-69 years when diagnosed, largely irrespective of the use of tamoxifen and of oestrogen receptor (ER) status, nodal status, or other tumour characteristics. Such regimens are significantly (2p=0 . 0001 for recurrence, 2p<0 . 00001 for breast cancer mortality) more effective than CMF chemotherapy. Few women of age 70 years or older entered these chemotherapy trials. For ER-positive disease only, allocation to about 5 years of adjuvant tamoxifen reduces the annual breast cancer death rate by 31% (SE 3), largely irrespective of the use of chemotherapy and of age (<50, 50-69, &GE; 70 years), progesterone receptor status, or other tumour characteristics. 5 years is significantly (2p<0 . 00001 for recurrence, 2p=0 . 01 for breast cancer mortality) more effective than just 1-2 years of tamoxifen. For ER-positive tumours, the annual breast cancer mortality rates are similar during years 0-4 and 5-14, as are the proportional reductions in them by 5 years of tamoxifen, so the cumulative reduction in mortality is more than twice as big at 15 years as at 5 years after diagnosis. These results combine six meta-analyses: anthracycline-based versus no chemotherapy (8000 women); CMF-based versus no chemotherapy (14 000); anthracycline-based versus CMF-based chemotherapy (14 000); about 5 years of tamoxifen versus none (15 000); about 1-2 years of tamoxifen versus none (33 000); and about 5 years versus 1-2 years of tamoxifen (18 000). Finally, allocation to ovarian ablation or suppression (8000 women) also significantly reduces breast cancer mortality, but appears to do so only in the absence of other systemic treatments. For middle-aged women with ER-positive disease (the commonest type of breast cancer), the breast cancer mortality rate throughout the next 15 years would be approximately halved by 6 months of anthracycline-based chemotherapy (with a combination such as FAC or FEC) followed by 5 years of adjuvant tamoxifen. For, if mortality reductions of 38% (age <50 years) and 20% (age 50-69 years) from such chemotherapy were followed by a further reduction of 31% from tamoxifen in the risks that remain, the final mortality reductions would be 57% and 45%, respectively (and, the trial results could well have been somewhat stronger if there had been full compliance with the allocated treatments). Overall survival would be comparably improved, since these treatments have relatively small effects on mortality from the aggregate of all other causes. Interpretation Some of the widely practicable adjuvant drug treatments that were being tested in the 1980s, which substantially reduced 5-year recurrence rates (but had somewhat less effect on 5-year mortality rates), also substantially reduce 15-year mortality rates. Further improvements in long-term survival could well be available from newer drugs, or better use of older drugs.
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| 4. |
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| 5. |
- Birney, Ewan, et al.
(author)
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Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project
- 2007
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 447:7146, s. 799-816
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Journal article (peer-reviewed)abstract
- We report the generation and analysis of functional data from multiple, diverse experiments performed on a targeted 1% of the human genome as part of the pilot phase of the ENCODE Project. These data have been further integrated and augmented by a number of evolutionary and computational analyses. Together, our results advance the collective knowledge about human genome function in several major areas. First, our studies provide convincing evidence that the genome is pervasively transcribed, such that the majority of its bases can be found in primary transcripts, including non-protein-coding transcripts, and those that extensively overlap one another. Second, systematic examination of transcriptional regulation has yielded new understanding about transcription start sites, including their relationship to specific regulatory sequences and features of chromatin accessibility and histone modification. Third, a more sophisticated view of chromatin structure has emerged, including its inter-relationship with DNA replication and transcriptional regulation. Finally, integration of these new sources of information, in particular with respect to mammalian evolution based on inter- and intra-species sequence comparisons, has yielded new mechanistic and evolutionary insights concerning the functional landscape of the human genome. Together, these studies are defining a path for pursuit of a more comprehensive characterization of human genome function.
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| 6. |
- Clark, Andrew G., et al.
(author)
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Evolution of genes and genomes on the Drosophila phylogeny
- 2007
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 450:7167, s. 203-218
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Journal article (peer-reviewed)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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| 7. |
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| 8. |
- Newton-Cheh, Christopher, et al.
(author)
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Genome-wide association study identifies eight loci associated with blood pressure
- 2009
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 41:6, s. 666-676
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Journal article (peer-reviewed)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. |
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| 10. |
- Liu, Kui, et al.
(author)
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Kallikrein genes are associated with lupus and glomerular basement membrane-specific antibody-induced nephritis in mice and humans
- 2009
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In: Journal of Clinical Investigation. - 0021-9738 .- 1558-8238. ; 119:4, s. 911-923
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Journal article (peer-reviewed)abstract
- Immune-mediated nephritis contributes to disease in systemic lupus erythematosus, Goodpasture syndrome (caused by antibodies specific for glomerular basement membrane [anti-GBM antibodies]), and spontaneous lupus nephritis. Inbred mouse strains differ in susceptibility to anti-GBM antibody-induced and spontaneous lupus nephritis. This study sought to clarify the genetic and molecular factors that maybe responsible for enhanced immune-mediated renal disease in these models. When the kidneys of 3 mouse strains sensitive to anti-GBM antibody-induced nephritis were compared with those of 2 control strains using microarray analysis, one-fifth of the underexpressed genes belonged to the kallikrein gene family,which encodes serine esterases. Mouse strains that upregulated renal and urinary kallikreins exhibited less evidence of disease. Antagonizing the kallikrein pathway augmented disease, while agonists dampened the severity of anti-GBM antibody-induced nephritis. In addition, nephritis-sensitive mouse strains had kallikrein haplotypes that were distinct from those of control strains, including several regulatory polymorphisms,some of which were associated with functional consequences. Indeed, increased susceptibility to anti-GBM antibody-induced nephritis and spontaneous lupus nephritis was achieved by breeding mice with a genetic interval harboring the kallikrein genes onto a disease-resistant background. Finally, both human SLE and spontaneous lupus nephritis were found to be associated with kallikrein genes, particularly KLK1 and the KLK3 promoter, when DNA SNPs from independent cohorts of SLE patients and controls were compared. Collectively, these studies suggest that kallikreins are protective disease-associated genes in anti-GBM antibody-induced nephritis and lupus.
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| 11. |
- Steer, S. J., et al.
(author)
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Isomeric Decay Studies In Neutron-Rich N Approximate To 126 Nuclei
- 2009
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In: International Journal Of Modern Physics E-Nuclear Physics. - 0218-3013. ; 18:4, s. 1002-1007
-
Conference paper (peer-reviewed)abstract
- Heavy neutron-rich nuclei were populated via relativistic energy fragmentation of a E/A= 1 GeV Pb-208 beam. The nuclei of interest were selected and identified by a fragment separator and then implanted in a passive plastic stopper. Delayed. rays following internal isomeric decays were detected by the RISING array. Experimental information was obtained on a number of nuclei with Z=73-80 (Ta-Hg), providing new information both on the prolate-oblate transitional region as well as on the N=126 closed shell nuclei.
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| 12. |
- Caceres, L. S., et al.
(author)
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Identification of Excited States in the N = Z Nucleus 82Nb
- 2007
-
In: Acta Physica Polonica. Series B: Elementary Particle Physics, Nuclear Physics, Statistical Physics, Theory of Relativity, Field Theory. - 0587-4254. ; 38:4, s. 1271-1275
-
Journal article (peer-reviewed)abstract
- Information on the first excited states in the N = Z = 41 nucleus Nb-82 sheds light on the competition of isospin T = 0 and T = 1 states in the A similar to 80 region. The measurement was performed at the GSI laboratory using fragmentation of a Ag-107 primary beam at 750 MeV/u on a 4 g/cm(2) Be-9 target. The fragments were separated and identified unambiguously in the FRagment Separator. Three excited states were observed and the half-life estimate for the isomeric state was extracted. A tentative spin assignment based on the isobaric analogue states systematics in the T-z = 1 nucleus Zr-82, and transition probabilities indicate T = 1 character of the first two excited states, and T = 0 for the isomeric state.
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| 13. |
- Caceres, L., et al.
(author)
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Spherical proton-neutron structure of isomeric states in Cd-128
- 2009
-
In: Physical Review C. Nuclear Physics. - 0556-2813 .- 1089-490X. ; 79:1, s. 011301-
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Journal article (peer-reviewed)abstract
- The gamma-ray decay of isomeric states in the even-even nucleus Cd-128 has been observed. The nucleus of interest was produced both by the fragmentation of Xe-136 and the fission of U-238 primary beams. The level scheme was unambiguously constructed based on.. coincidence relations in conjunction with detailed lifetime analysis employed for the first time on this nucleus. Large-scale shell-model calculations, without consideration of excitations across the N = 82 shell closure, were performed and provide a consistent description of the experimental level scheme. The structure of the isomeric states and their decays exhibit coexistence of proton, neutron, and strongly mixed configurations due to p. interaction in overlapping orbitals for both proton and neutron holes.
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| 14. |
- Elsik, Christine G., et al.
(author)
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The Genome Sequence of Taurine Cattle : A Window to Ruminant Biology and Evolution
- 2009
-
In: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 324:5926, s. 522-528
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Journal article (peer-reviewed)abstract
- To understand the biology and evolution of ruminants, the cattle genome was sequenced to about sevenfold coverage. The cattle genome contains a minimum of 22,000 genes, with a core set of 14,345 orthologs shared among seven mammalian species of which 1217 are absent or undetected in noneutherian (marsupial or monotreme) genomes. Cattle-specific evolutionary breakpoint regions in chromosomes have a higher density of segmental duplications, enrichment of repetitive elements, and species-specific variations in genes associated with lactation and immune responsiveness. Genes involved in metabolism are generally highly conserved, although five metabolic genes are deleted or extensively diverged from their human orthologs. The cattle genome sequence thus provides a resource for understanding mammalian evolution and accelerating livestock genetic improvement for milk and meat production.
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| 15. |
- Gorska, M., et al.
(author)
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Evolution of the N=82 Shell Gap below 132Sn Inferred from Core Excited States in 131In
- 2009
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In: Physics Letters. Section B: Nuclear, Elementary Particle and High-Energy Physics. - : Elsevier BV. - 0370-2693 .- 1873-2445. ; 672:4-5, s. 313-316
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Journal article (peer-reviewed)abstract
- The gamma-ray decay of ail excited state in In-131, the one proton hole neighbor of the doubly magic (132)sn has been measured. A high-spin, core-excited isomer with T-1/2 = 630(60) us was identified following production by both relativistic fragmentation of a Xe-136 beam and fission Of a U-238 beam. This state deexcites by a single gamma-ray branch of 3782(2) keV from which direct evidence for the size of the N = 82 shell gal) is inferred. The results are discussed in comparison to a shell-model Calculation including configurations across the closed shells at N = 82 and Z = 50. (C) 2009 Elsevier B.V. All rights reserved.
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| 16. |
- Sodergren, Erica, et al.
(author)
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The genome of the sea urchin Strongylocentrotus purpuratus.
- 2006
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In: Science. - : American Association for the Advancement of Science (AAAS). - 1095-9203 .- 0036-8075. ; 314:5801, s. 941-52
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Journal article (peer-reviewed)abstract
- We report the sequence and analysis of the 814-megabase genome of the sea urchin Strongylocentrotus purpuratus, a model for developmental and systems biology. The sequencing strategy combined whole-genome shotgun and bacterial artificial chromosome (BAC) sequences. This use of BAC clones, aided by a pooling strategy, overcame difficulties associated with high heterozygosity of the genome. The genome encodes about 23,300 genes, including many previously thought to be vertebrate innovations or known only outside the deuterostomes. This echinoderm genome provides an evolutionary outgroup for the chordates and yields insights into the evolution of deuterostomes.
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| 17. |
- Wadsworth, R., et al.
(author)
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THE NORTHWEST FRONTIER : SPECTROSCOPY OF N similar to Z NUCLEI BELOW MASS 100
- 2009
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In: Acta Physica Polonica B. - 0587-4254 .- 1509-5770. ; 40:3, s. 611-620
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Journal article (peer-reviewed)abstract
- The spectroscopy and structure of excited states of N similar to Z nuclei in the mass 70-100 region has been investigated using two techniques. In the A similar to 70-80 region fusion evaporation reactions coupled with the recoil-beta-tagging method have been employed at Jyvaskyla to study low-lying states in odd-odd N = Z nuclei. Results from these and other data for known odd-odd nuclei above mass 60 will be discussed. In the heavier mass 90 region a fragmentation experiment has been performed using the RIS-ING/FRS setup at GSI. This experiment was primarily aimed at searching for spin gap isomers in nuclei around A similar to 96. The objectives of the latter experiment will be discussed.
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| 18. |
- Abbadessa, G, et al.
(author)
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Unsung hero Robert C. Gallo
- 2009
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In: Science (New York, N.Y.). - : American Association for the Advancement of Science (AAAS). - 1095-9203 .- 0036-8075. ; 323:5911, s. 206-207
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Journal article (other academic/artistic)
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| 19. |
- Adewumi, Oluseun, et al.
(author)
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Characterization of human embryonic stem cell lines by the International Stem Cell Initiative
- 2007
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In: Nature Biotechnology. - : Springer Science and Business Media LLC. - 1087-0156 .- 1546-1696. ; 25:7, s. 803-816
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Journal article (peer-reviewed)abstract
- The International Stem Cell Initiative characterized 59 human embryonic stem cell lines from 17 laboratories worldwide. Despite diverse genotypes and different techniques used for derivation and maintenance, all lines exhibited similar expression patterns for several markers of human embryonic stem cells. They expressed the glycolipid antigens SSEA3 and SSEA4, the keratan sulfate antigens TRA-1-60, TRA-1-81, GCTM2 and GCT343, and the protein antigens CD9, Thy1 (also known as CD90), tissue- nonspecific alkaline phosphatase and class 1 HLA, as well as the strongly developmentally regulated genes NANOG, POU5F1 (formerly known as OCT4), TDGF1, DNMT3B, GABRB3 and GDF3. Nevertheless, the lines were not identical: differences in expression of several lineage markers were evident, and several imprinted genes showed generally similar allele-specific expression patterns, but some gene-dependent variation was observed. Also, some female lines expressed readily detectable levels of XIST whereas others did not. No significant contamination of the lines with mycoplasma, bacteria or cytopathic viruses was detected.
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| 20. |
- Al-Dahan, N., et al.
(author)
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Nuclear Structure "Southeast" of 208Pb: Isomeric states in 208Hg and 209Tl
- 2009
-
In: Physical Review C (Nuclear Physics). - 0556-2813. ; 80:6
-
Journal article (peer-reviewed)abstract
- The nuclear structure of neutron-rich N>126 nuclei has been investigated following their production via relativistic projectile fragmentation of a E/A=1 GeV U-238 beam. Metastable states in the N=128 isotones Hg-208 and Tl-209 have been identified. Delayed gamma-ray transitions are interpreted as arising from the decay of I-pi=(8(+)) and (17/2(+)) isomers, respectively. The data allow for the so far most comprehensive verification of the shell-model approach in the region determined by magic numbers Z < 82 and N>126.
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| 21. |
- Doornenbal, P., et al.
(author)
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RISING: Gamma‐ray Spectroscopy with Radioactive Beams at GSI
- 2007
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In: AIP Conference Proceedings. - : AIP. - 0094-243X. - 9780735413283 ; 891, s. 99-107
-
Conference paper (peer-reviewed)abstract
- The Rare Isotope Spectroscopic INvestigation at GSI (RISING) project is a major pan‐European collaboration. Its physics aims are the studies of exotic nuclear matter with abnormal proton‐to‐neutron ratios compared with naturally occurring isotopes. RISING combines the FRagment Separator (FRS) which allows relativistic energies and projectile fragmentation reactions with EUROBALL Ge Cluster detectors for γ spectroscopic research. The RISING setup can be used in two different configurations. Either the nuclei of interest are investigated after being stopped or the heavy ions hit a secondary target at relativistic energies and the thereby occurring excitations are studied. For the latter case, MINIBALL Ge detectors and the HECTOR array are used in addition. Example achievements of the Fast Beam setup are presented and compared to various shell model calculations, while for the Stopped Beam setup initial results are shown.
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| 22. |
- Farrelly, G. F., et al.
(author)
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Revision of the K-Isomer in 190W
- 2009
-
In: Acta Physica Polonica. Series B: Elementary Particle Physics, Nuclear Physics, Statistical Physics, Theory of Relativity, Field Theory. - 0587-4254. ; 40:3, s. 885-888
-
Journal article (peer-reviewed)abstract
- Gamma rays from the decay of an isomer in W-190(116) have been observed following projectile fragmentation of a 1 GeV per nucleon Pb-208 beam. An earlier experiment indicated decay from a (10(-)) isomer to the ground state rotational band. Improved statistics have enabled gamma coincidence and time-difference measurements to be made which alter the previous interpretation. Blocked BCS calculations have also been used together with reduced hindrance factors to indicate possible values of spin-parity for the isomer.
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| 23. |
- Garnsworthy, A. B., et al.
(author)
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Isomeric States in Neutron-deficient A~80-90 Nuclei Populated in the Fragmentation of 107Ag
- 2009
-
In: Physical Review C (Nuclear Physics). - 0556-2813. ; 80:6
-
Journal article (peer-reviewed)abstract
- The relativistic projectile fragmentation of a 750 MeV per nucleon beam of Ag-107 was used to populate isomeric states in neutron-deficient nuclei around A=80-90. Reaction products were separated and unambiguously identified using the GSI FRagment Separator (FRS) and its ancillary detectors. At the final focal plane, the fragments were slowed from relativistic energies by means of an aluminium degrader and implanted in a passive stopper in the center of the high-efficiency, high-granularity Stopped Rare Isotope Spectroscopic INvestigation at GSI (RISING) germanium array. This allowed the identification of excited states in the N=Z nuclei Tc-86(43) and, for the first time, Nb-82(41). Isomeric states have also been identified for the first time in Tc-87,Tc-88, and a previously unreported isomer was observed in Nb-84. Experimental results are presented along with a discussion on the structure of these nuclei based on interpretations provided by several theoretical models.
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| 24. |
- Garnsworthy, A. B., et al.
(author)
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Isomeric States in the Light Tc Isotopes
- 2007
-
In: Acta Physica Polonica. Series B: Elementary Particle Physics, Nuclear Physics, Statistical Physics, Theory of Relativity, Field Theory. - 0587-4254. ; 38:4, s. 1265-1269
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Journal article (peer-reviewed)abstract
- Preliminary results from the first experiment of the Stopped Beam RISING campaign are presented. The relativistic projectile fragmentation of a 750 MeV/u beam of Ag-107 populated isomeric states in very neutron deficient nuclei at the proton dripline around mass 80-90. Nuclei were unambiguously identified using the FRagment Separator (FRS) and its ancillary detectors located at GSI. The ions produced were slowed down from relativistic energies by means of an Al degrader and implanted in the centre of the high-efficiency Stopped RISING array. This allowed the identification of new excited states in the N = Z = 43 nucleus, Tc-86, populated following the de-excitation of a microsecond isomer. Preliminary results of this analysis, as well as previously unobserved isomeric states in Tc-87,Tc-88. are reported.
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| 25. |
- Garnsworthy, A B, et al.
(author)
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Neutron-proton pairing competition in N = Z nuclei: Metastable state decays in the proton dripline nuclei Nb-82(41) and Tc-86(43)
- 2008
-
In: Physics Letters. Section B: Nuclear, Elementary Particle and High-Energy Physics. - : Elsevier BV. - 0370-2693. ; 660:4, s. 326-330
-
Journal article (peer-reviewed)abstract
- The low-lying structures of the self-conjugate (N = Z) nuclei Nb-82(41)41 and Tc-86(43)43 have been investigated using isomeric-decay spectroscopy following the projectile fragmentation of a Ag-107 beam. These represent the heaviest odd-odd N = Z nuclei in which internal decays have been identified to date. The resulting level schemes shed light on the shape evolution along the N = Z line between the doubly-magic systems Ni-56(28) and Sn-100(50) and support a preference for T = 1 states in T-z = 0 odd-odd nuclei at low excitation energies associated with a T = 1 neutron-proton pairing gap. Comparison with Projected Shell Model calculations suggests that the decay in Nb-82 may be interpreted as an isospin-changing K isomer.
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| 26. |
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| 27. |
- Klionsky, Daniel J., et al.
(author)
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Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes
- 2008
-
In: Autophagy. - : Landes Bioscience. - 1554-8627 .- 1554-8635. ; 4:2, s. 151-175
-
Research review (peer-reviewed)abstract
- Research in autophagy continues to accelerate,1 and as a result many new scientists are entering the field. Accordingly, it is important to establish a standard set of criteria for monitoring macroautophagy in different organisms. Recent reviews have described the range of assays that have been used for this purpose.2,3 There are many useful and convenient methods that can be used to monitor macroautophagy in yeast, but relatively few in other model systems, and there is much confusion regarding acceptable methods to measure macroautophagy in higher eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers of autophagosomes versus those that measure flux through the autophagy pathway; thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from fully functional autophagy that includes delivery to, and degradation within, lysosomes (in most higher eukaryotes) or the vacuole (in plants and fungi). Here, we present a set of guidelines for the selection and interpretation of the methods that can be used by investigators who are attempting to examine macroautophagy and related processes, as well as by reviewers who need to provide realistic and reasonable critiques of papers that investigate these processes. This set of guidelines is not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to verify an autophagic response.
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| 28. |
- Lozeva, R. L., et al.
(author)
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New sub-us Isomers in 125Sn, 127Sn, 129Sn and Isomer Systematics of 124-130Sn
- 2008
-
In: Physical Review C (Nuclear Physics). - 0556-2813. ; 77:6
-
Journal article (peer-reviewed)abstract
- New sub-mu s isomers have been observed in the neutron-rich Sn isotopes. Sn-125,Sn-127,Sn-129 nuclei have been produced in a relativistic fission reaction of U-238 on a Be-9 target at 750 A.MeV and by the fragmentation of Xe-136 at 600 A.MeV populating high-spin yrast states. In addition to the already known mu s isomers, three new ones with sub-mu s half-lives have been observed. These yrast isomers are the high-spin members of the nu(d(3/2)(-1)h(11/2)(-2)) and nu h(11/2)(-n), seniority v = 3 multiplets leading to isomeric (23/2(+)) and (27/2(-)) states, respectively. Added to the already known 19/2(+)mu s isomers in this region the current work completes the systematic information of neutron-hole excitations toward the filling of the last h(11/2) orbital at N = 82. The results are discussed in the framework of state-of-the-art shell-model calculations using realistic interactions.
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| 29. |
- Morales, A. I., et al.
(author)
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beta -Delayed gamma -Ray Spectroscopy of Heavy Neutron Rich Nuclei "South" of Lead
- 2009
-
In: Acta Physica Polonica B. - 0587-4254. ; 40:3, s. 867-870
-
Conference paper (peer-reviewed)abstract
- Relativistic projectile fragmentation of a Pb-208 primary beam has been used to produce neutron-rich nuclei with proton-holes relative to the Z = 82 shell closure, i.e., "south" of Pb. beta-delayed gamma-ray spectroscopy allows to investigate the structural properties of such nuclei with A similar to 195 -> 205. The current work presents transitions de-exciting excited states in Au-204, which are the first spectroscopic information on this N = 125 isotone.
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| 30. |
- Myalski, S., et al.
(author)
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Isomeric Ratio for the I=8+ Yrast State in 96Pd Produced in the Relativistic Fragmentation of 107Ag
- 2007
-
In: Acta Physica Polonica. Series B: Elementary Particle Physics, Nuclear Physics, Statistical Physics, Theory of Relativity, Field Theory. - 0587-4254. ; 38:4, s. 1277-1282
-
Journal article (peer-reviewed)abstract
- We report on the preliminary results from a study of the decay of the I-pi = 8(+) T-1/2 = 2 mu s isomer in Pd-96 performed as part of the Stopped-Beam RISING campaign within the Rare Isotope Investigation at GSI (RISING). The Pd-96 ions were produced following the projectile fragmentation of a 750 MeV per nucleon Ag-107 primary beam. The reaction products were separated and identified by the in-flight method using the GSI Fragment Separator. The residues of interest were stopped in a perspex stopper surrounded by an array of 15, seven-element germanium Cluster detectors. One of the goals of the current work is to investigate the population of high-spin states produced projectile fragmentation reactions using isomeric ratio measurements to infer information on the angular momentum population distribution. In this short contribution the method and results of determining the isomeric ratio for the I-pi = 8(+) microsecond isomer in Pd-96 nucleus are presented.
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| 31. |
- Myalski, S., et al.
(author)
-
Isomeric Ratios For Nuclei With Z=62-67 And A=142-152 Produced In The Relativistic Fragmentation Of Pb-208
- 2009
-
In: Acta Physica Polonica. Series B: Elementary Particle Physics, Nuclear Physics, Statistical Physics, Theory of Relativity, Field Theory. - 0587-4254. ; 40:3, s. 879-883
-
Journal article (peer-reviewed)abstract
- Isomeric states in nuclei with Z = 62-67 and A = 142-152 produced in the fragmentation of the relativistic (1 GeV/nucleon) Pb-208 beam were investigated. Isomeric ratios were determined for 10 isomeric states. Significant differences between theoretical and experimental values were observed.
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| 32. |
- Neyens, G., et al.
(author)
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g-Factor Measurements on Relativistic Isomeric Beams Produced by Fragmentation and U-fission: The g-RISING Project at GSI
- 2007
-
In: Acta Physica Polonica. Series B: Elementary Particle Physics, Nuclear Physics, Statistical Physics, Theory of Relativity, Field Theory. - 0587-4254. ; 38:4, s. 1237-1247
-
Journal article (peer-reviewed)abstract
- Within the RISING (Rare ISotope INvestigations @ GSI) Collaboration at GSI, g factor measurements have been performed on isomeric states in neutron-rich isotopes approaching Sn-132 and in the neutron deficient Pb-region (the g-RISING campaign). We present the experimental technique and some typical aspects related to such studies on relativistic beams selected with the FRS fragment separator. First results are presented for the (19/2(+)) 4.5 mu s isomeric state in Sn-127, which has been produced by means of fission of a relativistic U-238 beam on the one hand, and by the fragmentation of a relativistic Xe-136 beam on the other hand. Spin-alignment has been observed in both reactions. It was the first time that spin-alignment has been established in a relativistic fission reaction.
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| 33. |
- Pietri, S., et al.
(author)
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First Results from the Stopped Beam Isomer RISING Campaign at GSI
- 2007
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In: Acta Physica Polonica. Series B: Elementary Particle Physics, Nuclear Physics, Statistical Physics, Theory of Relativity, Field Theory. - 0587-4254. ; 38:4, s. 1255-1264
-
Journal article (peer-reviewed)abstract
- The first results from a series of experiments focused on the study of the internal structure of nuclei at the extremes of N:Z ratio using isomer spectroscopy are reported. These experiments represent the first of the Stopped Beam section of the Rare Isotopes Investigations at GSI (RISING) project. Exotic nuclei were synthesized using relativistic projectile fragmentation of similar to 500 -> 1000 MeV/u beams of Ag-107, Pb-208, Xe-136 and Ni-58, or fission of 750 MeV/u U-238 provided by the SIS synchrotron at GSI. A detailed description of the RISING stopped beam set up is given, together with a report of the performance of the associated gamma-ray spectrometer array. Selected results of the first experimental campaign are presented together with a discussion on the use of isomeric spectroscopy to study GeV range nuclear fragmentation. Details on future research plans of this collaboration are also outlined.
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| 34. |
- Podolyak, Zs., et al.
(author)
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Isomeric Decay Studies Around 204Pt and 148Tb
- 2007
-
In: The European Physical Journal. Special Topics. - : Springer Science and Business Media LLC. - 1951-6355 .- 1951-6401. ; 150, s. 165-168
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Journal article (peer-reviewed)abstract
- Relativistic energy projectile fragmentation of Pb-208 has been used to produce a range of exotic nuclei. The nuclei of interest were studied by detecting delayed gamma rays following the decay of isomeric states. Experimental information on the excited states of the neutron-rich N = 126 nucleus, Pt-204, following internal decay of two isomeric states, was obtained for the first time. In addition, decays from the previously reported isomeric I=27h and I=(49/2)h states in Tb-148 and Gd-147, respectively, have been observed. These isomeric decays represent the highest spin discrete states observed to date following a projectile fragmentation reaction, and opens further the possibility of doing 'high-spin physics' using this technique.
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| 35. |
- Podolyak, Zs., et al.
(author)
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Structure of Neutron-rich Nuclei Around the N=126 Closed Shell; the Yrast Structure of 205Au up to Spin-parity I = (19/2+)
- 2009
-
In: European Physical Journal A. - : Springer Science and Business Media LLC. - 1434-6001 .- 1434-601X. ; 42:3, s. 489-493
-
Conference paper (peer-reviewed)abstract
- Heavy neutron-rich nuclei have been populated through the relativistic fragmentation of a Pb-208(82) beam at E/A = 1 GeV on a 2.5 g/cm(2) thick Be target. The synthesised nuclei were selected and identified in-flight using the fragment separator at GSI. Approximately 300 ns after production, the selected nuclei were implanted in an similar to 8 mm thick perspex stopper, positioned at the centre of the RISING gamma-ray detector spectrometer array. A previously unreported isomer with a half-life T-1/2 = 163(5) ns has been observed in the N = 126 closed-shell nucleus Au-205(79). Through gamma-ray singles and gamma-gamma coincidence analysis a level scheme was established. The comparison with a shell model calculation tentatively identifies the spin-parity of the excited states, including the isomer itself, which is found to be I-pi = (19/2(+)).
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| 36. |
- Podolyak, Zs., et al.
(author)
-
Weakly Deformed Oblate Structures in 198Os
- 2009
-
In: Physical Review C (Nuclear Physics). - 0556-2813. ; 79:3
-
Journal article (peer-reviewed)abstract
- Gamma rays de-exciting isomeric states in the neutron-rich nucleus Os-198(76)122 have been observed following relativistic projectile fragmentation of a 1 GeV per nucleon Pb-208 beam. The ground-state band has properties compatible with oblate deformation. The evolution of the structure of Os isotopes characterized by sudden prolate-oblate shape change is discussed and contrasted with the smooth change known in the Pt chain.
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| 37. |
- Regan, P. H., et al.
(author)
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First Results from the Stopped RISING Campaign at GSI: The Mapping of Isomeric Decays in Highly Exotic Nuclei
- 2007
-
In: AIP Conference Proceedings. - : AIP. - 0094-243X. - 9780735413283 ; 899, s. 19-22
-
Conference paper (peer-reviewed)abstract
- The first results from the Stopped Beam RISING experimental campaign performed at the GSI laboratory in Darmstadt, Germany, are presented. RISING (Rare ISotope INvestigations at GSI) constitutes a major new experimental program in European nuclear structure physics research aimed at using relativistic‐energy, projectile‐fragmentation reactions to study nuclei with exotic proton‐to‐neutron ratios. This paper introduces the physics aims of the Stopped RISING collaboration and presents some technical details and initial results from experiments using the RISING array to study decays from metastable nuclear states in both proton and neutron‐rich nuclei.
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| 38. |
- Rudolph, Dirk, et al.
(author)
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Exciting Isomers from the First Stopped-beam RISING Campaign
- 2007
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In: The European Physical Journal. Special Topics. - : Springer Science and Business Media LLC. - 1951-6355 .- 1951-6401. ; 150, s. 173-176
-
Journal article (peer-reviewed)abstract
- First results are reported from a major new initiative of experiments, which focus on nuclear structure studies at extreme isospin values by means of isomer spectroscopy. The experiments represent the first part of the so-called stopped-beam campaign within the Rare ISotope INvestigations at GSI (RISING) project. Time-correlated gamma decays from individually identified nuclear species have been measured, allowing the clean identification of isomeric decays in a wide range of exotic nuclei both at the proton drip-line and in heavy, neutron-rich systems. An overview of the experimental technique will be given, together with the performance of the new germanium detector array and future research plans for the collaboration.
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| 39. |
- Steer, S. J., et al.
(author)
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Single-particle Behavior at N=126: Isomeric Decays in Neutron-rich 204Pt
- 2008
-
In: Physical Review C (Nuclear Physics). - 0556-2813. ; 78:6
-
Journal article (peer-reviewed)abstract
- The four proton-hole nucleus Pt-204 was populated in the fragmentation of an E/A = 1 GeV Pb-208 beam. The yrast structure of Pt-204 has been observed up to angular momentum I = 10h by detecting delayed gamma-ray transitions originating from metastable states. These long-lived excited states have been identified to have spin-parities of I-pi = (10(+)), (7(-)), and (5(-)) and half-lives of T-1/2 = 146(14) ns, 55(3) mu s, and 5.5(7) mu s, respectively. The structure of the magic N = 126 Pt-204 nucleus is discussed and understood in terms of the spherical shell model. The data suggest a revision of the two-body interaction for N = 126, Z < 82, which determines the evolution of nuclear structure toward the r-process waiting point nuclei.
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| 40. |
- Al-Dahan, N., et al.
(author)
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Isomeric States In 208Hg And 209Tl Populated In Fragmentation Of 238U
- 2009
-
In: Acta Physica Polonica. Series B: Elementary Particle Physics, Nuclear Physics, Statistical Physics, Theory of Relativity, Field Theory. - 0587-4254. ; 40:3, s. 871-874
-
Journal article (peer-reviewed)abstract
- The nuclear structure of neutron-rich N > 126 nuclei has been investigated following their production via relativistic projectile fragmentation of a E/A = 1 GeV U-238 beam on a Be target. The preliminary analysis indicates the presence of previously unreported isomeric states in the N = 128 isotones Hg-208 and Tl-209.
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| 41. |
- Amundadottir, Laufey, et al.
(author)
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Genome-wide association study identifies variants in the ABO locus associated with susceptibility to pancreatic cancer.
- 2009
-
In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 41, s. 986-990
-
Journal article (peer-reviewed)abstract
- We conducted a two-stage genome-wide association study of pancreatic cancer, a cancer with one of the lowest survival rates worldwide. We genotyped 558,542 SNPs in 1,896 individuals with pancreatic cancer and 1,939 controls drawn from 12 prospective cohorts plus one hospital-based case-control study. We conducted a combined analysis of these groups plus an additional 2,457 affected individuals and 2,654 controls from eight case-control studies, adjusting for study, sex, ancestry and five principal components. We identified an association between a locus on 9q34 and pancreatic cancer marked by the SNP rs505922 (combined P = 5.37 x 10(-8); multiplicative per-allele odds ratio 1.20; 95% confidence interval 1.12-1.28). This SNP maps to the first intron of the ABO blood group gene. Our results are consistent with earlier epidemiologic evidence suggesting that people with blood group O may have a lower risk of pancreatic cancer than those with groups A or B.
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| 42. |
- Bacelar, A. M. Denis, et al.
(author)
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Angular Momentum Population In Fragmentation Reactions
- 2009
-
In: Acta Physica Polonica. Series B: Elementary Particle Physics, Nuclear Physics, Statistical Physics, Theory of Relativity, Field Theory. - 0587-4254. ; 40:3, s. 889-892
-
Journal article (peer-reviewed)abstract
- Neutron-deficient nuclei with N = 126 have been populated following projectile fragmentation of a U-238 beam with energy 1 GeV/A. The decay of several previously reported isomers has been measured. This will allow us to calculate high-spin isomeric ratios and compare them with model calculations to allow a better understanding of the reaction mechanism.
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| 43. |
- Ding, Li, et al.
(author)
-
Somatic mutations affect key pathways in lung adenocarcinoma
- 2008
-
In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 455:7216, s. 1069-1075
-
Journal article (peer-reviewed)abstract
- Determining the genetic basis of cancer requires comprehensive analyses of large collections of histopathologically well-classified primary tumours. Here we report the results of a collaborative study to discover somatic mutations in 188 human lung adenocarcinomas. DNA sequencing of 623 genes with known or potential relationships to cancer revealed more than 1,000 somatic mutations across the samples. Our analysis identified 26 genes that are mutated at significantly high frequencies and thus are probably involved in carcinogenesis. The frequently mutated genes include tyrosine kinases, among them the EGFR homologue ERBB4; multiple ephrin receptor genes, notably EPHA3; vascular endothelial growth factor receptor KDR; and NTRK genes. These data provide evidence of somatic mutations in primary lung adenocarcinoma for several tumour suppressor genes involved in other cancers--including NF1, APC, RB1 and ATM--and for sequence changes in PTPRD as well as the frequently deleted gene LRP1B. The observed mutational profiles correlate with clinical features, smoking status and DNA repair defects. These results are reinforced by data integration including single nucleotide polymorphism array and gene expression array. Our findings shed further light on several important signalling pathways involved in lung adenocarcinoma, and suggest new molecular targets for treatment.
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| 44. |
- Regan, P. H., et al.
(author)
-
Isomer Spectroscopy Using Relativistic Projectile Fragmentation at the N=Z Line for A~80-90
- 2007
-
In: Nuclear Physics, Section A. - : Elsevier BV. - 0375-9474. ; 787:1-4, s. 491-498
-
Journal article (peer-reviewed)abstract
- The preliminary results from the RISING Stopped Beam Isomer Campaign are presented, with specific focus on results of the initial experiment to investigate isomeric decays along the N=Z line around A similar to 80-90 following the projectile fragmentation of a Ag-107 primary beam at an energy of 750 MeV per nucleon. A description of the technical aspects behind the design of the RISING array is presented, together with evidence for previously unreported isomeric decays in Tc-87,Tc-88 and the N=Z nuclei Nb-82(41) and Tc-86(43).
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| 45. |
- Villa, Luisa L., et al.
(author)
-
Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions
- 2007
-
In: New England Journal of Medicine. - 0028-4793 .- 1533-4406. ; 356:19, s. 1915-1927
-
Journal article (peer-reviewed)abstract
- BACKGROUND: Human papillomavirus types 16 (HPV-16) and 18 (HPV-18) cause approximately 70% of cervical cancers worldwide. A phase 3 trial was conducted to evaluate a quadrivalent vaccine against HPV types 6, 11, 16, and 18 (HPV-6/11/16/18) for the prevention of high-grade cervical lesions associated with HPV-16 and HPV-18. METHODS: In this randomized, double-blind trial, we assigned 12,167 women between the ages of 15 and 26 years to receive three doses of either HPV-6/11/16/18 vaccine or placebo, administered at day 1, month 2, and month 6. The primary analysis was performed for a per-protocol susceptible population that included 5305 women in the vaccine group and 5260 in the placebo group who had no virologic evidence of infection with HPV-16 or HPV-18 through 1 month after the third dose (month 7). The primary composite end point was cervical intraepithelial neoplasia grade 2 or 3, adenocarcinoma in situ, or cervical cancer related to HPV-16 or HPV-18. RESULTS: Subjects were followed for an average of 3 years after receiving the first dose of vaccine or placebo. Vaccine efficacy for the prevention of the primary composite end point was 98% (95.89% confidence interval [CI], 86 to 100) in the per-protocol susceptible population and 44% (95% CI, 26 to 58) in an intention-to-treat population of all women who had undergone randomization (those with or without previous infection). The estimated vaccine efficacy against all high-grade cervical lesions, regardless of causal HPV type, in this intention-to-treat population was 17% (95% CI, 1 to 31). CONCLUSIONS: In young women who had not been previously infected with HPV-16 or HPV-18, those in the vaccine group had a significantly lower occurrence of high-grade cervical intraepithelial neoplasia related to HPV-16 or HPV-18 than did those in the placebo group.
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| 46. |
- Willer, Cristen J., et al.
(author)
-
Six new loci associated with body mass index highlight a neuronal influence on body weight regulation
- 2009
-
In: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 41:1, s. 25-34
-
Journal article (peer-reviewed)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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| 47. |
- Alkhomashi, N., et al.
(author)
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Beta(-)-Delayed And Isomer Spectroscopy Of Neutron-Rich Ta And W Isotopes
- 2009
-
In: Acta Physica Polonica B. - 0587-4254. ; 40:3, s. 875-878
-
Conference paper (peer-reviewed)abstract
- Decays of neutron-rich A similar to 190 nuclei have been studied following projectile fragmentation of a Pb-208 beam on a Be-9 target at the GSI Fragment Separator. Gamma-ray decays from previously reported isomeric states in Ta-188, W-190 and (192,193) Re were used as internal calibrations for the particle identification analysis, together with the identification of previously unreported isomeric decays in Ta-189 and W-191. The current work also identifies beta-delayed gamma rays following the decay of Ta-188 to W-188 for the first time.
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| 48. |
- Alkhomashi, N., et al.
(author)
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beta(-)-delayed spectroscopy of neutron-rich tantalum nuclei: Shape evolution in neutron-rich tungsten isotopes
- 2009
-
In: Physical Review C (Nuclear Physics). - 0556-2813. ; 80:6
-
Journal article (peer-reviewed)abstract
- The low-lying structure of W-188,W-190,W-192 has been studied following beta decays of the neutron-rich mother nuclei Ta-188,Ta-190,Ta-192 produced following the projectile fragmentation of a 1-GeV-per-nucleon Pb-208 primary beam on a natural beryllium target at the GSI Fragment Separator. The beta-decay half-lives of Ta-188, Ta-190, and Ta-192 have been measured, with gamma-ray decays of low-lying states in their respective W daughter nuclei, using heavy-ion beta-gamma correlations and a position-sensitive silicon detector setup. The data provide information on the low-lying excited states in W-188, W-190, and W-192, which highlight a change in nuclear shape at W-190 compared with that of lighter W isotopes. This evolution of ground-state structure along the W isotopic chain is discussed as evidence for a possible proton subshell effect for the A similar to 190 region and is consistent with maximization of the gamma-softness of the nuclear potential around N similar to 116.
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| 49. |
- Heard-Costa, Nancy L, et al.
(author)
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NRXN3 is a novel locus for waist circumference : a genome-wide association study from the CHARGE Consortium
- 2009
-
In: PLoS genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 5:6, s. e1000539-
-
Journal article (peer-reviewed)abstract
- Central abdominal fat is a strong risk factor for diabetes and cardiovascular disease. To identify common variants influencing central abdominal fat, we conducted a two-stage genome-wide association analysis for waist circumference (WC). In total, three loci reached genome-wide significance. In stage 1, 31,373 individuals of Caucasian descent from eight cohort studies confirmed the role of FTO and MC4R and identified one novel locus associated with WC in the neurexin 3 gene [NRXN3 (rs10146997, p = 6.4×10−7)]. The association with NRXN3 was confirmed in stage 2 by combining stage 1 results with those from 38,641 participants in the GIANT consortium (p = 0.009 in GIANT only, p = 5.3×10−8 for combined analysis, n = 70,014). Mean WC increase per copy of the G allele was 0.0498 z-score units (0.65 cm). This SNP was also associated with body mass index (BMI) [p = 7.4×10−6, 0.024 z-score units (0.10 kg/m2) per copy of the G allele] and the risk of obesity (odds ratio 1.13, 95% CI 1.07–1.19; p = 3.2×10−5 per copy of the G allele). The NRXN3 gene has been previously implicated in addiction and reward behavior, lending further evidence that common forms of obesity may be a central nervous system-mediated disorder. Our findings establish that common variants in NRXN3 are associated with WC, BMI, and obesity.
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| 50. |
- Loos, Ruth J. F., et al.
(author)
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Common variants near MC4R are associated with fat mass, weight and risk of obesity
- 2008
-
In: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 40:6, s. 768-775
-
Journal article (peer-reviewed)abstract
- To identify common variants influencing body mass index (BMI), we analyzed genome-wide association data from 16,876 individuals of European descent. After previously reported variants in FTO, the strongest association signal (rs17782313, P = 2.9 x 10(-6)) mapped 188 kb downstream of MC4R (melanocortin-4 receptor), mutations of which are the leading cause of monogenic severe childhood-onset obesity. We confirmed the BMI association in 60,352 adults (per-allele effect = 0.05 Z-score units; P = 2.8 x 10(-15)) and 5,988 children aged 7-11 (0.13 Z-score units; P = 1.5 x 10(-8)). In case-control analyses (n = 10,583), the odds for severe childhood obesity reached 1.30 (P = 8.0 x 10(-11)). Furthermore, we observed overtransmission of the risk allele to obese offspring in 660 families (P (pedigree disequilibrium test average; PDT-avg) 2.4 x 10(-4)). The SNP location and patterns of phenotypic associations are consistent with effects mediated through altered MC4R function. Our findings establish that common variants near MC4R influence fat mass, weight and obesity risk at the population level and reinforce the need for large-scale data integration to identify variants influencing continuous biomedical traits.
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