| 1. |
- Estrada, Karol, et al.
(författare)
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Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture.
- 2012
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 44:5, s. 491-501
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Tidskriftsartikel (refereegranskat)abstract
- Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 × 10(-8)). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 × 10(-4), Bonferroni corrected), of which six reached P < 5 × 10(-8), including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.
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| 2. |
- Zheng, Hou-Feng, et al.
(författare)
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Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 526:7571, s. 112-
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Tidskriftsartikel (refereegranskat)abstract
- The extent to which low-frequency (minor allele frequency (MAF) between 1-5%) and rare (MAF <= 1%) variants contribute to complex traits and disease in the general population is mainly unknown. Bone mineral density (BMD) is highly heritable, a major predictor of osteoporotic fractures, and has been previously associated with common genetic variants(1-8), as well as rare, population specific, coding variants(9). Here we identify novel non-coding genetic variants with large effects on BMD (n(total) = 53,236) and fracture (n(total) = 508,253) in individuals of European ancestry from the general population. Associations for BMD were derived from whole-genome sequencing (n = 2,882 from UK10K (ref. 10); a population-based genome sequencing consortium), whole-exome sequencing (n = 3,549), deep imputation of genotyped samples using a combined UK10K/1000 Genomes reference panel (n = 26,534), and de novo replication genotyping (n = 20,271). We identified a low-frequency non-coding variant near a novel locus, EN1, with an effect size fourfold larger than the mean of previously reported common variants for lumbar spine BMD8 (rs11692564(T), MAF51.6%, replication effect size510.20 s.d., P-meta = 2 x 10(-14)), which was also associated with a decreased risk of fracture (odds ratio = 0.85; P = 2 x 10(-11); ncases = 98,742 and ncontrols = 409,511). Using an En1cre/flox mouse model, we observed that conditional loss of En1 results in low bone mass, probably as a consequence of high bone turnover. We also identified a novel low frequency non-coding variant with large effects on BMD near WNT16 (rs148771817(T), MAF = 1.2%, replication effect size +10.41 s.d., P-meta = 1 x 10(-11)). In general, there was an excess of association signals arising from deleterious coding and conserved non-coding variants. These findings provide evidence that low-frequency non-coding variants have large effects on BMD and fracture, thereby providing rationale for whole-genome sequencing and improved imputation reference panels to study the genetic architecture of complex traits and disease in the general population.
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| 3. |
- Hervella, M., et al.
(författare)
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The mitogenome of a 35,000-year-old Homo sapiens from Europe supports a Palaeolithic back-migration to Africa
- 2016
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- After the dispersal of modern humans (Homo sapiens) Out of Africa, hominins with a similar morphology to that of present-day humans initiated the gradual demographic expansion into Eurasia. The mitogenome (33-fold coverage) of the Pestera Muierii 1 individual (PM1) from Romania (35 ky cal BP) we present in this article corresponds fully to Homo sapiens, whilst exhibiting a mosaic of morphological features related to both modern humans and Neandertals. We have identified the PM1 mitogenome as a basal haplogroup U6*, not previously found in any ancient or present-day humans. The derived U6 haplotypes are predominantly found in present-day North-Western African populations. Concomitantly, those found in Europe have been attributed to recent gene-flow from North Africa. The presence of the basal haplogroup U6* in South East Europe (Romania) at 35 ky BP confirms a Eurasian origin of the U6 mitochondrial lineage. Consequently, we propose that the PM1 lineage is an offshoot to South East Europe that can be traced to the Early Upper Paleolithic back migration from Western Asia to North Africa, during which the U6 lineage diversified, until the emergence of the present-day U6 African lineages.
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| 4. |
- Ladds, Marcus J. G. W., et al.
(författare)
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A DHODH inhibitor increases p53 synthesis and enhances tumor cell killing by p53 degradation blockage
- 2018
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- The development of non-genotoxic therapies that activate wild-type p53 in tumors is of great interest since the discovery of p53 as a tumor suppressor. Here we report the identification of over 100 small-molecules activating p53 in cells. We elucidate the mechanism of action of a chiral tetrahydroindazole (HZ00), and through target deconvolution, we deduce that its active enantiomer (R)-HZ00, inhibits dihydroorotate dehydrogenase (DHODH). The chiral specificity of HZ05, a more potent analog, is revealed by the crystal structure of the (R)-HZ05/DHODH complex. Twelve other DHODH inhibitor chemotypes are detailed among the p53 activators, which identifies DHODH as a frequent target for structurally diverse compounds. We observe that HZ compounds accumulate cancer cells in S-phase, increase p53 synthesis, and synergize with an inhibitor of p53 degradation to reduce tumor growth in vivo. We, therefore, propose a strategy to promote cancer cell killing by p53 instead of its reversible cell cycle arresting effect.
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| 5. |
- Massoud, Al-Shimaà A A, 1980, et al.
(författare)
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Bis 4,5-diazafluoren-9-one silver(I) nitrate: synthesis, X-ray structures, solution chemistry, hydrogel loading, DNA coupling and anti-bacterial screening
- 2011
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Ingår i: New Journal of Chemistry. - : Royal Society of Chemistry (RSC). - 1369-9261 .- 1144-0546. ; 35:3, s. 640-648
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Tidskriftsartikel (refereegranskat)abstract
- Synthesis of bis-4,5-diazafluoren-9-one silver(I) nitrate I (dafone = 4,5-diazafluoren-9-one) and the low temperature X-ray single crystal structure of [Ag(4,5-diazafluoren-9-one)2NO3], crystal form 1, and a re-determination of [Ag(4,5-diazafluoren-9-one)2]NO3 . H2O, crystal form 2 are presented. Crystal form 1 has a distorted trigonal planar coordination geometry around Ag(I) with an N-Ag-N bond angle of 123.45(7)o. Crystal form 2 has a perfect linear coordination around Ag, with N-Ag-N 180.0o. Compound I was characterized by 1H-NMR, biological activity and ESI-MS in DMSO at room temperature. The biological activity was determined against 6 different resistant clinical isolates; two Gram-positive (Staphylococcus aureus and Streptococcus pyogenes) and four Gram-negative (Pseudomonas aeruginosa, Klebsiella pneumoniae, Proteus mirabilis, and Salmonella sp.) in comparison with 15 known antibiotics used in the treatment of diabetic foot infections. Compound I showed broad spectrum activity against all the test organisms. P. mirabilis and S. aureus and K. pneumoniae were the most sensitive clinical isolates (MIC = 4, 6 and 4 μg ml-1, respectively). Three different hydrogels containing I or Ag2SO4 were prepared and the antimicrobial activity against Ps. aeruginosa (ATCC 15442) compared, showing more or less equal activity on a weight basis, but I seems to have a significant better performance per silver ion. The Ag(I) complex also binds more effectively to calf thymus DNA than the dafone ligand itself.
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| 6. |
- Rudolph, Dirk, et al.
(författare)
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Isospin and Deformation Studies in the Odd-odd N = Z Nucleus 54Co
- 2010
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Ingår i: Physical Review C (Nuclear Physics). - 0556-2813. ; 82:5
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Tidskriftsartikel (refereegranskat)abstract
- High-spin states in the odd-odd N = Z nucleus Co-54 have been investigated by the fusion-evaporation reaction Si-28(S-32,1 alpha 1p1n)Co-54. Gamma-ray information gathered with the Ge detector array Gammasphere was correlated with evaporated particles detected in the charged particle detector system Microball and a 1 pi neutron detector array. A significantly extended excitation scheme of Co-54 is presented, which includes a candidate for the isospin T = 1, 6(+) state of the 1f(7/2)(-2) multiplet. The results are compared to large-scale shell-model calculations in the fp shell. Effective interactions with and without isospin-breaking terms have been used to probe isospin symmetry and isospin mixing. A quest for deformed high-spin rotational cascades proved negative. This feature is discussed by means of cranking calculations.
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| 7. |
- Uhlén, Mathias, et al.
(författare)
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The human secretome
- 2019
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Ingår i: Science Signaling. - : American Association for the Advancement of Science (AAAS). - 1945-0877 .- 1937-9145. ; 12:609
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Tidskriftsartikel (refereegranskat)abstract
- The proteins secreted by human cells (collectively referred to as the secretome) are important not only for the basic understanding of human biology but also for the identification of potential targets for future diagnostics and therapies. Here, we present a comprehensive analysis of proteins predicted to be secreted in human cells, which provides information about their final localization in the human body, including the proteins actively secreted to peripheral blood. The analysis suggests that a large number of the proteins of the secretome are not secreted out of the cell, but instead are retained intracellularly, whereas another large group of proteins were identified that are predicted to be retained locally at the tissue of expression and not secreted into the blood. Proteins detected in the human blood by mass spectrometry-based proteomics and antibody-based immuno-assays are also presented with estimates of their concentrations in the blood. The results are presented in an updated version 19 of the Human Protein Atlas in which each gene encoding a secretome protein is annotated to provide an open-access knowledge resource of the human secretome, including body-wide expression data, spatial localization data down to the single-cell and subcellular levels, and data about the presence of proteins that are detectable in the blood.
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| 8. |
- Davis, Simon J. M., et al.
(författare)
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Molecular and osteometric sexing of cattle metacarpals : a case study from 15th century AD Beja, Portugal
- 2012
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Ingår i: Journal of Archaeological Science. - : Elsevier BV. - 0305-4403 .- 1095-9238. ; 39:5, s. 1445-1454
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Tidskriftsartikel (refereegranskat)abstract
- In the course of a zooarchaeological survey of Holocene sites in southern Portugal, a substantial size increase of cattle bones was noted following the Christian reconquista of the 11th-13th centuries AD. A size increase in the course of time within a lineage of domestic livestock is usually considered to represent animal improvement. However several other factors including sex may influence the average size of a sample of mammal bones - cattle exhibit considerable sexual size dimorphism, with bulls being larger than cows. A histogram of the distal widths of a large (n = 44) sample of cattle metacarpals from 15th century Beja (Alentejo, Portugal), revealed a bimodal distribution. It was assumed that the large measurements belonged to males and the small to females. In order to rule out the possibility of a post-Moslem change in the sex ratio of cattle, a sub-sample of 21 cattle metacarpals from Beja was selected and we used genetic markers to identify the sex of the animals to which these metacarpals belonged. The ancient DNA sex of all specimens agreed with the previously assumed sex as determined osteometrically. We conclude that the two nearly separated peaks for the metacarpal distal width measurements do indeed indicate sex. A similar bimodal distribution was obtained from another large but earlier sample of cattle metacarpals from Moslem Alcacova de Santarem (9th-12th century AD). Although these have not been molecularly sexed and since osteometric sexing has now been validated, we conclude that both small (female) and large (male) peaks are smaller than the 15th century ones and that there was an overall size increase or improvement of cattle in this region. Why the Christians improved cattle is unclear, but a selection for larger beeves for meat is one possibility as is the selection of more robust cattle for power. The spread of the quadrangular or chariot plough in Iberia is known to have occurred at this time. We then use the genetically sexed metacarpals to determine which measurements provide reasonable distinction between the sexes. Both the distal width (BFd; as already noted by Svensson et al., 2008; in Swedish medieval cattle) and the width of the lateral condyle (WCL) offer the best distinction. We also used them as a reference 'collection' to sex the medieval and post-medieval cattle metacarpals from Launceston Castle in England. This re-visit of the Launceston data corroborates other evidence indicating increased specialisation (milk and veal) in post-medieval cattle husbandry in England.
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| 9. |
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| 10. |
- Luda, Katarzyna M., et al.
(författare)
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IRF8 Transcription-Factor-Dependent Classical Dendritic Cells Are Essential for Intestinal T Cell Homeostasis
- 2016
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Ingår i: Immunity. - : Elsevier BV. - 1074-7613. ; 44:4, s. 860-874
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Tidskriftsartikel (refereegranskat)abstract
- The role of dendritic cells (DCs) in intestinal immune homeostasis remains incompletely defined. Here we show that mice lacking IRF8 transcription-factor-dependent DCs had reduced numbers of T cells in the small intestine (SI), but not large intestine (LI), including an almost complete absence of SI CD8αβ+ and CD4+CD8αα+ T cells; the latter requiring β8 integrin expression by migratory IRF8 dependent CD103+CD11b- DCs. SI homing receptor induction was impaired during T cell priming in mesenteric lymph nodes (MLN), which correlated with a reduction in aldehyde dehydrogenase activity by SI-derived MLN DCs, and inefficient T cell localization to the SI. These mice also lacked intestinal T helper 1 (Th1) cells, and failed to support Th1 cell differentiation in MLN and mount Th1 cell responses to Trichuris muris infection. Collectively these results highlight multiple non-redundant roles for IRF8 dependent DCs in the maintenance of intestinal T cell homeostasis.
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