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Sökning: WFRF:(Cheung Rebecca)

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  • Zheng, Hou-Feng, et al. (författare)
  • Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture.
  • 2015
  • Ingår i: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 526:7571, s. 112-117
  • 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, as well as rare, population-specific, coding variants. Here we identify novel non-coding genetic variants with large effects on BMD (ntotal = 53,236) and fracture (ntotal = 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 BMD (rs11692564(T), MAF = 1.6%, replication effect size = +0.20 s.d., Pmeta = 2 × 10(-14)), which was also associated with a decreased risk of fracture (odds ratio = 0.85; P = 2 × 10(-11); ncases = 98,742 and ncontrols = 409,511). Using an En1(cre/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 = +0.41 s.d., Pmeta = 1 × 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.
  • Chen, Han, et al. (författare)
  • LTBP-2 confers pleiotropic suppression and promotes dormancy in a growth factor permissive microenvironment in nasopharyngeal carcinoma
  • 2012
  • Ingår i: Cancer Letters. - : Elsevier. - 0304-3835 .- 1872-7980. ; 325:1, s. 89-98
  • Tidskriftsartikel (refereegranskat)abstract
    • This study identified LTBP-2 as a pleiotropic tumor suppressor in nasopharyngeal carcinoma, which safeguards against critical malignant behaviors of tumor cells. LTBP-2 expression was significantly decreased or lost in up to 100% of NPC cell lines (7/7) and 80% of biopsies (24/30). Promoter hypermethylation was found to be involved in LTBP-2 silencing. Using a tetracycline-regulated inducible expression system, we unveiled functional roles of LTBP-2 in suppressing colony formation, anchorage-independent growth, cell migration, angiogenesis, VEGF secretion, and tumorigenicity. Three-dimensional culture studies suggested the involvement of LTBP-2 in maintenance of tumor cell dormancy in a growth factor favorable microenvironment.
  • Cheung, William W. L., et al. (författare)
  • Building confidence in projections of the responses of living marine resources to climate change
  • 2016
  • Ingår i: ICES Journal of Marine Science. - 1054-3139 .- 1095-9289. ; 73:5, s. 1283-1296
  • Tidskriftsartikel (refereegranskat)abstract
    • The Fifth Assessment Report of the Intergovernmental Panel on Climate Change highlights that climate change and ocean acidification are challenging the sustainable management of living marine resources (LMRs). Formal and systematic treatment of uncertainty in existing LMR projections, however, is lacking. We synthesize knowledge of how to address different sources of uncertainty by drawing from climate model intercomparison efforts. We suggest an ensemble of available models and projections, informed by observations, as a starting point to quantify uncertainties. Such an ensemble must be paired with analysis of the dominant uncertainties over different spatial scales, time horizons, and metrics. We use two examples: (i) global and regional projections of Sea Surface Temperature and (ii) projection of changes in potential catch of sablefish (Anoplopoma fimbria) in the 21st century, to illustrate this ensemble model approach to explore different types of uncertainties. Further effort should prioritize understanding dominant, undersampled dimensions of uncertainty, as well as the strategic collection of observations to quantify, and ultimately reduce, uncertainties. Our proposed framework will improve our understanding of future changes in LMR and the resulting risk of impacts to ecosystems and the societies under changing ocean conditions.
  • Dwivedi, Om Prakash, et al. (författare)
  • Loss of ZnT8 function protects against diabetes by enhanced insulin secretion
  • Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036. ; , s. 1-22
  • Tidskriftsartikel (refereegranskat)abstract
    • A rare loss-of-function allele p.Arg138* in SLC30A8 encoding the zinc transporter 8 (ZnT8), which is enriched in Western Finland, protects against type 2 diabetes (T2D). We recruited relatives of the identified carriers and showed that protection was associated with better insulin secretion due to enhanced glucose responsiveness and proinsulin conversion, particularly when compared with individuals matched for the genotype of a common T2D-risk allele in SLC30A8, p.Arg325. In genome-edited human induced pluripotent stem cell (iPSC)-derived β-like cells, we establish that the p.Arg138* allele results in reduced SLC30A8 expression due to haploinsufficiency. In human β cells, loss of SLC30A8 leads to increased glucose responsiveness and reduced KATP channel function similar to isolated islets from carriers of the T2D-protective allele p.Trp325. These data position ZnT8 as an appealing target for treatment aimed at maintaining insulin secretion capacity in T2D.
  • Kwan, Johnny S H, et al. (författare)
  • Meta-analysis of genome-wide association studies identifies two loci associated with circulating osteoprotegerin levels.
  • 2014
  • Ingår i: Human Molecular Genetics. - 0964-6906 .- 1460-2083. ; 23:24, s. 6684-93
  • Tidskriftsartikel (refereegranskat)abstract
    • Osteoprotegerin (OPG) is involved in bone homeostasis and tumor cell survival. Circulating OPG levels are also important biomarkers of various clinical traits, such as cancers and atherosclerosis. OPG levels were measured in serum or in plasma. In a meta-analysis of genome-wide association studies in up to 10,336 individuals from European and Asian origin, we discovered that variants >100 Kb upstream of the TNFRSF11B gene encoding OPG and another new locus on chromosome 17q11.2 were significantly associated with OPG variation. We also identified a suggestive locus on chromosome 14q21.2 associated with the trait. Moreover, we estimated that over half of the heritability of OPG levels could be explained by all variants examined in our study. Our findings provide further insight into the genetic regulation of circulating OPG levels.
  • Mastropaolo, Enrico, et al. (författare)
  • Electrothermal actuation of silicon carbide ring resonators
  • 2009
  • Ingår i: Journal of Vacuum Science & Technology B. - 1071-1023 .- 1520-8567. ; 27:6, s. 3109-3114
  • Tidskriftsartikel (refereegranskat)abstract
    • Silicon carbide (SiC) ring resonators have been designed, simulated, and fabricated in order to achieve higher resonant frequency compared to beam resonators. The resonant frequency as a function of the ring radius and central hole radius, as well as the influence of the electrode design on the actuation efficiency have been investigated. Aluminum (Al) electrodes have been fabricated on top of the structures in order to study the electrothermal actuation of the structures. The bimorph Al/SiC ring resonators have been constructed by etching the SiC in inductively coupled plasma. The release of the Si sacrificial layer has been performed with a XeF2 chemical etching. The radial release and area release have been characterized as a function of the central hole dimension at chamber pressure of 1 and 2 Torr, whereby the release rates have been found to increase as the hole dimensions and the etching pressure increases. In addition, the release process has shown to be governed by aperture effects. The rings fabricated with different dimensions have been actuated mechanically and electrothermally, and the resonant frequency detected optically. The resonant frequency has been shown to increase as the ring radius decreases and the hole radius increases, both theoretically and experimentally.
  • Mastropaolo, Enrico, et al. (författare)
  • Fabrication of beam resonators from hot-wall chemical vapour deposited SiC
  • 2009
  • Ingår i: Microelectronic Engineering, Vol. 86. ; , s. 1194-1196
  • Konferensbidrag (refereegranskat)abstract
    • Single crystal and polycrystalline 3C-SiC have been grown in a hot-wall chemical vapour deposition reactor on 100 mm diameter p-type boron-doped (100) Si wafer. The crystal structure of the films has been determined by X-ray diffraction. Moreover, cantilever resonators have been fabricated from the two grown 3C-SiC films using a one-step dry etch and release process. The designed beam length has been varied between 50 and 200 mu m. Resonant frequencies in the range between 110 kHz-1.5 MHz and 50-750 kHz have been obtained for single crystal and polycrystalline Sic devices, respectively. Furthermore, the experimental resonance frequencies have been used to calculate Youngs Modulus E for both types of SiC. The single crystal Sic has shown a relatively high Youngs Modulus (446 GPa) and should be an optimal material for RF-MEMS applications. (c) 2008 Elsevier B.V. All rights reserved.
  • Nikoopour, Enayat, et al. (författare)
  • Vasostatin-1 antigenic epitope mapping for induction of cellular and humoral immune responses to chromogranin A autoantigen in NOD mice
  • 2014
  • Ingår i: European Journal of Immunology. - 0014-2980 .- 1521-4141. ; 44:4, s. 1170-1180
  • Tidskriftsartikel (refereegranskat)abstract
    • The chromogranin A (ChgA) 29-42 sequence is the antigenic epitope for the BDC2.5 CD4(+) T-cell receptor in NOD mice (H-2(g7)). We have now characterized the binding register of the ChgA 29-42 peptide for the I-A(g7) molecule. Truncation of the peptide demonstrated that the KCVLEVISD sequence 34-42 is the binding register and extension of this sequence by flanking residues increased its binding affinity and antigenic capacity. We employed anti-ChgA peptide antibodies generated against different fragments of ChgA for immunostaining of pancreatic islet sections from NOD mice. A strong immuno-staining pattern was observed for the ChgA 17-38 peptide antibodies that overlap with the ChgA 29-42 sequence. Moreover, sera from diabetic NOD mice showed elevated titers of autoantibodies to the ChgA 29-42 peptide. These findings indicate that peptides from the N-terminal region of ChgA are able to induce cellular and humoral immune responses in NOD mice.
  • Sodergren, Erica, et al. (författare)
  • The genome of the sea urchin Strongylocentrotus purpuratus.
  • 2006
  • Ingår i: Science. - : American Association for the Advancement of Science. - 1095-9203 .- 0036-8075. ; 314:5801, s. 941-52
  • Tidskriftsartikel (refereegranskat)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.
  • Tremblay, Mark S, et al. (författare)
  • Sedentary Behavior Research Network (SBRN) - Terminology Consensus Project process and outcome.
  • 2017
  • Ingår i: The international journal of behavioral nutrition and physical activity. - 1479-5868. ; 14:1
  • Tidskriftsartikel (refereegranskat)abstract
    • The prominence of sedentary behavior research in health science has grown rapidly. With this growth there is increasing urgency for clear, common and accepted terminology and definitions. Such standardization is difficult to achieve, especially across multi-disciplinary researchers, practitioners, and industries. The Sedentary Behavior Research Network (SBRN) undertook a Terminology Consensus Project to address this need.First, a literature review was completed to identify key terms in sedentary behavior research. These key terms were then reviewed and modified by a Steering Committee formed by SBRN. Next, SBRN members were invited to contribute to this project and interested participants reviewed and provided feedback on the proposed list of terms and draft definitions through an online survey. Finally, a conceptual model and consensus definitions (including caveats and examples for all age groups and functional abilities) were finalized based on the feedback received from the 87 SBRN member participants who responded to the original invitation and survey.Consensus definitions for the terms physical inactivity, stationary behavior, sedentary behavior, standing, screen time, non-screen-based sedentary time, sitting, reclining, lying, sedentary behavior pattern, as well as how the terms bouts, breaks, and interruptions should be used in this context are provided.It is hoped that the definitions resulting from this comprehensive, transparent, and broad-based participatory process will result in standardized terminology that is widely supported and adopted, thereby advancing future research, interventions, policies, and practices related to sedentary behaviors.
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