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| 2. |
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| 3. |
- Vaicik, M. K., et al.
(författare)
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Laminin alpha 4 Deficient Mice Exhibit Decreased Capacity for Adipose Tissue Expansion and Weight Gain
- 2014
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Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 9:10
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Tidskriftsartikel (refereegranskat)abstract
- Obesity is a global epidemic that contributes to the increasing medical burdens related to type 2 diabetes, cardiovascular disease and cancer. A better understanding of the mechanisms regulating adipose tissue expansion could lead to therapeutics that eliminate or reduce obesity-associated morbidity and mortality. The extracellular matrix (ECM) has been shown to regulate the development and function of numerous tissues and organs. However, there is little understanding of its function in adipose tissue. In this manuscript we describe the role of laminin alpha 4, a specialized ECM protein surrounding adipocytes, on weight gain and adipose tissue function. Adipose tissue accumulation, lipogenesis, and structure were examined in mice with a null mutation of the laminin alpha 4 gene (Lama4(+/+)) and compared to wild-type (Lama4(+/+)) control animals. Lama4(-/-) mice exhibited reduced weight gain in response to both age and high fat diet. Interestingly, the mice had decreased adipose tissue mass and altered lipogenesis in a depot-specific manner. In particular, epididymal adipose tissue mass was specifically decreased in knock-out mice, and there was also a defect in lipogenesis in this depot as well. In contrast, no such differences were observed in subcutaneous adipose tissue at 14 weeks. The results suggest that laminin alpha 4 influences adipose tissue structure and function in a depot-specific manner. Alterations in laminin composition offers insight into the roll the ECM potentially plays in modulating cellular behavior in adipose tissue expansion.
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| 4. |
- Barba, D., et al.
(författare)
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A thermodynamically consistent constitutive model for diffusion-assisted plasticity in Ni-based superalloys
- 2018
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Ingår i: International journal of plasticity. - : PERGAMON-ELSEVIER SCIENCE LTD. - 0749-6419 .- 1879-2154. ; 105, s. 74-98
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Tidskriftsartikel (refereegranskat)abstract
- An elasto-viscoplastic thermodynamically consistent constitutive model for diffusion-assisted phase transformations is presented here. The model accounts for the different deformation mechanisms, their time dependence, the crystal rotations produced by microtwin propagation and the chemistry-plasticity coupling occurring at high temperature. It is applied to the study of the chemically assisted microtwinning observed in Ni-based superalloys in the temperature range of 600-800 degrees C. The model parameters are calibrated against multi-directional mechanical data from tensile creep tests of single crystal superalloy MD2. The constitutive model is then implemented into a crystal plasticity finite element code to study the activation of the different deformation mechanisms within single crystal and polycrystalline aggregates. Doing so, a relation between the rotations of the crystal and the creep life of the different crystal orientations is established. The results eventually reveal the critical role of the strong anisotropy of microtwin formation on the asymmetric behavior of the alloy and its relevant role on the mechanical performance.
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| 5. |
- Brommage, Robert, et al.
(författare)
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NOTUM inhibition increases endocortical bone formation and bone strength
- 2019
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Ingår i: Bone Research. - : Springer Science and Business Media LLC. - 2095-4700 .- 2095-6231. ; 7:2
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Tidskriftsartikel (refereegranskat)abstract
- The disability, mortality and costs caused by non-vertebral osteoporotic fractures are enormous. Existing osteoporosis therapies are highly effective at reducing vertebral but not non-vertebral fractures. Cortical bone is a major determinant of non-vertebral bone strength. To identify novel osteoporosis drug targets, we phenotyped cortical bone of 3 366 viable mouse strains with global knockouts of druggable genes. Cortical bone thickness was substantially elevated in Notum(-/-) mice. NOTUM is a secreted WNT lipase and we observed high NOTUM expression in cortical bone and osteoblasts but not osteoclasts. Three orally active small molecules and a neutralizing antibody inhibiting NOTUM lipase activity were developed. They increased cortical bone thickness and strength at multiple skeletal sites in both gonadal intact and ovariectomized rodents by stimulating endocortical bone formation. Thus, inhibition of NOTUM activity is a potential novel anabolic therapy for strengthening cortical bone and preventing non-vertebral fractures.
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| 6. |
- Chen, Z., et al.
(författare)
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Plastic Deformation and Residual Stress in High Speed Turning of AD730™ Nickel-based Superalloy with PCBN and WC Tools
- 2018
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Ingår i: Procedia CIRP. - AMSTERDAM, NETHERLANDS : Elsevier BV. - 2212-8271. ; 71, s. 440-445, s. 440-445
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Konferensbidrag (refereegranskat)abstract
- A higher gas turbine efficiency can be achieved by increasing the operating temperature in hot sections. AD730™ is a recently-developed wrought/cast nickel-based superalloy which can maintain excellent mechanical properties above 700. However, machining of AD730™ could be a difficult task like other nickel-based superalloys. Therefore, studies are needed with respect to the machinability of this new alloy. In this paper, high-speed turning was performed on AD730™ using polycrystalline cubic boron nitride (PCBN) tools and coated tungsten carbide (WC) tools at varied cutting speeds. The surface integrity was assessed in two important aspects, i.e., surface and sub-surface plastic deformation and residual stresses. The PCBN tools generally showed better performance compared with the WC tools since it led to reduced machining time without largely compromising the surface integrity achieved. The optimal cutting speed was identified in the range of 200-250 m/min when using the PCBN tools, which gives rise to a good combination of machining efficiency and surface integrity. The further increase of the cutting speed to 300 m/min resulted in severe and deep plastic deformation. Meanwhile, a continuous white layer was formed at the machined surface. When turning with the WC tools, the increased cutting speed from 80 m/min to 100 m/min showed very little effect with respect to the plastic deformation on the machined surface. It was found that tensile residual stresses were developed on all machined surfaces no matter when the PCBN or WC tools were used, and the surface tension was generally increased with increasing cutting speed. The tensile layer might need to be modified by e.g., post-machining surface treatments such as shot peening, if taking good fatigue performance into consideration.
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| 7. |
- Farman, Helen H., 1983, et al.
(författare)
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Membrane estrogen receptor alpha is essential for estrogen signaling in the male skeleton
- 2018
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Ingår i: Journal of Endocrinology. - : Bioscientifica. - 0022-0795 .- 1479-6805. ; 239:3, s. 303-312
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Tidskriftsartikel (refereegranskat)abstract
- The importance of estrogen receptor alpha (ER alpha) for the regulation of bone mass in males is well established. ERa mediates estrogenic effects both via nuclear and membraneinitiated ER alpha (mER alpha) signaling. The role of mERa signaling for the effects of estrogen on bone in male mice is unknown. To investigate the role of mERa signaling, we have used mice (Nuclear-Only-ER; NOER) with a point mutation (C451A), which results in inhibited trafficking of ER alpha to the plasma membrane. Gonadal-intact male NOER mice had a significantly decreased total body areal bone mineral density (aBMD) compared to WT littermates at 3, 6 and 9 months of age as measured by dual-energy X-ray absorptiometry (DEXA). High-resolution microcomputed tomography (mu CT) analysis of tibia in 3-month-old males demonstrated a decrease in cortical and trabecular thickness in NOER mice compared to WT littermates. As expected, estradiol (E2) treatment of orchidectomized (ORX) WT mice increased total body aBMD, trabecular BV/TV and cortical thickness in tibia compared to placebo treatment. E2 treatment increased these skeletal parameters also in ORX NOER mice. However, the estrogenic responses were significantly decreased in ORX NOER mice compared with ORX WT mice. In conclusion, mER alpha is essential for normal estrogen signaling in both trabecular and cortical bone in male mice. Increased knowledge of estrogen signaling mechanisms in the regulation of the male skeleton may aid in the development of new treatment options for male osteoporosis.
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| 8. |
- Gustafsson, Karin L., 1987, et al.
(författare)
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The role of membrane ER alpha signaling in bone and other major estrogen responsive tissues
- 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
- Estrogen receptor a (ER alpha) signaling leads to cellular responses in several tissues and in addition to nuclear ER alpha-mediated effects, membrane ER alpha (mER alpha) signaling may be of importance. To elucidate the significance, in vivo, of mER alpha signaling in multiple estrogen-responsive tissues, we have used female mice lacking the ability to localize ER alpha to the membrane due to a point mutation in the palmitoylation site (C451A), so called Nuclear-Only-ER (NOER) mice. Interestingly, the role of mER alpha signaling for the estrogen response was highly tissue-dependent, with trabecular bone in the axial skeleton being strongly dependent (>80% reduction in estrogen response in NOER mice), cortical and trabecular bone in long bones, as well as uterus and thymus being partly dependent (40-70% reduction in estrogen response in NOER mice) and effects on liver weight and total body fat mass being essentially independent of mER alpha (<35% reduction in estrogen response in NOER mice). In conclusion, mER alpha signaling is important for the estrogenic response in female mice in a tissue-dependent manner. Increased knowledge regarding membrane initiated ER alpha actions may provide means to develop new selective estrogen receptor modulators with improved profiles.
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| 9. |
- Henning, Petra, 1974, et al.
(författare)
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The novel cytotoxic polybisphosphonate osteodex decreases bone resorption by enhancing cell death of mature osteoclasts without affecting osteoclastogenesis of RANKL-stimulated mouse bone marrow macrophages
- 2024
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Ingår i: INVESTIGATIONAL NEW DRUGS. - : Springer. - 0167-6997 .- 1573-0646. ; 42, s. 207-220
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Tidskriftsartikel (refereegranskat)abstract
- It has previously been demonstrated that the polybisphosphonate osteodex (ODX) inhibits bone resorption in organ-cultured mouse calvarial bone. In this study, we further investigate the effects by ODX on osteoclast differentiation, formation, and function in several different bone organ and cell cultures. Zoledronic acid (ZOL) was used for comparison. In retinoid-stimulated mouse calvarial organ cultures, ODX and ZOL significantly reduced the numbers of periosteal osteoclasts without affecting Tnfsf11 or Tnfrsf11b mRNA expression. ODX and ZOL also drastically reduced the numbers of osteoclasts in cell cultures isolated from the calvarial bone and in vitamin D3-stimulated mouse crude bone marrow cell cultures. These data suggest that ODX can inhibit osteoclast formation by inhibiting the differentiation of osteoclast progenitor cells or by directly targeting mature osteoclasts. We therefore assessed if osteoclast formation in purified bone marrow macrophage cultures stimulated by RANKL was inhibited by ODX and ZOL and found that the initial formation of mature osteoclasts was not affected, but that the bisphosphonates enhanced cell death of mature osteoclasts. In agreement with these findings, ODX and ZOL did not affect the mRNA expression of the osteoclastic genes Acp5 and Ctsk and the osteoclastogenic transcription factor Nfatc1. When bone marrow macrophages were incubated on bone slices, ODX and ZOL inhibited RANKL-stimulated bone resorption. In conclusion, ODX does not inhibit osteoclast formation but inhibits osteoclastic bone resorption by decreasing osteoclast numbers through enhanced cell death of mature osteoclasts.
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| 10. |
- Jiang, S., et al.
(författare)
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Micromechanical behavior of multilayered Ti/Nb composites processed by accumulative roll bonding : An in-situ synchrotron X-ray diffraction investigation
- 2021
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Ingår i: Acta Materialia. - Oxford, United Kingdom : Elsevier. - 1359-6454 .- 1873-2453. ; 205
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Tidskriftsartikel (refereegranskat)abstract
- Heterophase interfaces play a crucial role in deformation microstructures and thus govern mechanical properties of multilayered composites. Here, we fabricated Ti/Nb multilayers by accumulative roll bonding (ARB) where shear bands became predominant with increasing rolling cycles. To explore correlation between micromechanical behavior and mechanical properties of the composites with various lamellar morphologies, in-situ high-energy X-ray diffraction tensile tests were performed. The results quantitatively reveal that the rapid strengthening of the composites with increasing ARB cycles mainly originates from the Nb layers strengthened by dislocations, grain boundaries and heterophase interfaces, and the {211} grains mostly contribute to the global strain hardening. The softer Ti grains also extend global strain hardening to a wide range and postpone necking. Furthermore, complete stress state analysis show that in the presence of extensive shear bands, significant load partitioning between the neighboring metals leads to triaxial stresses in each constituent and dislocations tend to slip along the shear direction. This promotes dislocation multiplication and motion, which is conducive to overall strength enhancement while maintaining a satisfactory ductility. These findings elucidate the effect of strong constraints of the interfaces on mechanical properties, which provides a fundamental understanding of load partitioning and strengthening mechanisms of the multilayers processed by multiple ARB cycles.
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| 11. |
- Karsten, Carley, et al.
(författare)
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Evaluating the Performance of Two Automated Anti-drug Antibodies Assays for Infliximab and Adalimumab Without Acid Dissociation
- 2024
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Ingår i: AAPS Journal. - : Springer. - 1550-7416. ; 26:5
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Tidskriftsartikel (refereegranskat)abstract
- Monitoring anti-drug antibodies (ADAs) to infliximab and adalimumab is critical to treatment management in various autoimmune disorders. The growing need for proactive therapeutic monitoring further requires the detection of ADAs in the presence of measurable concentrations of infliximab or adalimumab. To provide robust analytical assays for clinical application, we evaluated two automated immunoassays developed using ImmunoCAP™ technology and based on the bridging format to measure serum ADAs to infliximab and adalimumab respectively. Without an acid-dissociation step, these research prototype assays can detect a positive control monoclonal ADA towards infliximab and adalimumab, ranging from < 25 ng/ml to 10,000 ng/mL. Both assays exhibit imprecision less than 20% at different ADA titer levels and can distinguish ADAs towards different drug targets. In method comparison using authentic patient samples, the quantitative results of the ADA assays are not directly comparable to two existing clinical immunoassays for ADAs (correlation coefficient rs = 0.673 for infliximab ADAs; rs = 0.510 for adalimumab ADAs), presumably due to the lack of commutable ADA standards and the polyclonal nature of ADAs. Nevertheless, there is qualitative agreement between the methods when evaluating putative positive and negative patient samples (overall agreement 0.83 for infliximab ADAs; 0.76 for adalimumab ADAs). Biotin and high levels of rheumatoid factors may interfere with the performance of the automated assays due to competitive binding with the biotinylated drug and non-specific formation of bridging complexes. The two ImmunoCAP assays can provide new analytical methods for proactive therapeutic monitoring of adalimumab and infliximab.
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| 12. |
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| 13. |
- Lundholm, Lovisa, et al.
(författare)
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Gene expression profiling identifies liver X receptor alpha as an estrogen-regulated gene in mouse adipose tissue.
- 2004
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Ingår i: Journal of molecular endocrinology. - : Bioscientifica. - 0952-5041 .- 1479-6813. ; 32:3, s. 879-92
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Tidskriftsartikel (refereegranskat)abstract
- Estrogens reduce adipose tissue mass in both humans and animals. The molecular mechanisms for this effect are, however, not well characterized. We took a gene expression profiling approach to study the direct effects of estrogen on mouse white adipose tissue (WAT). Female ovariectomized mice were treated for 10, 24 and 48 h with 17beta-estradiol or vehicle. RNA was extracted from gonadal fat and hybridized to Affymetrix MG-U74Av2 arrays. 17beta-Estradiol was shown to decrease mRNA expression of liver X receptor (LXR) alpha after 10 h of treatment compared with the vehicle control. The expression of several LXRalpha target genes, such as sterol regulatory element-binding protein 1c, apolipoprotein E, phospholipid transfer protein, ATP-binding cassette A1 and ATP-binding cassette G1, was similarly decreased. We furthermore identified a 1.5 kb LXRalpha promoter fragment that is negatively regulated by estrogen. Several genes involved in lipogenesis and lipolysis were identified as novel targets that could mediate estrogenic effects on adipose tissue. Finally, we show that ERalpha is the main estrogen receptor expressed in mouse white adipose tissue (WAT) with mRNA levels several hundred times higher than those of ERbeta mRNA.
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| 14. |
- Moverare, Johan, 1973-, et al.
(författare)
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A New Single Crystal Superalloy for Power Generation Applications :
- 2011
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Ingår i: Proceeding of the 8th International Charles Parsons TurbineConference 2011. ; , s. G2-2-
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Konferensbidrag (refereegranskat)abstract
- A newly developed single crystal superalloy (known as STAL15) is described which is suitable for use in first stage blades of highly efficient industrial gas turbines (IGTs). With 15 wt% Cr and 4.55 wt% Al, the alloy combines good corrosion and oxidation resistance with sufficient creep and fatigue performance. Thus a novel and useful balance of environmental and mechanical properties is displayed. In this paper, the details of the development project are described. The new alloy is shown to be an alumina (Al2O3) former; the mechanisms behind the Al2O3-formation process are studied and the effects arising from changes in the chemical composition have been modelled. In addition, the mechanical properties in terms of creep and fatigue resistance are evaluated together with the alloy stability during long term (up to 10,000 hours) exposure. For such applications, the new alloy is superior to existing nickel-based single crystal superalloys designed for aero engine applications and which are optimized for very high creep resistance; experience has shown that they are not ideal for use in IGTs of the type used for power generation or mechanical drive, due to their low corrosion resistance. The main reason for this is that IGTs are exposed to more harsh conditions in terms of air quality through the turbine and significantly longer time between overhaul/inspection. Traditionally this has been handled by use of polycrystalline alloys such as IN792 and IN738LC or the single crystal alloy PWA1484; unfortunately these do not form a protective Al2O3 layer and hence display limited resistance to environmental degradation. The new alloy does not display this weakness and is therefore highly optimised for IGT applications.
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| 19. |
- Nilsson, Karin H., et al.
(författare)
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RSPO3 is important for trabecular bone and fracture risk in mice and humans
- 2021
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Genetic association signals for fractures have been reported at the RSPO3 locus, but the causal gene and the underlying mechanism are unknown. Here, the authors show that RSPO3 exerts an important role for vertebral trabecular bone mass and bone strength in mice and fracture risk in humans. With increasing age of the population, countries across the globe are facing a substantial increase in osteoporotic fractures. Genetic association signals for fractures have been reported at the RSPO3 locus, but the causal gene and the underlying mechanism are unknown. Here we show that the fracture reducing allele at the RSPO3 locus associate with increased RSPO3 expression both at the mRNA and protein levels, increased trabecular bone mineral density and reduced risk mainly of distal forearm fractures in humans. We also demonstrate that RSPO3 is expressed in osteoprogenitor cells and osteoblasts and that osteoblast-derived RSPO3 is the principal source of RSPO3 in bone and an important regulator of vertebral trabecular bone mass and bone strength in adult mice. Mechanistic studies revealed that RSPO3 in a cell-autonomous manner increases osteoblast proliferation and differentiation. In conclusion, RSPO3 regulates vertebral trabecular bone mass and bone strength in mice and fracture risk in humans.
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| 20. |
- Stekovic, Svjetlana, et al.
(författare)
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DevTMF - Towards code of practice for thermo-mechanical fatigue crack growth
- 2020
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Ingår i: International Journal of Fatigue. - : ELSEVIER SCI LTD. - 0142-1123 .- 1879-3452. ; 138
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Tidskriftsartikel (refereegranskat)abstract
- The current paper presents work on identification and evaluation of a range of factors influencing accuracy and comparability of data generated by three laboratories carrying out stress-controlled thermo-mechanical fatigue crack growth tests. It addresses crack length measurements, heating methods and temperature measurement techniques. It also provides guidance for pre-cracking and use of different specimen geometries as well as Digital Image Correlation imaging for crack monitoring. The majority of the tests have been carried out on a coarse grain polycrystalline nickel-base superalloy using two phase angles, Out-of-Phase and In-Phase cycles with a triangular waveform and a temperature range of 400-750 degrees C.
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| 21. |
- Zheng, Hou-Feng, et al.
(författare)
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WNT16 influences bone mineral density, Cortical bone thickness, bone strength, and Osteoporotic fracture risk
- 2012
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Ingår i: PLoS genetics. - SAN FRANCISCO, USA : PUBLIC LIBRARY SCIENCE. - 1553-7404. ; 8:7, s. e1002745-
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Tidskriftsartikel (refereegranskat)abstract
- We aimed to identify genetic variants associated with cortical bone thickness (CBT) and bone mineral density (BMD) by performing two separate genome-wide association study (GWAS) meta-analyses for CBT in 3 cohorts comprising 5,878 European subjects and for BMD in 5 cohorts comprising 5,672 individuals. We then assessed selected single-nucleotide polymorphisms (SNPs) for osteoporotic fracture in 2,023 cases and 3,740 controls. Association with CBT and forearm BMD was tested for ∼2.5 million SNPs in each cohort separately, and results were meta-analyzed using fixed effect meta-analysis. We identified a missense SNP (Thr>Ile; rs2707466) located in the WNT16 gene (7q31), associated with CBT (effect size of -0.11 standard deviations [SD] per C allele, P = 6.2×10(-9)). This SNP, as well as another nonsynonymous SNP rs2908004 (Gly>Arg), also had genome-wide significant association with forearm BMD (-0.14 SD per C allele, P = 2.3×10(-12), and -0.16 SD per G allele, P = 1.2×10(-15), respectively). Four genome-wide significant SNPs arising from BMD meta-analysis were tested for association with forearm fracture. SNP rs7776725 in FAM3C, a gene adjacent to WNT16, was associated with a genome-wide significant increased risk of forearm fracture (OR = 1.33, P = 7.3×10(-9)), with genome-wide suggestive signals from the two missense variants in WNT16 (rs2908004: OR = 1.22, P = 4.9×10(-6) and rs2707466: OR = 1.22, P = 7.2×10(-6)). We next generated a homozygous mouse with targeted disruption of Wnt16. Female Wnt16(-/-) mice had 27% (P<0.001) thinner cortical bones at the femur midshaft, and bone strength measures were reduced between 43%-61% (6.5×10(-13)
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