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- 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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- 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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- 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. - : 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.
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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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