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- Baranasic, D, et al.
(författare)
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Multiomic atlas with functional stratification and developmental dynamics of zebrafish cis-regulatory elements
- 2022
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 54:7, s. 1037-
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Tidskriftsartikel (refereegranskat)abstract
- Zebrafish, a popular organism for studying embryonic development and for modeling human diseases, has so far lacked a systematic functional annotation program akin to those in other animal models. To address this, we formed the international DANIO-CODE consortium and created a central repository to store and process zebrafish developmental functional genomic data. Our data coordination center (https://danio-code.zfin.org) combines a total of 1,802 sets of unpublished and re-analyzed published genomic data, which we used to improve existing annotations and show its utility in experimental design. We identified over 140,000 cis-regulatory elements throughout development, including classes with distinct features dependent on their activity in time and space. We delineated the distinct distance topology and chromatin features between regulatory elements active during zygotic genome activation and those active during organogenesis. Finally, we matched regulatory elements and epigenomic landscapes between zebrafish and mouse and predicted functional relationships between them beyond sequence similarity, thus extending the utility of zebrafish developmental genomics to mammals.
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| 4. |
- Bergström, I., et al.
(författare)
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Compressive loading of the murine tibia reveals site-specific micro-scale differences in adaptation and maturation rates of bone
- 2017
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Ingår i: Osteoporosis International. - : Springer Science and Business Media LLC. - 0937-941X .- 1433-2965. ; 28:3, s. 1121-1131
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Tidskriftsartikel (refereegranskat)abstract
- Summary: Loading increases bone mass and strength in a site-specific manner; however, possible effects of loading on bone matrix composition have not been evaluated. Site-specific structural and material properties of mouse bone were analyzed on the macro- and micro/molecular scale in the presence and absence of axial loading. The response of bone to load is heterogeneous, adapting at molecular, micro-, and macro-levels. Introduction: Osteoporosis is a degenerative disease resulting in reduced bone mineral density, structure, and strength. The overall aim was to explore the hypothesis that changes in loading environment result in site-specific adaptations at molecular/micro- and macro-scale in mouse bone. Methods: Right tibiae of adult mice were subjected to well-defined cyclic axial loading for 2 weeks; left tibiae were used as physiologically loaded controls. The bones were analyzed with μCT (structure), reference point indentation (material properties), Raman spectroscopy (chemical), and small-angle X-ray scattering (mineral crystallization and structure). Results: The cranial and caudal sites of tibiae are structurally and biochemically different within control bones. In response to loading, cranial and caudal sites increase in cortical thickness with reduced mineralization (−14 and −3%, p < 0.01, respectively) and crystallinity (−1.4 and −0.3%, p < 0.05, respectively). Along the length of the loaded bones, collagen content becomes more heterogeneous on the caudal site and the mineral/collagen increases distally at both sites. Conclusion: Bone structure and composition are heterogeneous, finely tuned, adaptive, and site-specifically responsive at the micro-scale to maintain optimal function. Manipulation of this heterogeneity may affect bone strength, relative to specific applied loads.
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- Mathavan, N., et al.
(författare)
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Do osteoporotic fractures constitute a greater recalcitrant challenge for skeletal regeneration? Investigating the efficacy of BMP-7 and zoledronate treatment of diaphyseal fractures in an open fracture osteoporotic rat model
- 2017
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Ingår i: Osteoporosis International. - : Springer Science and Business Media LLC. - 0937-941X .- 1433-2965. ; 28:2, s. 697-707
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Tidskriftsartikel (refereegranskat)abstract
- Summary: Osteoporotic fractures may pose a challenge for skeletal regeneration. This study investigates if pharmaceutical interventions such as bone morphogenetic protein 7 (BMP-7) alone or in combination with Zoledronate have equivalent efficacy in osteoporotic bone? Our findings suggest they do and that an osteoporotic bone environment may increase sensitivity to BMP-7. Introduction: Osteoporosis is thought to contribute to delayed or impaired bone healing. Bone morphogenetic protein 7 (BMP-7) alone or synergistically combined with zoledronate (ZA) has proven effective in augmenting the regenerative response in healthy young male rats. Yet their comparative efficacy in an osteoporotic bone environment is unknown. Our study aimed to answer the following questions using the ovariectomized (OVX) rat model of osteoporosis: Do osteoporotic fractures pose a greater challenge for skeletal regeneration? Are interventions with BMP-7-alone or combined with ZA of equivalent efficacy in osteoporotic bone? Methods: Sham operations (n = 33) or ovariectomies (n = 34) were performed in 12-week-old female Sprague-Dawley rats. Mid-diaphyseal open femoral osteotomies were created at 24 weeks of age and the rats allocated to either (i) untreated, (ii) BMP-7-only or (iii) BMP-7 + ZA treatment groups. At 6 weeks post-osteotomy, fracture healing was evaluated by radiography, μCT and 3-point bending mechanical tests. Results: Cumulatively, radiological, micro-structural and mechanical measures were equivalent in both healthy and osteoporotic environments. A reduced response to BMP-7-alone was observed in healthy rats that may be age/gender- or protocol/fracture-model dependent. Conversely, the BMP-7-only treated OVX group attained 100 % union in addition to significantly increased measures of mineralized bone volume, total callus volume, peak force and absorbed energy relative to untreated OVX fractures. Conclusions: Our findings refute the hypothesis that osteoporotic fractures constitute a greater recalcitrant challenge for skeletal regeneration. Furthermore, our results suggest that an oestrogen-deficient environment may in fact cause an increased sensitivity to BMP-7.
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