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- Miguel-Escalada, Irene, et al.
(author)
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Human pancreatic islet three-dimensional chromatin architecture provides insights into the genetics of type 2 diabetes
- 2019
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 51:7, s. 1137-1148
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Journal article (peer-reviewed)abstract
- Genetic studies promise to provide insight into the molecular mechanisms underlying type 2 diabetes (T2D). Variants associated with T2D are often located in tissue-specific enhancer clusters or super-enhancers. So far, such domains have been defined through clustering of enhancers in linear genome maps rather than in three-dimensional (3D) space. Furthermore, their target genes are often unknown. We have created promoter capture Hi-C maps in human pancreatic islets. This linked diabetes-associated enhancers to their target genes, often located hundreds of kilobases away. It also revealed >1,300 groups of islet enhancers, super-enhancers and active promoters that form 3D hubs, some of which show coordinated glucose-dependent activity. We demonstrate that genetic variation in hubs impacts insulin secretion heritability, and show that hub annotations can be used for polygenic scores that predict T2D risk driven by islet regulatory variants. Human islet 3D chromatin architecture, therefore, provides a framework for interpretation of T2D genome-wide association study (GWAS) signals.
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- Valero, C., et al.
(author)
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Challenges in the Modeling of Wound Healing Mechanisms in Soft Biological Tissues
- 2015
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In: Annals of Biomedical Engineering. - : Springer Science and Business Media LLC. - 1573-9686 .- 0090-6964. ; 43:7, s. 1654-1665
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Journal article (peer-reviewed)abstract
- Numerical models have become one of the most powerful tools in biomechanics and mechanobiology allowing highly detailed simulations. One of the fields in which they have broadly evolved during the last years is in soft tissue modeling. Particularly, wound healing in the skin is one of the processes that has been approached by computational models due to the difficulty of performing experimental investigations. During the last decades wound healing simulations have evolved from numerical models which considered only a few number of variables and simple geometries to more complex approximations that take into account a higher number of factors and reproduce more realistic geometries. Moreover, thanks to improved experimental observations, a larger number of processes, such as cellular stress generation or vascular growth, that take place during wound healing have been identified and modeled. This work presents a review of the most relevant wound healing approximations, together with an identification of the most relevant criteria that can be used to classify them. In addition, and looking towards the actual state of the art in the field, some future directions, challenges and improvements are analyzed for future developments.
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- Valero, C., et al.
(author)
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Modeling of anisotropic wound healing
- 2015
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In: Journal of the Mechanics and Physics of Solids. - : Elsevier BV. - 1873-4782 .- 0022-5096. ; 79, s. 80-91
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Journal article (peer-reviewed)abstract
- Biological soft tissues exhibit non-linear complex properties, the quantification of which presents a challenge. Nevertheless, these properties, such as skin anisotropy, highly influence different processes that occur in soft tissues, for instance wound healing, and thus its correct identification and quantification is crucial to understand them. Experimental and computational works are required in order to find the most precise model to replicate the tissues' properties. In this work, we present a wound healing model focused on the proliferative stage that includes angiogenesis and wound contraction in three dimensions and which relies on the accurate representation of the mechanical behavior of the skin. Thus, an anisotropic hyperelastic model has been considered to analyze the effect of collagen fibers on the healing evolution of an ellipsoidal wound. The implemented model accounts for the contribution of the ground matrix and two mechanically equivalent families of fibers. Simulation results show the evolution of the cellular and chemical species in the wound and the wound volume evolution. Moreover, the local strain directions depend on the relative wound orientation with respect to the fibers. (C) 2015 Elsevier Ltd. All rights reserved.
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