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      Structural and compositional diversity of fibrillin microfibrils in human tissues

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          Abstract

          Elastic fibers comprising fibrillin microfibrils and elastin are present in many tissues, including the skin, lungs, and arteries, where they confer elasticity and resilience. Although fibrillin microfibrils play distinct and tissue-specific functional roles, it is unclear whether their ultrastructure and composition differ between elastin-rich (skin) and elastin-poor (ciliary body and zonule) organs or after in vitro synthesis by cultured cells. Here, we used atomic force microscopy, which revealed that the bead morphology of fibrillin microfibrils isolated from the human eye differs from those isolated from the skin. Using newly developed pre-MS preparation methods and LC-MS/MS, we detected tissue-specific regions of the fibrillin-1 primary structure that were differentially susceptible to proteolytic extraction. Comparing tissue- and culture-derived microfibrils, we found that dermis- and dermal fibroblast–derived fibrillin microfibrils differ in both bead morphology and periodicity and also exhibit regional differences in fibrillin-1 proteolytic susceptibility. In contrast, collagen VI microfibrils from the same dermal or fibroblast samples were invariant in ultrastructure (periodicity) and protease susceptibility. Finally, we observed that skin- and eye-derived microfibril suspensions were enriched in elastic fiber– and basement membrane–associated proteins, respectively. LC-MS/MS also identified proteins (such as calreticulin and protein-disulfide isomerase) that are potentially fundamental to fibrillin microfibril biology, regardless of their tissue source. Fibrillin microfibrils synthesized in cell culture lacked some of these key proteins (MFAP2 and -4 and fibrillin-2). These results showcase the structural diversity of these key extracellular matrix assemblies, which may relate to their distinct roles in the tissues where they reside.

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          WSXM: a software for scanning probe microscopy and a tool for nanotechnology.

          In this work we briefly describe the most relevant features of WSXM, a freeware scanning probe microscopy software based on MS-Windows. The article is structured in three different sections: The introduction is a perspective on the importance of software on scanning probe microscopy. The second section is devoted to describe the general structure of the application; in this section the capabilities of WSXM to read third party files are stressed. Finally, a detailed discussion of some relevant procedures of the software is carried out.
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            Empirical Statistical Model To Estimate the Accuracy of Peptide Identifications Made by MS/MS and Database Search

            We present a statistical model to estimate the accuracy of peptide assignments to tandem mass (MS/MS) spectra made by database search applications such as SEQUEST. Employing the expectation maximization algorithm, the analysis learns to distinguish correct from incorrect database search results, computing probabilities that peptide assignments to spectra are correct based upon database search scores and the number of tryptic termini of peptides. Using SEQUEST search results for spectra generated from a sample of known protein components, we demonstrate that the computed probabilities are accurate and have high power to discriminate between correctly and incorrectly assigned peptides. This analysis makes it possible to filter large volumes of MS/MS database search results with predictable false identification error rates and can serve as a common standard by which the results of different research groups are compared.
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              Molecular aspects of skin ageing.

              Ageing of human skin may result from both the passage of time (intrinsic ageing) and from cumulative exposure to external influences (extrinsic ageing) such as ultraviolet radiation (UVR) which promote wrinkle formation and loss of tissue elasticity. Whilst both ageing processes are associated with phenotypic changes in cutaneous cells, the major functional manifestations of ageing occur as a consequence of structural and compositional remodeling of normally long-lived dermal extracellular matrix proteins. This review briefly considers the effects of ageing on dermal collagens and proteoglycans before focusing on the mechanisms, functional consequences and treatment of elastic fibre remodeling in ageing skin. The early stages of photoageing are characterised by the differential degradation of elastic fibre proteins and whilst the activity of extracellular matrix proteases is increased in photoexposed skin, the substrate specificity of these enzymes is low. We have recently shown however, that isolated fibrillin microfibrils are susceptible to direct degradation by physiologically attainable doses of UV-B radiation and that elastic fibre proteins as a group are highly enriched in UV-absorbing amino acid residues. Functionally, elastic fibre remodeling events may adversely impact on: the mechanical properties of tissues, the recruitment and activation of immune cells, the expression of matrix metalloproteinases and cytokine signaling (by perturbing fibrillin microfibril sequestration of TGFβ). Finally, newly developed topical interventions appear to be capable of regenerating elements of the elastic fibre system in ageing skin, whilst systemic treatments may potentially prevent the pathological tissue remodeling events which occur in response to elastic fibre degradation. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.
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                Author and article information

                Journal
                J Biol Chem
                J. Biol. Chem
                jbc
                jbc
                JBC
                The Journal of Biological Chemistry
                American Society for Biochemistry and Molecular Biology (11200 Rockville Pike, Suite 302, Rockville, MD 20852-3110, U.S.A. )
                0021-9258
                1083-351X
                6 April 2018
                16 February 2018
                16 February 2018
                : 293
                : 14
                : 5117-5133
                Affiliations
                From the []Division of Cell Matrix Biology and Regenerative Medicine,
                the [§ ]Division of Musculoskeletal and Dermatological Sciences,
                the []School of Biological Sciences, and
                the [** ]Wellcome Trust Centre for Cell-Matrix Research, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PT, United Kingdom and
                the []NIHR Manchester Biomedical Research Centre, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester M13 9PT, United Kingdom
                Author notes
                [2 ] To whom correspondence should be addressed: 1.529 Stopford Bldg., University of Manchester, Oxford Rd., Manchester M13 9PT, United Kingdom. Tel.: 44-161-275-1439; Fax: 44-161-275-5171; E-mail: michael.sherratt@ 123456manchester.ac.uk .
                [1]

                Supported by Biotechnology and Biological Sciences Research Council (BBSRC) Grant BB/N015398/1.

                Edited by Gerald W. Hart

                Article
                RA117.001483
                10.1074/jbc.RA117.001483
                5892578
                29453284
                b3b3d284-a4e9-4dd3-b8a8-54ccbccf77cd
                © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.

                Author's Choice—Final version free via Creative Commons CC-BY license.

                History
                : 15 December 2017
                : 7 February 2018
                Funding
                Funded by: Walgreens Boots Alliance
                Award ID: Programme Grant
                Categories
                Glycobiology and Extracellular Matrices

                Biochemistry
                extracellular matrix,skin,eye,fibroblast,proteomics,atomic force microscopy (afm),protein structure,collagen vi,fibrillin microfibril

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