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Fibroblasts play a key role in stricture formation in Crohn's disease (CD) but understanding its pathogenesis requires a systems-level investigation to uncover new treatment targets. We studied full-thickness CD tissues to characterize fibroblast heterogeneity and function by generating the first single-cell RNA sequencing (scRNAseq) atlas of strictured bowel and providing proof of principle for therapeutic target validation. We performed scRNAseq of 13 fresh full-thickness CD resections containing noninvolved, inflamed nonstrictured, and strictured segments as well as 7 normal non-CD bowel segments. Each segment was separated into mucosa/submucosa or muscularis propria and analyzed separately for a total of 99 tissue samples and 409,001 cells. We validated cadherin-11 (CDH11) as a potential therapeutic target by using whole tissues, isolated intestinal cells, NanoString nCounter, next-generation sequencing, proteomics, and animal models. Our integrated dataset revealed fibroblast heterogeneity in strictured CD with the majority of stricture-selective changes detected in the mucosa/submucosa, but not the muscle layer. Cell-cell interaction modeling revealed CXCL14+ as well as MMP/WNT5A+ fibroblasts displaying a central signaling role in CD strictures. CDH11, a fibroblast cell-cell adhesion molecule, was broadly expressed and up-regulated, and its profibrotic function was validated using NanoString nCounter, RNA sequencing, tissue target expression, in vitro gain- and loss-of-function experiments, proteomics, and knock-out and antibody-mediated CDH11 blockade in experimental colitis. A full-thickness bowel scRNAseq atlas revealed previously unrecognized fibroblast heterogeneity and interactions in CD strictures and CDH11 was validated as a potential therapeutic target. These results provide a new resource for a better understanding of CD stricture formation and open potential therapeutic developments. This work has been posted as a preprint on Biorxiv under doi: 10.1101/2023.04.03.534781. [Display omitted] This work creates an understanding of which cell types are present in Crohn's disease strictures and control tissues and how they interact with each other to cause disease. These findings were used to identify a potential novel treatment target. [ABSTRACT FROM AUTHOR]

High Damping Rubber (HDR) is used in High Damping Rubber Bearings (HDRB) which, in themselves, are dissipating devices in structural systems. The behaviour of HDRB is essentially linked to that of HDR which combines many phenomena such as nonlinearity, time dependence and memory of the loading history, the so called Mullins effect. Mastering the behaviour of bearings implies an accurate understanding of the response of HDR. Consequently, the purpose of this paper is to present a phenomenological material model for a nonlinear rheological mechanical behaviour accounting for Mullins effect of HDR. Many details of its numerical implementation are given. Based on experimental results and literature review, the Distribution of NonLinear Relaxation (DNLR) approach is explored to develop a new numerical model able to simulate nonlinear rheological response of HDR. Modifying the relaxation time regarding von Mises stress is one of the originalities of this model. A relatively simple way of memorising the loading history is implemented in the finite element program Cast3M© to describe the Mullins effect. Experimental tests are simulated. In order to determine model parameters, strategies for parameter identification are proposed. Firstly, parameters of the nonlinear rheological mechanism are optimised by means of relaxation test simulations and monotonic compression tests. Secondly, parameters of the Mullins effect are identified by using simulation of cyclic tensile tests. Finally, comparisons between experimental and numerical results in quasi-static compression and the cyclic shear of HDR are given in order to validate the model. [ABSTRACT FROM AUTHOR]