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Disruption of endogenous glucocorticoid signalling in bone cells attenuates osteoarthritis (OA) in aged mice, however, the role of endogenous glucocorticoids in chondrocytes is unknown. Here, we investigated whether deletion of the glucocorticoid receptor, specifically in chondrocytes, also alters OA progression. Knee OA was induced by surgical destabilisation of the medial meniscus (DMM) in male 22-week-old tamoxifen-inducible glucocorticoid receptor knockout (chGRKO) mice and their wild-type (WT) littermates (n = 7–9/group). Mice were harvested 2, 4, 8 and 16 weeks after surgery to examine the spatiotemporal changes in molecular, cellular, and histological characteristics. At all time points following DMM, cartilage damage was significantly attenuated in chGRKO compared to WT mice. Two weeks after DMM, WT mice exhibited increased chondrocyte and synoviocyte hypoxia inducible factor (HIF)-2α expression resulting in extensive synovial activation characterised by synovial thickening and increased interleukin-1 beta expression. At 2 and 4 weeks after DMM, WT mice displayed pronounced chondrocyte senescence and elevated catabolic signalling (reduced Yes-associated protein 1 (YAP1) and increased matrix metalloprotease [MMP]-13 expression). Contrastingly, at 2 weeks after DMM, HIF-2α expression and synovial activation were much less pronounced in chGRKO than in WT mice. Furthermore, chondrocyte YAP1 and MMP-13 expression, as well as chondrocyte senescence were similar in chGRKO-DMM mice and sham-operated controls. Endogenous glucocorticoid signalling in chondrocytes promotes synovial activation, chondrocyte senescence and cartilage degradation by upregulation of catabolic signalling through HIF-2α in murine posttraumatic OA. These findings indicate that inhibition of glucocorticoid signalling early after injury may present a promising way to slow osteoarthritic cartilage degeneration. [ABSTRACT FROM AUTHOR]

Neuroinflammation is a feature of both neurodegenerative disease and normal brain aging. The roles of type I interferon (IFN-I) in the aged brain are incompletely understood. A recent article by Roy et al. reveals pervasive IFN-I activity in normal mouse brain aging, and highlights the importance of microglial IFN-I signaling in neuroinflammation. [ABSTRACT FROM AUTHOR]

Aim of this study was to describe the real-world use of extracorporeal photopheresis (ECP) and assess its impact on clinical outcomes in the modern era of heart transplantation. Seven transplant centers from 5 European countries participated in this retrospective, observational, single-arm chart review study. All patients received ECP after heart transplantation in 2015 or later. Data were extracted from medical records between November 2020 and December 2021. Overall, 105 patients were enrolled and followed for an average of 2 years after initiation of ECP. Reasons to start ECP were acute cellular rejection (35.2%), rejection prevention (32.4%), mixed rejection (18.1%), and antibody-mediated rejection (14.3%). Rejection ISHLT grades improved from start to end of ECP treatment in 92% of patients treated with ECP for rejection. Of patients who started ECP to prevent rejection, 88% remained free from any rejection despite a reduction of calcineurin inhibitors. Overall survival was 95%, and no deaths were related to ECP. Safety events occurred in 18 patients, of which 13 experienced complications with venous access. This study, the largest European ECP study in heart transplantation, demonstrates that ECP can effectively be used to treat different rejection types and to prevent rejection in the modern era of immunosuppression. Patients with rejections who have received ECP have shown high response as measured by histological improvements in ISHLT classification. A high percentage of patients in the prevention group remained free from rejection despite reduction in immunosuppression, in particular calcineurin inhibitors. [ABSTRACT FROM AUTHOR]

[Display omitted] • Hierarchical architected materials achieve enhanced mechanical properties. • A deep learning approach based on an attention-based diffusion model is capable of providing both, forward and inverse predictions. • We discover hierarchical microstructure candidates for a specified nonlinear mechanical response. • We demonstrate single-shot end-to-end performance in both forward/inverse directions across the entire deformation regime. • Biologically inspired materials design for high-throughput discovery specifically for diverse nonlinear constitutive relationships is provided. Inspired by natural materials, hierarchical architected materials can achieve enhanced properties including achieving tailored mechanical responses. However, the design space for such materials is often exceedingly large, and both predicting mechanical properties of complex hierarchically organized materials and designing such materials for specific target properties can be extremely difficult. In this paper we report a deep learning approach using an attention-based diffusion model, capable of providing both, forward predictions of nonlinear mechanical properties as a function of the hierarchical material structure as well as solving inverse design problems in order to discover hierarchical microstructure candidates for a specified nonlinear mechanical response. We exemplify the method for a system of compressively loaded four-hierarchy level materials derived from a family of honeycomb structures, where patterns of distributed buckling events are unitary deformation events that control small- and large-scale deformation behavior. Our model offers exquisite single-shot end-to-end performance in both forward and inverse directions across the entire range of deformation regime, and is capable of rapidly discovering multiple solutions that satisfy a design objective in accordance with the known physical behavior elucidated by, and validated with, coarse-grained simulations. The model provides an effective way towards biologically inspired materials design for high-throughput discovery in order to achieve diverse nonlinear constitutive relationships. [ABSTRACT FROM AUTHOR]