Description: Filamin C ( FLNC ) mutations in humans cause myofibrillar myopathy (MFM) and cardiomyopathy, characterized by protein aggregation and myofibrillar degeneration. We generated the first patient-mimicking knock-in mouse harbouring the most common disease-causing filamin C mutation (p.W2710X). These heterozygous mice developed muscle weakness and myofibrillar instability, with formation of filamin C- and Xin-positive lesions streaming between Z-discs. These lesions, which are distinct from the classical MFM protein aggregates by their morphology and filamentous appearance, were greatly increased in number upon acute physical exercise in the mice. This pathology suggests that mutant filamin influences the mechanical stability of myofibrillar Z-discs, explaining the muscle weakness in mice and humans. Re-evaluation of biopsies from MFM-filaminopathy patients with different FLNC mutations revealed a similar, previously unreported lesion pathology, in addition to the classical protein aggregates, and suggested that structures previously interpreted as aggregates may be in part sarcomeric lesions. We postulate that these lesions define preclinical disease stages, preceding the formation of protein aggregates.

Description: 3D atmosphere model results are used to comparatively study the kinetic, non-equilibrium cloud formation in the atmospheres of two example planets guided by the giant gas planets HD 209458b and HD 189733b. Rather independently of hydrodynamic model differences, our cloud modelling suggest that both planets are covered in mineral clouds throughout the entire modelling domain. Both planets harbour chemically complex clouds that are made of mineral particles that have a height-dependent material composition and size. The remaining gas-phase element abundances strongly affect the molecular abundances of the atmosphere in the cloud-forming regions. Hydrocarbon and cyanopolyyne molecules can be rather abundant in the inner, dense part of the atmospheres of HD 189733b and HD 209458b. No one value for metallicity and the C/O ratio can be used to describe an extrasolar planet. Our results concerning the presence and location of water in relation to the clouds explain some of the observed difference between the two planets. In HD 189733b, strong water features have been reported while such features appear less strong for HD 209458b. By considering the location of the clouds in the two atmospheres, we see that obscuring clouds exist high in the atmosphere of HD 209458b, but much deeper in HD 189733b. We further conclude that the (self-imposed) degeneracy of cloud parameters in retrieval methods can only be lifted if the cloud formation processes are accurately modelled in contrast to prescribing them by independent parameters.

Description: Aims Diastolic dysfunction is central to the development of heart failure. To date, there is no effective treatment and only limited understanding of its molecular basis. Recently, we showed that the transmembrane proteoglycan syndecan-4 increases in the left ventricle after pressure overload in mice and man, and that syndecan-4 via calcineurin/nuclear factor of activated T-cells (NFAT) promotes myofibroblast differentiation and collagen production upon mechanical stress. The aim of this study was to investigate whether syndecan-4 affects collagen cross-linking and myocardial stiffening in the pressure-overloaded heart. Methods and results Aortic banding (AB) caused concentric hypertrophy and increased passive tension of left ventricular muscle strips, responses that were blunted in syndecan-4 –/– mice. Disruption of titin anchoring by salt extraction of actin and myosin filaments revealed that the effect of syndecan-4 on passive tension was due to extracellular matrix remodelling. Expression and activity of the cross-linking enzyme lysyl oxidase (LOX) increased with mechanical stress and was lower in left ventricles and cardiac fibroblasts from syndecan-4 –/– mice, which exhibited less collagen cross-linking after AB. Expression of osteopontin (OPN), a matricellular protein able to induce LOX in cardiac fibroblasts, was up-regulated in hearts after AB, in mechanically stressed fibroblasts and in fibroblasts overexpressing syndecan-4, calcineurin, or NFAT, but down-regulated in fibroblasts lacking syndecan-4 or after NFAT inhibition. Interestingly, the extracellular domain of syndecan-4 facilitated LOX-mediated collagen cross-linking. Conclusions Syndecan-4 exerts a dual role in collagen cross-linking, one involving its cytosolic domain and NFAT signalling leading to collagen, OPN, and LOX induction in cardiac fibroblasts; the other involving the extracellular domain promoting LOX-dependent cross-linking.