Lumican accumulates with fibrillar collagen in fibrosis in hypertrophic cardiomyopathy

Aims Familial hypertrophic cardiomyopathy (HCM) is the most common form of inherited cardiac disease. It is characterized by myocardial hypertrophy and diastolic dysfunction, and can lead to severe heart failure, arrhythmias, and sudden cardiac death. Cardiac fibrosis, defined by excessive accumulation of extracellular matrix (ECM) components, is central to the pathophysiology of HCM. The ECM proteoglycan lumican is increased during heart failure and cardiac fibrosis, including HCM, yet its role in HCM remains unknown. We provide an in-depth assessment of lumican in clinical and experimental HCM. Methods Left ventricular (LV) myectomy specimens were collected from patients with hypertrophic obstructive cardiomyopathy (n = 15), and controls from hearts deemed unsuitable for transplantation (n = 8). Hearts were harvested from a mouse model of HCM; Myh6 R403Q mice administered cyclosporine A and wild-type littermates (n = 8–10). LV tissues were analysed for mRNA and protein expression. Patient myectomy or mouse mid-ventricular sections were imaged using confocal microscopy, direct stochastic optical reconstruction microscopy (dSTORM), or electron microscopy. Human foetal cardiac fibroblasts (hfCFBs) were treated with recombinant human lumican (n = 3) and examined using confocal microscopy. Results Lumican mRNA was increased threefold in HCM patients (P 2 = 0.60, P 2 = 0.58, P < 0.01). Lumican protein was increased by 40% in patients with HCM (P 2 = 0.28, P = 0.05) and interstitial (R2 = 0.30, P < 0.05) fibrosis. In mice with HCM, lumican mRNA increased fourfold (P < 0.001), and lumican protein increased 20-fold (P < 0.001) in insoluble ECM lysates. Lumican and fibrillar collagen were located together throughout fibrotic areas in HCM patient tissue, with increased co-localization measured in patients and mice with HCM (patients: +19%, P < 0.01; mice: +13%, P < 0.01). dSTORM super-resolution microscopy was utilized to image interstitial ECM which had yet to undergo overt fibrotic remodelling. In these interstitial areas, collagen I deposits located closer to ( 15 nm, P < 0.05), overlapped more frequently with (+7.3%, P < 0.05) and to a larger degree with (+5.6%, P < 0.05) lumican in HCM. Collagen fibrils in such deposits were visualized using electron microscopy. The effect of lumican on collagen fibre formation was demonstrated by adding lumican to hfCFB cultures, resulting in thicker (+53.8 nm, P < 0.001), longer (+345.9 nm, P < 0.001), and fewer ( 8.9%, P < 0.001) collagen fibres. Conclusions The ECM proteoglycan lumican is increased in HCM and co-localizes with fibrillar collagen throughout areas of fibrosis in HCM. Our data suggest that lumican may promote formation of thicker collagen fibres in HCM

Cell-based non-invasive prenatal testing for monogenic disorders:confirmation of unaffected fetuses following preimplantation genetic testing

PURPOSE: Proof of concept of the use of cell-based non-invasive prenatal testing (cbNIPT) as an alternative to chorionic villus sampling (CVS) following preimplantation genetic testing for monogenic disorders (PGT-M). METHOD: PGT-M was performed by combined testing of short tandem repeat (STR) markers and direct mutation detection, followed by transfer of an unaffected embryo. Patients who opted for follow-up of PGT-M by CVS had blood sampled, from which potential fetal extravillous throphoblast cells were isolated. The cell origin and mutational status were determined by combined testing of STR markers and direct mutation detection using the same setup as during PGT. The cbNIPT results with respect to the mutational status were compared to those of genetic testing of the CVS. RESULTS: Eight patients had blood collected between gestational weeks 10 and 13, from which 33 potential fetal cell samples were isolated. Twenty-seven out of 33 isolated cell samples were successfully tested (82%), of which 24 were of fetal origin (89%). This corresponds to a median of 2.5 successfully tested fetal cell samples per case (range 1–6). All fetal cell samples had a genetic profile identical to that of the transferred embryo confirming a pregnancy with an unaffected fetus, in accordance with the CVS results. CONCLUSION: These findings show that although measures are needed to enhance the test success rate and the number of cells identified, cbNIPT is a promising alternative to CVS. TRIAL REGISTRATION NUMBER: N-20180001 SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10815-021-02104-5

Study of the "Fast SCR" -like mechanism of H2-assisted SCR of NOx with ammonia over Ag/Al2O3

It is shown that Ag/Al2O3 is a unique catalytic system for H-2-assisted selective catalytic reduction of NOx by NH3 (NH3-SCR) with both Ag and alumina being necessary components of the catalyst. The ability of Ag/Al2O3 and pure Al2O3 to catalyse SCR of mixtures of NO and NO2 by ammonia is demonstrated, the surface species occurring discussed, and a "Fast SCR"-like mechanism of the process is proposed. The possibility of catalyst surface blocking by adsorbed NOx and the influence of hydrogen on desorption of NOx were evaluated by FTIR and OFT calculations

Cryptic Behaviour of Juvenile Turbot &lt;i&gt;Psetta maxima&lt;/i&gt; L. and European Flounder &lt;i&gt;Platichthys flesus&lt;/i&gt; L.

The aim of this study was to examine the burying behaviour of hatchery-reared European flounder Platichthys flesus and turbot Psetta maxima, and whether conditioning on a sandy substrate would improve burying efficiency. Both species buried shortly after release on a sandy substrate. However, the study revealed interspecies differences; the flounder buried immediately after release, while the turbot buried gradually. No significant difference in burying efficiency was observed between naïve and conditioned flounder and turbot. An effect of size on burial efficiency was observed for both flounder and turbot with a tendency for larger fish to bury more efficiently than smaller fish, despite previous conditioning. Size at settlement was found to be &gt;2 cm for flounder and &gt;3 cm for turbot

The effect of seasonal weather changes on the performance of databased models of the thermodynamic behaviour of buildings

Several studies have indicated that Model Predictive Control (MPC) of space heating systems can utilize the thermal mass of residential buildings as short-term thermal storage for various demand response purposes. Realization of this potential relies heavily on the accuracy of the model used to represent the thermodynamics of the building. Such models, whether they are grey box or black box, are calibrated using relevant data obtained from initial measurements, and the performance of the calibrated model is validated using data from a subsequent period. However, many studies use validation periods with weather conditions similar to those of the calibration period. Only a few studies investigate whether the calibrated model performs satisfactory when subjected to significantly different conditions. This paper presents data from a simulation-based study on the effect of seasonal weather changes on the performance of a black-box model. The study was conducted using 11 years of Danish weather data (2008-2018). The results indicate that the performance of the black-box model deteriorate as the weather data conditions become increasingly different from those used in the initial model calibration. Further, the results show that calibration in heating season leads to satisfactory model performance through the heating season, but lower performance in transitional seasons (especially spring). Results also show that calibration in February led to highest model performance through heating season, while calibration in March led to satisfactory model performance in the whole heating and fall season