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Mitochondrial transcription factor A (TFAM) controls the transcription of core proteins required for mitochondrial homeostasis. This study was undertaken to investigate changes in TFAM expression in systemic sclerosis (SSc), to analyze mitochondrial function, and to evaluate the consequences for fibroblast activation.TFAM expression was analyzed by immunofluorescence and Western blotting. The effects of TFAM knockout were investigated in cultured fibroblasts and in murine models of bleomycin-induced skin fibrosis, bleomycin-induced lung fibrosis, and skin fibrosis induced by overexpression of constitutively active transforming growth factor β type I receptor (TGFβRΙ).TFAM expression was down-regulated in fibroblasts in SSc skin and in cultured SSc fibroblasts. The down-regulation of TFAM was associated with decreased mitochondrial number and accumulation of damaged mitochondria with release of mitochondrial DNA (mtDNA), accumulation of deletions in mtDNA, metabolic alterations with impaired oxidative phosphorylation, and release of the mitokine GDF15. Normal fibroblasts subjected to long-term, but not acute, exposure to TGFβ mimicked SSc fibroblasts, with down-regulation of TFAM and accumulation of mitochondrial damage. Down-regulation of TFAM promoted fibroblast activation with up-regulation of fibrosis-relevant Gene Ontology terms in RNA-Seq, partially in a reactive oxygen species-dependent manner. Mice with fibroblast-specific knockout of Tfam were prone to fibrotic tissue remodeling, with fibrotic responses even to NaCl instillation and enhanced sensitivity to bleomycin injection and overexpression of constitutively active TGFβRI. TFAM knockout fostered Smad3 signaling to promote fibroblast activation.Alterations in the key mitochondrial transcription factor TFAM in response to prolonged activation of TGFβ and associated mitochondrial damage induce transcriptional programs that promote fibroblast-to-myofibroblast transition and drive tissue fibrosis.

Titanium dioxide nanocomposites/multi-walled carbon nanotubes (TiO2/MWCNTs) were successfully synthesized by hydrothermal method. The synthesized TiO2/MWCNTs nanocomposites (10, 30 and 50% TiO2/MWCNTs) nanocomposites were characterized with powder X-ray diffraction (XRD), transmission electron microscope(TEM) and UV–visible diffuse reflection spectrum (DRS). The photocatalytic activity of TiO2/MWCNTs nanocomposite for the degradation of Rhodamin B (RhB) under visible light irradiation was studied. Compared with pure TiO2 nanoparticles, the TiO2/MWCNTs nanocomposite displayed higher photocatalytic activity for the degradation of RhB and the 30% TiO2/MWCNTs photocatalyst exhibited the highest photocatalytic activity.

In this work, we investigated the crystal formation of anisotropic nanoparticles, namely Janus particles, at the water-oil interface using the dissipative particle dynamics simulation method. By considering three different interface templates, including planar, droplet, and rod, we observe an increase of the disorder-order transition packing fraction with increasing the curvature radius of the templates. Furthermore, the nanoparticles in the planar template assemble into a hexagonal lattice, while for the two remaining templates they aggregate into colloidsome-like structures.

Chronic graft-versus-host disease (cGVHD) is a major life-threatening complication of allogeneic hematopoietic stem cell transplantation. The molecular mechanisms underlying cGVHD remain poorly understood, and targeted therapies for clinical use are not well established. Here, we examined the role of the canonical WNT pathway in sclerodermatous cGVHD (sclGVHD). WNT signaling was activated in human sclGVHD with increased nuclear accumulation of the transcription factor β-catenin and a WNT-biased gene expression signature in lesional skin. Treatment with the highly selective tankryase inhibitor G007-LK, the CK1α agonist pyrvinium, or the LRP6 inhibitor salinomycin abrogated the activation of WNT signaling and protected against experimental cGVHD, without a significant impact on graft-versus-leukemia effect (GVL). Treatment with G007-LK, pyrvinium, or salinomycin almost completely prevented the development of clinical and histological features in the B10.D2 (H-2d) → BALB/c (H-2d) and LP/J (H-2b) → C57BL/6 (H-2b) models of sclGVHD. Inhibition of canonical WNT signaling reduced the release of extracellular matrix from fibroblasts and reduced leukocyte influx, suggesting that WNT signaling stimulates fibrotic tissue remodeling by direct effects on fibroblasts and by indirect inflammation-dependent effects in sclGVHD. Our findings may have direct translational potential, because pyrvinium is in clinical use, and tankyrase inhibitors are in clinical trials for other indications.

In recent years, scientists have been focusing on coding metamaterials absorbers to take full advantage of digital technology. This technology is mostly based on the fact that the absorption spectrum of a full-sized metamaterial varies with the different number and position of the defect elements in conventional unit cells (UCs) in it. However, both of their traditional methods namely simple random sample and combination of fundamental meta-block struggle with the enormous number of possible configurations especially when the number of UCs increases. In this article, we represent 5 configurations with different numbers of UCs, 2x2, 3x3, 4x4, 5x5, and 6x6 UCs, all of which maintain average absorption higher than 90% over a 10 GHz wide frequency range of interest between 17 GHz and 27 GHz. These results are obtained by using a genetic algorithm to generate configurations with higher optical loss through the process. Comparing to the conventional methods' result, our approach has achieved a significant improvement in the absorption spectrum. Furthermore, our methods could be applied to more structures with different sizes and numbers of UCs, thus provided a reliable tool to design practical metamaterials that serve the real work demands.

ObjectivesFibrosis is a complex pathophysiological process involving interplay between multiple cell types. Experimental modelling of fibrosis is essential for the understanding of its pathogenesis and for testing of putative antifibrotic drugs. However, most current models employ either phylogenetically distant species or rely on human cells cultured in an artificial environment. Here we evaluated the potential of vascularised in vitro human skin equivalents as a novel model of skin fibrosis and a platform for the evaluation of antifibrotic drugs.MethodsSkin equivalents were assembled on a three-dimensional extracellular matrix by sequential seeding of endothelial cells, fibroblasts and keratinocytes. Fibrotic transformation on exposure to transforming growth factor-β (TGFβ) and response to treatment with nintedanib as an established antifibrotic agent were evaluated by quantitative polymerase chain reaction (qPCR), capillary Western immunoassay, immunostaining and histology.ResultsSkin equivalents perfused at a physiological pressure formed a mature, polarised epidermis, a stratified dermis and a functional vessel system. Exposure of these models to TGFβ recapitulated key features of SSc skin with activation of TGFβ pathways, fibroblast to myofibroblast transition, increased release of collagen and excessive deposition of extracellular matrix. Treatment with the antifibrotic agent nintedanib ameliorated this fibrotic transformation.ConclusionOur data provide evidence that vascularised skin equivalents can replicate key features of fibrotic skin and may serve as a platform for evaluation of antifibrotic drugs in a pathophysiologically relevant human setting.

In this paper, we study the convergence for martingale sequences of random bounded operators. The condition for the existence of such a infinite product is established

Using small colloidal clusters with dumbbell, triplet, tetrahedral, octahedral geometry as elementary building blocks, we investigate the templated-assisted cluster-cluster aggregation into hierarchical clusters, namely superclusters, by means of Monte Carlo simulations. We find that the colloidal superclusters made of dumbbells and triplets produces a unique structural motif that is similar to that of clusters of single colloids, whereas the superclusters composed of tetrahedral and octahedral clusters possess a more complex structure. However, despite their complexity, such structures can be predicted based on a decomposition using triplets as a core and the number of initial “building block” clusters. In particular, a majority of the observable superclusters are members of a particular category of nonconvex deltahedra (Cundy deltahedra). These findings could be useful in preparation of complex colloidal molecules.