P2X7 receptor-mediated TG2 externalization: a link to inflammatory arthritis?

Transglutaminases have important roles in stabilizing extracellular protein assemblies in tissue repair processes but some reaction products can stimulate immune activation, leading to chronic inflammatory conditions or autoimmunity. Exacerbated disease in models of inflammatory arthritis has been ascribed to sustained extracellular enzyme activity alongside formation of select protein modifications. Here, we review the evidence, with a focus on the link between P2X7R signaling and TG2 export, a pathway that we have recently discovered which ties extracellular protein modifications into the danger signal-mediated innate immune response. These recent insights offer new opportunities for therapeutic intervention

Light-induced magnetization reversal of high-anisotropy TbCo alloy films

Magnetization reversal using circularly polarized light provides a new way to control magnetization without any external magnetic field and has the potential to revolutionize magnetic data storage. However, in order to reach ultra-high density data storage, high anisotropy media providing thermal stability are needed. Here, we evidence all-optical magnetization switching for different TbxCo1-x ferrimagnetic alloy composition and demonstrate all-optical switching for films with anisotropy fields reaching 6 T corresponding to anisotropy constants of 3x106 ergs/cm3. Optical magnetization switching is observed only for alloys which compensation temperature can be reached through sample heating

Transglutaminase 6 antibodies in gluten neuropathy

BACKGROUND: TG6 antibodies have been shown to be a marker of gluten ataxia but their presence in the context of other neurological manifestations of gluten sensitivity has not been explored. We investigated the presence of TG6 antibodies in gluten neuropathy (GN), defined as as an otherwise idiopathic peripheral neuropathy associated with serological markers of gluten sensitivity (one or more of antigliadin IgG and/or IgA, endomysial and transglutaminase-2 antibodies). METHODS: This was a cross-sectional study conducted at the Sheffield Institute of Gluten Related Diseases, Royal Hallamshire Hospital, Sheffield, UK. Blood samples were collected whilst the patients were on a gluten containing diet. Duodenal biopsies were performed to establish the presence of enteropathy. RESULTS: Twenty-eight patients were recruited (mean age 62.5±13.7 years). Fifteen (53.6%) had sensory ganglionopathy, 12 (42.9%) had symmetrical axonal neuropathy and 1 had mononeuritis multiplex. The prevalence of TG6 antibodies was 14 of 28 (50%) compared to 4% in the healthy population. TG6 antibodies were found in 5/15 (33.3%) patients with sensory ganglionopathy and in 8/12 (66.7%) with symmetrical axonal neuropathy. Twenty-four patients underwent duodenal biopsy 11 (45.8%) of which had enteropathy. The prevalence of TG6 was not significantly different when comparing those with or without enteropathy. CONCLUSIONS: We found a high prevalence of antibodies against TG6 in patients with GN. This suggests that TG6 involvement is not confined to the central nervous system. The role of transglutaminase 6 in peripheral nerve function remains to be determined but TG6 antibodies may be helpful in the diagnosis of GN

Transglutaminase-catalyzed matrix cross-linking in differentiating cartilage: identification of osteonectin as a major glutaminyl substrate

The expression of tissue transglutaminase in skeletal tissues is strictly regulated and correlates with chondrocyte differentiation and cartilage calcification in endochondral bone formation and in maturation of tracheal cartilage (Aeschlimann, D., A. Wetterwald, H. Fleisch, and M. Paulsson. 1993. J. Cell Biol. 120:1461-1470). We now demonstrate the transglutaminase reaction product, the gamma-glutamyl-epsilon-lysine cross-link, in the matrix of hypertrophic cartilage using a novel cross-link specific antibody. Incorporation of the synthetic transglutaminase substrate monodansylcadaverine (amine donor) in cultured tracheal explants reveals enzyme activity in the pericellular matrix of hypertrophic chondrocytes in the central, calcifying areas of the horseshoe-shaped cartilages. One predominant glutaminyl substrate (amine acceptor) in the chondrocyte matrix is osteonectin as revealed by incorporation of the dansyl label in culture. Indeed, nonreducible osteonectin-containing complexes of approximately 65, 90, and 175 kD can be extracted from mature tracheal cartilage. In vitro cross-linking of osteonectin by tissue transglutaminase gives similar products of approximately 90 and 175 kD, indicating that the complexes in cartilage represent osteonectin oligomers. The demonstration of extracellular transglutaminase activity in differentiating cartilage, i.e., cross-linking of osteonectin in situ, shows that tissue transglutaminase-catalyzed cross-linking is a physiological mechanism for cartilage matrix stabilization

Virtual Reality as a Vehicle to Empower Motor-Cognitive Neurorehabilitation

In this paper, we advocate the combination of four key ingredients that we believe are necessary to design long-lasting effective treatments for neurorehabilitation: (i) motor-cognitive training, (ii) evidence-based neuroscience principles, in particular those related to body perception, (iii) motivational games, and (iv) empowerment techniques. Then, we propose virtual reality (VR) as the appropriate medium to encompass all the requirements mentioned above. VR is arguably one of the most suitable technologies for neurorehabilitation able to integrate evidence-based neurorehabilitation techniques and neuroscience principles into motivating training approaches that promote self-management by empowering patients to own their recovery process. We discuss the advantages and challenges of such an approach on several exemplary applications and outline directions for future developments. We strongly believe that the combination of positive psychology and positive technology mediated by VR-based interventions can heavily impact the rehabilitation outcomes of motor-cognitive functions along all the stages of the rehabilitation path

High Spatial Resolution Quantitative Imaging by Cross-calibration Using Laser Ablation Inductively Coupled Plasma Mass Spectrometry and Synchrotron Micro-X-ray Fluorescence Technique

High spatial resolution, quantitative chemical imaging is of importance to various scientific communities, however high spatial resolution and robust quantification are not trivial to attain at the same time. In order to achieve microscopic chemical imaging with enhanced quantification capabilities, the current study links the independent and complementary advantages of two micro-analytical techniques – Synchrotron Radiation-based micro X-ray Fluorescence (SR-microXRF) and Laser Ablation Inductively Coupled Plasma Mass Spectrometry (LA-ICPMS). A cross-calibration approach is established between these two techniques and validated by one experimental demonstration. In the presented test case, the diffusion pattern of trace level Cs migrating into a heterogeneous geological medium is imaged quantitatively with high spatial resolution. The one-dimensional line scans and the two-dimensional chemical images reveal two distinct types of geochemical domains: calcium carbonate rich domains and clay rich domains. During the diffusion, Cs shows a much higher interfacial reactivity within the clay rich domain, and turns out to be nearly non-reactive in the calcium carbonate domains. Such information obtained on the micrometer scale improves our chemical knowledge concerning reactive solute transport mechanism in heterogeneous media. Related to the chosen demonstration study, the outcome of the quantitative, microscopic chemical imaging contributes to a refined safety assessment of potential host rock materials for deep-geological nuclear waste storage repositories

P2X7 receptor activation regulates rapid unconventional export of transglutaminase-2

Transglutaminases (TG) are externalized from cells via an unknown unconventional secretory pathway. We show for the first time that purinergic signaling regulates active secretion of TG2, an enzyme with a pivotal role in stabilizing extracellular matrices and modulating cell-matrix interactions in tissue repair. Extracellular ATP promotes TG2 secretion by macrophages, and this can be blocked by a purinergic receptor P2X7 (P2X7R)-selective antagonist. Introduction of functional P2X7R into HEK293 cells is sufficient to confer rapid, regulated TG2 export. By employing pharmacological agents, TG2 release could be separated from P2X7R-mediated microvesicle shedding. Neither, Ca2+ signaling alone nor membrane depolarization triggered TG2 secretion which occurred only upon receptor membrane pore formation and without pannexin channel involvement. A gain-of-function mutation in P2X7R associated with autoimmune disease caused enhanced TG2 externalization from cells, and this correlated with increased pore activity. These results provide a mechanistic explanation for a link between active TG2 secretion and inflammatory responses, and aberrant enhanced TG2 activity in certain autoimmune conditions

Mutations in TGM6 induce the unfolded protein response in SCA35

Spinocerebellar ataxia type 35 (SCA35) is a rare autosomal-dominant neurodegenerative disease caused by mutations in the TGM6 gene, which codes for transglutaminase 6 (TG6). Mutations in TG6 induce cerebellar degeneration by an unknown mechanism. We identified seven patients bearing new mutations in TGM6. To gain insights into the molecular basis of mutant TG6-induced neurotoxicity, we analyzed all of the seven new TG6 mutants and the five TG6 mutants previously linked to SCA35. We found that wild-type (TG6-WT) mainly localized to the nucleus and perinuclear area, whereas five TG6 mutations showed nuclear depletion, increased accumulation in the perinuclear area, insolubility and loss of enzymatic function. Aberrant accumulation of these TG6 mutants in the perinuclear area led to activation of the unfolded protein response (UPR), suggesting that specific TG6 mutants elicit an endoplasmic reticulum (ER) stress response. Mutations associated with activation of the UPR caused death of primary neurons and reduced the survival of novel D. melanogaster models of SCA35. These results indicate that mutations differently impacting on TG6 function cause neuronal dysfunction and death through diverse mechanisms and highlight the UPR as a potential therapeutic target for patient treatment