Hyper-IgG4 disease: report and characterisation of a new disease

BACKGROUND: We highlight a chronic inflammatory disease we call 'hyper-IgG4 disease', which has many synonyms depending on the organ involved, the country of origin and the year of the report. It is characterized histologically by a lymphoplasmacytic inflammation with IgG4-positive cells and exuberant fibrosis, which leaves dense fibrosis on resolution. A typical example is idiopathic retroperitoneal fibrosis, but the initial report in 2001 was of sclerosing pancreatitis. METHODS: We report an index case with fever and severe systemic disease. We have also reviewed the histology of 11 further patients with idiopathic retroperitoneal fibrosis for evidence of IgG4-expressing plasma cells, and examined a wide range of other inflammatory conditions and fibrotic diseases as organ-specific controls. We have reviewed the published literature for disease associations with idiopathic, systemic fibrosing conditions and the synonyms: pseudotumour, myofibroblastic tumour, plasma cell granuloma, systemic fibrosis, xanthofibrogranulomatosis, and multifocal fibrosclerosis. RESULTS: Histology from all 12 patients showed, to varying degrees, fibrosis, intense inflammatory cell infiltration with lymphocytes, plasma cells, scattered neutrophils, and sometimes eosinophilic aggregates, with venulitis and obliterative arteritis. The majority of lymphocytes were T cells that expressed CD8 and CD4, with scattered B-cell-rich small lymphoid follicles. In all cases, there was a significant increase in IgG4-positive plasma cells compared with controls. In two cases, biopsies before and after steroid treatment were available, and only scattered plasma cells were seen after treatment, none of them expressing IgG4. Review of the literature shows that although pathology commonly appears confined to one organ, patients can have systemic symptoms and fever. In the active period, there is an acute phase response with a high serum concentration of IgG, and during this phase, there is a rapid clinical response to glucocorticoid steroid treatment. CONCLUSION: We believe that hyper-IgG4 disease is an important condition to recognise, as the diagnosis can be readily verified and the outcome with treatment is very good

Nuclear localisation of Aurora-A: its regulation and significance for Aurora-A functions in cancer.

The Aurora-A kinase regulates cell division, by controlling centrosome biology and spindle assembly. Cancer cells often display elevated levels of the kinase, due to amplification of the gene locus, increased transcription or post-translational modifications. Several inhibitors of Aurora-A activity have been developed as anti-cancer agents and are under evaluation in clinical trials. Although the well-known mitotic roles of Aurora-A point at chromosomal instability, a hallmark of cancer, as a major link between Aurora-A overexpression and disease, recent evidence highlights the existence of non-mitotic functions of potential relevance. Here we focus on a nuclear-localised fraction of Aurora-A with oncogenic roles. Interestingly, this pool would identify not only non-mitotic, but also kinase-independent functions of the kinase. We review existing data in the literature and databases, examining potential links between Aurora-A stabilisation and localisation, and discuss them in the perspective of a more effective targeting of Aurora-A in cancer therapy

Various challenging aspects of hybrid propulsion

The hybrid technology appears as an innovative, high performance, and promising propulsion technique in a number of space missions. By combining functions and advantages taken from both solid and liquid propulsion, this technology is expected to provide mainly high performance with throttleability and stop-restart capabilities. The safety conditions of engine operation and design reliability almost similar to solid propulsion increase the interest to this technology. However, the standard fuels (mainly based on a carbon polymer) exhibit low regression rates that require complex grain shapes and low loading ratio. Thanks to a dedicated study supported by the European Space Agency (ESA), SNPE in collaboration with Avio and University of Naples (DIAS department) performed an exhaustive state-of-the-art and a market survey of accomplishments in hybrid propulsion. Based on the resulting tradeoff study on potential future launchers and spacecraft applications, the most promising applications are selected to conduct preliminary designs. These applications can also be seen as the vector of hybrid propulsion development. This study concentrates on hybrid propulsion systems with advanced hybrid fuels for Lander platform and Upper Stage. High throttleability and high propulsive performance associated with stop and restart capability are needed to meet mission requirements for Lander and Upper Stage, respectively. Preliminary design shows the advantages provided by hybrid propulsion: a significant payload mass increase for the upper stage case and a soft landing for the Lander case

Selective targeting of the alpha C and DFG out pocket in p38 MAPK

The p38 MAPK cascade is a key signaling pathway linked to a multitude of physiological functions and of central importance in inflammatory and autoimmune diseases. Although studied extensively, little is known about how conformation specific inhibitors alter signaling outcomes. Here, we have explored the highly dynamic back pocket of p38 MAPK with allosteric urea fragments. However, screening against known off targets showed that these fragments maintained the selectivity issues of their parent compound BIRB 796, while combination with the hinge binding motif of VPC 00628 greatly enhanced inhibitor selectivity. Further efforts focused therefore on the exploration of the amp; 945;C out pocket of p38 MAPK, yielding compound 137 as a highly selective type II inhibitor. Even though 137 is structurally related to a recent p38 type II chemical probe, SR 318, the data presented here provide valuable insights into back pocket interactions that are not addressed in SR 318 and it provides an alternative chemical tool with good cellular activity targeting also the p38 back pocke

Transcriptomic analysis of diabetic kidney disease and neuropathy in mouse models of type 1 and type 2 diabetes

Diabetic kidney disease (DKD) and diabetic peripheral neuropathy (DPN) are common complications of type 1 (T1D) and type 2 (T2D) diabetes. However, the mechanisms underlying pathogenesis of these complications are unclear. In this study, we optimized a streptozotocin-induced db/+ murine model of T1D and compared it to our established db/db T2D mouse model of the same C57BLKS/J background. Glomeruli and sciatic nerve transcriptomic data from T1D and T2D mice were analyzed by self-organizing map and differential gene expression analysis. Consistent with prior literature, pathways related to immune function and inflammation were dysregulated in both complications in T1D and T2D mice. Gene-level analysis identified a high degree of concordance in shared differentially expressed genes (DEGs) in both complications and across diabetes type when using mice from the same cohort and genetic background. As we have previously shown a low concordance of shared DEGs in DPN when using mice from different cohorts and genetic backgrounds, this suggests that genetic background may influence diabetic complications. Collectively, these findings support the role of inflammation and indicate that genetic background is important in complications of both T1D and T2D. © 2023 Company of Biologists Ltd. All rights reserved.Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

High-order computation of burning propellant surface and simulation of fluid flow in solid rocket chamber

International audienceIn this paper, we present a numerical approach for predicting fluid flows in solid rocket motor (SRM) chambers. We use a novel high-order technique to track the burning grain surface. Spectral convergence toward the exact burning surface is achieved thanks to Fourier differentiation. In addition, we make use of a body-fitted mesh deforming with the burning surface and present a method to avoid manual remeshing. We describe several methods to deform the volume mesh and to keep good mesh element quality during the computation. We then couple the surface and volume approaches. The resulting coupled method is able to handle the formation of geometric singularities on the burning surface while keeping constant surface and volume mesh topology. This geometrical approach is integrated into a complex code for compressible, multi-species, turbulent flow simulations. Applications to the simulation of the internal flow in realistic solid rocket motors with complex grain geometry are then presented