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Physiological effects of cellular hypoxia are sensed by prolyl hydroxylase (PHD) enzymes, which regulate HIFs. Genetic interventions on HIF/PHD pathways have revealed multiple phenotypes that extend the known biology of hypoxia. Recent studies have unexpectedly implicated HIF in aspects of multiple immune and inflammatory pathways. However, such studies are often limited by systemic lethal effects and/or use tissue- specific recombination systems, which are inherently irreversible, unphysiologically restricted, and difficult to time. To study these processes better, we developed recombinant mice that expressed tetracycline-regulated shRNAs broadly targeting the main components of the HIF/ PHD pathway, permitting timed bidirectional intervention. We show that stabilization of HIF levels in adult mice through PHD2 enzyme silencing by RNA interference or inducible recombination of floxed alleles results in multilineage leukocytosis and features of autoimmunity. This phenotype was rapidly normalized on reestablishment of the hypoxia-sensing machinery when shRNA expression was discontinued. In both situations, these effects were mediated principally through the Hif2[alpha] isoform. Assessment of cells bearing Treg markers from these mice revealed defective function and proinflammatory effects in vivo. We believe our findings reveal a new role for the PHD2/Hif2[alpha] pathway in the reversible regulation of T cell and immune activity., Introduction HIFs are transcription factors composed of 1 of 3 a chains (HIF1[alpha], Hif2[alpha], and HIF3[alpha]) dimerized to a [beta] chain that mediates the transcriptional response to low oxygen tension [...]

Braided carbon fiber reinforced plastics (CFRPs) can be employed in the construction of pressurized vessels to increase performance and reduce overall weight. However, owing to the complex braiding structures resulting from the braiding process, an analysis of the elastic modulus is important as it affects the hoop stress on the pressure vessel. In this study, braided preformed CFRP constructed on a steel cylinder subjected to internal pressure was experimentally investigated using a simple approach that involved estimating the elastic modulus and hoop stress. Five types of braided preformed CFRP with different braiding angles and number of applied layers were analyzed. The elastic modulus and hoop stress can be estimated from these measurements of the internal pressure. The differences in the braided structures result in different strain values and affect the elastic modulus. High braiding angles tend to be more stable against high internal pressure, and exhibit small strain differences and high elastic modulus in the hoop direction. Similar results were observed when additional layers were applied. Increasing the braiding angle and the number of layers can increase the average elastic modulus. [ABSTRACT FROM AUTHOR]

Background: Thrombomodulin (TM) is a promising therapeutic natural anti-coagulant, which exerts the effects to control disseminated intravascular coagulation. However, little is known whether TM on micro-vessels could play an important role in the regulation of intimal hyperplasia. We investigated the vessel-protective effect of TM in the survival of fully major histocompatibility complex (MHC)-mismatched murine cardiac allograft transplantation.Methods: CBA recipients transplanted with a C57BL/6 heart received intraperitoneal administration of normal saline or 0.2, 2.0, and 20.0 μg/day of TM for 7 days (n = 5, 7, 11, and 11, respectively). Immunohistochemical and fluorescent staining studies were performed to determine whether CD4+Foxp3+ regulatory T cell were generated at 2 and 4 weeks after grafting. Morphometric analysis for neointimal formation in the coronary arteries of the transplanted allograft was conducted at 2 and 4 weeks after grafting.Results: Untreated CBA recipients rejected C57BL/6 cardiac grafts acutely (median survival time [MST], 7 days). CBA recipients exposed with the above doses had significantly prolonged allograft survival (MSTs, 17, 24 and 50 days, respectively). Morphometric assessment showed that intimal hyperplasia was clearly suppressed in the left and right coronary arteries or allografts from TM-exposed recipients 2 and 4 weeks. Immunohistochemical studies at 2 weeks showed more CD4+Foxp3+ cells and lower myocardial damage in the allografts from TM-exposed recipients. Notably, fluorescent staining studies demonstrated that TM-exposed recipients 4 weeks post-engraftment had strong aggregation of CD4+Foxp3+ cells in the intima of the coronary arteries of the cardiac allografts.Conclusions: TM may prolong the survival of fully MHC-mismatched cardiac allografts through suppressing intimal hyperplasia and inducing the accumulation of regulatory CD4+Foxp3+ cells within coronary arteries. [ABSTRACT FROM AUTHOR]

Physiological effects of cellular hypoxia are sensed by prolyl hydroxylase (PHD) enzymes which regulate HIFs. Genetic interventions on HIF/PHD pathways reveal multiple phenotypes that extend the known biology of hypoxia. Recent studies unexpectedly implicate HIF in aspects of multiple immune and inflammatory pathways. However such studies are often limited by systemic lethal effects and/or use tissue-specific recombination systems, which are inherently irreversible, un-physiologically restricted and difficult to time. To study these processes better we developed recombinant mice which express tetracycline-regulated shRNAs broadly targeting the main components of the HIF/PHD pathway, permitting timed bi-directional intervention. We have shown that stabilization of HIF levels in adult mice through PHD2 enzyme silencing by RNA interference, or inducible recombination of floxed alleles, results in multi-lineage leukocytosis and features of autoimmunity. This phenotype was rapidly normalized on re-establishment of the hypoxia-sensing machinery when shRNA expression was discontinued. In both situations these effects were mediated principally through the Hif2a isoform. Assessment of cells bearing regulatory T cell markers from these mice revealed defective function and pro-inflammatory effects in vivo. We believe our findings have shown a new role for the PHD2/Hif2a couple in the reversible regulation of T cell and immune activity. [ABSTRACT FROM AUTHOR]