A Model Reference Adaptive Re-Entry Flight Control System

The pitch plane equations of motion of a rigid body maneuvering ballistic re-entry vehicle are reviewed. A quasi-linear analysis of these equations is made about a nominal re-entry trajectory. It is demonstrated that in a large number of cases constant gain compensation for the flight control system will not be satisfactory due primarily to variations in dynamic pressure and static margin. A brief review of the adaptive concept is presented. It is shown that a model reference adaptive feedback system which has lift acceleration as the controlled variable and pitch rate as a stabilizing feedback is capable of handling the re-entry control problem. Current research involving fast identification techniques is described

Hyperphosphatemia-induced nanocrystals upregulate the expression of bone morphogenetic protein-2 and osteopontin genes in mouse smooth muscle cells in vitro

Vascular calcification, which contributes to cardiovascular disease in patients with uremic hyperphosphatemia, is associated with vascular cell expression of osteogenic genes, including bone morphogenetic protein (BMP)-2 and osteopontin (OPN). High inorganic phosphate levels in vitro stimulate the osteogenic conversion of smooth muscle cells; however, the mechanism governing this is not clear. We found that high-phosphate medium increased the expression of BMP-2 and OPN in mouse smooth muscle cells in culture. However, this effect was lost in the presence of the mineralization inhibitor, pyrophosphate, suggesting a contribution of calcium phosphate crystals. Addition of 1–2 mmol/l phosphate alone to growth medium was sufficient to induce nanosized crystals after 1 day at 37 °C. Isolated crystals were about 160 nm in diameter and had a calcium to phosphate ratio of 1.35, consistent with the hydroxyapatite precursor octacalcium phosphate. Nanocrystal formation increased fourfold in the absence of serum, was blocked by fetuin-A, and was dependent on time and on the concentrations of phosphate and calcium. Purified synthetic hydroxyapatite nanocrystals and isolated high-phosphate-induced nanocrystals, but not nanocrystal-free high-phosphate medium, also induced BMP-2 and OPN. Thus, our results suggest that BMP-2 and OPN are induced by calcium phosphate nanocrystals, rather than soluble phosphate. This mechanism may contribute, in part, to hyperphosphatemia-related vascular cell differentiation and calcification

Multiple potential roles for B cells in atherosclerosis.

The development of atherosclerosis is the major etiological factor causing cardiovascular disease and constitutes a lipid-induced, chronic inflammatory and autoimmune disease of the large arteries. A long-standing view of the protective role of B cells in atherosclerosis has been challenged by recent studies using B cell depletion in animal models. Whereas complete B cell deficiency increases atherosclerosis, depletion of B2 but not B1 cells reduces atherosclerosis. This has led to a re-evaluation of the multiple potential pathways by which B cells can regulate atherosclerosis, and the apparent opposing roles of B1 and B2 cells. B cells, in addition to having the unique ability to produce antibodies, are now recognized to play a number of important roles in the immune system, including cytokine production and direct regulation of T cell responses. This review summarizes current knowledge on B cell subsets and functions, and how these could distinctly influence atherosclerosis development.This is the author accepted manuscript. The final version is available from Taylor & Francis at http://dx.doi.org/10.3109/07853890.2014.900272

From the vulnerable plaque to the vulnerable patient: Current concepts in atherosclerosis

Cardiovascular disease affects a significant proportion of the population with global prevalence of 6081 per 100,000 (Virani et al., 2020). Most core risk factors are well characterized and can be controlled with interventions, also meaning it is possible to identify most people at increased risk of acute events, defined as a 10 year risk of events of >20% . However, the real world occurrence of events in this at risk population is relatively low suggesting there is still much to be learnt or identified in spotting the vulnerable patient harbouring vulnerable atherosclerotic plaque at the earliest possible time.British Heart Foundatio

Adaptive (T and B cells) immunity and control by dendritic cells in atherosclerosis.

Chronic inflammation in response to lipoprotein accumulation in the arterial wall is central in the development of atherosclerosis. Both innate and adaptive immunity are involved in this process. Adaptive immune responses develop against an array of potential antigens presented to effector T lymphocytes by antigen-presenting cells, especially dendritic cells. Functional analysis of the role of different T-cell subsets identified the Th1 responses as proatherogenic, whereas regulatory T-cell responses exert antiatherogenic activities. The effect of Th2 and Th17 responses is still debated. Atherosclerosis is also associated with B-cell activation. Recent evidence established that conventional B-2 cells promote atherosclerosis. In contrast, innate B-1 B cells offer protection through secretion of natural IgM antibodies. This review discusses the recent development in our understanding of the role of T- and B-cell subsets in atherosclerosis and addresses the role of dendritic cell subpopulations in the control of adaptive immunity.H A-O, ZM and AT are supported by Institut National de la Santé et de la Recherche Médicale (INSERM). AS and ZM are supported by the British Heart Foundation.This is the author accepted manuscript. The final version is available from the American Heart Association at http://dx.doi.org/10.1161/CIRCRESAHA.114.302761

Targeting B cells in atherosclerosis: closing the gap from bench to bedside.

Atherosclerotic plaque formation is strongly influenced by different arms of the immune system, including B lymphocytes. B cells are divided into 2 main families: the B1 and the B2 cells. B1 cells are atheroprotective mainly via the production of natural IgM antibodies that bind oxidized low-density lipoprotein and apoptotic cells. B2 cells, which include follicular and marginal zone B cells, are suggested to be proatherogenic. Antibody-mediated depletion of B cells has become a valuable treatment option for certain autoimmune diseases, such as systemic lupus erythematosus and rheumatoid arthritis that are also characterized by the development of premature atherosclerosis. Thus, B cells represent a novel interesting target for therapeutic modulation of the atherosclerotic disease process. Here, we discuss the effect of different of B-cell subsets in experimental atherosclerosis, their mechanism of action as well as potential ways to exploit these findings for the treatment of human disease.CJB is supported by grants of the Austrian Science Fund (SFB F30 and F54) and the European Union (FP7). APS and ZM are supported by grants from the British Heart Foundation.This is the author accepted manuscript. The final version is available from the American Heart Association at http://dx.doi.org/10.1161/ATVBAHA.114.303569

MHC class II-restricted antigen presentation by plasmacytoid dendritic cells drives proatherogenic T cell immunity

Background—Plasmacytoid dendritic cells (pDCs) bridge innate and adaptive immune responses and are important regulators of immuno-inflammatory diseases. However, their role in atherosclerosis remains elusive. Methods and Results—Here, we used genetic approaches to investigate the role of pDCs in atherosclerosis. Selective pDC deficiency in vivo was achieved using CD11c-Cre × Tcf4–/flox bone marrow transplanted into Ldlr–/– mice. Compared with control Ldlr–/– chimeric mice, CD11c-Cre × Tcf4–/flox mice had reduced atherosclerosis levels. To begin to understand the mechanisms by which pDCs regulate atherosclerosis, we studied chimeric Ldlr–/– mice with selective MHCII deficiency on pDCs. Significantly, these mice also developed reduced atherosclerosis compared with controls without reductions in pDC numbers or changes in conventional DCs. MHCII-deficient pDCs showed defective stimulation of apolipoprotein B100–specific CD4+ T cells in response to native low-density lipoprotein, whereas production of interferon-α was not affected. Finally, the atheroprotective effect of selective MHCII deficiency in pDCs was associated with significant reductions of proatherogenic T cell–derived interferon-γ and lesional T cell infiltration, and was abrogated in CD4+ T cell–depleted animals. Conclusions—This study supports a proatherogenic role for pDCs in murine atherosclerosis and identifies a critical role for MHCII-restricted antigen presentation by pDCs in driving proatherogenic T cell immunity

Myocardin regulates vascular smooth muscle cell inflammatory activation and disease.

OBJECTIVE: Atherosclerosis, the cause of 50% of deaths in westernized societies, is widely regarded as a chronic vascular inflammatory disease. Vascular smooth muscle cell (VSMC) inflammatory activation in response to local proinflammatory stimuli contributes to disease progression and is a pervasive feature in developing atherosclerotic plaques. Therefore, it is of considerable therapeutic importance to identify mechanisms that regulate the VSMC inflammatory response. APPROACH AND RESULTS: We report that myocardin, a powerful myogenic transcriptional coactivator, negatively regulates VSMC inflammatory activation and vascular disease. Myocardin levels are reduced during atherosclerosis, in association with phenotypic switching of smooth muscle cells. Myocardin deficiency accelerates atherogenesis in hypercholesterolemic apolipoprotein E(-/-) mice. Conversely, increased myocardin expression potently abrogates the induction of an array of inflammatory cytokines, chemokines, and adhesion molecules in VSMCs. Expression of myocardin in VSMCs reduces lipid uptake, macrophage interaction, chemotaxis, and macrophage-endothelial tethering in vitro, and attenuates monocyte accumulation within developing lesions in vivo. These results demonstrate that endogenous levels of myocardin are a critical regulator of vessel inflammation. CONCLUSIONS: We propose myocardin as a guardian of the contractile, noninflammatory VSMC phenotype, with loss of myocardin representing a critical permissive step in the process of phenotypic transition and inflammatory activation, at the onset of vascular disease.This work was supported by Wellcome Trust funding for MAJ (Studentship 086799/Z/08/Z), British Heart Foundation grants (PG/10/007/28184) for AT, and (RG/08/009/25841) for MRB, and SS (FS/13/29/30024), the Cambridge NIHR Biomedical Research Centre and the NIH for JM (NIH HL-117907).This is the accepted manuscript of a paper published in Arteriosclerosis, Thrombosis, and Vascular Biology, 2015, doi: 10.1161/ATVBAHA.114.30521