Neuropilins 1 and 2 mediate neointimal hyperplasia and re-endothelialization following arterial injury

AIMS: Neuropilins 1 and 2 (NRP1 and NRP2) play crucial roles in endothelial cell migration contributing to angiogenesis and vascular development. Both NRPs are also expressed by cultured vascular smooth muscle cells (VSMCs) and are implicated in VSMC migration stimulated by PDGF-BB, but it is unknown whether NRPs are relevant for VSMC function in vivo. We investigated the role of NRPs in the rat carotid balloon injury model, in which endothelial denudation and arterial stretch induce neointimal hyperplasia involving VSMC migration and proliferation. METHODS AND RESULTS: NRP1 and NRP2 mRNAs and proteins increased significantly following arterial injury, and immunofluorescent staining revealed neointimal NRP expression. Down-regulation of NRP1 and NRP2 using shRNA significantly reduced neointimal hyperplasia following injury. Furthermore, inhibition of NRP1 by adenovirally overexpressing a loss-of-function NRP1 mutant lacking the cytoplasmic domain (ΔC) reduced neointimal hyperplasia, whereas wild-type (WT) NRP1 had no effect. NRP-targeted shRNAs impaired, while overexpression of NRP1 WT and NRP1 ΔC enhanced, arterial re-endothelialization 14 days after injury. Knockdown of either NRP1 or NRP2 inhibited PDGF-BB-induced rat VSMC migration, whereas knockdown of NRP2, but not NRP1, reduced proliferation of cultured rat VSMC and neointimal VSMC in vivo. NRP knockdown also reduced the phosphorylation of PDGFα and PDGFβ receptors in rat VSMC, which mediate VSMC migration and proliferation. CONCLUSION: NRP1 and NRP2 play important roles in the regulation of neointimal hyperplasia in vivo by modulating VSMC migration (via NRP1 and NRP2) and proliferation (via NRP2), independently of the role of NRPs in re-endothelialization

Emerging Roles for Neuropilin-2 in Cardiovascular Disease

Cardiovascular disease, the leading cause of death worldwide, is predominantly associated with atherosclerosis. Atherosclerosis is a chronic inflammatory disease characterised by the narrowing of large to medium-sized arteries due to a build-up of plaque. Atherosclerotic plaque is comprised of lipids, extracellular matrix, and several cell types, including endothelial, immune, and vascular smooth muscle cells. Such narrowing of the blood vessels can itself restrict blood flow to vital organs but most severe clinical complications, including heart attacks and strokes, occur when lesions rupture, triggering the blood to clot and obstructing blood flow further down the vascular tree. To circumvent such obstructions, percutaneous coronary intervention or bypass grafts are often required; however, re-occlusion of the treated artery frequently occurs. Neuropilins (NRPs), a multifunctional family of cell surface co-receptors, are expressed by endothelial, immune, and vascular smooth muscle cells and are regulators of numerous signalling pathways within the vasculature. Here, we review recent studies implicating NRP2 in the development of occlusive vascular diseases and discuss how NRP2 could be targeted for therapeutic intervention

Logical Dreams

We discuss the past and future of set theory, axiom systems and independence results. We deal in particular with cardinal arithmetic

Gender, Epistemology, and Education: An Exploration of the Knowledge Construction of Female and Male Pupils

This study explores gender differences in the knowledge constructed about World War II by 11- and 12-year-old Scottish pupils. Data collected over seven months included field notes, interviews, students\u27 reading and writing, and audiotapes of discussions. Examination revealed the young women\u27s work showcased individuals while the young men framed World War II information using a world view. The findings illustrate the epistemological differences that can exist between our male and female students as they construct their own understanding of topics

Analysis of MERCATOR data Part I: variable B stars

We re-classified 31 variable B stars which were observed more than 50 times in the Geneva photometric system with the P7 photometer attached to the MERCATOR telescope (La Palma) during its first 3 years of scientific observations. HD89688 is a possible beta Cephei/slowly pulsating B star hybrid and the main mode of the COROT target HD180642 shows non-linear effects. The Maia candidates are re-classified as either ellipsoidal variables or spotted stars. Although the mode identification is still ongoing, all the well-identified modes so far have a degree l = 0, 1 or 2.Comment: 4 pages, 3 figures. To appear in: Proceedings of JENAM 2005 'Distant worlds', Communications in Asteroseismolog

A Class of Topological Actions

We review definitions of generalized parallel transports in terms of Cheeger-Simons differential characters. Integration formulae are given in terms of Deligne-Beilinson cohomology classes. These representations of parallel transport can be extended to situations involving distributions as is appropriate in the context of quantized fields.Comment: 41 pages, no figure

Survival and prognosis with osteosarcoma: outcomes in more than 2000 patients in the EURAMOS-1 cohort

BACKGROUND: High-grade osteosarcoma is a primary malignant bone tumour mainly affecting children and young adults. EURAMOS-1 is a collaboration of four study groups aiming to improve outcomes in this rare disease by facilitating the conduct of randomised controlled trials. METHODS: Patients eligible for EURAMOS-1 were aged ≤40 years with M0 or M1 skeletal high-grade osteosarcoma where complete surgical resection at all sites was deemed possible. A three-drug combination with methotrexate, doxorubicin and cisplatin was defined as standard chemotherapy, and between Apr-2005 and Jun-2011, 2260 patients were registered. We report survival outcomes and prognostic factors in the full cohort of registered patients. RESULTS: For all registered patients at a median follow-up of 54 months (IQR: 38-73) from biopsy, 3-year and 5-year event-free survival were 59% (95%CI 57%-61%) and 54% (95%CI 52%-56%) respectively. Multivariate analyses showed the most adverse factors at diagnosis were pulmonary metastases (HR=2.34, 95%CI 1.95-2.81), non-pulmonary metastases (HR=1.94, 95%CI 1.38-2.73) or an axial skeleton tumour site (HR=1.53, 95%CI 1.10-2.13). The histological subtypes telangiectatic (HR=0.52, 95%CI 0.33-0.80) and unspecified conventional (HR=0.67, 95%CI 0.52-0.88) were associated with a favourable prognosis compared to chondroblastic subtype. The 3-year and 5-year overall survival from biopsy were 79% (95%CI 77%-81%) and 71% (95%CI 68%-73%) respectively. For patients with localised disease at presentation and in complete remission after surgery, having a poor histological response was associated with worse outcome after surgery (HR=2.13, 95%CI 1.76-2.58). In radically operated patients, there was no good evidence that axial tumour site was associated with worse outcome. CONCLUSIONS: In conclusion, data from > 2,000 patients registered to EURAMOS-1 demonstrated survival rates in concordance with institution- or group-level osteosarcoma trials. Further efforts are required to drive improvements for patients who can be identified as at higher risk of adverse outcome. This trial reaffirms known prognostic factors, and due to the large numbers of patients registered, sheds light on some additional factors to consider

Critical Exponents of the N-vector model

Recently the series for two RG functions (corresponding to the anomalous dimensions of the fields phi and phi^2) of the 3D phi^4 field theory have been extended to next order (seven loops) by Murray and Nickel. We examine here the influence of these additional terms on the estimates of critical exponents of the N-vector model, using some new ideas in the context of the Borel summation techniques. The estimates have slightly changed, but remain within errors of the previous evaluation. Exponents like eta (related to the field anomalous dimension), which were poorly determined in the previous evaluation of Le Guillou--Zinn-Justin, have seen their apparent errors significantly decrease. More importantly, perhaps, summation errors are better determined. The change in exponents affects the recently determined ratios of amplitudes and we report the corresponding new values. Finally, because an error has been discovered in the last order of the published epsilon=4-d expansions (order epsilon^5), we have also reanalyzed the determination of exponents from the epsilon-expansion. The conclusion is that the general agreement between epsilon-expansion and 3D series has improved with respect to Le Guillou--Zinn-Justin.Comment: TeX Files, 27 pages +2 figures; Some values are changed; references update

Osteopontin is linked with AKT, FoxO1, and myostatin in skeletal muscle cells

Introduction: Osteopontin (OPN) polymorphisms are associated with muscle size and modify disease progression in Duchenne muscular dystrophy (DMD). We hypothesized that OPN may share a molecular network with myostatin (MSTN). Methods: Studies were conducted in the golden retriever (GRMD) and mdx mouse models of DMD. Follow-up in-vitro studies were employed in myogenic cells and the mdx mouse treated with recombinant mouse (rm) or human (Hu) OPN protein. Results: OPN was increased and MSTN was decreased and levels correlated inversely in GRMD hypertrophied muscle. RM-OPN treatment led to induced AKT1 and FoxO1 phosphorylation, microRNA-486 modulation, and decreased MSTN. An AKT1 inhibitor blocked these effects, whereas an RGD-mutant OPN protein and an RGDS blocking peptide showed similar effects to the AKT inhibitor. RMOPN induced myotube hypertrophy and minimal Feret diameter in mdx muscle. Discussion: OPN may interact with AKT1/MSTN/FoxO1 to modify normal and dystrophic muscle