Protein kinase a-regulated assembly of a MEF2·HDAC4 repressor complex controls c-jun expression in vascular smooth muscle cells

Vascular smooth muscle cells (VSMCs) maintain the ability to modulate their phenotype in response to changing environmental stimuli. This phenotype modulation plays a critical role in the development of most vascular disease states. In these studies, stimulation of cultured vascular smooth muscle cells with platelet-derived growth factor resulted in marked induction of c-jun expression, which was attenuated by protein kinase Cδ and calcium/calmodulin-dependent protein kinase inhibition. Given that these signaling pathways have been shown to relieve the repressive effects of class II histone deacetylases (HDACs) on myocyte enhancer factor (MEF) 2 proteins, we ectopically expressed HDAC4 and observed repression of c-jun expression. Congruently, suppression of HDAC4 by RNA interference resulted in enhanced c-jun expression. Consistent with these findings, mutation of the MEF2 cis-element in the c-jun promoter resulted in promoter activation during quiescent conditions, suggesting that the MEF2 cis-element functions as a repressor in this context. Furthermore, we demonstrate that protein kinase A attenuates c-Jun expression by promoting the formation of a MEF2-HDAC4 repressor complex by inhibiting salt-inducible kinase 1. Finally, we document a physical interaction between c-Jun and myocardin, and we document that forced expression of c-Jun represses the ability of myocardin to activate smooth muscle gene expression. Thus, MEF2 and HDAC4 act to repress c-Jun expression in quiescent VSMCs, protein kinase A enhances this repression, and platelet-derived growth factor derepresses c-Jun expression through calcium/calmodulin-dependent protein kinases and novel protein kinase Cs. Regulation of this molecular "switch" on the c-jun promoter may thus prove critical for toggling between the activated and quiescent VSMC phenotypes

In vitro and in vivo mRNA delivery using lipid-enveloped pHresponsive polymer nanoparticles

Biodegradable core−shell structured nanoparticles with a poly(β-amino ester) (PBAE) core enveloped by a phospholipid bilayer shell were developed for in vivo mRNA delivery with a view toward delivery of mRNA-based vaccines. The pH-responsive PBAE component was chosen to promote endosome disruption, while the lipid surface layer was selected to minimize toxicity of the polycation core. Messenger RNA was efficiently adsorbed via electrostatic interactions onto the surface of these net positively charged nanoparticles. In vitro, mRNA-loaded particle uptake by dendritic cells led to mRNA delivery into the cytosol with low cytotoxicity, followed by translation of the encoded protein in these difficult-to-transfect cells at a frequency of 30%. Particles loaded with mRNA administered intranasally (i.n.) in mice led to the expression of the reporter protein luciferase in vivo as soon as 6 h after administration, a time point when naked mRNA given i.n. showed no expression. At later time points, luciferase expression was detected in naked mRNA-treated mice, but this group showed a wide variation in levels of transfection, compared to particle-treated mice. This system may thus be promising for noninvasive delivery of mRNA-based vaccines.United States. Dept. of Defense (Institute for Soldier Nanotechnology, contract W911NF-07-D-0004)Ragon Institute of MGH, MIT and HarvardSingapore. Agency for Science, Technology and ResearchHoward Hughes Medical Institute (Investigator

Replication through partnership: the evolution of partnerships between community land trusts and housing associations in England

© 2016 Informa UK Limited, trading as Taylor & Francis Group. Community land trusts (CLTs) have emerged as an innovative way of addressing the affordable housing crisis in England, as they seek to control and own housing to ensure lasting affordability and to democratically manage assets through voluntarism and community ownership structures. However, there can be difficulties that impede their progress, including legitimacy as new forms of housing organisation, access to finance, and voluntary capacity. CLTs have increasingly begun to partner with housing associations to overcome these issues, combining community leadership with professional expertise and experience. While partnerships may be critiqued for standardising community initiatives or for marrying contrasting institutional logics, housing association support has led directly to the growth of the CLT sector and created new frameworks in which communities can pursue local goals. This paper reports on empirical research into the constitution and effectiveness of partnerships, and considers their implications for future community-led housing development

Own Clinical Observations of Treatment Outcome in Acute Type B Aortic Dissection

The aim of the study was to analyse early results of treatment of acute type B aortic dissection.Material and methods. 59 patients, treated between 1998 and 2011, were divided into four groups. Group I comprised ten patients in whom hybrid procedures were performed: extra-anatomical by-pass graft from the brachio-cephalic trunk to the left carotid artery in six patients, transposition of the left carotid artery to the right one in two patients, and reversed Y prosthesis from the brachio-cephalic trunk to both carotids in the remaining 2 patients, to facilitate stent-grafting. Group II comprised 13 patientsin whom endovascular procedures were performed (stent-grafting). Group III comprised 21 patients in whom conventional surgery was done. Group IV comprised 15 patients who were treated conservatively.Results. In group I, a very good clinical outcome, without complications, was achieved in six patients (60% of cases). The total mortality rate was 40%. One patient died on the operation table, following stent-grafting, due to the rupture of the aortic arch. Two patients died as a result of brain damage (cerebral aneurysm rupture in one, and ischemic stroke in the other). In one patient, an aorto-oesophageal fistula developed. In group II, one patient died during endovascular procedure. Another patient suffered from type 1 endoleak, requiring repeated endovascular surgery. In group III, 15 patients (72%) died. Moreover, four patients required acorrective cardiac surgery (Bentall procedure)which in three patients resulted in death. Thus, the total mortality rate in this group was as high as 85%. In group IV, the mortality rate was 13%.Conclusions. We noticed a clear superiority of endovascular procedures over conventional surgeries-for acute type B aortic dissection. Hybrid procedures for acute, complicated type B aortic dissection evidently reduce mortality and postoperative morbidity. Uncomplicated acute type B aortic dissections should be treated conservatively at intensivecare units

Ownership, Narrative, Things

This book uses a case study of a low-cost home ownership initiative at the margins of renting and owning provided by social landlords – known as shared ownership – to challenge everyday assumptions held about the ‘social’ and the ‘legal’ in property. The authors provide a study of the construction of property ownership, from the creation of this idea through to the present day, and offer a fresh consideration of key issues surrounding property, ownership, and the social. Analysing a diverse range of sources (from archives to micro-blogs, observation of housing providers, and interviews with shared owners), the authors explain the significance of the things (from the formal documents like leases, to odd materials like sweet wrappers and cigarette butts) commonly found in the narratives around shared ownership which are used to construct it as private ownership in everyday life. Ultimately, they uncover how this dream of ownership can become tarnished when people’s identities as ‘owners’ come under threat, and as such, these findings will provide fascinating insight into the intricacies of so-called home ownership for scholars of Law, Criminology, and Sociology

Shared Ownership and Housing Policy

This chapter presents a study of housing policy from the periphery. As we develop below, it is not its numerical significance as a tenure that makes shared ownership so important; rather, it is its totemic significance in housing policy and its location as a social housing low-cost homeownership “product” which make it an object of study. Our argument is that, in the very way in which it is discussed and represented in policy and by policy-makers, shared ownership appears as a very simple “product”, albeit one which has gone through a series of different iterations. And, most of all, shared ownership is constructed as ownership. That very simple ownership product, at heart, is how shared ownership came to be represented and translated by a range of others, including buyers—to adopt the metaphor widely used in policy documents, enabling people to “get a foot on the ladder” of “homeownership”. And, of course, these are very legal translations