The Role of Regulation in the Control of Housing Conditions

Historically the control of housing conditions was based upon a concern for the health of the community and was safeguarded by the enforced repair and improvement of substandard property. In the United Kingdom the high cost of repair eventually induced a policy based upon subsidy to both home owners and private landlords as the price of healthier housing. This paper outlines the process by which the legislative standards invoked to protect health were modified to distribute subsidy. In 1989 the standards are poised to become criteria for the measurement of poverty rather than the identification of unhealthy housing conditions. In this process the protection of public health is being overlooked. There is strong evidence to suggest that the health of occupiers is at risk from modern and traditional housing hazards. Unless health is readopted as a concern of housing policy, the regulatory response needs radical rethinking

Mechanotransduction and nuclear function

Many signaling pathways converge on the nucleus to regulate critical nuclear events such as transcription, DNA replication and cell cycle progression. While the vast majority of research in this area has focused on signals generated in response to hormones or other soluble factors, the nucleus also responds to mechanical forces. During the past decade or so, much has been learned about how mechanical force can affect transcription, as well as the growth and differentiation of cells. Much has also been learned about how force is transmitted via the cytoskeleton to the nucleus and then across the nuclear envelope to the nuclear lamina and chromatin. In this brief review, we focus on some of the key proteins that transmit mechanical signals across the nuclear envelope

Tension on JAM-A activates RhoA via GEF-H1 and p115 RhoGEF

Junctional adhesion molecule A (JAM-A) is a broadly expressed adhesion molecule that regulates cell–cell contacts and facilitates leukocyte transendothelial migration. The latter occurs through interactions with the integrin LFA-1. Although we understand much about JAM-A, little is known regarding the protein’s role in mechanotransduction or as a modulator of RhoA signaling. We found that tension imposed on JAM-A activates RhoA, which leads to increased cell stiffness. Activation of RhoA in this system depends on PI3K-mediated activation of GEF-H1 and p115 RhoGEF. These two GEFs are further regulated by FAK/ERK and Src family kinases, respectively. Finally, we show that phosphorylation of JAM-A at Ser-284 is required for RhoA activation in response to tension. These data demonstrate a direct role of JAM-A in mechanosignaling and control of RhoA and implicate Src family kinases in the regulation of p115 RhoGEF

Phase-slip avalanches in the superflow of 4^4He through arrays of nanopores

Recent experiments by Sato et al. [1] have explored the dynamics of $^4$He superflow through an array of nanopores. These experiments have found that, as the temperature is lowered, phase-slippage in the pores changes its character, from synchronous to asynchronous. Inspired by these experiments, we construct a model to address the characteristics of phase-slippage in superflow through nanopore arrays. We focus on the low-temperature regime, in which the current-phase relation for a single pore is linear, and thermal fluctuations may be neglected. Our model incorporates two basic ingredients: (1) each pore has its own random value of critical velocity (due, e.g., to atomic-scale imperfections), and (2) an effective inter-pore coupling, mediated through the bulk superfluid. The inter-pore coupling tends to cause neighbours of a pore that has already phase-slipped also to phase-slip; this process may cascade, creating an avalanche of synchronously slipping phases. As the temperature is lowered, the distribution of critical velocities is expected to effectively broaden, owing to the reduction in the superfluid healing length, leading to a loss of synchronicity in phase-slippage. Furthermore, we find that competition between the strength of the disorder in the critical velocities and the strength of the inter-pore interaction leads to a phase transition between non-avalanching and avalanching regimes of phase-slippage. [1] Sato, Y., Hoskinson, E. Packard, R. E. cond-mat/0605660.Comment: 8 pages, 5 figure

The construction of discursive difficulty: the circulation of, and resistance to, moral asymmetries in the public debate over the invasion of Iraq in 2003

This thesis examines the operation of morally asymmetrical distinctions in the discourse produced in advance of the invasion of Iraq in March 2003. It does not set out to explain the invasion's occurrence, but, based upon the analysis of media texts, parliamentary debates, and political speeches, focuses upon aspects of the processes of justification and criticism preceding invasion. It blends together aspects of the work of Michel Foucault and Niklas Luhmann, with insights drawn from various approaches to the analysis of discourse and communication, in pursuit of an understanding of how the discursive space available to contributors to debate is restricted. It pays close attention to the closely related processes of 'disclaiming' and 'ontological gerrymandering' - interventions which are concerned with controlling what is, and is not, the case - particularly in terms of the way that they are orientated towards controlling how the person making them is to be observed. It is argued that the circulation of the illegitimacy of various positions puts some contributors at risk of being observed according to the more negative side of a morally asymmetrical distinction. It is argued that this creates 'difficulty' for them, and incites their engagement in particular forms of discursive work in the attempt to avoid illegitimacy themselves. Close attention is paid to any observable regularities in the ways in which contributors attempted to avoid having their position associated with, amongst other things, 'anti-Americanism', 'appeasement', 'pacifism', 'warmongering', or a 'pro-Saddam' stance, all of which would threaten their legitimacy. A variety of techniques are identified, including the invocation of a contributor's history of positions (their 'communicative career'), as well as their use of their allegedly less legitimate context-specific allies as a contrastive foil, at the expense of whom they claim their own legitimacy

The transformation of earth-system observations into information of socio-economic value in GEOSS

The Group on Earth Observations System of Systems, GEOSS, is a co-ordinated initiative by many nations to address the needs for earth-system information expressed by the 2002 World Summit on Sustainable Development. We discuss the role of earth-system modelling and data assimilation in transforming earth-system observations into the predictive and status-assessment products required by GEOSS, across many areas of socio-economic interest. First we review recent gains in the predictive skill of operational global earth-system models, on time-scales of days to several seasons. We then discuss recent work to develop from the global predictions a diverse set of end-user applications which can meet GEOSS requirements for information of socio-economic benefit; examples include forecasts of coastal storm surges, floods in large river basins, seasonal crop yield forecasts and seasonal lead-time alerts for malaria epidemics. We note ongoing efforts to extend operational earth-system modelling and assimilation capabilities to atmospheric composition, in support of improved services for air-quality forecasts and for treaty assessment. We next sketch likely GEOSS observational requirements in the coming decades. In concluding, we reflect on the cost of earth observations relative to the modest cost of transforming the observations into information of socio-economic value

N-glycosylation controls the function of junctional adhesion molecule-A

Junctional adhesion molecule-A (JAM-A) is an adherens and tight junction protein expressed by endothelial and epithelial cells. JAM-A serves many roles and contributes to barrier function and cell migration and motility, and it also acts as a ligand for the leukocyte receptor LFA-1. JAM-A is reported to contain N-glycans, but the extent of this modification and its contribution to the protein’s functions are unknown. We show that human JAM-A contains a single N-glycan at N185 and that this residue is conserved across multiple mammalian species. A glycomutant lacking all N-glycans, N185Q, is able to reach the cell surface but exhibits decreased protein half-life compared with the wild- type protein. N-glycosylation of JAM-A is required for the protein’s ability to reinforce barrier function and contributes to Rap1 activity. We further show that glycosylation of N185 is required for JAM-A–mediated reduction of cell migration. Finally, we show that N-glycosylation of JAM-A regulates leukocyte adhesion and LFA-1 binding. These findings identify N-glycosylation as critical for JAM-A’s many functions

Unique Structural and Nucleotide Exchange Features of the Rho1 GTPase of Entamoeba histolytica

The single-celled human parasite Entamoeba histolytica possesses a dynamic actin cytoskeleton vital for its intestinal and systemic pathogenicity. The E. histolytica genome encodes several Rho family GTPases known to regulate cytoskeletal dynamics. EhRho1, the first family member identified, was reported to be insensitive to the Rho GTPase-specific Clostridium botulinum C3 exoenzyme, raising the possibility that it may be a misclassified Ras family member. Here, we report the crystal structures of EhRho1 in both active and inactive states. EhRho1 is activated by a conserved switch mechanism, but diverges from mammalian Rho GTPases in lacking a signature Rho insert helix. EhRho1 engages a homolog of mDia, EhFormin1, suggesting a role in mediating serum-stimulated actin reorganization and microtubule formation during mitosis. EhRho1, but not a constitutively active mutant, interacts with a newly identified EhRhoGDI in a prenylation-dependent manner. Furthermore, constitutively active EhRho1 induces actin stress fiber formation in mammalian fibroblasts, thereby identifying it as a functional Rho family GTPase. EhRho1 exhibits a fast rate of nucleotide exchange relative to mammalian Rho GTPases due to a distinctive switch one isoleucine residue reminiscent of the constitutively active F28L mutation in human Cdc42, which for the latter protein, is sufficient for cellular transformation. Nonconserved, nucleotide-interacting residues within EhRho1, revealed by the crystal structure models, were observed to contribute a moderating influence on fast spontaneous nucleotide exchange. Collectively, these observations indicate that EhRho1 is a bona fide member of the Rho GTPase family, albeit with unique structural and functional aspects compared with mammalian Rho GTPases