Pharmacogenomic Profiling and Pathway Analyses Identify MAPK-Dependent Migration as an Acute Response to SN38 in p53 Null and p53-Mutant Colorectal Cancer Cells.

The topoisomerase I inhibitor irinotecan is used to treat advanced colorectal cancer and has been shown to have p53-independent anticancer activity. The aim of this study was to identify the p53-independent signaling mechanisms activated by irinotecan. Transcriptional profiling of isogenic HCT116 p53 wild-type and p53 null cells was carried out following treatment with the active metabolite of irinotecan, SN38. Unsupervised analysis methods showed that p53 status had a highly significant impact on gene expression changes in response to SN38. Pathway analysis indicated that pathways involved in cell motility [adherens junction, focal adhesion, mitogen-activated protein kinase (MAPK), and regulation of the actin cytoskeleton] were significantly activated in p53 null cells, but not p53 wild-type cells, following SN38 treatment. In functional assays, SN38 treatment increased the migratory potential of p53 null and p53-mutant colorectal cancer cell lines, but not p53 wild-type lines. Moreover, p53 null SN38-resistant cells were found to migrate at a faster rate than parental drug-sensitive p53 null cells, whereas p53 wild-type SN38-resistant cells failed to migrate. Notably, cotreatment with inhibitors of the MAPK pathway inhibited the increased migration observed following SN38 treatment in p53 null and p53-mutant cells. Thus, in the absence of wild-type p53, SN38 promotes migration of colorectal cancer cells, and inhibiting MAPK blocks this potentially prometastatic adaptive response to this anticancer drug.

Imaging adiabatic control of charge transfer in molecules

Charge transfer is a subfemtosecond process in molecules that creates chemical and electronic structure changes. At the quantum level the process can be coherently controlled by ultrashort light pulses. We show how the charge transfer process can be manipulated using a combination of dynamic and static fields and predict how this can be observed experimentally by imaging with photoionization.

Connective tissue growth factor [CTGF]/CCN2 stimulates mesangial cell migration through integrated dissolution of focal adhesion complexes and activation of cell polarization

Connective tissue growth factor [CTGF]/CCN2 is a prototypic member of the CCN family of regulatory proteins. CTGF expression is up-regulated in a number of fibrotic diseases, including diabetic nephropathy, where it is believed to act as a downstream mediator of TGF-beta function; however, the exact mechanisms whereby CTGF mediates its effects remain unclear. Here, we describe the role of CTGF in cell migration and actin disassembly in human mesangial cells, a primary target in the development of renal glomerulosclerosis. The addition of CTGF to primary mesangial cells induced cell migration and cytoskeletal rearrangement but had no effect on cell proliferation. Cytoskeletal rearrangement was associated with a loss of focal adhesions, involving tyrosine dephosphorylation of focal adhesion kinase and paxillin, increased activity of the protein tyrosine phosphatase SHP-2, with a concomitant decrease in RhoA and Rac1 activity. Conversely, Cdc42 activity was increased by CTGF. These functional responses were associated with the phosphorylation and translocation of protein kinase C-zeta to the leading edge of migrating cells. Inhibition of CTGF-induced protein kinase C-zeta activity with a myristolated PKC-zeta inhibitor prevented cell migration. Moreover, transient transfection of human mesangial cells with a PKC-zeta kinase inactive mutant (dominant negative) expression vector also led to a decrease in CTGF-induced migration compared with wild-type. Furthermore, CTGF stimulated phosphorylation and activation of GSK-3beta. These data highlight for the first time an integrated mechanism whereby CTGF regulates cell migration through facilitative actin cytoskeleton disassembly, which is mediated by dephosphorylation of focal adhesion kinase and paxillin, loss of RhoA activity, activation of Cdc42, and phosphorylation of PKC-zeta and GSK-3beta. These changes indicate that the initial stages of CTGF mediated mesangial cell migration are similar to those involved in the process of cell polarization. These findings begin to shed mechanistic light on the renal diabetic milieu, where increased CTGF expression in the glomerulus contributes to cellular dysfunction.

A Life Course Perspective on Urban–Rural Migration: the Importance of the Local Context

The relationship between migration and age has long been established, and most recently, there have been calls for the inclusion of a life course perspective to migration research. In this paper, we explore Northern Ireland’s internal migration patterns, and in particular, we test for the importance of urban to rural migration at different stages of the life course. Data from the Northern Ireland Longitudinal Study are used for the first time to analyse urban–rural migration patterns. The resulting modelling demonstrates unique aspects of urban to rural migration within Northern Ireland, which up until now have gone largely
unreported. Results from logistic regression modelling suggest that there is an age selectivity to urban– rural mobility but not necessarily at the life course stages predicted from a review of the life course migration literature. Individuals in younger age groups (at the household and family formation stages of the life course) are most likely to make an urban to rural move in Northern Ireland, with a decline in the likelihood of this move type with age. Possible explanations are offered linked to Northern Ireland’s settlement hierarchy, rural planning policy, and family farming traditions. The findings challenge researchers to pay due attention to how migration processes may play out differently in varying geographical, social, and planning contexts and emphasise the importance of structural factors to explain migration patterns.

The Other Side of the Fence:Reconceptualizing the “Camp” and Migration Zones at the Borders of Spain

This article explores the dynamics of the space of exception at the borders of Europe in the Spanish enclave of Melilla, and the neighboring Moroccan city of Oujda. Building upon field research conducted in the spring of 2008, I ask how we can understand the political space of migration not simply as exceptional, but as shaped by the mobility of the irregular migrants moving outside of the frameworks, policies, and practices of the state. By privileging the migrant narrative and making use of Rancière's conception of politics as shaped by the demands of those who “have no part,” I suggest an alternative way of understanding the politics of exception and agency of non-citizens—that is, one of disruption and demands to open up powerful potentials for change in an otherwise rigid regime.

Time-dependent density functional theory study of charge transfer in collisions

We study the charge transfer between colliding ions, atoms, or molecules, within time-dependent density functional theory. Two particular cases are presented, the collision between a proton and a Helium atom, and between a gold atom and a butane molecule. In the first case, proton kinetic energies between 16 keV and 1.2 MeV are considered, with impact parameters between 0.31 and 1.9 angstrom. The partial transfer of charge is monitored with time. The total cross-section is obtained as a function of the proton kinetic energy. In the second case, we analyze one trajectory and discuss spin-dependent charge transfer between the different fragments.