A phenomenological density-scaling approach to lamellipodial actin dynamics

The integration of protein function studied in vitro in a dynamic system like the cell lamellipodium remains a significant challenge. One reason is the apparent contradictory effects that perturbations of some proteins can have on the overall lamellipodium dynamics, depending on exact conditions. Theoretical modeling offers one approach for understanding the balance between the mechanisms that drive and regulate actin network growth and decay. Most models use a \bottom-up" approach, involving explicitly assembling biochemical components to simulate observable behaviour. Their correctness therefore relies on both the accurate characterisation of all the components and the completeness of the relevant processes involved. To avoid potential pitfalls due to this uncertainty, we used an alternative \top-down" approach, in which measurable features of lamellipodium behaviour, here observed in two different cell types (HL60 and B16-F1), directly inform the development of a simple phenomenological model of lamellipodium dynamics. We show that the kinetics of F-actin association and dissociation scales with the local F-actin density, with no explicit location dependence. This justifies the use of a simplified kinetic model of lamellipodium dynamics that yields predictions testable by pharmacological or genetic intervention. A length-scale parameter (the lamellipodium width), emerges from this analysis as an experimentally accessible probe of network regulatory processes

Temperature dependent resistivity of spin-split subbands in GaAs 2D hole system

We calculate the temperature dependent resistivity in spin-split subbands induced by the inversion asymmetry of the confining potential in GaAs 2D hole systems. By considering both temperature dependent multisubband screening of impurity disorder and hole-hole scattering we find that the strength of the metallic behavior depends on the symmetry of the confining potential (i.e., spin-splitting) over a large range of hole density. At low density above the metal-insulator transition we find that effective disorder reduces the enhancement of the metallic behavior induced by spin-splitting. Our theory is in good qualitative agreement with existing experiments

Mechanisms of leading edge protrusion in interstitial migration.

While the molecular and biophysical mechanisms underlying cell protrusion on two-dimensional substrates are well understood, our knowledge of the actin structures driving protrusion in three-dimensional environments is poor, despite relevance to inflammation, development and cancer. Here we report that, during chemotactic migration through microchannels with 5 μm × 5 μm cross-sections, HL60 neutrophil-like cells assemble an actin-rich slab filling the whole channel cross-section at their front. This leading edge comprises two distinct F-actin networks: an adherent network that polymerizes perpendicular to cell-wall interfaces and a 'free' network that grows from the free membrane at the cell front. Each network is polymerized by a distinct nucleator and, due to their geometrical arrangement, the networks interact mechanically. On the basis of our experimental data, we propose that, during interstitial migration, medial growth of the adherent network compresses the free network preventing its retrograde movement and enabling new polymerization to be converted into forward protrusion

Metallicity and its low temperature behavior in dilute 2D carrier systems

We theoretically consider the temperature and density dependent transport properties of semiconductor-based 2D carrier systems within the RPA-Boltzmann transport theory, taking into account realistic screened charged impurity scattering in the semiconductor. We derive a leading behavior in the transport property, which is exact in the strict 2D approximation and provides a zeroth order explanation for the strength of metallicity in various 2D carrier systems. By carefully comparing the calculated full nonlinear temperature dependence of electronic resistivity at low temperatures with the corresponding asymptotic analytic form obtained in the $T/T_F \to 0$ limit, both within the RPA screened charged impurity scattering theory, we critically discuss the applicability of the linear temperature dependent correction to the low temperature resistivity in 2D semiconductor structures. We find quite generally that for charged ionized impurity scattering screened by the electronic dielectric function (within RPA or its suitable generalizations including local field corrections), the resistivity obeys the asymptotic linear form only in the extreme low temperature limit of $T/T_F \le 0.05$. We point out the experimental implications of our findings and discuss in the context of the screening theory the relative strengths of metallicity in different 2D systems.Comment: We have substantially revised this paper by adding new materials and figures including a detailed comparison to a recent experimen

The relative importance of electron-electron interactions compared to disorder in the two-dimensional "metallic" state

The effect of substrate bias and surface gate voltage on the low temperature resistivity of a Si-MOSFET is studied for electron concentrations where the resistivity increases with increasing temperature. This technique offers two degrees of freedom for controlling the electron concentration and the device mobility, thereby providing a means to evaluate the relative importance of electron-electron interactions and disorder in this so-called ``metallic'' regime. For temperatures well below the Fermi temperature, the data obey a scaling law where the disorder parameter ($k_{\rm{F}}l$), and not the concentration, appears explicitly. This suggests that interactions, although present, do not alter the Fermi-liquid properties of the system fundamentally. Furthermore, this experimental observation is reproduced in results of calculations based on temperature-dependent screening, in the context of Drude-Boltzmann theory.Comment: 5 pages, 6 figure

Invasive characteristics of human prostatic epithelial cells: understanding the metastatic process

Prostate cancer has a predilection to metastasise to the bone marrow stroma (BMS) by an as yet uncharacterised mechanism. We have defined a series of coculture models of invasion, which simulate the blood/BMS boundary and allow the elucidation of the signalling and mechanics of trans-endothelial migration within the complex bone marrow environment. Confocal microscopy shows that prostate epithelial cells bind specifically to bone marrow endothelial-to-endothelial cell junctions and initiate endothelial cell retraction. Trans-endothelial migration proceeds via an epithelial cell pseudopodial process, with complete epithelial migration occurring after 232±43 min. Stromal-derived factor-1 (SDF-1)/CXCR4 signalling induced PC-3 to invade across a basement membrane although the level of invasion was 3.5-fold less than invasion towards BMS (P=0.0007) or bone marrow endothelial cells (P=0.004). Maximal SDF-1 signalling of invasion was completely inhibited by 10 μM of the SDF-1 inhibitor T140. However, 10 μM T140 only reduced invasion towards BMS and bone marrow endothelial cells by 59% (P=0.001) and 29% (P=0.011), respectively. This study highlights the need to examine the potential roles of signalling molecules and/or inhibitors, not just in single-cell models but in coculture models that mimic the complex environment of the bone marrow

Clinical applications of donor lymphocyte infusion from an HLA-haploidentical donor: consensus recommendations from the Acute Leukemia Working Party of the EBMT

Donor lymphocyte infusion has been used in the management of relapsed hematologic malignancies after allogeneic hematopoietic cell transplantation. It can eradicate minimal residual disease or be used to rescue a hematologic relapse, being able to induce durable remissions in a subset of patients. With the increased use of haploidentical hematopoietic cell transplantation, there is renewed interest in the use of donor lymphocytes to either treat or prevent disease relapse post transplant. Published retrospective and small prospective studies have shown encouraging results with therapeutic donor lymphocyte infusion in different haploidentical transplantation platforms. In this consensus paper, finalized on behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation, we summarize the available evidence on the use of donor lymphocyte infusion from haploidentical donor, and provide recommendations on its therapeutic, pre-emptive and prophylactic use in clinical practice