WH2 and proline-rich domains of WASP-family proteins collaborate to accelerate actin filament elongation.

WASP-family proteins are known to promote assembly of branched actin networks by stimulating the filament-nucleating activity of the Arp2/3 complex. Here, we show that WASP-family proteins also function as polymerases that accelerate elongation of uncapped actin filaments. When clustered on a surface, WASP-family proteins can drive branched actin networks to grow much faster than they could by direct incorporation of soluble monomers. This polymerase activity arises from the coordinated action of two regulatory sequences: (i) a WASP homology 2 (WH2) domain that binds actin, and (ii) a proline-rich sequence that binds profilin-actin complexes. In the absence of profilin, WH2 domains are sufficient to accelerate filament elongation, but in the presence of profilin, proline-rich sequences are required to support polymerase activity by (i) bringing polymerization-competent actin monomers in proximity to growing filament ends, and (ii) promoting shuttling of actin monomers from profilin-actin complexes onto nearby WH2 domains. Unoccupied WH2 domains transiently associate with free filament ends, preventing their growth and dynamically tethering the branched actin network to the WASP-family proteins that create it. Collaboration between WH2 and proline-rich sequences thus strikes a balance between filament growth and tethering. Our work expands the number of critical roles that WASP-family proteins play in the assembly of branched actin networks to at least three: (i) promoting dendritic nucleation; (ii) linking actin networks to membranes; and (iii) accelerating filament elongation

Cost-Effectiveness of Second-Line Chemotherapy/Biologics among Elderly Metastatic Colon Cancer Patients

INTRODUCTION: Advancements in chemotherapy treatment have improved the clinical management of metastatic colon cancer (mCC) patients. An increasing number of elderly mCC patients receive various combinations of regimens in second-line chemotherapy/biologics treatment (Tx2) after first-line treatment (Tx1) to prolong survival and/or palliate symptoms, but these regimens have higher costs. This analysis investigated the survival benefit and incremental cost associated with Tx2 among elderly mCC patients. METHODS: Elderly (aged ≥66 years) SEER-Medicare patients diagnosed with mCC in 2003–2007 were identified and followed until death or the end of 2009. Cox regression and partitioned least squares regression were utilized to obtain the survival benefit and incremental cost associated with Tx2 within a 5-year study period. A time-varying model was used to reduce bias due to sequential ordering of Tx1 and Tx2. The regressions controlled for patient demographic characteristics, clinical variables, and a proxy for poor performance. Bootstrapping was used to generate 95% confidence intervals (CI). RESULTS: Of the 3,266 elderly mCC patients who received Tx1, 2,744 (84%) died within the observation period; 1,440 (44%) received Tx2. The survival benefit associated with receipt of Tx2 was 0.33 years (95% CI 0.19–0.43), and the associated incremental cost was $40,888 (95$123,903 per life year gained (95% CI 9,600–216,082). CONCLUSION: The estimated survival benefit of receiving second-line chemotherapy/biologics was about 4 months, which is consistent with evidence from clinical trials. This improved survival was associated with an ICER that exceeds the traditional threshold. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s12325-014-0134-8) contains supplementary material, which is available to authorized users

Profile scaling in decay of nanostructures

The flattening of a crystal cone below its roughening transition is studied by means of a step flow model. Numerical and analytical analyses show that the height profile, h(r,t), obeys the scaling scenario dh/dr = F(r t^{-1/4}). The scaling function is flat at radii r<R(t) \sim t^{1/4}. We find a one parameter family of solutions for the scaling function, and propose a selection criterion for the unique solution the system reaches.Comment: 4 pages, RevTex, 3 eps figure

Decay of one dimensional surface modulations

The relaxation process of one dimensional surface modulations is re-examined. Surface evolution is described in terms of a standard step flow model. Numerical evidence that the surface slope, D(x,t), obeys the scaling ansatz D(x,t)=alpha(t)F(x) is provided. We use the scaling ansatz to transform the discrete step model into a continuum model for surface dynamics. The model consists of differential equations for the functions alpha(t) and F(x). The solutions of these equations agree with simulation results of the discrete step model. We identify two types of possible scaling solutions. Solutions of the first type have facets at the extremum points, while in solutions of the second type the facets are replaced by cusps. Interactions between steps of opposite signs determine whether a system is of the first or second type. Finally, we relate our model to an actual experiment and find good agreement between a measured AFM snapshot and a solution of our continuum model.Comment: 18 pages, 6 figures in 9 eps file

Altered resting state neuromotor connectivity in men with chronic prostatitis/chronic pelvic pain syndrome: A MAPP: Research Network Neuroimaging Study.

Brain network activity associated with altered motor control in individuals with chronic pain is not well understood. Chronic Prostatitis/Chronic Pelvic Pain Syndrome (CP/CPPS) is a debilitating condition in which previous studies have revealed altered resting pelvic floor muscle activity in men with CP/CPPS compared to healthy controls. We hypothesized that the brain networks controlling pelvic floor muscles would also show altered resting state function in men with CP/CPPS. Here we describe the results of the first test of this hypothesis focusing on the motor cortical regions, termed pelvic-motor, that can directly activate pelvic floor muscles. A group of men with CP/CPPS (N = 28), as well as group of age-matched healthy male controls (N = 27), had resting state functional magnetic resonance imaging scans as part of the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network study. Brain maps of the functional connectivity of pelvic-motor were compared between groups. A significant group difference was observed in the functional connectivity between pelvic-motor and the right posterior insula. The effect size of this group difference was among the largest effect sizes in functional connectivity between all pairs of 165 anatomically-defined subregions of the brain. Interestingly, many of the atlas region pairs with large effect sizes also involved other subregions of the insular cortices. We conclude that functional connectivity between motor cortex and the posterior insula may be among the most important markers of altered brain function in men with CP/CPPS, and may represent changes in the integration of viscerosensory and motor processing

The profile of a decaying crystalline cone

The decay of a crystalline cone below the roughening transition is studied. We consider local mass transport through surface diffusion, focusing on the two cases of diffusion limited and attachment-detachment limited step kinetics. In both cases, we describe the decay kinetics in terms of step flow models. Numerical simulations of the models indicate that in the attachment-detachment limited case the system undergoes a step bunching instability if the repulsive interactions between steps are weak. Such an instability does not occur in the diffusion limited case. In stable cases the height profile, h(r,t), is flat at radii r<R(t)\sim t^{1/4}. Outside this flat region the height profile obeys the scaling scenario \partial h/\partial r = {\cal F}(r t^{-1/4}). A scaling ansatz for the time-dependent profile of the cone yields analytical values for the scaling exponents and a differential equation for the scaling function. In the long time limit this equation provides an exact description of the discrete step dynamics. It admits a family of solutions and the mechanism responsible for the selection of a unique scaling function is discussed in detail. Finally we generalize the model and consider permeable steps by allowing direct adatom hops between neighboring terraces. We argue that step permeability does not change the scaling behavior of the system, and its only effect is a renormalization of some of the parameters.Comment: 25 pages, 18 postscript figure

Novel continuum modeling of crystal surface evolution

We propose a novel approach to continuum modeling of the dynamics of crystal surfaces. Our model follows the evolution of an ensemble of step configurations, which are consistent with the macroscopic surface profile. Contrary to the usual approach where the continuum limit is achieved when typical surface features consist of many steps, our continuum limit is approached when the number of step configurations of the ensemble is very large. The model can handle singular surface structures such as corners and facets. It has a clear computational advantage over discrete models.Comment: 4 pages, 3 postscript figure

Wetting layer thickness and early evolution of epitaxially strained thin films

We propose a physical model which explains the existence of finite thickness wetting layers in epitaxially strained films. The finite wetting layer is shown to be stable due to the variation of the non-linear elastic free energy with film thickness. We show that anisotropic surface tension gives rise to a metastable enlarged wetting layer. The perturbation amplitude needed to destabilize this wetting layer decreases with increasing lattice mismatch. We observe the development of faceted islands in unstable films.Comment: 4 pages, 3 eps figure

Traffic Equations and Granular Convection

We investigate both numerically and analytically the convective instability of granular materials by two dimensional traffic equations. In the absence of vibrations the traffic equations assume two distinctive classes of fixed bed solutions with either a spatially uniform or nonuniform density profile. The former one exists only when the function V(\rho) that monitors the relaxation of grains assumes a cut off at the closed packed density, \rho_c, with V(\rho_c)=0, while the latter one exists for any form of V. Since there is little difference between the uniform and nonuniform solution deep inside the bed, the convective instability of the bulk may be studied by focusing on the stability of the uniform solution. In the presence of vibrations, we find that the uniform solution bifurcates into a bouncing solution, which then undergoes a supercritical bifurcation to the convective instability. We determine the onset of convection as a function of control parameters and confirm this picture by solving the traffic equations numerically, which reveals bouncing solutions, two convective rolls, and four convective rolls. Further, convective patterns change as the aspect ratio changes: in a vertically long container, the rolls move toward the surface, and in a horizontally long container, the rolls move toward the walls. We compare these results with those reported previously with a different continuum model by Hayakawa, Yue and Hong[Phys. Rev. Lett. 75,2328, 1995]. Finally, we also present a derivation of the traffic equations from Enskoq equation.Comment: 34 pages, 10 figure

A 6-item scale for overall, emotional, and social loneliness: Confirmatory tests on survey data

Loneliness is an indicator of social well-being and pertains to the feeling of missing an intimate relationship (emotional loneliness) or missing a wider social network (social loneliness). The 11-item De Jong Gierveld Loneliness Scale has proved to be a valid and reliable measurement instrument for overall, emotional, and social loneliness, although its length has sometimes rendered it difficult to use in large surveys. In this study, the authors empirically tested a shortened version of the scale on data from two surveys (N = 9,448). Confirmatory factor analyses confirmed the specification of two latent factors. Congruent validity and the relationship with determinants (partner status, health) proved to be optimal. The 6-item De Jong Gierveld Loneliness Scale is a reliable and valid measurement instrument for overall, emotional, and social loneliness that is suitable for large surveys