Lessons from LIMK1 enzymology and their impact on inhibitor design

LIM domain kinase 1 (LIMK1) is a key regulator of actin dynamics. It is thereby a potential therapeutic target for the prevention of fragile X syndrome and amyotrophic lateral sclerosis. Herein, we use X-ray crystallography and activity assays to describe how LIMK1 accomplishes substrate specificity, to suggest a unique ‘rock-and-poke’ mechanism of catalysis and to explore the regulation of the kinase by activation loop phosphorylation. Based on these findings, a differential scanning fluorimetry assay and a RapidFire mass spectrometry activity assay were established, leading to the discovery and confirmation of a set of small-molecule LIMK1 inhibitors. Interestingly, several of the inhibitors were inactive towards the closely related isoform LIMK2. Finally, crystal structures of the LIMK1 kinase domain in complex with inhibitors (PF-477736 and staurosporine, respectively) are presented, providing insights into LIMK1 plasticity upon inhibitor binding

Active Mass Under Pressure

After a historical introduction to Poisson's equation for Newtonian gravity, its analog for static gravitational fields in Einstein's theory is reviewed. It appears that the pressure contribution to the active mass density in Einstein's theory might also be noticeable at the Newtonian level. A form of its surprising appearance, first noticed by Richard Chase Tolman, was discussed half a century ago in the Hamburg Relativity Seminar and is resolved here.Comment: 28 pages, 4 figure

Glioma Associated Stem Cells (GASCs) Isolation and Culture.

Glioma Associated Stem Cells (GASCs) represent a population of nontumorigenic multipotent stem cells hosted in the microenvironment of human gliomas. In vitro, these cells are able, through the release of exosomes, to increase the biological aggressiveness of glioma-initiating cells. The clinical importance of this finding is supported by the strong prognostic value associated with the GASCs surface immunophenotype thus suggesting that this patient-based approach can provide a groundbreaking method to predict prognosis and to exploit novel strategies that target the tumor strom

Gradient catastrophe and flutter in vortex filament dynamics

Gradient catastrophe and flutter instability in the motion of vortex filament within the localized induction approximation are analyzed. It is shown that the origin if this phenomenon is in the gradient catastrophe for the dispersionless Da Rios system which describes motion of filament with slow varying curvature and torsion. Geometrically this catastrophe manifests as a rapid oscillation of a filament curve in a point that resembles the flutter of airfoils. Analytically it is the elliptic umbilic singularity in the terminology of the catastrophe theory. It is demonstrated that its double scaling regularization is governed by the Painlev\'e-I equation.Comment: 11 pages, 3 figures, typos corrected, references adde

Classification of integrable Weingarten surfaces possessing an sl(2)-valued zero curvature representation

In this paper we classify Weingarten surfaces integrable in the sense of soliton theory. The criterion is that the associated Gauss equation possesses an sl(2)-valued zero curvature representation with a nonremovable parameter. Under certain restrictions on the jet order, the answer is given by a third order ordinary differential equation to govern the functional dependence of the principal curvatures. Employing the scaling and translation (offsetting) symmetry, we give a general solution of the governing equation in terms of elliptic integrals. We show that the instances when the elliptic integrals degenerate to elementary functions were known to nineteenth century geometers. Finally, we characterize the associated normal congruences

ZZ--Z′Z' mixing and oblique corrections in an SU(3)×U(1){\rm SU(3) \times U(1)} model

A global fit for experiments is included in this revised version.Comment: IFP-460-UNC, TRI-PP-93-11, 20 pages, 2 figures are appende

Fourier and Gegenbauer expansions for a fundamental solution of the Laplacian in the hyperboloid model of hyperbolic geometry

Due to the isotropy $d$-dimensional hyperbolic space, there exist a spherically symmetric fundamental solution for its corresponding Laplace-Beltrami operator. On the $R$-radius hyperboloid model of $d$-dimensional hyperbolic geometry with $R>0$ and $d\ge 2$, we compute azimuthal Fourier expansions for a fundamental solution of Laplace's equation. For $d\ge 2$, we compute a Gegenbauer polynomial expansion in geodesic polar coordinates for a fundamental solution of Laplace's equation on this negative-constant sectional curvature Riemannian manifold. In three-dimensions, an addition theorem for the azimuthal Fourier coefficients of a fundamental solution for Laplace's equation is obtained through comparison with its corresponding Gegenbauer expansion.Comment: arXiv admin note: substantial text overlap with arXiv:1201.440

Natalizumab affects T-cell phenotype in multiple sclerosis: implications for JCV reactivation

The anti-CD49d monoclonal antibody natalizumab is currently an effective therapy against the relapsing-remitting form of multiple sclerosis (RRMS). Natalizumab therapeutic efficacy is limited by the reactivation of the John Cunningham polyomavirus (JCV) and development of progressive multifocal leukoencephalopathy (PML). To correlate natalizumab-induced phenotypic modifications of peripheral blood T-lymphocytes with JCV reactivation, JCV-specific antibodies (serum), JCV-DNA (blood and urine), CD49d expression and relative abundance of peripheral blood T-lymphocyte subsets were longitudinally assessed in 26 natalizumab-treated RRMS patients. Statistical analyses were performed using GraphPad Prism and R. Natalizumab treatment reduced CD49d expression on memory and effector subsets of peripheral blood T-lymphocytes. Moreover, accumulation of peripheral blood CD8+ memory and effector cells was observed after 12 and 24 months of treatment. CD4+ and CD8+ T-lymphocyte immune-activation was increased after 24 months of treatment. Higher percentages of CD8+ effectors were observed in subjects with detectable JCV-DNA. Natalizumab reduces CD49d expression on CD8+ T-lymphocyte memory and effector subsets, limiting their migration to the central nervous system and determining their accumulation in peripheral blood. Impairment of central nervous system immune surveillance and reactivation of latent JCV, can explain the increased risk of PML development in natalizumab-treated RRMS subjects

The ecology of exercise: mechanisms underlying Individual variation in behavior, activity, and performance: an introduction to symposium

Wild animals often engage in intense physical activity while performing tasks vital for their survival and reproduction associated with foraging, avoiding predators, fighting, providing parental care, and migrating. In this theme issue we consider how viewing these tasks as “exercise”—analogous to that performed by human athletes—may help provide insight into the mechanisms underlying individual variation in these types of behaviors and the importance of physical activity in an ecological context. In this article and throughout this issue, we focus on four key questions relevant to the study of behavioral ecology that may be addressed by studying wild animal behavior from the perspective of exercise physiology: (1) How hard do individual animals work in response to ecological (or evolutionary) demands?; (2) Do lab-based studies of activity provide good models for understanding activity in free-living animals and individual variation in traits?; (3) Can animals work too hard during “routine” activities?; and (4) Can paradigms of “exercise” and “training” be applied to free-living animals? Attempts to address these issues are currently being facilitated by rapid technological developments associated with physiological measurements and the remote tracking of wild animals, to provide mechanistic insights into the behavior of free-ranging animals at spatial and temporal scales that were previously impossible. We further suggest that viewing the behaviors of non-human animals in terms of the physical exercise performed will allow us to fully take advantage of these technological advances, draw from knowledge and conceptual frameworks already in use by human exercise physiologists, and identify key traits that constrain performance and generate variation in performance among individuals. It is our hope that, by highlighting mechanisms of behavior and performance, the articles in this issue will spur on further synergies between physiologists and ecologists, to take advantage of emerging cross-disciplinary perspectives and technologies

Magnetoluminescence

Pulsar Wind Nebulae, Blazars, Gamma Ray Bursts and Magnetars all contain regions where the electromagnetic energy density greatly exceeds the plasma energy density. These sources exhibit dramatic flaring activity where the electromagnetic energy distributed over large volumes, appears to be converted efficiently into high energy particles and gamma-rays. We call this general process magnetoluminescence. Global requirements on the underlying, extreme particle acceleration processes are described and the likely importance of relativistic beaming in enhancing the observed radiation from a flare is emphasized. Recent research on fluid descriptions of unstable electromagnetic configurations are summarized and progress on the associated kinetic simulations that are needed to account for the acceleration and radiation is discussed. Future observational, simulation and experimental opportunities are briefly summarized.Comment: To appear in "Jets and Winds in Pulsar Wind Nebulae, Gamma-ray Bursts and Blazars: Physics of Extreme Energy Release" of the Space Science Reviews serie