Targeting Gbeta gamma signaling in arterial vascular smooth muscle proliferation: a novel strategy to limit restenosis.

Restenosis continues to be a major problem limiting the effectiveness of revascularization procedures. To date, the roles of heterotrimeric G proteins in the triggering of pathological vascular smooth muscle (VSM) cell proliferation have not been elucidated. betagamma subunits of heterotrimeric G proteins (Gbetagamma) are known to activate mitogen-activated protein (MAP) kinases after stimulation of certain G protein-coupled receptors; however, their relevance in VSM mitogenesis in vitro or in vivo is not known. Using adenoviral-mediated transfer of a transgene encoding a peptide inhibitor of Gbetagamma signaling (betaARKct), we evaluated the role of Gbetagamma in MAP kinase activation and proliferation in response to several mitogens, including serum, in cultured rat VSM cells. Our results include the striking finding that serum-induced proliferation of VSM cells in vitro is mediated largely via Gbetagamma. Furthermore, we studied the effects of in vivo adenoviral-mediated betaARKct gene transfer on VSM intimal hyperplasia in a rat carotid artery restenosis model. Our in vivo results demonstrated that the presence of the betaARKct in injured rat carotid arteries significantly reduced VSM intimal hyperplasia by 70%. Thus, Gbetagamma plays a critical role in physiological VSM proliferation, and targeted Gbetagamma inhibition represents a novel approach for the treatment of pathological conditions such as restenosis.

Energy recovery in individuals with knee osteoarthritis.

OBJECTIVE: Pathological gaits have been shown to limit transfer between potential (PE) and kinetic (KE) energy during walking, which can increase locomotor costs. The purpose of this study was to examine whether energy exchange would be limited in people with knee osteoarthritis (OA). METHODS: Ground reaction forces during walking were collected from 93 subjects with symptomatic knee OA (self-selected and fast speeds) and 13 healthy controls (self-selected speed) and used to calculate their center of mass (COM) movements, PE and KE relationships, and energy recovery during a stride. Correlations and linear regressions examined the impact of energy fluctuation phase and amplitude, walking velocity, body mass, self-reported pain, and radiographic severity on recovery. Paired t-tests were run to compare energy recovery between cohorts. RESULTS: Symptomatic knee OA subjects displayed lower energetic recovery during self-selected walking speeds than healthy controls (P = 0.0018). PE and KE phase relationships explained the majority (66%) of variance in recovery. Recovery had a complex relationship with velocity and its change across speeds was significantly influenced by the self-selected walking speed of each subject. Neither radiographic OA scores nor subject self-reported measures demonstrated any relationship with energy recovery. CONCLUSIONS: Knee OA reduces effective exchange of PE and KE, potentially increasing the muscular work required to control movements of the COM. Gait retraining may return subjects to more normal patterns of energy exchange and allow them to reduce fatigue.

Sticky central limit theorems on open books

Given a probability distribution on an open book (a metric space obtained by gluing a disjoint union of copies of a half-space along their boundary hyperplanes), we define a precise concept of when the Fréchet mean (barycenter) is sticky. This nonclassical phenomenon is quantified by a law of large numbers (LLN) stating that the empirical mean eventually almost surely lies on the (codimension 1 and hence measure 0) spine that is the glued hyperplane, and a central limit theorem (CLT) stating that the limiting distribution is Gaussian and supported on the spine.We also state versions of the LLN and CLT for the cases where the mean is nonsticky (i.e., not lying on the spine) and partly sticky (i.e., is, on the spine but not sticky). © Institute of Mathematical Statistics, 2013.

Human Non-neutralizing HIV-1 Envelope Monoclonal Antibodies Limit the Number of Founder Viruses during SHIV Mucosal Infection in Rhesus Macaques.

HIV-1 mucosal transmission begins with virus or virus-infected cells moving through mucus across mucosal epithelium to infect CD4+ T cells. Although broadly neutralizing antibodies (bnAbs) are the type of HIV-1 antibodies that are most likely protective, they are not induced with current vaccine candidates. In contrast, antibodies that do not neutralize primary HIV-1 strains in the TZM-bl infection assay are readily induced by current vaccine candidates and have also been implicated as secondary correlates of decreased HIV-1 risk in the RV144 vaccine efficacy trial. Here, we have studied the capacity of anti-Env monoclonal antibodies (mAbs) against either the immunodominant region of gp41 (7B2 IgG1), the first constant region of gp120 (A32 IgG1), or the third variable loop (V3) of gp120 (CH22 IgG1) to modulate in vivo rectal mucosal transmission of a high-dose simian-human immunodeficiency virus (SHIV-BaL) in rhesus macaques. 7B2 IgG1 or A32 IgG1, each containing mutations to enhance Fc function, was administered passively to rhesus macaques but afforded no protection against productive clinical infection while the positive control antibody CH22 IgG1 prevented infection in 4 of 6 animals. Enumeration of transmitted/founder (T/F) viruses revealed that passive infusion of each of the three antibodies significantly reduced the number of T/F genomes. Thus, some antibodies that bind HIV-1 Env but fail to neutralize virus in traditional neutralization assays may limit the number of T/F viruses involved in transmission without leading to enhancement of viral infection. For one of these mAbs, gp41 mAb 7B2, we provide the first co-crystal structure in complex with a common cyclical loop motif demonstrated to be critical for infection by other retroviruses.

How to beat the Rayleigh limit?

The problem of achieving super-resolution, i.e. resolution beyond the classical Rayleigh distance of half a wavelength, is a real challenge in several imaging problems. The development of computer-assisted instruments and the possibility of inverting the recorded data has clearly modified the traditional concept of resolving power of an instrument. We show that, in the framework of inverse problem theory, the achievable resolution limit arises no longer from a universal rule but instead from a practical limitation due to noise amplification in the data inversion process. We analyze under what circumstances super-resolution can be achieved and we show how to assess the actual resolution limits in a given experiment, as a function of the noise level and of the available a priori knowledge about the object function. We emphasize the importance of the a priori knowledge of its effective support and we show that significant super-resolution can be achieved for "subwavelength sources", i.e. objects which are smaller than the probing wavelength.

Object Restoration Beyond the Rayleigh Limit in the Presence of Noise

info:eu-repo/semantics/published

Resolution beyond the diffraction limit for regularized object restoration

We propose a new formulation of Miller's regularization theory, which is particularly suitable for object restoration problems. By means of simple geometrical arguments, we obtain upper and lower bounds for the errors on regularized solutions. This leads to distinguish between ' Holder continuity ' which is quite good for practical computations and ` logarithmic continuity ' which is very poor. However, in the latter case, one can reconstruct local weighted averages of the solution. This procedure allows for precise valuations of the resolution attainable in a given problem. Numerical computations, made for object restoration beyond the diffraction limit in Fourier optics, show that, when logarithmic continuity holds, the resolution is practically independent of the data noise level. © 1980 Taylor & Francis Group, LLC.

Two fluid approach to high speed impact interaction amongst solid structures

The issues surrounding collision of projectiles with structures has gained a high profile since the events of 11th September 2001. In such collision problems, the projectile penetrates the stucture so that tracking the interface between one material and another becomes very complex, especially if the projectile is essentially a vessel containing a fluid, e.g. fuel load. The subsequent combustion, heat transfer and melting and re-solidification process in the structure render this a very challenging computational modelling problem. The conventional approaches to the analysis of collision processes involves a Lagrangian-Lagrangian contact driven methodology. This approach suffers from a number of disadvantages in its implementation, most of which are associated with the challenges of the contact analysis component of the calculations. This paper describes a 'two fluid' approach to high speed impact between solid structures, where the objective is to overcome the problems of penetration and re-meshing. The work has been carried out using the finite volume, unstructured mesh multi-physics code PHYSICA+, where the three dimensional fluid flow, free surface, heat transfer, combustion, melting and re-solidification algorithms are approximated using cell-centred finite volume, unstructured mesh techniques on a collocated mesh. The basic procedure is illustrated for two cases of Newtonian and non-Newtonian flow to test various of its component capabilities in the analysis of problems of industrial interest.

Evaluation of particle degradation due to high-speed impacts in a pneumatic handling system

Particle degradation can be a significant issue in particulate solids handling and processing, particularly in pneumatic conveying systems, in which high-speed impact is usually the main contributory factor leading to changes in particle size distribution (comparing the material to its virgin state). However, other factors may strongly influence particles breakage as well, such as particle concentrations, bend geometry,and hardness of pipe material. Because of such complex influences, it is often very difficult to predict particle degradation accurately and rapidly for industrial processes. In this article, a general method for evaluating particle degradation due to high-speed impacts is described, in which the breakage properties of particles are quantified using what are known as "breakage matrices". Rather than a pilot-size test facility, a bench-scale degradation tester has been used. Some advantages of using the bench-scale tester are briefly explored. Experimental determination of adipic acid has been carried out for a range of impact velocities in four particle size categories. Subsequently, particle breakage matrices of adipic acid have been established for these impact velocities. The experimental results show that the "breakage matrices" of particles is an effective and easy method for evaluation of particle degradation due to high-speed impacts. The possibility of the "breakage matrices" approach being applied to a pneumatic conveying system is also explored by a simulation example.