Cyclophilin-A is bound to through its peptidylprolyl isomerase domain to the cytoplasmic dynein motor protein complex

Although cyclophilin A (CyP-A) is a relatively abundant small immunophilin present in the cytoplasm of all mammalian cells, its general function(s) in the absence of the immunosuppressant drug cyclosporin A is not known. In contrast, the high molecular weight hsp90-binding immunophilins appear to play a role in protein trafficking in that they have been shown to link glucocorticoid receptor-hsp90 and p53.hsp90 complexes to the dynein motor protein for retrograde movement along microtubules. These immunophilins link to cytoplasmic dynein indirectly through the association of the immunophilin peptidylprolyl isomerase (PPIase) domain with dynamitin, a component of the dynein-associated dynactin complex (Galigniana, M. D., Harrell, J. M., O'Hagen, H. M., Ljungman, M., and Pratt, W. B. (2004) J. Biol. Chem. 279, 22483-22489). Here, we show that CyP-A exists in native heterocomplexes containing cytoplasmic dynein that can be formed in cell-free systems. Prolyl isomerase activity is not required for forming the dynein complex, but the PPIase domain fragment of FKBP52 blocks complex formation and CyP-A binds to dynamitin in a PPIase domain-dependent manner. CyP-A heterocomplexes containing tubulin and dynein can be formed in cytosol prepared under microtubule-stabilizing conditions, and CyP-A colocalizes in mouse fibroblasts with microtubules. Colocalization with microtubules is disrupted by overexpression of the PPIase domain fragment. Thus, we conclude that CyP-A associates in vitro and in vivo with the dynein/dynactin motor protein complex and we suggest that CyP-A may perform a general function related to the binding of cargo for retrograde movement along microtubules.Fil: Galigniana, Mario Daniel. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. University of Michigan; Estados UnidosFil: Morishima, Yoshihiro. University of Michigan; Estados UnidosFil: Gallay, Philippe A.. The Scripps Research Institute; Estados UnidosFil: Pratt, William B.. University of Michigan; Estados Unido

Extra-large crystal emulsion detectors for future large-scale experiments

Photographic emulsion is a particle tracking device which features the best spatial resolution among particle detectors. For certain applications, for example muon radiography, large-scale detectors are required. Therefore, a huge surface has to be analyzed by means of automated optical microscopes. An improvement of the readout speed is then a crucial point to make these applications possible and the availability of a new type of photographic emulsions featuring crystals of larger size is a way to pursue this program. This would allow a lower magnification for the microscopes, a consequent larger field of view resulting in a faster data analysis. In this framework, we developed new kinds of emulsion detectors with a crystal size of 600-1000 nm, namely 3-5 times larger than conventional ones, allowing a 25 times faster data readout. The new photographic emulsions have shown a sufficient sensitivity and a good signal to noise ratio. The proposed development opens the way to future large-scale applications of the technology, e.g. 3D imaging of glacier bedrocks or future neutrino experiments.Comment: Version accepted for publication in JINS

Free vibration of a three-layered sandwich beam using the dynamic stiffness method and experiment

In this paper, an accurate dynamic stiffness model for a three-layered sandwich beam of unequal thicknesses is developed and subsequently used to investigate its free vibration characteristics. Each layer of the beam is idealised by the Timoshenko beam theory and the combined system is reduced to a tenth-order system using symbolic computation. An exact dynamic stiffness matrix is then developed by relating amplitudes of harmonically varying loads to those of the responses. The resulting dynamic stiffness matrix is used with particular reference to the Wittrick-Williams algorithm to carry out the free vibration analysis of a few illustrative examples. The accuracy of the theory is confirmed both by published literature and by experiment. The paper closes with some concluding remarks. (c) 2007 Elsevier Ltd. All rights reserved

Development of Nuclear Emulsion Detector for Muon Radiography

AbstractMuon radiography is the non-destructive testing technique of large-scale constructions with cosmic ray muon. Cosmic ray muon has high penetrating power and it always comes from the whole sky. In the same way of taking a X-ray photograph, we can obtain integrated density of constructions which thickness are several tens to several hundreds. We had ever applied this technique to nuclear reactors, volcanos, and so on. Nuclear emulsion is three dimensional track detector with micrometric position accuracy. Thanks to high position resolution, Nuclear emulsion has mrad angular resolution. In addition, the features which require no power supply and can observe in a large area suitable for muon radiography. In Nagoya University, we launched emulsion manufacturing equipment at 2010. It has become possible to flexible development of our detector and succeeded to development of high sensitive nuclear emulsion film (Nagoya emulsion). An important factor is the temperature characteristic to withstand the outdoor observation as a detector to be used in the muon radiography. There is a phenomenon of a latent image fading, whichit is well known in the photographic industry, and this phenomenon is known that temperature and water are involved. So we examined temperature and humidity characteristic of latent image fading about Nagoya emulsion. As a result, we found latent image fading is strongly depends on both temperature and humidity. By dehydrating emulsion film in RH8%, over 95% (Grain Density>40) detection efficiency of muon track keeps over 3months in 25degree, for 2months in 35degree. Additionally it was showed in this test that increasing back ground noise “fog”, which may have occurred by sealing emulsion film in a narrow space, is reduced by buffer space in the bag

Aggregation number distributions and mesoglobules in dilute solutions of diblock and triblock copolymers

We investigate the aggregation number and size distributions for inter-molecular clusters of amphiphilic diblock and triblock copolymers in poor solvent at very low concentrations. Diblocks and triblocks with hydrophilic ends are shown to possess narrow distributions corresponding to formation of monodispersed mesoglobules. Diblocks with hydrophobic ends are found to produce inter-cluster multimers due to bridging by the hydrophilic middle blocks, resulting in polydisperse distributions. Implications of these observations for preparation of monodispersed nanoparticles and, potentially, understanding of the quaternary structure of proteins are discussed.Comment: 4 pages, 4 PS figures. Accepted for publication in EP

A local prescription for the softening length in self-gravitating gaseous discs

In 2D-simulations of self-gravitating gaseous discs, the potential is often computed in the framework of "softened gravity" initially designed for N-body codes. In this special context, the role of the softening length LAMBDA is twofold: i) to avoid numerical singularities in the integral representation of the potential (i.e., arising when the relative separation vanishes), and ii) to acount for stratification of matter in the direction perpendicular to the disc mid-plane. So far, most studies have considered LAMBDA as a free parameter and various values or formulae have been proposed without much mathematical justification. In this paper, we demonstrate by means of a rigorous calculus that it is possible to define LAMBDA such that the gravitational potential of a flat disc coincides at order zero with that of a geometically thin disc of the same surface density. Our prescription for LAMBDA, valid in the local, axisymmetric limit, has the required properties i) and ii). It is mainly an analytical function of the radius and disc thickness, and is sensitive to the vertical stratification. For mass density profiles considered (namely, profiles expandable over even powers of the altitude), we find that LAMBDA : i) is independant of the numerical mesh, ii) is always a fraction of the local thickness H, iii) goes through a minimum at the singularity (i.e., at null separation), and iv) is such that 0.13 < LAMBDA/H < 0.29 typically (depending on the separation and on density profile). These results should help us to improve the quality of 2D- and 3D-simulations of gaseous discs in several respects (physical realism, accuracy, and computing time).Comment: accepted in A&A, 7 pages, 7 figures, web link for the F90 code and on-line calculations : http://www.obs.u-bordeaux1.fr/radio/JMHure/intro2single.ph

High-resolution tracking in a GEM-Emulsion detector

SHiP (Search for Hidden Particles) is a beam dump experiment proposed at the CERN SPS aiming at the observation of long lived particles very weakly coupled with ordinary matter mostly produced in the decay of charmed hadrons. The beam dump facility of SHiP is also a copious factory of neutrinos of all three kinds and therefore a dedicated neutrino detector is foreseen in the SHiP apparatus. The neutrino detector exploits the Emulsion Cloud Chamber technique with a modular structure, alternating walls of target units and planes of electronic detectors providing the time stamp to the event. GEM detectors are one of the possible choices for this task. This paper reports the results of the first exposure to a muon beam at CERN of a new hybrid chamber, obtained by coupling a GEM chamber and an emulsion detector. Thanks to the micrometric accuracy of the emulsion detector, the position resolution of the GEM chamber as a function of the particle inclination was evaluated in two configurations, with and without the magnetic fiel

Universal Role for HLA-C and KIR2Dl Ligand Mismatch in Severe Acute Graft-Versus-Host Disease After Unrelated Donor Hematopoietic Stem Cell Transplantation (U-HSCT) in Japanese and Caucasian Transplant Recipients: An Analysis on Behalf of International Histocompatibility Working Group in Hematopoietic Cell Transplantation

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Tbx1 expression in pharyngeal epithelia is necessary for pharyngeal arch artery development.

During embryonic life, the initially paired pharyngeal arch arteries (PAAs) follow a precisely orchestrated program of persistence and regression that leads to the formation of the mature aortic arch and great vessels. When this program fails, specific cardiovascular defects arise that may be life threatening or mild, according to the identity of the affected artery. Fourth PAA-derived cardiovascular defects occur commonly in DiGeorge syndrome and velocardiofacial syndrome (22q11DS), and in Tbx1(+/-) mice that model the 22q11DS cardiovascular phenotype. Tbx1 is expressed in pharyngeal mesoderm, endoderm and ectoderm, and, in addition, we show that it is expressed in precursors of the endothelial cells that line the PAAs, thus expanding the number of tissues in which Tbx1 is potentially required for fourth PAA development. In this study, we have used cell fate mapping and tissue-specific gene deletion, driven by six different Cre lines, to explore Tbx1 gene-dosage requirements in the embryonic pharynx for fourth PAA development. Through this approach, we have resolved the spatial requirements for Tbx1 in this process, and we show pharyngeal epithelia to be a critical tissue. We also thereby demonstrate conclusively that the role of Tbx1 in fourth PAA development is cell non-autonomous

The Mre11-Rad50-Nbs1 complex mediates activation of TopBP1 by ATM

The activation of ATR-ATRIP in response to double-stranded DNA breaks (DSBs) depends upon ATM in human cells and Xenopus egg extracts. One important aspect of this dependency involves regulation of TopBP1 by ATM. In Xenopus egg extracts, ATM associates with TopBP1 and thereupon phosphorylates it on S1131. This phosphorylation enhances the capacity of TopBP1 to activate the ATR-ATRIP complex. We show that TopBP1 also interacts with the Mre11-Rad50-Nbs1 (MRN) complex in egg extracts in a checkpoint-regulated manner. This interaction involves the Nbs1 subunit of the complex. ATM can no longer interact with TopBP1 in Nbs1-depleted egg extracts, which suggests that the MRN complex helps to bridge ATM and TopBP1 together. The association between TopBP1 and Nbs1 involves the first pair of BRCT repeats in TopBP1. In addition, the two tandem BRCT repeats of Nbs1 are required for this binding. Functional studies with mutated forms of TopBP1 and Nbs1 suggested that the BRCT-dependent association of these proteins is critical for a normal checkpoint response to DSBs. These findings suggest that the MRN complex is a crucial mediator in the process whereby ATM promotes the TopBP1-dependent activation of ATR-ATRIP in response to DSBs