Retinitis pigmentosa is a group of hereditary retinal dystrophies that normally result in photoreceptor cell death and vision loss both in animal models and in affected patients. The rd10 mouse, ...which carries a missense mutation in the Pde6b gene, has been used to characterize the underlying pathophysiology and develop therapies for this devastating and incurable disease. Here we show that increased photoreceptor cell death in the rd10 mouse retina is associated with calcium overload and calpain activation, both of which are observed before the appearance of signs of cell degeneration. These changes are accompanied by an increase in the activity of the lysosomal protease cathepsin B in the cytoplasm of photoreceptor cells, and a reduced colocalization of cathepsin B with lysosomal markers, suggesting that lysosomal membrane permeabilization occurs before the peak of cell death. Moreover, expression of the autophagosomal marker LC3-II (lipidated form of LC3) is reduced and autophagy flux is blocked in rd10 retinas before the onset of photoreceptor cell death. Interestingly, we found that cell death is increased by the induction of autophagy with rapamycin and inhibited by calpain and cathepsin inhibitors, both ex vivo and in vivo. Taken together, these data suggest that calpain-mediated lysosomal membrane permeabilization underlies the lysosomal dysfunction and downregulation of autophagy associated with photoreceptor cell death.
We give a new characterization for the convergence in distribution to a standard normal law of a sequence of multiple stochastic integrals of a fixed order with variance one, in terms of the ...Malliavin derivatives of the sequence. We also give a new proof of the main theorem in D. Nualart, G. Peccati, Central limit theorems for sequences of multiple stochastic integrals, Ann. Probab. 33 (2005) 177–193 using techniques of Malliavin calculus. Finally, we extend our result to the multidimensional case and prove a weak convergence result for a sequence of square integrable random vectors, giving an application.
The Discrete Element Method (DEM) has been used for modelling continua, like concrete or rocks. However, it requires a big calibration effort, even to capture just the linear elastic behavior of a ...continuum modelled via the classical force-displacement relationships at the contact interfaces between particles. In this work we propose a new way for computing the contact forces between discrete particles. The newly proposed forces take into account the surroundings of the contact, not just the contact itself. This brings in the missing terms that provide an accurate approximation to an elastic continuum, and avoids calibration of the DEM parameters for the purely linear elastic range.
Sensory nerve endings in ligaments play an important role for the proprioceptive function. Clinical trials show that the sense of body position does not fully recover in the knee joint after ...reconstructive surgery of the ruptured anterior cruciate ligament. The aim of this study is to identify sensory corpuscles in autogenous and allogenous transplants of the ligament and to compare their quantity between the used allografts and autografts.
Thirty-three patients were included in this study. Three patellar tendon allografts, 14 patellar tendon autografts and 12 semitendinosus autografts were harvested during revision surgery after traumatic rerupture of the graft. The control consisted of 4 healthy anterior cruciate ligaments after fresh rupture. After haematoxylin staining, immunohistochemical analysis was performed using antibodies against S100, p75 and PGP9.5. Microscopical examination was carried out, and the number of mechanoreceptors was counted. Statistical analysis was performed using the Mann-Whitney U test.
Two types of mechanoreceptors were identified in each graft: Ruffini corpuscles and free nerve endings. The number of Ruffini corpuscles per square centimeter was the highest in the control. Comparing the grafts, the highest number of receptors could be detected in the semitendinosus autograft. The amount of free nerve endings was higher in the semitendinosus and patellar tendon autografts than in the control; the allografts showed the lowest number of receptors. With increasing time after reconstruction, the number of both types of receptors showed a decrease in the semitendinosus graft, whereas it increased in the patellar tendon graft and allograft. The number of mechanoreceptors in the semitendinosus and patellar tendon graft decreased over time after graft-failure, whereas it increased slightly in the allograft.
This study was the first to identify mechanoreceptors in human transplants of the anterior cruciate ligament. The partial increase in the number of receptors over time after reconstruction could indicate a reinnervation of the grafts.
•Devices operating in the harsh environment work at high level of radiation.•Hostile environment is characterized by high level of radiation and magnetic field.•Supplies for the electronic circuits ...often operate in hostile environment.•Long time high reliability operation in presence of magnetic field is mandatory.
The paper deals with the magnetic field (often denoted also as B-field) behavior of Point of Load devices developed in order to meet the requirement in term of magnetic field and radiation hardness mandatory for experiments operating at LHC. Devices have been tested under magnetic field up to about 1.2 T at the Laboratorio Acceleratori e Superconduttività Applicata (LASA), a laboratory located in Milan (Italy). The obtained experimental results are here presented in detail and, finally, discussed. The device here used has been designed to meet the stringent specification given for experiments at LHC taking also into account the planned upgrade for the denoted High Luminosity LHC (HL-LHC). The ability to operate in the hostile environment of the device presented in this paper (a DC-DC converter) is very interesting especially when the device is used in measurement systems: such as the Liquid Argon Calorimeter (LAr) of the ATLAS experiment at CERN. In this case, in fact, the simultaneous presence of radiation and strong static magnetic fields impose particularly harsh working conditions to semiconductor devices, for the presence of radiation, and to the coils, for the presence of magnetic field. In this paper, the experimental results obtained during the tests planned to verify the capability to work in hostile environment of a particular device designed by a research group at CERN has been presented. Details on trend of the output voltage, ripple, efficiency of the device are given and discussed.
We present a numerical procedure for elastic and nonlinear analysis (including fracture situations) of solid materials and structures using the discrete element method. It can be applied to strongly ...cohesive frictional materials such as concrete and rocks. The method consists on defining nonlocal constitutive equations at the contact interfaces between discrete particles using the information provided by the stress tensor over the neighbor particles. The method can be used with different yield surfaces, and in the paper, it is applied to the analysis of fracture of concrete samples. Good comparison with experimental results is obtained.
•3D thermo-fluid-dynamic modeling of water heat sinks for power converters.•Thermal characterization to validate the numerical model and verify its accuracy.•Comparison of different layouts to ...improve the converter cooling solution.•Performance assessment of the designed heat sink by simulations and measurements.
The aim of this work is to show how it is possible to improve the reliability of a power converter by means of thermal–fluid dynamic numerical analysis. Power electronic converters such as those for High Energy Physics Experiments (HEPEs), must operate in hostile environment with tight thermal constraints and the reliability must be high because of the inaccessibility during the experiments and the high costs of the overall setup. Due to the high power density, the presence of closed environments and the requirement of non-thermal interaction with other subsystems, a liquid cooling system is mandatory. 3D FEM and/or FVM simulations can be used to analyze thermal fluid dynamic behavior of those systems and can be a useful support to design heat sinks optimized for specific applications. We show a comparison of different heat sink solutions to improve the thermal management of a 1.5kW DC/DC hybrid power module.
•Devices operating in the harsh environment are called to work at high level of radiation.•Hostile environment for electronic devices is characterized by both high level of radiation and magnetic ...field.•Equipment devoted to generate the supply for the electronic circuits can be often called to operate in hostile environment.•GaN power devices to be used in PoL converters are very promising.
Devices used in future experiments at LHC will have to work in a very hostile environment. Power supply is a key aspect in this scenario and new converters must be designed in order to meet the future requirements. This is particularly true for Point of Load (PoL) converters that, being located as close as possible to the loads, must operate in a very harsh environment. This paper presents an experimental activity aimed to verify the compliance with a high stationary magnetic field of a commercial PoL, as well as experimental measurements aimed to test the performance of new GaN power devices used in PoL converters.
In particular, a highly integrated commercial PoL converter, that includes in the same package the output filter inductor, is considered for the magnetic test, while an ad-hoc PoL converter, employing 40V, 33A normally off GaN MOSFETs has been designed and, finally, tested. Dynamic RDSon measurements of the same devices are also included.
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