Animal model and molecular interactions of Cln5

Neuronal ceroid lipofuscinoses (NCLs) are a family of inherited pediatric neurodegenerative disorders, leading to retinal degeneration, death of selective neuronal populations and accumulation of autofluorscent ceroid-lipopigments. The clinical manifestations are generally similar in all forms. The Finnish variant late infantile neuronal ceroid lipofuscinosis (vLINCLFin) is a form of NCL, especially enriched in the Finnish population. The aim of this thesis was to analyse the brain pathology of vLINCLFin utilising the novel Cln5-/- mouse model. Gene expression profiling of the brains of already symptomatic Cln5-/- mice revealed that inflammation, neurodegeneration and defects in myelinization are the major characteristics of the later stages of the disease. Histological characterization of the brain pathology confirmed that the thalamocortical system is affected in Cln5-/- mice, similarly to the other NCL mouse models. However, whereas the brain pathology in all other analyzed NCL mice initiate in the thalamus and spread only months later to the cortex, we observed that the sequence of events is uniquely reversed in Cln5-/- mice; beginning in the cortex and spreading to the thalamus only months later. We could also show that even though neurodegeneration is inititated in the cortex, reactive gliosis and loss of myelin are evident in specific nuclei of the thalamus already in the 1 month old brain. To obtain a deeper insight into the disturbed metabolic pathways, we performed gene expression profiling of presymptomatic mouse brains. We validated these findings with immunohistological analyses, and could show that cytoskeleton and myelin were affected in Cln5-/- mice. Comparison of gene expression profiling results of Cln5-/- and Cln1-/- mice, further highlighted that these two NCL models share a common defective pathway, leading to disturbances in the neuronal growth cone and cytoskeleton. Encouraged by the evidence of this defected pathway, we analyzed the molecular interactions of NCL-proteins and observed that Cln5 and Cln1/Ppt1 proteins interact with each other. Furthermore, we demonstrated that Cln5 and Cln1/Ppt1 share an interaction partner, the F1-ATP synthase, potentially linking both vLINCLFIN and INCL diseases to disturbed lipid metabolism. In addition, Cln5 was shown to interact with other NCL proteins; Cln2, Cln3, Cln6 and Cln8, implicating a central role for Cln5 in the NCL pathophysiology. This study is the first to describe the brain pathology and gene expression changes in the Cln5-/- mouse. Together the findings presented in this thesis represent novel information of the disease processes and the molecular mechanisms behind vLINCLFin and have highlighted that vLINCLFin forms a very important model to analyze the pathophysiology of NCL diseases.

The formation of ?-FeSiAl5 and Be---Fe phases in Al---7Si---0.3Mg alloy containing Be

Thermal analysis and interrupted quench experiments have been carried out to study the formation of beta-FeSiAl5 and (Be-Fe)-BeSiFe2Al8 phases in Al-7Si-0.3Mg alloy with and without Be addition. In the base alloy with 0.6% Fe (without Be addition), a needle- and plate-shaped beta-phase is present in the interdendritic regions and is formed by a ternary eutectic reaction. In the Be- added alloy with 0.6% Fe, a Be-Fe phase of Chinese script and polygon shapes grows along with the primary alpha-Al dendrites, leading to superior mechanical properties. It is proposed that this Be-Fe phase is formed by a peritectic reaction. Be addition has also resulted in some grain refinement.

Surface pressure and heat transfer measurements in the unsteady separated hypersonic flow field over double cones

Reliable bench mark experimental database in the separated hypersonic flow regime is necessary to validate high resolution CFD codes. In this paper we report the surface pressure and heat transfer measurements carried out on double cones (first cone semi-apex angle = 15, 25 deg.; second cone semi-apex angle= 35, 68 deg.) at hypersonic speeds that will be useful for CFD code validation studies. The surface pressure measurements are carried out at nominal Mach number of 8.35 in the IISc hypersonic wind tunnel. On the other hand the surface heat transfer measurements are carried out at a nominal Mach number of 5.75 in the IISc hypersonic shock tunnel. The flow separation point on the first cone, flow reattachment on the second cone and the wild fluctuation of the transmitted shock on the second cone surface (25/68 deg. double cone) in the presence of severe adverse pressure gradient are some of the flow features captured in the measurements. The results from the CFD studies indicate good agreement with experiments in the attached flow regime while considerable differences are noticeable in the separated flow regime.

Influence of stack geometry and resonator length on the performance of thermoacoustic engine

Thermoacoustic engines convert heat energy into high amplitude sound waves, which is used to drive thermoacoustic refrigerator or pulse tube cryocoolers by replacing the mechanical pistons such as compressors. The increasing interest in thermoacoustic technology is of its potentiality of no exotic materials, low cost and high reliability compared to vapor compression refrigeration systems. The experimental setup has been built based on the linear thermoacoustic model and some simple design parameters. The engines produce acoustic energy at the temperature difference of 325-450 K imposed along the stack of the system. This work illustrates the influence of stack parameters such as plate thickness (PT) and plate spacing (PS) with resonator length on the performance of thermoacoustic engine, which are measured in terms of onset temperature difference, resonance frequency and pressure amplitude using air as a working fluid. The results obtained from the experiments are in good agreement with the theoretical results from DeltaEc. (C) 2012 Elsevier Ltd. All rights reserved.

Numerical study of solidification of A356 aluminum alloy flowing on an oblique plate with experimental validation

Molten A356 aluminum alloy flowing on an oblique plate is water cooled from underneath. The melt partially solidifies on plate wall with continuous formation of columnar dendrites. These dendrites are continuously sheared off into equiaxed/fragmented grains and carried away with the melt by producing semisolid slurry collected at plate exit. Melt pouring temperature provides required solidification whereas plate inclination enables necessary shear for producing slurry of desired solid fraction. A numerical model concerning transport equations of mass, momentum, energy and species is developed for predicting velocity, temperature, macrosegregation and solid fraction. The model uses FVM with phase change algorithm, VOF and variable viscosity. The model introduces solid phase movement with gravity effect as well. Effects of melt pouring temperature and plate inclination on hydrodynamic and thermo-solutal behaviors are studied subsequently. Slurry solid fractions at plate exit are 27%, 22%, 16%, and 10% for pouring temperatures of 620 degrees C, 625 degrees C, 630 degrees C, and 635 degrees C, respectively. And, are 27%, 25%, 22%, and 18% for plate inclinations of 30, 45, 60, and 75, respectively. Melt pouring temperature of 625 degrees C with plate inclination of 60 generates appropriate quality of slurry and is the optimum. Both numerical and experimental results are in good agreement with each other. (C) 2015 Taiwan Institute of Chemical Engineers. Published by Elsevier B.V. All rights reserved.

Integration property of a wedge-elliptic cone waverider with scramjet engine

The hypersonic waverider forebody is designed in this paper. For the present waverider, the undersurface is carved out as a stream surface of a hypersonic inviscid flow field around wedge-elliptic cone, and the upper surface is assumed to be a freestream surface. A finite-volume code is used to generate the three-dimensional flow field. The leading edge is determined by satisfying the condition that the lip is situated at the intersection line of shocks.

Riemannian metric and geometric mean for positive semidefinite matrices of fixed rank

This paper introduces a new metric and mean on the set of positive semidefinite matrices of fixed-rank. The proposed metric is derived from a well-chosen Riemannian quotient geometry that generalizes the reductive geometry of the positive cone and the associated natural metric. The resulting Riemannian space has strong geometrical properties: it is geodesically complete, and the metric is invariant with respect to all transformations that preserve angles (orthogonal transformations, scalings, and pseudoinversion). A meaningful approximation of the associated Riemannian distance is proposed, that can be efficiently numerically computed via a simple algorithm based on SVD. The induced mean preserves the rank, possesses the most desirable characteristics of a geometric mean, and is easy to compute. © 2009 Society for Industrial and Applied Mathematics.

The impact of sand slugs against beams and plates: Coupled discrete particle/finite element simulations

The impact of a slug of dry sand particles against a metallic sandwich beam or circular sandwich plate is analysed in order to aid the design of sandwich panels for shock mitigation. The sand particles interact via a combined linear-spring-and-dashpot law whereas the face sheets and compressible core of the sandwich beam and plate are treated as rate-sensitive, elastic-plastic solids. The majority of the calculations are performed in two dimensions and entail the transverse impact of end-clamped monolithic and sandwich beams, with plane strain conditions imposed. The sand slug is of rectangular shape and comprises a random loose packing of identical, circular cylindrical particles. These calculations reveal that loading due to the sand is primarily inertial in nature with negligible fluid-structure interaction: the momentum transmitted to the beam is approximately equal to that of the incoming sand slug. For a slug of given incoming momentum, the dynamic deflection of the beam increases with decreasing duration of sand-loading until the impulsive limit is attained. Sandwich beams with thick, strong cores significantly outperform monolithic beams of equal areal mass. This performance enhancement is traced to the "sandwich effect" whereby the sandwich beams have a higher bending strength than that of the monolithic beams. Three-dimensional (3D) calculations are also performed such that the sand slug has the shape of a circular cylindrical column of finite height, and contains spherical sand particles. The 3D slug impacts a circular monolithic plate or sandwich plate and we show that sandwich plates with thick strong cores again outperform monolithic plates of equal areal mass. Finally, we demonstrate that impact by sand particles is equivalent to impact by a crushable foam projectile. The calculations on the equivalent projectile are significantly less intensive computationally, yet give predictions to within 5% of the full discrete particle calculations for the monolithic and sandwich beams and plates. These foam projectile calculations suggest that metallic foam projectiles can be used to simulate the loading by sand particles within a laboratory setting. © 2013 Elsevier Ltd.

Influence of mix proprtions on rheolgy of cement grouts containing limestone powder

In this paper the parameters of cement grout affecting rheological behaviour and compressive strength are investigated. Factorial experimental design was adopted in this investigation to assess the combined effects of the following factors on fluidity, rheological properties, induced bleeding and compressive strength: water/binder ratio (W/B), dosage of superplasticiser (SP), dosage of viscosity agent (VA), and proportion of limestone powder as replacement of cement (LSP). Mini-slump test, Marsh cone, Lombardi plate cohesion meter, induced bleeding test, coaxial rotating cylinder viscometer were used to evaluate the rheology of the cement grout and the compressive strengths at 7 and 28 days were measured. A two-level fractional factorial statistical model was used to model the influence of key parameters on properties affecting the fluidity, the rheology and compressive strength. The models are valid for mixes with 0.35-0.42 W/B, 0.3-1.2% SP, 0.02-0.7% VA (percentage of binder) and 12-45% LSP as replacement of cement. The influences of W/B, SP, VA and LSP were characterised and analysed using polynomial regression which can identify the primary factors and their interactions on the measured properties. Mathematical polynomials were developed for mini-slump, plate cohesion meter, inducing bleeding, yield value, plastic viscosity and compressive strength as function of W/B, SP, VA and proportion of LSP. The statistical approach used highlighted the limestone powder effect and the dosage of SP and VA on the various rheological characteristics of cement grout

Genetic programming based formulation for fresh and hardened properties of self-compacting concrete containing pulverised fuel ash

Self-compacting concrete (SCC) flows into place and around obstructions under its own weight to fill the formwork completely and self-compact without any segregation and blocking. Elimination of the need for compaction leads to better quality concrete and substantial improvement of working conditions. This investigation aimed to show possible applicability of genetic programming (GP) to model and formulate the fresh and hardened properties of self-compacting concrete (SCC) containing pulverised fuel ash (PFA) based on experimental data. Twenty-six mixes were made with 0.38 to 0.72 water-to-binder ratio (W/B), 183–317 kg/m³ of cement content, 29–261 kg/m³ of PFA, and 0 to 1% of superplasticizer, by mass of powder. Parameters of SCC mixes modelled by genetic programming were the slump flow, JRing combined to the Orimet, JRing combined to cone, and the compressive strength at 7, 28 and 90 days. GP is constructed of training and testing data using the experimental results obtained in this study. The results of genetic programming models are compared with experimental results and are found to be quite accurate. GP has showed a strong potential as a feasible tool for modelling the fresh properties and the compressive strength of SCC containing PFA and produced analytical prediction of these properties as a function as the mix ingredients. Results showed that the GP model thus developed is not only capable of accurately predicting the slump flow, JRing combined to the Orimet, JRing combined to cone, and the compressive strength used in the training process, but it can also effectively predict the above properties for new mixes designed within the practical range with the variation of mix ingredients.

Comparison of Experimental PIV Data and CFD Simulations for Flow in a Diesel Particulate Filter Inlet Diffuser

Flow maldistribution of the exhaust gas entering a Diesel Particulate Filter (DPF) can cause uneven soot distribution during loading and excessive temperature gradients during the regeneration phase. Minimising the magnitude of this maldistribution is therefore an important consideration in the design of the inlet pipe and diffuser, particularly in situations where packaging constraints dictate bends in the inlet pipe close to the filter, or a sharp diffuser angle. This paper describes the use of Particle Image Velocimetry (PIV) to validate a Computational Fluid Dynamic (CFD) model of the flow within the inlet diffuser of a DPF so that CFD can be used with confidence as a tool to minimise this flow maldistribution. PIV is used to study the flow of gas into a DPF over a range of steady state flow conditions. The distribution of flow approaching the front face of the substrate was of particular interest to this study. Optically clear diffusing cones were designed and placed between pipe and substrate to allow PIV analysis to take place. Stereoscopic PIV was used to eliminate any error produced by the optical aberrations caused by looking through the curved wall of the inlet cone. In parallel to the experiments, numerical analysis was carried out using a CFD program with an incorporated DPF model. Boundary conditions for the CFD simulations were taken from the experimental data, allowing an experimental validation of the numerical results. The CFD model incorporated a DPF model, the cement layers seen in segmented filters and the intumescent matting that is commonly used to pack the filter into a metal casing. The mesh contained approximately 580,000 cells and used the realizable ?-e turbulence model. The CFD simulation predicted both pressure drop across the DPF and the velocity field within the cone and at the DPF face with reasonable accuracy, providing confidence in the use the CFD in future work to design new, more efficient cones.

Cation complexation by chemically modified calixarenes. 11. Complexation and extraction of alkali cations by calix[5]- and -[6]arene ketones. Crystal and molecular structures of calix[5]arene ketones and Na+ and Rb+ complexes

A series of four calix[5]arenes and three calix[6]arenes (R-calixarene-OCH2COR1) (R = H or Bu-t) with alkyl ketone residues (R-1 = Me or Bu-t) on the lower rim have been synthesized, and their affinity for complexation of alkali cations has been assessed through phase-transfer experiments and stability constant measurements. The conformations of these ketones have been probed by H-1 NMR and X-ray diffraction analysis, and by molecular mechanics calculations. Pentamer 3 (R R-1 = Bu-t) possesses a symmetrical cone conformation in solution and a very distorted cone conformation in the solid state. Pentamer 5 (R = H, R-1 = Bu-t) exists in a distorted 1,2-alternate conformation in the solid state, but in solution two slowly interconverting conformations, one a cone and the other presumed to be 1,2-alternate, can be detected. X-ray structure analysis of the sodium and rubidium perchlorate complexes of 3 reveal the cations deeply encapsulated by the ethereal and carbonyl oxygen atoms in distorted cone conformations which can be accurately reproduced by molecular mechanics calculations. The phase-transfer and stability constant data reveal that the extent of complexation depends on calixarene size and the nature of the alkyl residues adjacent to the ketonic carbonyls with tert-butyl much more efficacious than methyl.

Fast plasma heating in a cone-attached geometry - towards fusion ignition

We have developed a PW (0.5 ps/500J) laser system to demonstrate fast heating of imploded core plasmas using a hollow cone shell target. Significant enhancement of thermal neutron yield has been realized with PW-laser heating, confirming that the high heating efficiency is maintained as the short-pulse laser power is substantially increased to a value nearly equivalent to the ignition condition. It appears that the efficient heating is realized by the guiding of the PW laser pulse energy within the hollow cone and by self-organized relativistic electron transport. Based on the experimental results, we are developing a 10kJ-PW laser system to study the fast heating physics of high-density plasmas at an ignition-equivalent temperature.

A Longitudinal Study of Stargardt Disease: Clinical and Electrophysiologic Assessment, Progression, and Genotype Correlations

Purpose: To investigate the clinical and electrophysiologic natural history of Stargardt disease and correlate with the genotype. Design: Cohort study of 59 patients. Methods: Clinical history, examination, and electrophysiologic assessment were undertaken in a longitudinal survey. Patients were classified into 3 groups based on electrophysiologic findings, as previously published: Group 1 had dysfunction confined to the macula; Group 2 had macular and generalized cone system dysfunction; and Group 3 had macular and both generalized cone and rod system dysfunction. At baseline, there were 27 patients in Group 1, 17 in Group 2, and 15 in Group 3. Amplitude reduction of >50% in the relevant electroretinogram (ERG) component or a peak time shift of >3 ms for the 30 Hz flicker ERG or bright flash a-wave was considered clinically significant ERG deterioration. Molecular screening of ABCA4 was undertaken. Results: The mean age at baseline was 31.7 years, with the mean follow-up interval being 10.5 years. A total of 22% of patients from Group 1 showed ERG group transition during follow-up, with 11% progressing to Group 2 and 11% to Group 3. Forty-seven percent of patients in Group 2 progressed to Group 3. There was clinically significant ERG deterioration in 54% of all subjects: 22% of Group 1, 65% of Group 2, and 100% of Group 3. At least 1 disease-causing ABCA4 variant was identified in 47 patients. Conclusions: All patients with initial rod ERG involvement demonstrated clinically significant electrophysiologic deterioration; only 20% of patients with normal full-field ERGs at baseline showed clinically significant progression. Such data assist counseling by providing more accurate prognostic information and are also highly relevant in the design, patient selection, and monitoring of potential therapeutic interventions. © 2013 Elsevier Inc. All rights reserved.

Xenopus cytoplasmic linker-associated protein 1 (XCLASP1) promotes axon elongation and advance of pioneer microtubules

Dynamic microtubules (MTs) are required for neuronal guidance, in which axons extend directionally toward their target tissues. We found that depletion of the MT-binding protein Xenopus cytoplasmic linker-associated protein 1 (XCLASP1) or treatment with the MT drug Taxol reduced axon outgrowth in spinal cord neurons. To quantify the dynamic distribution of MTs in axons, we developed an automated algorithm to detect and track MT plus ends that have been fluorescently labeled by end-binding protein 3 (EB3). XCLASP1 depletion reduced MT advance rates in neuronal growth cones, very much like treatment with Taxol, demonstrating a potential link between MT dynamics in the growth cone and axon extension. Automatic tracking of EB3 comets in different compartments revealed that MTs increasingly slowed as they passed from the axon shaft into the growth cone and filopodia. We used speckle microscopy to demonstrate that MTs experience retrograde flow at the leading edge. Microtubule advance in growth cone and filopodia was strongly reduced in XCLASP1-depleted axons as compared with control axons, but actin retrograde flow remained unchanged. Instead, we found that XCLASP1-depleted growth cones lacked lamellipodial actin organization characteristic of protrusion. Lamellipodial architecture depended on XCLASP1 and its capacity to associate with MTs, highlighting the importance of XCLASP1 in actin-microtubule interactions.