GCase and LIMP2 Abnormalities in the Liver of Niemann Pick Type C Mice

The lysosomal storage disease Niemann–Pick type C (NPC) is caused by impaired cholesterol efflux from lysosomes, which is accompanied by secondary lysosomal accumulation of sphingomyelin and glucosylceramide (GlcCer). Similar to Gaucher disease (GD), patients deficient in glucocerebrosidase (GCase) degrading GlcCer, NPC patients show an elevated glucosylsphingosine and glucosylated cholesterol. In livers of mice lacking the lysosomal cholesterol efflux transporter NPC1, we investigated the expression of established biomarkers of lipid-laden macrophages of GD patients, their GCase status, and content on the cytosol facing glucosylceramidase GBA2 and lysosomal integral membrane protein type B (LIMP2), a transporter of newly formed GCase to lysosomes. Livers of 80-week-old Npc1^−/− mice showed a partially reduced GCase protein and enzymatic activity. In contrast, GBA2 levels tended to be reciprocally increased with the GCase deficiency. In Npc1^−/− liver, increased expression of lysosomal enzymes (cathepsin D, acid ceramidase) was observed as well as increased markers of lipid-stressed macrophages (GPNMB and galectin-3). Immunohistochemistry showed that the latter markers are expressed by lipid laden Kupffer cells. Earlier reported increase of LIMP2 in Npc1^−/− liver was confirmed. Unexpectedly, immunohistochemistry showed that LIMP2 is particularly overexpressed in the hepatocytes of the Npc1^−/− liver. LIMP2 in these hepatocytes seems not to only localize to (endo)lysosomes. The recent recognition that LIMP2 harbors a cholesterol channel prompts the speculation that LIMP2 in Npc1^−/− hepatocytes might mediate export of cholesterol into the bile and thus protects the hepatocytes.     

Effect of high temperature heat treatment on intergranular corrosion of AlMgSi(Cu) model alloy

Copper containing 6000-series aluminium alloys may become susceptible to intergranular corrosion (IGC) as a result of improper thermomechanical processing. Effect of cooling rate after solution heat treatment on the corrosion behaviour of a model AlMgSi(Cu) alloy of nominal composition (wt%) 0.6 Mg, 0.6 Si, 0.2 Fe, 0.2 Mn and 0.1 Cu was investigated. Slow cooling rates were simulated by isothermal treatment for predetermined times in lower temperature baths immediately after solution heat treatment. Treatment for 10-100 s at temperatures below 400 °C introduced susceptibility to IGC. Longer heat treatment at the same temperatures introduced susceptibility to pitting. A corrosion resistant time zone was found between the zones of IGC and pitting at temperatures lower than 350 °C. Quenching in water after solution heat treatment prevented IGC. IGC was related to microgalvanic coupling between the noble Q-phase (Al₄Mg₈Si₇Cu₂) grain boundary precipitates and the adjacent depleted zone. Pitting was attributed to coarse particles in the matrix. Possible mechanisms causing the corrosion resistant intermediate zone are discussed. The results indicate possible methods for obtaining increased corrosion resistance of similar alloys by proper thermal processing.     

Biomimetic Polymer Nanostructures by Injection Molding

The nanometer scale topography of self‐assembling structural protein complexes in animals is believed to induce favorable cell responses. An important example of such nanostructured biological complexes is fibrillar collagen that possesses a cross‐striation structure with a periodicity of 69 nm and a peak‐to‐valley distance of 4–6 nm. Bovine collagen type I was assembled into fibrillar structures in vitro and sedimented onto solid supports. Their structural motif was transferred into a nickel replica by physical vapor deposition of a small‐grained metal layer followed by galvanic plating. The resulting inverted nickel structure was found to faithfully present most of the micrometer and nanometer scale topography of the biological original. This nickel replica was used as a die for the injection molding of a range of different thermoplastic polymers. Total injection molding cycle times were in the range of 30–45 seconds. One of the polymer materials investigated, polyethylene, displayed poor replication of the biological nanotopographical motif. However, the majority of the polymers showed very high replication fidelity as witnessed by their ability to replicate the cross‐striation features of less than 5 nm height difference. The latter group of materials includes poly(propylene), poly(methyl methacrylate), poly(L ‐lactic acid), polycaprolactone, and a copolymer of cyclic and linear olefins (COC). This work suggests that the current limiting factor for the injection molding of nanometer scale topography in thermoplastic polymers lies with the grain size of the initial metal coating of the mold rather than the polymers themselves.

     

Effect of artificial aging on intergranular corrosion of extruded AlMgSi alloy with small Cu content

The effect of artificial aging parameters on the corrosion performance of air cooled AlMgSi(Cu) model alloy extrusions was investigated. Accelerated corrosion test revealed that the extrusions were highly susceptible to intergranular corrosion (IGC) in the naturally aged condition. However, IGC susceptibility was reduced, and finally eliminated, by artificial aging. Overaging introduced slight pitting susceptibility. EDS X-ray mapping in FE-TEM revealed Mg₂Si and Q-phase (Al₄Cu₂Mg₈Si₇) grain boundary precipitates and a continuous Cu-enriched grain boundary film. IGC susceptibility was related to the Cu-enriched grain boundary film. Increased IGC resistance was caused by coarsening of the grain boundary film by aging. Pitting susceptibility by over aging evolved due to coarsening of the Q-phase particles in the grain bodies.     

(Approximate) Uncertain Skylines

Given a set of points with uncertain locations, we consider the problem of computing the probability of each point lying on the skyline, that is, the probability that it is not dominated by any other input point. If each point’s uncertainty is described as a probability distribution over a discrete set of locations, we improve the best known exact solution. We also suggest why we believe our solution might be optimal. Next, we describe simple, near-linear time approximation algorithms for computing the probability of each point lying on the skyline. In addition, some of our methods can be adapted to construct data structures that can efficiently determine the probability of a query point lying on the skyline.     

Little effect of transfer technique instruction and physical fitness training in reducing low back pain among nurses: a cluster randomised intervention study

The aim of this study was to evaluate the effect of a transfer technique education programme (TT) alone or in combination with physical fitness training (TTPT) compared with a control group, who followed their usual routine. Eleven clinical hospital wards were cluster randomised to either intervention (six wards) or to control (five wards). The intervention cluster was individually randomised to TT (55 nurses) and TTPT (50 nurses), control (76 nurses). The transfer technique programme was a 4-d course of train-the-trainers to teach transfer technique to their colleagues. The physical training consisted of supervised physical fitness training 1 h twice per week for 8 weeks. Implementing transfer technique alone or in combination with physical fitness training among a hospital nursing staff did not, when compared to a control group, show any statistical differences according to self-reported low back pain (LBP), pain level, disability and sick leave at a 12-month follow-up. However, the individual randomised intervention subgroup (transfer technique/physical training) significantly improved the LBP-disability (p = 0.001). Although weakened by a high withdrawal rate, teaching transfer technique to nurses in a hospital setting needs to be thoroughly considered. Other priorities such as physical training may be taken into consideration. The current study supports the findings of other studies that introducing transfer technique alone has no effect in targeting LBP. However, physical training seems to have an influence in minimising the LBP consequences and may be important in the discussion of how to prevent LBP or the recurrence of LBP among nursing personnel.     

Optimal infinite scheduling for multi-priced timed automata

This paper is concerned with the derivation of infinite schedules for timed automata that are in some sense optimal. To cover a wide class of optimality criteria we start out by introducing an extension of the (priced) timed automata model that includes both costs and rewards as separate modelling features. A precise definition is then given of what constitutes optimal infinite behaviours for this class of models. We subsequently show that the derivation of optimal non-terminating schedules for such double-priced timed automata is computable. This is done by a reduction of the problem to the determination of optimal mean-cycles in finite graphs with weighted edges. This reduction is obtained by introducing the so-called corner-point abstraction, a powerful abstraction technique of which we show that it preserves optimal schedules. This work has been mostly done while visiting CISS at Aalborg University in Denmark and has been supported by CISS and by ACI Cortos, a program of the French Ministry of Research.     

Optimization of friction stir welding using space mapping and manifold mapping—an initial study of thermal aspects

The aim of this paper is to optimize a thermal model of a friction stir welding process by finding optimal welding parameters. The optimization is performed using space mapping and manifold mapping techniques in which a coarse model is used along with the fine model to be optimized. Different coarse models are applied and the results and computation time are compared to gradient based optimization using the full model. It is found that the use of space and manifold mapping reduces the computational cost significantly due to the fact that fewer function evaluations and no fine model gradient information is required.