Mucopolysaccharidoses (MPS) are a group of genetic deficiencies of lysosomal enzymes that catabolize glycosaminoglycans (GAG). Here we describe a novel MPS-like disease caused by a specific mutation in the VPS33A gene. We identified several Yakut patients showing typical manifestations of MPS: coarse facial features, skeletal abnormalities, hepatosplenomegaly, respiratory problems, mental retardation, and excess secretion of urinary GAG. However, these patients could not be diagnosed enzymatically as MPS. They showed extremely high levels of plasma heparan sulphate (HS, one of GAG); 60 times the normal reference range and 6 times that of MPS patients. Additionally, most patients developed heart, kidney, and hematopoietic disorders, which are not typical symptoms for conventional MPS, leading to a fatal outcome between 1 and 2-years old. Using whole exome and Sanger sequencing, we identified homozygous c.1492C > T (p.Arg498Trp) mutations in the VPS33A gene of 13 patients. VPS33A is involved in endocytic and autophagic pathways, but the identified mutation did not affect either of these pathways. Lysosomal over-acidification and HS accumulation were detected in patient-derived and VPS33A-depleted cells, suggesting a novel role of this gene in lysosomal functions. We hence propose a new type of MPS that is not caused by an enzymatic deficiency.

IFMIF, the International Fusion Materials Irradiation Facility, is presently in its engineering validation and engineering design activities (EVEDA) phase under the Broader Approach Agreement. The engineering design activity (EDA) phase was successfully accomplished within the allocated time. The engineering validation activity (EVA) phase has focused on validating the Accelerator Facility (AF), the Target Facility and the Test Facility (TF) by constructing prototypes. The ELTL at JAEA, Oarai successfully demonstrated the long-term stability of a Li flow under the IFMIF’s nominal operational conditions keeping the specified free-surface fluctuations below  ±1 mm in a continuous manner for 25 d. A full-scale prototype of the high flux test module (HFTM) was successfully tested in the HELOKA loop (KIT, Karlsruhe), where it was demonstrated that the irradiation temperature can be set individually and kept uniform. LIPAc, designed and constructed in European labs under the coordination of F4E, presently under installation and commissioning in the Rokkasho Fusion Institute, aims at validating the concept of IFMIF accelerators with a D+ beam of 125 mA continuous wave (CW) and 9 MeV. The commissioning phases of the H+/D+ beams at 100 keV are progressing and should be concluded in 2017; in turn, the commissioning of the 5 MeV beam is due to start during 2017. The D+ beam through the superconducting cavities is expected to be achieved within the Broader Approach Agreement time frame with the superconducting cryomodule being assembled in Rokkasho. The realisation of a fusion-relevant neutron source is a necessary step for the successful development of fusion. The ongoing success of the IFMIF/EVEDA involves ruling out concerns about potential technical showstoppers which were raised in the past. Thus, a situation has emerged where soon steps towards constructing a Li(d,xn) fusion-relevant neutron source could be taken, which is also justified in the light of costs which are marginal to those of a fusion plant.

Krabbe disease, one of the autosomal-recessive lysosomal storage disorders (LSDs), is caused by a deficiency of galactocerebrosidase (GALC) activity, resulting in the intracellular accumulation of psychosine, which is cytotoxic for neuronal cells. Genetically pathogenic mutations result in conformational changes in GALC and disrupt the lysosmal trafficking of cargos, which subsequently accumulate in the endoplasmic reticulum (ER). Recently, ER stress together with the activation of the unfolded protein response (UPR) has been suggested to play a key role in the pathogenesis of LSDs. In this study, we hence investigated whether the UPR is activated in Krabbe disease using COS-7 cells expressing pathogenic GALC mutants and skin fibroblasts (SFs) from Krabbe disease patients with various phenotypes, using a combination of semiquantitative and quantitative real-time polymerase chain reactions. We found that UPR activation in Krabbe disease depends on the mutations and cell types, and there is the possibility that multiple pathways, involving ER chaperones, inositol-requiring kinase 1, and protein kinase regulated by RNA-like ER kinase are activated by mutations associated with the infantile form. These results indicate that in Krabbe disease, each misfolded/unfolded protein evokes different UPR activation depending on the mutation, and that the activated pathways affect the phenotypes.

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We report a 26-year-old woman with Creutzfeldt-Jakob disease (CJD) who had received cadaveric dural material 33 months before the onset of neurologic symptoms. This is the fourth case in which a dural graft was the putative source of the CJD agent. All four cases had the grafting before changes in the sterilization procedure adopted in 1987 to inactivate the CJD agent.

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The engineering validation and engineering design activity (EVEDA) for the International Fusion Materials Irradiation Facility (IFMIF) is proceeding as one of the ITER broader approach activities. In the concept of the IFMIF, two 40 MeV deuteron beams are injected into a liquid Li stream (Li target) flowing at a velocity of 15 m s −1. The EVEDA Li test loop (ELTL) is aimed at validating the hydraulic stability of the Li target at a velocity up to 20 m s −1 under a vacuum condition of 10 −3 Pa as the most important issue. Construction of the ELTL, which is the largest liquid metal loop possessing 5.0 m 3 Li for the fusion research ever, was completed in the O-arai Research & Development Center in the Japan Atomic Energy Agency on 22 November 2010. This paper presents the design and fabrication technology of a target assembly called integrated target assembly, in which the Li target is produced by a contraction nozzle along a concave channel. There are two concepts regarding the target assembly: the integrated target assembly and the bayonet target assembly. Both target assemblies are outlined in this paper, and then the newly proposed design of the integrated target assembly for the ELTL and its fabrication technology are given. The integrated target assembly was processed by a five-axis milling machine and the processing accuracy was measured by 3D measurement tools. Finally, methods applied for the validation of the stability of the Li target are introduced in this paper.

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