A Novel LRRK2 Variant p.G2294R in the WD40 Domain Identified in Familial Parkinson’s Disease Affects LRRK2 Protein Levels

Leucine-rich repeat kinase 2 (LRRK2) is a major causative gene of late-onset familial Parkinson’s disease (PD). The suppression of kinase activity is believed to confer neuroprotection, as most pathogenic variants of LRRK2 associated with PD exhibit increased kinase activity. We herein report a novel LRRK2 variant—p.G2294R—located in the WD40 domain, detected through targeted gene-panel screening in a patient with familial PD. The proband showed late-onset Parkinsonism with dysautonomia and a good response to levodopa, without cognitive decline or psychosis. Cultured cell experiments revealed that p.G2294R is highly destabilized at the protein level. The LRRK2 p.G2294R protein expression was upregulated in the patient’s peripheral blood lymphocytes. However, macrophages differentiated from the same peripheral blood showed decreased LRRK2 protein levels. Moreover, our experiment indicated reduced phagocytic activity in the pathogenic yeasts and α-synuclein fibrils. This PD case presents an example wherein the decrease in LRRK2 activity did not act in a neuroprotective manner. Further investigations are needed in order to elucidate the relationship between LRRK2 expression in the central nervous system and the pathogenesis caused by altered LRRK2 activity.     

Systematic packaging design tools integrating functional and environmental consequences on product life cycle: Case studies on laundry detergent and milk

This study presents systematic packaging design tools integrating functional and environmental consequences on product life cycle. To design packaging for sustainability, the trade-offs between functional and environmental aspects of packaging throughout the product life cycle should be considered. However, it is difficult for packaging designers to understand the overall trade-offs because the extent of the design consequences on the entire life cycle of packaging and its contents is unclear. We developed two tools for packaging design: the Life Cycle Association Matrix (LCAM) and the Function Network Diagram (FND). The following three steps, based on literature reviews and interviews with industrial experts, were applied. Firstly, we listed the product functions and design variables related to the functions as the attributes allocated to the product life cycle. Secondly, the attributes were connected appropriately based on causal relationships. Lastly, we identified the factors to support decision making in the packaging design procedure. As a result, the LCAM depicts the design consequences on the life cycle, and the FND determines the stakeholders affected by the design consequences. Two case studies were demonstrated to analyze the trade-offs by using our tools. In the case studies, a liquid laundry detergent bottle and a milk carton were redesigned. The tools identified the design consequences and stakeholders affected by the redesign of the usability and protective function for the detergent and milk cases, respectively. The results showed the significance of understanding the design consequences on the product life cycle by integrating the functional and environmental aspects.     

New high-resolution positive and negative photoresist method for ?/4-shifted DFB lasers

High-resolution positive and negative photoresists were used to fabricate ?/4-phase-shifted corrugations by holographic exposure. To avoid mixing these photoresists, cyclised polyisoprene was used as a midlayer. The shape and depth of the corrugations on the positive and negative photoresist regions were almost the same. Single-mode operation at the Bragg wavelength was confirmed in lasers with the corrugation.     

Elastic, anelastic, and piezoelectric coefficients of langasite: resonance ultrasound spectroscopy with laser-Doppler interferometry

This paper presents advanced techniques to determine all independent elastic-stiffness coefficients C/sub ij/, the associated internal friction Q/sub ij//sup -1/, and piezoelectric coefficients e/sub ij/ of monocrystal langasite (La/sub 3/Ga/sub 5/SiO/sub 14/) using a single rectangular parallelepiped specimen. Langasite's crystal structure belongs to the trigonal system with point group 32, and thus possesses six independent C/sub ij/, two e/sub ij/, and two dielectric coefficients /spl epsiv//sub ij/. All of the elastic and piezoelectric coefficients affect the mechanical resonance frequencies of the solid specimen, and measuring them very accurately permits one to determine the C/sub ij/ and e/sub ij/ with known density, dimensions, and e/sub ij/. We developed a piezoelectric tripod to support the specimen upward and measured the free-vibration resonance frequencies with minimum load from its own weight. This weak and stable acoustic coupling ensures accuracy of the frequency measurement better than 10/sup -5/, enough to determine the coefficients reliably. Our C/sub ij/ fall in the range of results measured with previous (conventional) methods. Our e/sub 11/ is smaller than the reported values by 1.2-13%, and e/sub 14/ is larger by 44-97%. For the internal friction measurement, we used a solenoid coil to vibrate the specimen without any contact. The longitudinal-wave internal friction considerably exceeds the shear-wave internal friction, which can be explained by phonon-phonon interactions.     

Molecular cloning and characterization of rat lin-10

In Caenorhabditis elegans, the vulval induction is mediated by tyrosine kinase receptor/Ras signal transduction pathway composed of the lin-3, let-23, and let-60 products. In addition to these gene products, the lin-2, lin-7, and lin-10 products are also implicated in this pathway. Lin-2 encodes a MAGUK and lin-7 encodes a small protein with one PDZ domain. The lin-10 product has no homology to known proteins. Here, we have cloned a rat homologue of the lin-10 product and characterized it. Rat lin-10 is ubiquitously expressed in various rat tissues and distributed in both the cytosol and membrane fractions. In brain, however, rat lin-10 is distributed only in the membrane fraction and enriched in the synaptic plasma membrane and postsynaptic density fractions. These results suggest that rat lin-10 is involved at least in synaptic functions in brain.     

The role of prostate specific antigen in diagnosis of localized adenocarcinoma of the prostate. Nara Uro-Oncology Research Group

The number of cases of prostate carcinoma (PCA) is steadily inceasing in Japan. The clinical application of a reliable tumor marker, prostate specific antigen (PSA) for the diagnosis, as well as the increasing elderly population in Japan may account for this increase. The subjects were patients at the Nara Medical University and its affiliated hospitals; 1) 687 cases without PCA were evaluated for age-specific PSA and the incidence of abnormal PSA following urological manipulations, 2) 135 cases with histological proven BPH by transurethral resection of prostate (TUR-P) were examined for PSA density (PSAD) and positive PSA rate in BPH, 3) 135 cases receiving a needle biopsy with suspicion of PCA were examined for the efficacy of PSA and PSAD and other parameters, and 4) 459 PCA cases treated between 1988 and 1994, were examined for specific PSA and PSAD values by stage and degree of cell differentiation. The PSA assay used in this study was MARKIT-M PA (normal range < or = 3.6 ng/ml). The PSA was decreased gradually with age in non-PCA patients, and abnormal PSA was found in 5.5% of these patients following manipulations. The average PSA was 2.95 +/- 2.03 ng/ml in 130 BPH patients (mean age: 71.1 +/- 7.0 years old. and average prostate volume: 32.9 +/- 16.1 ml). And abnormal PSA level (more than 3.61 ng/ml) was found in 22.3%. The mean PSAD was 0.1.0 +/- 0.06, and PSAD was below 0.15 in 86.1% of these BPH cases. Among the 135 cases receiving a needle biopsy, 33 cases had PSA values between 3.61 and 10.0 ng/ml. Of these cases, PCA was found in 18.5% of the 27 cases with a PSAD below 1.5, and in 33.3% of the 6 cases with a PSAD over 1.5. PSA and PSAD were proportionally increased with stage, and a significant difference in the PSA value was observed between stage B1 and B2, and stage C and D (P < 0.05). However, PSA and PSAD values were not significantly correlated with the cell differentiation in PCA stage A2-C. In total, PSA was 18.1 ng/ml in well, 23.9 ng/ml in moderately and 35.9 ng/ml in poorly differentiated type PCA. The positive rate of PSA was 22.3, 65.4 and 83.5%, that of prostate acid phosphatase (PAP) was 10.0, 17.8 and 45.8%, and that of GSM was 25.0, 14.7 and 68.4%, in BPH, stage A PCA and stage BPCA, respectively. In conclusion, PSA is the most reliable tool in the diagnosis of localized PCA. However, the differential diagnosis of BPH and localized PCA is difficult when the PSA value is between 3.61 and 10.0 ng/ml, and accurate staging of localized PCA is difficult with PSA or PSAD alone. At present, it is necessary to use all possible tools for the early detection of localized PCA, and to perform the needle biopsy in all PCA-suspicious cases.     

High-Strength and High-Fracture-Toughness Ceramics in the Al2O3/LaAl11O18 Systems

Control of microstructure in the Al₂O₃/LaAl₁₁O₁₈ system was performed. Elongated alumina grains were formed by doping with small addition of silica, and 20 vol% lanthana- luminate was formed in situ by the reaction of LaAlO₃- A1₂O₃ in an alumina matrix. Strengths of over 600 MPa and a high fracture toughness (6 MPa.m^1/2) were achieved in the material with both elongated A1₂O₃ grains and LaAl₁₁O₁₈ platelets. Generally antagonistic properties such as strength and fracture toughness have been made compatible in the same ceramic system.     

Highly Transparent Lu-α-SiAlON

Novel Lu-α-SiAlON ceramics were produced by hot pressing mixtures of Si₃N₄, Lu₂O₃, AlN, and Al₂O₃ at 1950°C for 2 h in a nitrogen atmosphere. The resultant SiAlON was fully dense and possessed a uniform, equiaxed microstructure with a grain size of ∼1 μm, which resulted in a high hardness of >19 GPa. In addition to high hardness, the sample showed very high optical transparency in the visible light region, with >70% transmission at higher wavelengths. This high transparency was attributed to the uniform, dense microstructure and lack of residual grain-boundary phase.     

Formation and Properties of Ln-Si-O-N Glasses (Ln = Lanthanides or Y)

Homogeneous Y-Si-O-N glasses containing 15 or 20 eq% nitrogen (N) were prepared from compositions with Y/Si ratios in the vicinity of that of the lowest eutectic point on the Y₂O₃–SiO₂ phase diagram. The liquidus on the phase diagram shifted toward lower temperatures by incorporation of N. The density, the elastic moduli, and the glass transition temperature of the Y-Si-O-N glasses increased with incorporation of N. This is due to the closer packing of atoms in the glasses by the substitution of N, which is in three-fold coordination with Si, for O which is in two-fold coordination, and the stronger covalent nature of the Si–N bond compared with the Si–O bond. The coefficient of thermal expansion of the Y-Si-O-N glasses increased with increasing Y content, because the discontinuity of the glass network developed with increasing nonbridging anions by the introduction of Y. In contrast, the glass transition temperature and the elastic moduli increased with Y content due to the high coordination of Y for O, and the relatively high cationic field strength of Y. Furthermore, the effect of cationic field strength on properties of Ln-Si-O-N glasses (Ln = lanthanides or Y) is discussed.