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.     

Improvement in the DOA estimation of broadband signals usingpartially IIR beamformers

An ideal broadband beamformer requires an increased number of taps for each filter, which in turn increases the complexity of the design. It is shown that for angles near the broadside of the antenna the beamforming is more accurate compared to the angles near the endfire, and it is advantageous to use recursive filters combined with a computed number of zeros for angles near the endfire. The proposed method is used for estimating the arrival angle of the incoming signals and displays uniform accuracy for all angles     

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.     

Eosinophil chemotaxis induced by several biologically active substances and the effects of apafant on it in vitro

Chemotaxis of guinea pig eosinophils induced by various stimuli in use of a modified Boyden chamber technique in vitro and the effect of a platelet-activating factor (PAF) antagonist, apafant (CAS 105219-56-5, WEB 2086 BS), on it were examined. The eosinophils were obtained by bronchoalveolar lavage from the animals treated by i.v. injection with Sephadex G-200 and purified by Percoll density gradient centrifugation. PAF significantly and potently induced the chemotaxis at a broad range of 10(-17) to 10(-7) mol/l, where no concentration-dependency was observed. Leukotriene B4 also induced the chemotaxis in a concentration-dependent manner at 10(-14) to 10(-12) mol/l and the enhanced migration was not declined until 10(-7) mol/l. Interleukin-5 (IL-5), IL-8 and regulated on activation normal T expressed and secreted (RANTES) only modestly enhanced the chemotaxis in some concentrations at 10(-13) to 10(-7) mol/l with or without significance and with no concentration-dependency while formyl-methionyl-leucyl-phenylalanine (FMLP), a known chemoattractant, increased the migration at 10(-7) to 10(-5) mol/l. Apafant at 10(-8) to 10(-6) mol/l strongly and concentration-dependently inhibited 10(-8) mol/l PAF-induced chemotaxis. However, the drug showed nominal or no influences on their chemotaxis stimulated by the other agonists, at the concentrations of which the enhanced migration was observed. From these results, it is concluded that IL-5, IL-8 and RANTES, different from PAF and LTB4, are not potent stimuli for the eosinophil chemotaxis and that apafant is a selective antagonist of PAF, which is expected to be therapeutically effective for PAF-associated diseases including bronchial asthma.     

Percutaneous ethanol injection therapy by ethanol mixed with CO2 microbubble for hepatocellular carcinoma

One of the shortcomings of percutaneous ethanol injection therapy (PEIT) for hepatocellular carcinoma (HCC) is that many sessions are necessary to accomplish the treatment. This may be caused by which the ultrasonography (US) image does not reflect correctly to the kinetics of injected ethanol into HCC nodule. It is considered that number of treatment sessions are able to be reduced if we just enough injected labelled ethanol under US into HCC nodule. Therefore, we tried PEIT by ethanol mixed with CO2 microbubble (CO2 ethanol). The injected CO2 ethanol was aquired as hyperechoic image without strong acoustic shadow to the end of injection. Consequently we could reduce the number of treatment sessions to almost 1 for lesions < or = 3 cm in diameter and markedly reduce total dose of injected ethanol. The detectable rate of CO2 ethanol leaked out HCC nodule was high. No serious complication occurred. There have been only 1 lesion of local recurrence and no case of intrahepatic and peritoneal dissemination for 11.5 months on average of observation after PEIT by CO2 ethanol (CO2PEIT). These findings suggest that CO2PEIT is useful method for reducing the number of treatment sessions and total dose of injected ethanol, moreover preventing complication by ethanol leakage.     

Effects of pramipexole on contraversive rotation and functional motor impairments in 1-methyl-4-phenyl1,2,3, 6-tetrahydropyridine-induced chronic hemiparkinsonian monkeys

Rotational and functional motor behavioral changes were studied in five MPTP lesioned chronic hemiparkinsonian Macaca nemestrina monkeys after i.m. pramipexole, a predominant D2 subfamily agonist. Pramipexole induced contraversive rotations in a dose-dependent manner with an optimal dose of 56 microg/kg for approximately 2 to 4 hr after injection. Three different rating scales were used to determine drug-induced functional improvement. They included a monkey parkinsonism rating scale, volitional responses to fruit presentations, and number of hand movements that appeared volitional. A dose of 56 microg/kg of pramipexole produced functional improvements on hand disability, and on a parkinsonian rating scale for monkeys in a dose-dependent manner from 32 to 100 microg/kg. These doses produced an increase in significant hand movements in the affected (contralateral) as well as in the normal (ipsilateral) hand to the side of the brain lesion compared with 5% dextrose in water vehicle control. With a dose of 100 microg/kg, the therapeutic effects of pramipexole on hand movements were less than with 56 microg/kg, due to side effects such as scratching.     

Phonons and spin excitations in the extended t-J model

We consider the effects of spin-phonon coupling within the slave-boson mean-field treatment of the extended t-J model. With no additional assumptions the theory is found to give a semi-quantitative account of the frequency and linewidth anomalies observed for certain phonon modes in Y Ba₂Cu₃O₇ at the superconducting transition. We report also investigations of the role of this coupling in affecting thermodynamic properties and spin dynamics.     

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.