Comprehensive Research on Past and Future Therapeutic Strategies Devoted to Treatment of Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a rapidly debilitating fatal neurodegenerative disorder, causing muscle atrophy and weakness, which leads to paralysis and eventual death. ALS has a multifaceted nature affected by many pathological mechanisms, including oxidative stress (also via protein aggregation), mitochondrial dysfunction, glutamate-induced excitotoxicity, apoptosis, neuroinflammation, axonal degeneration, skeletal muscle deterioration and viruses. This complexity is a major obstacle in defeating ALS. At present, riluzole and edaravone are the only drugs that have passed clinical trials for the treatment of ALS, notwithstanding that they showed modest benefits in a limited population of ALS. A dextromethorphan hydrobromide and quinidine sulfate combination was also approved to treat pseudobulbar affect (PBA) in the course of ALS. Globally, there is a struggle to prevent or alleviate the symptoms of this neurodegenerative disease, including implementation of antisense oligonucleotides (ASOs), induced pluripotent stem cells (iPSCs), CRISPR-9/Cas technique, non-invasive brain stimulation (NIBS) or ALS-on-a-chip technology. Additionally, researchers have synthesized and screened new compounds to be effective in ALS beyond the drug repurposing strategy. Despite all these efforts, ALS treatment is largely limited to palliative care, and there is a strong need for new therapeutics to be developed. This review focuses on and discusses which therapeutic strategies have been followed so far and what can be done in the future for the treatment of ALS.     

Effect of cholestyramine on bile acid metabolism in conventional rats

Effects of cholestyramine on biliary secretion of cholesterol, phospholipids and bile acids and fecal excretion of sterols and bile acids were examined in Wistar male rats. Six rats were fed a basal diet, and the other six were fed a basal diet supplemented with 5% cholestyramine for eight days. Bile flow and biliary secretion of bile acids and phospholipids (per hour per rat) decreased with cholestyramine treatment, while biliary cholesterol secretion (per hour per rat) remained unchanged. In the biliary bile acid composition, a marked increase of chenodeoxycholic acid with a concomitant decrease of β-muricholic acid was observed in cholestyramine-treated rats. Fecal excretion of total sterols and bile acids increased about three-and four-fold, respectively, after cholestyramine treatment. The increase of fecal bile acids derived from cholic acid was more predominant than that derived from chenodeoxylcholic acid, resulting in an increase of the cholic acid group/chenodeoxycholic acid group ratio.     

Design for analysis: A new strategy to improve the design process

The concept ofdesign for analysis (DA) as a strategy for designing a product or system is studied. DA states that designers should be constrained to work with only those designs which can be analyzed easily and quickly by simple tools. DA imposes some discipline and constraints on the designers. Nevertheless, it is conjectured that this will lead to shorter design times as well as designs that are superior in a number of senses. This paper presents our initial investigation of DA, which aims to determine whether it has potential as a design strategy. First, we refine the definition of DA and pose some hypotheses regarding its impact on the design process. Then we describe five case studies on actual design processes which show that DA could significantly improve the design process. Finally, design steps based on DA are presented. While these results are still preliminary, we propose that DA as a design strategy has the potential of being an important strategic weapon for gaining competitive advantage.Currently on leave from Mitsubishi Heavy Industries, Ltd., Japan.     

Influence of growth conditions on deep levels in molecular-beam-epitaxial GaAs

Molecular-bearn-epitaxially grown undoped GaAs layers are studied with regard to the relation between growth conditions and deep-level trap generation. Both carrier concentration and electron trap density have a minimum value in samples grown at close to the minimum As/Ga flux ratio under As-stabilised conditions. Growth under these conditions leads to suppression of defect generation and unintentional impurity incorporation.     

Fabrication of a spiral microcoil using a 3D-LIGA process

LIGA processes have been developed generally in the 2.5D world. We introduced techniques of 3D X-ray lithography and worm injection molding with a unscrewing release mechanism, and succeeded in the development to three dimensions of LIGA process. We called this technology 3D-LIGA process, and came to be able to fabricate the plastic molded product with a spiral microstructure. Furthermore, we succeeded in the trial production of a spiral microcoil using 3D-LIGA process and metallization technique combining flat and smooth electroplating with a leveling agent and an isotropic chemical etching. The diameter of this microcoil was 0.5 mm and the length was 1 mm. The width of the Cu coil line was 10 μm, and the pitch was 20 μm. Moreover, we measured characteristics of this microcoil as an inductor. The inductance and the quality factor at the frequency of 1 GHz were 91 nH and 5.8, respectively. This is the first time successful fabrication of an electric device with a 3D form like a spiral microcoil using the 3D-LIGA process has been achieved.     

Deposition of Si-DLC film and its microstructural, tribological and corrosion properties

Silicon-incorporated diamond-like carbon (Si-DLC) films were deposited using a bipolar-type plasma based ion implantation and deposition technique, and the effects of Si-incorporation on the microstructural, tribological, anti-corrosion and lubricant bonding properties of the Si-DLC films were investigated. The analysis of Raman spectroscopy exhibited that the sp³ bonds in the DLC film increase due to Si addition. XPS analysis revealed that a thick oxide layer exists on the Si-DLC film surfaces. These explain the high lubricant bonding properties of the Si-DLC films compared to that of the Si-free DLC films. The silicon oxide layer on the Si-DLC film and the transferred silicon oxide layer on the steel ball prevents from the metal/DLC contact between the Si-DLC film and steel ball when sliding, which results in a low friction. Incorporation of Si in DLC films led to significant improvements in the corrosion resistance due to low internal stress and thick insulating oxide layer.     

Controlled Markov Set-chains with Set-valued Rewards—The Average Case

In this paper, the average case of finite state controlled Markov set-chains with R ^p -set-valued rewards are considered. The optimization is done by a pseudo-order relation on the set of all convex and compact subsets of R ^p induced by a closed convex cone. We introduce a v -step contractive property (minorization condition) for the average case and by use of this method the average expected reward set from a periodic policy is characterized. And, applying the scalarization technique, a Pareto optimal policy is obtained. Also, a numerical example is given to comprehend our results.     

Effects of humic substances on the pattern of oxidation products of pentachlorophenol induced by a biomimetic catalytic system using tetra(p-sulfophenyl)porphineiron(III) and KHSO5

In the presence of humic substances (HSs), the oxidative conversion of pentachlorophenol (PCP) was found to be efficiently catalyzed by tetra(p-sulfophenyl)porphineiron(III) (Fe(III)-TPPS) using KHSO5 as an oxygen donor. Ortho-tetrachloroquinone (o-TeCQ), 2-hydroxyl-nonachlorodiphenyl ether (2H-NCDE), 4-hydroxyl-nonachlorodiphenyl ether (4H-NCDE), and octachlorodibenzo-p-dioxin (OCDD) were identified as the major byproducts of the reaction. Decreased amounts of these byproducts were produced in the presence of HS. In particular, the addition of HSs with a lower degree of humification resulted in a large decrease in the formation of dimers, such as 2H-NCDE, 4H-NCDE, and OCDD. More than 60% of the chlorine, which was released from PCP, was found in the HS fractions after the reaction. This suggests that chlorinated intermediates from PCP were incorporated into the HS. Pyrolysis-GC/MS and 13C NMR studies confirmed that the binding of the chlorinated intermediates was covalent in nature and that the intermediates were copolymerized with HS via oxidative coupling reactions. A Microtox test demonstrated that the toxicity of the HS fraction containing PCP-derived intermediates was much lower than that of the mixture of PCP and HS in the absence of a catalytic reaction.     

Promoter of Arabidopsis thaliana phosphate transporter gene drives root-specific expression of transgene in rice

The PHT1 promoter::GUS fusion gene was constructed and introduced into Arabidopsis and rice by Agrobacterium-mediated transformation. Strong beta-glucuronidase (GUS) activity was detected in roots and showed phosphate starvation induction both in Arabidopsis and rice. In contrast, GUS activity in aerial tissues such as those of the leaf and stem was low. In situ GUS staining of root tissue indicated that PHT1 was expressed in root hairs and the outer layer of the main roots, but not in root tips. The PHT1 promoter has a desirable character for biotechnological transgene expression in monocot rice plants.     

Prediction of simultaneous adsorption of Cu(II) and Pb(II) onto activated carbon by conventional Langmuir type equations

Removal of Cu(II) and Pb(II) by adsorption onto activated carbon was examined in single- and binary-component aqueous solutions representative of contaminated solutions containing heavy metals. Reversibility of adsorption of the heavy metals on the activated carbon was evaluated by desorption experiments. The number of the maximum adsorption sites and adsorption equilibrium constants of Cu(II) and Pb(II) were estimated by the results of single-component systems assuming the Langmuir adsorption model. The adsorption sites per gram of activated carbon resulted in similar values for Cu(II) and Pb(II) from the isotherms. The adsorption constant for Pb(II) was nearly 1.8 times greater than that of Cu(II). Rate constants of adsorption and desorption were also estimated from the kinetic analysis. Using the single set of common parameters obtained from the single-component systems, the experimental results for a binary-component system were quantitatively predicted. Competitive adsorption of Cu(II) and Pb(II) on the same adsorption sites was confirmed by both experimental and predicted results of adsorption in the binary mixture.