Multifaceted Mechanisms of Action of Metformin Which Have Been Unraveled One after Another in the Long History

While there are various kinds of drugs for type 2 diabetes mellitus at present, in this review article, we focus on metformin which is an insulin sensitizer and is often used as a first-choice drug worldwide. Metformin mainly activates adenosine monophosphate-activated protein kinase (AMPK) in the liver which leads to suppression of fatty acid synthesis and gluconeogenesis. Metformin activates AMPK in skeletal muscle as well, which increases translocation of glucose transporter 4 to the cell membrane and thereby increases glucose uptake. Further, metformin suppresses glucagon signaling in the liver by suppressing adenylate cyclase which leads to suppression of gluconeogenesis. In addition, metformin reduces autophagy failure observed in pancreatic β-cells under diabetic conditions. Furthermore, it is known that metformin alters the gut microbiome and facilitates the transport of glucose from the circulation into excrement. It is also known that metformin reduces food intake and lowers body weight by increasing circulating levels of the peptide hormone growth/differentiation factor 15 (GDF15). Furthermore, much attention has been drawn to the fact that the frequency of various cancers is lower in subjects taking metformin. Metformin suppresses the mechanistic target of rapamycin (mTOR) by activating AMPK in pre-neoplastic cells, which leads to suppression of cell growth and an increase in apoptosis in pre-neoplastic cells. It has been shown recently that metformin consumption potentially influences the mortality in patients with type 2 diabetes mellitus and coronavirus infectious disease (COVID-19). Taken together, metformin is an old drug, but multifaceted mechanisms of action of metformin have been unraveled one after another in its long history.     

Preparation of pyrochlores. A1−xHxTaO3·nH2O (A=Na,K)

Pyrochlores of A_1?xH_xTaO₃·nH₂O (A=Na,K) were prepared under the hydrothermal conditions. The values of x for these compounds were increased from 0.3 to 0.5 for A=Na and from 0.2 to 0.5 for A=K by treatment with the distilled water. The compounds with x<0.5 were decomposed to a mixture of NaTaO₃ and Na₂Ta₄O₁₁ for A=Na, or to a mixture of KTaO₃ and a tetragonal tungsten bronze phase, and those with x=0.5 to a single phase of A₂Ta₄O₁₁ at elevated temperatures. Below the decomposition temperatures, defect pyrochlores with oxygen vacancies, $\text{A}{}_{\mathrm{<mtext>1?</mtext><mtext>x</mtext>}}\text{TaO}{}_{\mathrm{<mtext>3?</mtext><mtext>x</mtext><mtext>2</mtext>}}$, were produced. They were hygroscopic, and in the case of A=K and x=0.5 the original phase was recovered by leaving in air for several hours.     

Study on axiomatic rules for building up relationships between requirement and source programs

The purpose of our study is to build up relationships between requirement and source programs with our originally thought-out rules. When other rules to be derived from these original rules are applied to software development, even a single instruction in a programming language could be determined, and the program would satisfy the requirement. More specifically speaking, these rules will turn into a formula or a prototype of software programs. Hence, when the variables in the requirement are placed in the formula, we can get a required program in an automatic way.     

Investigation into the therapeutic efficacy of continuous isoproterenol inhalation in relation to respiratory infections in asthmatic children

In our Department, continuous isoproterenol inhalation therapy has been conducted on status asthmatics over the last 10 years. In the present study, we investigated whether there are any differences in the therapeutic efficacy of continuous inhalation of isoproterenol in the presence or absence of respiratory infections which may induce or aggravate asthma attacks. The treatment period was significantly longer in patients with pneumonia. Further prolongation of the treatment period was noted in patients with atelectasis. However, there were no apparent differences in therapeutic efficacy according to age or the severity of attacks. These findings suggest that continuous inhalation of isoproterenol is very effective for status asthmatics if respiratory infections are thoroughly controlled.     

Robust stabilization of a magnetic suspension system using H∞ Control Theory

This paper presents the robust control design of a magnetic suspension system for a flexible beam which is a simplified model of an elastic rotor in a magnetic bearing system. To stabilize this magnetic suspension system which is unstable in nature, the H^infin; control theory is applied for a design of the control system. To apply the H^infin; control theory, a statespace model of an augmented plant with frequency-weighting functions is constructed. This augmented plant has two inputs which are the exogenous inputs and the control inputs, and two outputs which are the sensor outputs and the regulated outputs. Here we consider the mixed sensitivity problem. The H^infin; controller is implemented by a digital controller which is able to execute the computations very quickly. For the evaluation of the control performance, several experiments are made. The robustness of the closed-loop system is confirmed by the experimental results. The result of this study is useful for the control design of a magnetic bearing system.     

Design of electrofusion joints and evaluation of fusion strength using fusion simulation technology

Fusion simulation is one of the key techniques in designing and producing electrofusion (EF) joints for gas distribution and in evaluating fusion joint integrity. This paper describes the result of a numerical simulation of a thermal fusion process, using the finite element method. A nonlinear heat transfer computer program was used to obtain the temperature profile of a large electrofusion joint at fusion. The effects of applied voltage, heating time, wire pitch, and ambient temperature were examined for designing a 150-mm EF joint. A method to shorten the cooling time was also investigated. The fusion condition range suitable for a 150-mm EF joint was found to be slightly narrower than that suitable for a 50-mm EF joint. Examination of the effect of wire pitch revealed that if the pitch is extremely large, thermal degradation starts in the resin close to the wire before the fusion-interface strength reaches the maximum value. We have developed a program to simulate the process of closing the gap between the pipe and the joint due to resin expansion and melting after the power is supplied.     

Scientific Screening of Raw Diamond for an Ultraprecision Cutting Tool with High Durability

The wide scattering in tool life of natural mono-crystalline diamond tools is considered to depend on intrinsic crystalline defects due to nitrogen impurities in raw diamond. In this paper, the correlation was investigated between the amounts and types of the impurity evaluated by infrared absorption (IRA) and the crater wear and chipping resistances. As a result, diamonds including less total amount of impurity show larger wear resistance and that with larger amount of B2-aggregates show larger chipping resistance. This suggests that the inspection by IRA can be a useful method for screening of raw diamond for highly durable cutting tools.     

Ion exchange of intercalation compounds from WOP2O7 and intercalation ofn-alkylamines

Ion exchange of Na _x WOP₂O₇ ·nH₂O (x 1.4) prepared from WOP₂O₇ was attempted, using alkaline and alkaline earth ions. The degree of exchange was observed to be >50% at 90° C except for Mg²⁺. The basal spacing of ion-exchanged materials for the hydrated phase were dependent on the number of water molecules in the interlayer spaces, while those for the dehydrated phase increased with the size of ions in the interlayer spaces. The network of water molecules linked by the hydrogen bond in the interlayer spaces seems to determine the basal spacing. By the ion-exchange reaction,n-alkylammonium ions were intercalated into the interlayer spaces of Na _x WOP₂O₇ ·nH₂O (x 1.4) and Sn _x H _y WOP₂O₇ ·nH₂O (2x +y 0.5). In spite of the difference in the charge density of the host layer, a similar arrangement of alkyl chains in the interlayer spaces resulted, and neutral amines were considered to be intercalated as well as ammonium ions. Direct reaction ofn-alkylamine with WOP₂O₇ produced an intercalation compound without reduction of tungsten. The arrangement of the amines in the interlayer spaces is similar to that supposed to the ion-exchanged derivatives when heated at 140° Cin vacuo.     

Biocompatibility of surface treated pure titanium and titanium alloy by<Emphasis Type="Italic">in vivo</Emphasis> and<Emphasis Type="Italic">in vitro</Emphasis> test

In the present study, commercial pure Ti and Ti-6Al-4V alloy specimens with and without alkali and heat treatments were implanted in the abdominal connective tissue of mice. Conventional stainless steel 316L was also implanted for comparison. After three months, their biocompatibility was evaluated byin vitro andin vivo experiments. Surface structural changes of specimens due to the alkali treatment and soaking in Hank’s solution were analyzed by XRD, SEM, XPS and AES. An apatite layer, which accelerates the connection with bone, was formed more easily on the alkali treated specimens than the non-treated specimens. The number of macrophages, which is known to increase as the inflammatory reaction proceeds, was much lower for the alkali and heat treated specimens than for the others. The average thickness of the fibrous capsule formed around the implant was much thinner for the alkali and heat treated specimens than for the others.