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.     

Monomeric, monovalent derivative of Maackia amurensis leukoagglutinin. Preparation and application to the study of cell surface glycoconjugates by flow cytometry

A stable subunit of Maackia amurensis leukoagglutinin (MMAL) was prepared by the selective reduction of disulfide bridges between the subunits followed by alkylation with 4-vinylpyridine. MMAL failed to precipitate fetuin, whereas it retained its ability to bind to the same glycoprotein coated on a plastic plate, indicating the monovalency of this derivative. This binding to immobilized fetuin was inhibited by a haptenic sugar, Neu5Ac alpha 2-3lactose, with the same inhibitory potency as against the native M. amurensis leukoagglutinin. Microscopic observation as well as flow cytometric analyses showed that Chinese hamster ovary cells were clearly stained with fluorescein isothiocyanate-labeled MMAL without any detectable agglutination. This staining was inhibited by the addition of fetuin or by the sugar chains of fetuin. Differences in the types of sialylated glycoconjugates on the cell surface of several cell lines were detected by the combined use of fluorescein isothiocyanate-labeled MMAL and the monomeric derivative of elderberry bark lectin (specific for the Neu5Ac alpha 2-6Gal/GalNAc sequence) by flow cytometry. These results demonstrate the usefulness of these monovalent derivatives of sialylated oligosaccharide-specific lectins as probes for the analysis of cell surface glycoconjugates containing sialic acid by the technique of flow cytometry.     

Mean molal activity coefficients of aqueous scandium chloride, nitrate, bromide and perchlorate solutions at 25.0°

The mean molal activity coefficients of aqueous scandium chloride, nitrate, bromide and perchlorate solutions were determined at 25.0° for dilute to saturated concentrations, together with the activities of water. In the dilute solutions of scandium halides, the activity coefficients were obtained from electromotive force measurements on galvanic cells, and the osmotic coefficients of all four solutions above 0.1 mol kg⁻¹ were determined from the isopiestic measurements. Least-squares equations were fitted to these coefficients, which were then used to calculate the mean molal activity coefficients and water activities. The relationships between these results and the corresponding activity data for other rare earth salts, and to the cation hydration and ionic interactions, are discussed. The results on scandium perchlorate solutions suggested that the inner-sphere hydration number of tervalent scandium ion may be seven.     

Endogenous adenosine exerts inhibitory effects upon the development of spreading depression and glutamate release induced by microdialysis with high K+ in rat hippocampus

Spreading depression (SD) is known to be involved in the N-methyl-D-aspartate receptor-mediated neuronal damage. In urethane-anesthetized rats, we examined the release of adenosine and glutamate during SD induced by microdialysis of high K+ perfusate through the hippocampal CA1 area. The effects of endogenous adenosine upon SD were studied by applying an adenosine antagonist, theophylline (1 mM) and by a simultaneous application of adenosine uptake blockers, dipyridamole (DPR) (100 microM) and nitrobenzylthioinosine (NBI) (50 microM). The dialysates were sampled every 5 or 10 min and analyzed by HPLC. SD was identified by flattening of background EEg and disappearance of population spikes recorded from the pyramidal cell layer of CA1 area by a glass microelectrode. Adenosine and glutamate release was enhanced significantly in association with the occurrence of SD. Theophylline increased the release of glutamate and the incidence of SD and decreased the latency of the SD occurrence. DPR+NBI decreased the release of glutamate and the occurrence of SD, but increased extracellular adenosine concentration. The effects of DPR+NBI were blocked by application of a selective antagonist of adenosine A1 receptor, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, 0.1 microM). These findings suggest that endogenous adenosine exerts inhibitory influences upon the development of SD and the glutamate release through the A1 receptor in rat hippocampus.     

A novel technique for a DC brushless motor without position sensors

A dc brushless motor is a kind of synchronous motor driven by an inverter and requires sensors to detect the rotor position. As one of the methods, the induced voltages of a brushless motor have been utilized in practice. However, there are some problems in this method, e.g., the motor can obtain insufficient torque due to the low induced voltages in a low-speed range. This paper proposes a new method which controls the inverter angular frequency ω₁ by using inherent characteristics wherein the torque current i_r is almost proportional to the internal phase angle φ where the primary flux of a synchronous motor is controlled to be constant. If the parameters of a motor are given exactly, the speed regulation is quite small and the transient characteristics with high response and high starting torque are obtained. Furthermore, it is possible to operate a synchronous motor in the field-weakening range. Here, the principle of the control method and the performance characteristics of a dc brushless motor having no position sensors are discussed. The simulation and the experimental results of the tested machine show that the proposed method is very useful for practical applications.     

Path tracking control of Lagrange systems with obstacle avoidance

This paper addresses a path tracking problem with obstacle avoidance for Lagrange systems. The proposed method is based on field potential methods in combination with navigation functions for obstacle avoidance. First, it is shown that a simple combination of the navigation function with the conventional path tracking controller does not work. Therefore, in order to cope with this problem, a new feedback law is proposed for a path parameter which characterizes the reference path. It is proved that the proposed controller achieves both path following and collision avoidance. Moreover, since the method adopts bounded navigation functions, the proposed controllers generate bounded input signals even when target systems approach obstacles. Finally, an experimental evaluation is performed with a two-link manipulator to illustrate the effectiveness of the proposed method.     

Drawing plane graphs nicely

Summary This paper presents two efficient algorithms for drawing plane graphs nicely. Both draw all edges of a graph as straight line segments without crossing lines. The first draws a plane graph convex if possible, that is, in a way that every inner face and the complement of the outer face are convex polygons. The second, using the first, produces a pleasing drawing of a given plane graph that satisfies the following property as far as possible: the complements of 3-connected components, together with inner faces and the complement of the outer face, are convex polygons. The running time and storage space of both algorithms are linear in the number of vertices of the graph.     

Making exhaustive search programs deterministic

This paper presents a technique for compiling a Horn-clause program intended for exhaustive search into a GHC (Guarded Horn Clauses) program. The technique can be viewed also as a transformation technique for Prolog programs which compiles away the ‘bagof’ primitive and non-determinate bindings. The class of programs to which our technique is applicable is shown with a static checking algorithm; it is nontrivial and could be extended. An experiment on a compiler-based Prolog system showed that our technique improved the efficiency of exhaustive search by 6 times for a permutation generator program. This compilation technique is important also in that it exploits the AND-parallelism of GHC for parallel search.     

Real-time simulation of lightweight rigid bodies

Unlike common rigid bodies, lightweight rigid bodies have special and spectacular motions that are known as free fall, such as fluttering (oscillation from side to side) and tumbling (rotation and sideways drifting). However, computer graphics applications cannot simulate the dynamics of lightweight rigid bodies in various environments realistically and efficiently. In this study, we first analyze the physical characteristics of free-fall motions in quiescent flow and propose a new procedural motion-synthesis method for modeling free-fall motions in interactive environments. Six primitive motions of lightweight rigid bodies are defined in a phase diagram and analyzed separately using a trajectory-search tree and precomputed trajectory database. The global paths of free-fall motions are synthesized on the basis of these primitive motions by using a free-fall motion graph whose edges are connected in the Markov-chain model. Then, our approach integrates external forces (e.g., a wind field) by using an improved noise-based algorithm under different force magnitudes and object release heights. This approach exhibits not only realistic simulation results in various environments but also fast computation to meet real-time requirements.