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.     

Radiophotoluminescence phenomenon in copper-doped aluminoborosilicate glass

Radiophotoluminescence phenomena have been widely investigated on various types of materials for dosimetry applications. We report that an aluminoborosilicate glass containing 0.005 mol% copper exhibits intense photoluminescence in the visible region induced by X-ray and γ-ray irradiation. The luminescence is assigned to the 3d⁹4s¹ → 3d¹⁰ transition of Cu⁺. The proportionality of the intensity of the induced photoluminescence to the irradiation dose was confirmed up to 0.5 kGy using ⁶⁰Co γ-ray irradiation. Based on the spectroscopic results, a potential mechanism was proposed for the enhancement of the photoluminescence. The exposure to the ionizing radiation generates electron-hole pairs in the glass, and the electrons are subsequently captured by the Cu²⁺ ions, which are converted to Cu⁺ and emit the luminescence. For the glass containing 0.01 mol% copper, the pronounced enhancement of the photoluminescence was not observed because the reverse reaction, ie, the capture of the holes by the Cu⁺ ions, becomes prominent. The photoluminescence induced by the irradiation was stably observed for the glasses kept at room temperature and even for the glasses heat-treated at 150°C. However, the induced photoluminescence could be eliminated by the heat treatment at a temperature at 500°C, and the glass returned to the initial pre-irradiation state. The Cu-doped aluminoborosilicate glass is a potential candidate for use in dosimetry applications.     

Finite element beam propagation method for three-dimensionaloptical waveguide structures

A beam propagation method (BPM) based on the finite element method (FEM) is described for longitudinally varying three-dimensional (3-D) optical waveguides. In order to avoid nonphysical reflections from the computational window edges, the transparent boundary condition is introduced. The present algorithm using the Pade approximation is, to our knowledge, the first wide-angle finite element beam propagation method for 3-D waveguide structures. To show the validity and usefulness of this approach, numerical results are shown for Gaussian-beam excitation of a straight rib waveguide and guided-mode propagation in a Y-branching rib waveguide     

Subsurface structures in initial stage of FeSi2 growth studied by high-resolution Rutherford backscattering spectroscopy

The initial stage of iron silicide formation is investigated by high-resolution Rutherford backscattering spectroscopy. During the Fe deposition on Si(001) at 470 °C, the formation of FeSi₂ is confirmed by the surface peak analysis. Initially, FeSi₂ grows epitaxially so that one of the major crystallographic axes is parallel to the <111> axis of the Si substrate. With increasing Fe deposition, the deviation between the major crystallographic axis of the silicide region and Si<111> increases although the electron diffraction pattern is independent of the amount of Fe deposition. Therefore, the subsurface crystallographic structure of iron silicide is transformed from a cubic-like to a low-symmetry structure.     

Improvement of Mechanical Properties of Machinable Glass-Ceramics through Postmachining Heat Treatments

A mica-based machinable glass-ceramic has been converted to a glass-ceramic containing cordiertie and body-centered cubic chondrodite through heat treatment at temperatures higher than that used for the crystallization of mica. The machinability is lost, microhardness increases, and the thermal expansion coefficient decreases with the change of the crystalline phase from mica to cordierite and chondrodite.     

NiCoFe/C cathode electrocatalysts for direct ethanol fuel cells

A direct ethanol fuel cell (DEFC), which is less prone to ethanol crossover, is reported. The cell consists of PtRu/C catalyst as the anode, Nafion^® 117 membrane, and Ni–Co–Fe (NCF) composite catalyst as the cathode. The NCF catalyst was synthesized by mixing Ni, Co, and Fe complexes into a polymer matrix (melamine-formaldehyde resins), followed by heating the mixture at 800 °C under inert atmosphere. TEM and EDX experiments suggest that the NCF catalyst has alloy structures of Ni, Co and Fe. The catalytic activity of the NCF catalyst for the oxygen reduction reaction (ORR) was compared with that of commercially available Pt/C (CAP) catalyst at different ethanol concentrations. The decrease in open circuit voltage (V_oc) of the DEFC equipped with the NCF catalysts was less than that of CAP catalyst at higher ethanol concentrations. The NCF catalyst was less prone to ethanol oxidation at cathode even when ethanol crossover occurred through the Nafion^®117 film, which prevents voltage drop at the cathode. However, the CAP catalyst did oxidize ethanol at the cathode and caused a decrease in voltage at higher ethanol concentrations.     

2D artificial life system using network-type assembly-like language: influence of change in environment with costs of instructions

To unlock the full potential of evolution in digital media, a Tierra-like system using network-type assembly-like language has been constructed. In the system, like Avida, digital creatures, self-replicating programs, live in a discrete 2D torus space and an interaction between creatures is restricted locally. Bearing a genetic network in mind, network structure is introduced. In the previous works, it is shown that the possibility that the network-type model has more potential of evolution than a linear-type model like Avida in a simple environment. In this paper, to study the potential of evolution more precisely, we model the effects of environment other than creatures. As one of the simplest models of such environment, the cost of execution, i.e. executing time, is introduced. The difficult environment to live in costs high to execute instructions, the easy environment does low. In computer experiments, we have investigated the influence of change in environment by analyzing the process of evolution and diversity of the system. Experimental results show that the network-type system keeps more stable diversity than the linear-type system does, even when the environment changes drastically. This indicates the possibility that the network-type system has more potential of evolution than the linear-type system has. This work was presented in part at the 13th International Symposium on Artificial Life and Robotics, Oita, Japan, January 31–February 2, 2008     

The tricarboxylic acid cycle in Dictyostelium discoideum. Systemic effects of including protein turnover in the current model

The current model for the tricarboxylic acid cycle in Dictyostelium discoideum is based on extensive experimental studies of enzyme kinetics in vitro and of metabolite fluxes measured in vivo. In the previous papers (Shiraishi, F., and Savageau, M. A. (1992) J. Biol. Chem. 267, 22912-22918; 22919-22925; 22926-22933; 22934-22943) of this series we have carried out extensive analyses of the current model within the framework of biochemical systems theory with a view toward understanding the behavior of the integrated system. The model was found to be ill determined with respect to at least three of its features. In this paper we propose a minimal modification in the model that is consistent with previous experimental data but also includes recycling of amino acids for protein synthesis, one of the neglected features identified as important in the previous analysis. We again perform an analysis within the framework of biochemical systems theory to determine the systemic consequences of this change. The results show that the robustness of the modified model, as determined by the parameter sensitivities, is improved by 2 orders of magnitude over that of the previous model. Analysis of the dynamics shows that the turnover times for the pools of alanine, glutamate, and aspartate are reduced by 2 orders of magnitude and made more physiologically realistic. The distribution of flux is no longer rigidly fixed, and problems previously centered on the metabolism of pyruvate have been partially alleviated. Continued discrepancies lead us to question the degree to which kinetic data obtained with purified enzymes in vitro faithfully reflect the kinetic behavior of the integrated enzyme system in vivo. We must continue to re-examine the manner in which the kinetics of reactions in vivo are represented and to reassess the physical conditions that prevail in vitro and in vivo. Results in this paper direct our attention toward specific aspects of the system where these efforts should be focused. Thus, a minimal modification of the previous model has led to several improvements that make it more representative of the tricarboxylic acid cycle in D. discoideum, and the analysis in this paper leads to further predictions for improving the model.     

《最终幻想Ⅺ》的更新系统设计

对于如何提供补丁下载，单机PC游戏开发人员已经是轻车熟路了，这些补丁包里通常包含玩家需要手动更新的数据和二进制文件．但基本上．他们很少会为了补丁下载而创建一个“更新系统”。