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.     

Membrane separation of indigenous noroviruses from sewage sludge and treated wastewater.

In this study, feasibility of membrane separation for the removal of indigenous noroviruses (NVs) is evaluated. The indigenous NV gene was never detected from ultrafiltration (UF) permeates of sewage sludge and treated wastewater. Indigenous NV gene was also not detected from permeates of sewage sludge and treated wastewater by microfiltration (MF) with a pore size of 0.1 microm (MF0.1). Even though the pore size of MF (0.1 microm) was much larger than the diameter of virus particle (approximately 30-40nm), more than 4-log10 reduction value (LRV) at maximum was achieved by membrane separation with MF0.1. NV genes were often detected from permeates of sewage sludge and treated wastewater by MF with a pore size of 0.45 microm (MF0.45), although the maximum log10 reduction values were more than 3.59 for sewage sludge and more than 2.90 for treated wastewater. It is important to verify factors determining the removal efficiency of viruses with MF membranes.     

Crosslinked acrylic pressure‐sensitive adhesives. II. Effect of humidity on the crosslinking reaction

The effect of humidity during storage on the crosslinking reactions of isocyanate groups was investigated with attenuated total reflectance Fourier transform infrared spectroscopy with pressure‐sensitive adhesives composed of poly[ethyl acrylate‐co‐(2‐ethylhexyl acrylate)‐co‐(2‐hydroxyethyl methacrylate)] as a base resin and polyisocyanate as a crosslinker. A peak‐resolving analysis of the amide II region revealed four bands. According to an analysis of the Fourier transform infrared spectra of the model compounds, these four bands were assigned to free urethane linkages, hydrogen‐bonded urethane linkages, free urea linkages, and hydrogen‐bonded urea linkages. As expected, storage under humid conditions led to the formation of free and hydrogen‐bonded urea linkages corresponding to the promotion of isocyanate consumption. Peak resolution of the amide II region was found to be a reasonable way of monitoring urethane and urea linkages during crosslinking reactions. © 2003 Wiley Periodicals, Inc. J Appl Polym Sci 89: 3039–3045, 2003     

Effect of light source spectral modulation on wavelength interrogation in fiber Bragg grating sensors and its reduction

In the fiber Bragg grating sensing using a superluminescent diode as the light source and an arrayed waveguide grating as the wavelength interrogator, the wavelength measurement error due to the spectral modulation of the superluminescent diode is theoretically formulated and quantitatively analyzed by computer simulation. It is shown that the wavelength measurement errors produced with the use of real superluminescent diodes are in very good agreement with the theoretical results. In order to reduce the wavelength measurement error due to the spectral modulation of superluminescent diode, two different types of remedies are proposed that utilize the temperature switching of superluminescent diode and that adjust the bandwidths of fiber Bragg grating and arrayed waveguide grating, and their efficacies are experimentally demonstrated together with good quantitative agreement with the theoretical calculation.     

Stability,cure properties,and applicability as one part adhesives of systems of divalent metal salts of mono(hydroxyethyl) phthalate–anhydride–bisepoxide

Heterogeneous curable compositions of divalent metal salts of mono(hydroxyethyl) phthalate–anhydride–bisphenol A diglycidyl ether (BADG) systems were prepared by merely mixing these components at room temperature. Stability at room temperature and cure properties at high temperature of the compositions were investigated for evaluating their applicability as one part adhesive. It was found that the systems containing Mg were generally more stable than those containing Ca. Similarly, at 150°C the Ca-containing systems showed generally shorter gelation time than the Mg-containing ones, due to the fact that the Ca salt dissolves more rapidly and enters into the addition reaction with the anhydride, leading to the faster appearance of the catalytic activities of the Ca carboxylate group. Among the various combinations of components, the metal salt–succinic anhydride (SA)–BADG systems were stable at room temperature for more than 6 months and rapidly cured at high temperature, showing excellent adhesive properties. This result indicates that the SA-containing systems should be of interest in applications to one part adhesives.     

A 322 MHz random-cycle embedded DRAM with high-accuracy sensing and tuning

A 16 Mb embedded DRAM macro in a fully CMOS logic compatible 90 nm process with a low noise core architecture and a high-accuracy post-fabrication tuning scheme has been developed. Based on the proposed techniques, 61% improvement of the sensing accuracy is realized. Even with the smallest 5 fF/cell capacitance, a 322 MHz random-cycle access while 32 ms data retention time which contributes to save the data retention power down to 60 /spl mu/W are achieved.     

Geochemical characteristics of the Yufuin outflow plume, Beppu hydrothermal system, Japan

Thermal water at Yufuin (Kyushu Island, Japan) is tapped through about 820 shallow wells and used mainly for hot-spring bathing purposes. Chemical and isotopic data for fluids from wells and fumaroles in Yufuin and Beppu indicate that the thermal activity at Yufuin represents a dilute, westward-flowing hydrothermal outflow plume from the Beppu hydrothermal system. Two other (eastward-flowing) outflow plumes have long been recognized at Beppu, but the Yufuin outflow plume is first recognized here. The Yufuin outflow plume is apparently a mixture of two end-member fluids: (1) deep high-temperature (250–300°C) fluid from the Beppu system having high chloride concentration (1400–1600 mg/L) and a δ¹⁸O value near −6.0%, and (2) meteoric water having low chloride concentration (≤7 mg/L) and a δ¹⁸O value near −9.2%.A permeable conduit for the vertical and lateral transport of deep fluid from the Beppu system is provided by the Yufuin Fault zone, which extends westward from the southern flank of Mt. Tsurumi volcano to the town of Yufuin. Stable isotope ratios and chloride concentrations for shallow groundwaters near the eastern end of the fault, at an elevation near 700 m, are consistent with those required for the low-chloride meteoric end-member of the Yufuin thermal waters. Recharge of this meteoric water, as well as mixing with the Beppu deep fluid, may occur along the Yufuin Fault. Enthalpy-chloride relations indicate additional conductive heating of the Yufuin waters, in the amount of 350–500 kJ/kg beyond that which can be accounted for by mixing between Beppu deep fluid and meteoric water. This could be a result of conductive heating with convection to a depth of 1–2 km. Estimates of the magnitude of the heat source for the Beppu hydrothermal system should take into account the heat being discharged at Yufuin.     

Galvanic cell measurements on supersaturated activities of oxygen in Fe-Al-M (M=C, Te, Mn, Cr, Si, Ti, Zr, and Ce) melts

Using a mullite (3Al₂O₃ · 2SiO₂)-tube and ZrO₂-9 mol pct MgO-plug type solid electrolyte galvanic cells, the activities of supersaturated oxygen in Fe-0.0017 to 0.41 mass pct Al-M (M=C, Te, Mn, Cr, Si, Ti, Zr, and Ce) alloys were measured as a function of total Al or M contents at 1873 K in an alumina crucible. Based on these results, the effects of alloying elements on the supersaturated oxygen activity with respect to alumina precipitation were studied. In the Fe-Al-M (M=C, Te, Mn, Cr, and Si) alloys, the supersaturated oxygen activities for a given Al level approach the equilibrium values with increasing contents of alloying elements. However, the oxygen activities for a given Al level are still supersaturated in the Fe-Al-M (M=Ti, Zr, and Ce) alloys even in the presence of considerable amounts of the alloying elements.