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.     

On the Limitation of Net Algorithm for Enumerating Isomeric Structures of Giant Fullerenes

Application of our net algorithm to the generation of all possible IPR isomers for giant fullerenes C_n, n=102 to 120, missed nine out of 39,621 possible structures. Analysis revealed that the omission of too small and too large cap triangles was the reason. Within the range of fullerenes studied, the missed structures are of high-energy and do not affect the distribution of significantly low-energy isomers.     

Doubly Bonded C60 Dimers and Congeners: Computational Studies of Structures, Bond Energies and Transformations

Initial steps of thermal transformation from doubly bonded [2+2] (1) and [4+4] (2) dimers of C₆₀ have been analyzed on the basis of computed structural features and Pople's energy partition scheme. Completely conjugated C₁₂₀ structures 3 and 4 are found to be considerably stable and proposed to be important intermediates. The linkage patterns in 3 and 4 are also likely to appear in the repeating units of the metastable dimer and polymer phases of A₁ crystals.     

Hot-carrier effects in scaled MOS devices

A universal guideline and state-of-the-art hot-carrier effects in scaled MOSFETs are reviewed and discussed from the viewpoints of 1) DC and AC hot-carrier effects, 2) hot-carrier detrapping phenomena, 3) mechanical stress effects on hot-carrier phenomena, and 4) hot-carrier resistant device structures.In the deep-submicron region, the hot-carrier applicable voltage is less than 3 V, so AC hot-carrier effects from the dynamic operation of actual circuits should be taken into account. Despite much experimentation and analysis, there is still no universally accepted theory that explain the AC degradation mechanism. This is because the noise caused by the wiring inductance in ULSI circuits and in measurement systems screens the intrinsic AC hot-carrier effects.Here, AC hot-carrier degradation enhanced by gate pulse-induced-noise is analyzed experimentally and theoretically. After eliminating the noise problem, it is found that AC hot-carrier degradation in LDD (Lightly doped drain) and GOLD (gate-drain overlapped device) structures can be estimated based on DC degradation in terms of the effective stress time which takes the duty ratio into account. In addition, it is found that the noise is negligible when the wiring inductance is smaller that 80 nH (250 mω), which is important for future circuit design.Furthermore, hot-carrier detrapping effects, especially in p-channel MOS devices, and hot-carrier phenomena under mechanical stress are investigated experimentally to better understand the underlying hot-carrier physics. Finally, future hot-carrier resistant device structures are discussed.     

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.     

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.     

Numerical analysis of wave-type heat transfer propagating in a thin foil irradiated by short-pulsed laser

This paper presents a numerical simulation of wave-type heat transfer phenomena propagating in an aluminum thin foil irradiated by a pulsed laser using the cubic interpolated propagation method coupled with a thermo-convective model. We did not use the two-step model and dual-phase lag model, which are generally known as the non-Fourier heat conduction law, but wave-type heat transfer phenomena could be observed by our method. The main characteristic of the method is to solve the governing equation including the equation of continuity, the equation of motion, the equation of energy and the equation of state. It is found that when the pulse duration is under the order of picosecond, the pure heat conduction is hardly observed and heat transfer toward the inside of materials occurs only by a thermal shock wave. The heat conduction mode after pulse laser irradiation is strongly dependent upon the value of total incident laser energy density E_in and the threshold value for pure heat conduction is 5.0 × 10⁴ J/m² for an aluminum.     

Thermal Transformation of Ring-Opened [2 2] C60 Dimer into a Wide-Bridged C120 Isomer. A Computational Evaluation of Fulvalene-Naphthalene Rearrangements

As a continuation of the studies on thermal transformation of the [2+2] C₆₀ dimer (1), the consequence of the pyracylene-rearrangement-like valence isomerization of the fulvalene partial structure at the bridge of the ring-opened product from 1, namely 2, was searched by dynamic reaction coordinate /AM1 semiempirical MO calculations. It is predicted that the fulvalene bridge of 2 rearranges into naphthalene partial structure by the concerted 'in-plane' mechanism to give a wide-bridged C₁₂₀ intermediate having twenty five-membered rings and two ten-membered rings (3). The computed energy of activation (145 kcal/mol) is 40 kcal/mol lower than those computed for pyracylene rearrangements. In contrast, the recently reported analogous rearrangement of indigo (13) to dibenzonaphthyridindione (14) is computed to occur by the stepwise 'sp³' mechanism.     

Series resonant ZCS‐PFM DC‐DC power converter with high‐frequency high‐voltage transformer link for high‐power magnetron drive

This paper presents a single lossless inductive snubber‐assisted ZCS‐PFM series resonant DC‐DC power converter with a high‐frequency high‐voltage transformer link for industrial‐use high‐power magnetron drive. The current flowing through the active power switches rises gradually at a turned‐on transient state with the aid of a single lossless snubber inductor, and ZCS turn‐on commutation based on overlapping current can be achieved via the wide range pulse frequency modulation control scheme. The high‐frequency high‐voltage transformer primary side resonant current always becomes continuous operation mode, by electromagnetic loose coupling design of the high‐frequency high‐voltage transformer and the magnetizing inductance of the high‐frequency high‐voltage transformer. As a result, this high‐voltage power converter circuit for the magnetron can achieve a complete zero current soft switching under the condition of broad width gate voltage signals. Furthermore, this high‐voltage DC‐DC power converter circuit can regulate the output power from zero to full over audible frequency range via the two resonant frequency circuit design. Its operating performances are evaluated and discussed on the basis of the power loss analysis simulation and the experimental results from a practical point of view. © 2005 Wiley Periodicals, Inc. Electr Eng Jpn, 153(3): 79–87, 2005; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/eej.20126