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.     

A copper/polyimide Metal-base packaging technology

A unique substrate MCPM (Mitsubishi Copper Polyimide Metal-base) technology has been developed by applying our basic copper/polyimide technology.¹ This new substrate technology MCPM is suited for a high-density, multi-layer, multi-chip, high-power module/package, such as used for a computer. The new MCPM was processed using a copper metal base (110 × 110 mm), full copper system (all layers) with 50-μm fine lines. As for pad metallizations for the IC assembly, we evaluated both Ni/Au for chip and wire ICs and solder for TAB ICs. The total number of assembled ICs is 25. To improve the thermal dispersion, copper thermal vias are simultaneously formed by electro-plating. This thermal via is located between the IC chip and copper metal base, and promotes heat dispersion. We employed one large thermal via (4.5 mm^?) and four small vias (1.0 mm^?) for each IC pad. The effect of thermal vias and/or base metal is simulated by a computer analysis and compared with an alumina base substrate. The results show that the thermal vias are effective at lowering the temperature difference between the IC and base substrate, and also lowering the temperature rise of the IC chip. We also evaluated the substrate’s reliability by adhesion test, pressure cooker test, etc.     

Properties of Va metal-B films prepared by r.f.-sputtering

Ta_100-x B _x alloy films were prepared by r.f.-sputtering in the chemical composition range 45 x 77. Ta_100-x B _x (45 x 58) films consist of the amorphous phase, while the TaB₂ crystal phase was observed in Ta_100-x B _x (66 x 77) films. A remarkable preferred orientation with the (001) plane of TaB₂ parallel to the film surface was observed in Ta₃₄B₆₆. The d.c. electrical conductivity of Ta_100-x B _x (45 x 77) films decreases with increasing boron content in the range 6.7 × 10³ to 1.3 × 10^3–1 cm^–1. The micro-Vickers hardness of Ta_100-x B _x (45 x 77) films was in the range 2200 to 2600 kg mm^–2.     

Preparation of Co-N films by rf-sputtering

Co-N films in the wide compositional range can be prepared by reactive sputtering. Co-N sputtered films consist of one or two phases, such as CoN, Co₂N, Co₃N, Co₄N and -Co. Co₄N phase with a cubic unit cell is observed, and its lattice constant isa = 0.3586 nm. The preferred orientation is observed on the Co-N films, CoN (200) plane, Co₄N (1 1 1) plane and -Co (002) plane parallel to the film surface, respectively. Saturation magnetization _s of Co-N sputtered film decreases from 160 to 1.7 e.m.u. g^–1 with increasing content of N from 0 to 21.7 at%, and coercive force_I H _c is the range of 43 to 5000e at room temperature.     

Preparation and properties of graft and block copolymers of poly(p-phenylene terephthalamide) with polybutadiene

Graft copolymers of polybutadiene (PBD) onto poly(p-phenylene terephthalamide) (PPTA) were prepared by the nucleophilic substitution of N-metalated PPTA with telechelic PBD having bromide end groups. Block copolymers were synthesized by the condensation reaction of telechelic PBD having acid chloride end groups with amino-group-terminated PPTA. The structure of these copolymers was identified by IR spectra. Graft and block copolymers contained PBD segments up to 85 wt % and 45 wt %, respectively. Thermomechanical analyses (TMA) proved the existence of distinctive primary absorption peak corresponding with T_g of PBD for both graft and block copolymers. The T_g's of both types of the copolymers were further ascertained by the DSC curves. TMA curves suggested that the microphase separation occurred between PPTA and PBD. The incorporation of PPTA segments into PBD increased the decomposition temperature compared with the blend polymer composed of PPTA and PBD with the same composition.     

Preparation of poly(p-phenylene terephthalamide)/poly(vinyl chloride) molecular composite and its thermal and mechanical properties

Poly(p-phenylene terephthalamide) (PPTA) was blended with poly(vinyl chloride) (PVC) by solution-blending method. PPTA was metalated for dissolving in dimethyl sulfoxide. Dimethyl sulfoxide was used as a common solvent. In PPTA/PVC composite, PPTA accelerated the thermal degradation of PVC. PPTA molecules are aggregated as microfibrillar form in PVC matrix. Such microfibrils are dispersed homogeneously in PVC matrix, according to polarizing microscopic observation. The average diameter of the microfibrils becomes smaller in the composite with lower content of PPTA. In the surface region of PPTA microfibrils the intermolecular hydrogen bonds between C? Cl of PVC and N? H of PPTA are formed. Young's modulus and the yield stress at room temperature were higher in the composites than those in PVC. The modulus of the composites was higher, especially at the high temperatures above their glass transition temperatures, than that in PVC. The temperature dependence of modulus can be calculated by using the mechanical model equivalent to the quasi-3-dimensional microfibrillar model which will be approximately applied to the composite structure. It becomes apparent that the modulus of the PPTA microfibrils evaluated by using the mechanical model is higher in the higher molecular weight PPTA.     

Characterization and application of polypropylene films modified with stimuli‐sensitive copolymers with an Ar‐plasma postpolymerization technique

Surface‐modified polypropylene (PP) films with thermally and photochemically sensitive copolymers consisting of N‐(2‐hydroxypropyl)methacrylamide (HPMA) and 4‐(4‐methoxyphenylazo)phenyl methacrylate (MPAP), poly(HPMA‐co‐MPAP)‐g‐PP (abbreviated g‐PP) film, were prepared by graft copolymerization with an Ar‐plasma postpolymerization technique. The surfaces of the g‐PP films were characterized by means of X‐ray photoelectron spectroscopy; the percentage grafting of poly(HPMA‐co‐MPAP) with a number‐average molecular weight of 3.28 × 10⁴ was 7.12%, and the molar ratio of HPMA–MPAH in the copolymer was 0.75:0.25. The stimuli‐sensitive adsorption of albumin and polystyrene microspheres on the g‐PP film was also measured. © 2003 Wiley Periodicals, Inc. J Appl Polym Sci 90: 143–148, 2003     

Reliability and mechanical durability tests of flexible OLED with ALD coating

To improve the reliability and mechanical durability of a flexible organic light‐emitting diode display, the entire flexible display is coated with an aluminum oxide film by atomic layer deposition (ALD). Because the step coverage of ALD is excellent, the AlO_x film was deposited not only on the front and back surfaces but also on the side surfaces of the display. A high‐temperature and high‐humidity preservation test, repetitive bending tests, and a pencil hardness test were conducted on the flexible display with ALD‐AlO_x coating. The display survived 500 h of a 65°C, 95% preservation test, endured a 100,000‐time repetitive bending test with a curvature radius of 4 mm, and was found to have a pencil hardness of 4H.     

Generalized multiplicative stochastic processes arising from one-dimensional maps with noise

Artificial Life and Robotics - We propose a class of generalized multiplicative stochastic processes obtained by introducing an endo-perspective into one-dimensional maps with additive noise. We...