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.     

Polarity Effect and Electromagnetic Radiation of Partial Discharge Accompanying Growth of Electrical Tree

We have investigated the characteristics of radiated electromagnetic (EM) waves from positive and negative partial discharges (PD) in epoxy resin and cross‐linked polyethylene. We found that there is a correlation among the EM level from PD, the positive PD current, and electrical trees. Therefore, the growth of an electrical tree produces a lot of positive PD. We have also investigated the characteristics of the frequency region of EM waves from PD in air, insulating oil, and liquid epoxy in addition to the above insulators. EM waves were detected in the frequency region of 40 MHz to 300 MHz from positive and negative PD in epoxy resin and cross‐linked polyethylene. EM waves were also detected in the frequency region of 40 MHz to 150 MHz from positive and negative PD in air. In the case of insulating oil and liquid epoxy, EM waves were detected in the frequency regions of 40 MHz to 150 MHz from positive PD, and 40 MHz to 250 MHz from negative PD. The frequency region differed depending on the material and the discharge polarity. Our investigation indicates that the cause is differences in electric field strength at the time of PD occurrence.     

Recovery of fluorocarbons in Japan as a measure for abating global warming

The objective of this study is to evaluate the potential for recovering fluorocarbons as measures for the abatement of global warming. In this study, we focused on the three different kinds of fluorocarbons: CFCs, HCFCs and HFCs, and targeted refrigerant use because of the availability of relevant data. We first estimated future fluorocarbon emissions from the targeted appliances; we next compared those emissions in the units of CO₂ equivalent to the level of CO₂ emissions in 1990 from a quantitative point of view. As the result of this study, it was found that fluorocarbon emissions in 1999 and 2010 would be equal to approximately 7 and 3% of the level of CO₂ emissions in 1990 respectively. Moreover, if we implement a 100% recovery rate in every recovery route, we can reduce a large amount of emissions which correspond to approximately 2–5% of the level of CO₂ emissions in 1990, even if we take into account the energy-related CO₂ emissions by the transportation and decomposition of fluorocarbons.     

Temporal Specificity of Extinction in Autoshaping.

Three experiments investigated the effects of varying the conditioned stimulus (CS) duration between training and extinction. Ring doves (Streptopelia risoria) were autoshaped on a fixed CS-unconditioned stimulus (US) interval and extinguished with CS presentations that were longer, shorter, or the same as the training duration. During a subsequent test session, the training CS duration was reintroduced. Results suggest that the cessation of responding during an extinction session is controlled by generalization of excitation between the training and extinction CSs and by the number of nonreinforced CS presentations. Transfer of extinction to the training CS is controlled by the similarity between the extinction and training CSs. Extinction learning is temporally specific. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Survey of switching techniques in high-speed networks and their performance

One of the most promising approaches for high speed networks for integrated service applications is fast packet switching, or ATM (asynchronous transfer mode). ATM can be characterized by very high speed transmission links and simple, hard-wired protocols within a network. To match the transmission speed of the network links, and to minimize the overhead due to the processing of network protocols, the switching of cells is done in hardware switching fabrics in ATM networks. A number of designs have been proposed for implementing ATM switches. Although many differences exist among the proposals, the vast majority of them are based on self-routeing multistage interconnection networks. This is because of the desirable features of multi-stage interconnection networks such as self-routeing capability and suitability for VLSI implementation. Existing ATM switch architectures can be classified into two major classes: blocking switches, where blockings of cells may occur within a switch when more than one cell contends for the same internal link, and non-blocking switches, where no internal blocking occurs. A large number of techniques have also been proposed to improve the performance of blocking and non-blocking switches. In this paper, we present an extensive survey of the existing proposals for ATM switch architectures, focusing on their performance issues.     

Analysis of T-cell receptor beta of the T-cell clones reactive to the human PDC-E2 163-176 peptide in the context of HLA-DR53 in patients with primary biliary cirrhosis

T-cell-mediated autoimmune mechanisms are considered to be involved in the pathogenesis of primary biliary cirrhosis (PBC). In the previous study, we identified the immunodominant T-cell epitope on the E2 component of pyruvate dehydrogenase complex (PDC-E2) in patients with PBC who have HLA-DRB4*0101. In this report, we revealed that the frequency of the T cells reactive to the human PDC-E2 163-176 peptide is significantly increased in the peripheral blood of patients with PBC as compared with healthy subjects. We also confirmed that these T cells were all restricted with HLA-DRB4*01 (DR53) by using HLA-DR-transfected L cells. These results together with the evidence that the immunodominant B-cell epitope overlaps with the human T-cell epitope of the PDC-E2 antigen indicate that the T cells reactive to this epitope are closely associated with the pathogenesis of PBC at least in patients who have HLA-DR53. Therefore, we analyzed the T-cell receptor (TCR) Vbeta sequence of the five different T-cell clones and the three T-cell clones derived from three patients with PBC and healthy subjects, respectively, which are reactive to the human PDC-E2 163-176 peptide in the context of HLA-DR53. The Vbeta- and the Jbeta-gene usages were diverse among the T-cell clones (Vbeta11-Jbeta1.4, Vbeta8-Jbeta1.2, Vbeta12-Jbeta2.1, Vbeta10-Jbeta1.5, and Vbeta20-Jbeta2.1) in patients with PBC. By contrast, in the third complementarity determining region (CDR3), G was frequently found and GXG or GXS motif was identified in all T-cell clones. Moreover, RGXG motif was found in three clones generated from two patients. In healthy subjects, the Vbeta- and the Jbeta-gene usages were also diverse, and GXG and RGXG motif were found. These results indicate that the T cells may recognize the ligand (the human PDC-E2 163-176 peptide/HLA-DR53 complex) using the limited motif in the CDR3 region and that the design of CDR3-specific immunotherapy would be possible using these motifs.     

Detection and modification of confusing color combinations for red‐green dichromats to achieve a color universal design

Color‐vision deficiency is a relatively common genetic condition, which often leads to the obstruction of necessary information in colored images. It is important to minimize such inconvenient effects in communication using colored images from a universal design perspective. The universal design principle stipulates that all environments and products should be usable by all people, regardless of age, physical attributes, and ability. This article proposes a method to detect color combinations in a given image that would confuse color dichromats, and suggests a way in which to modify them to make the image easily distinguishable for both normal and dichromatic observers. Confusing color combinations were detected based on a color‐difference calculation using simulations of how the color would appear to dichromats. The confusing colors were then modified based on the minimization of an evaluation function, which was defined as the sum of the degree of confusion and the degree of color change from the original image. Several colored images obtained by the proposed method were compared with the originals by red–green dichromatic observers who judged them to be clearer, thereby confirming that the proposed method was effective for color rendering for universal design. © 2008 Wiley Periodicals, Inc. Col Res Appl, 33, 203–211, 2008     

Effects of cysteinyl-leukotriene receptor antagonist, thromboxane A2 receptor antagonist, and thromboxane A2 synthetase inhibitor on antigen-induced bronchoconstriction in patients with asthma

BACKGROUND: Leukotriene (LT) and thromboxane A2 (TXA2) receptor antagonists have been used in the treatment of asthma. OBJECTIVES: We examined the effects of an LT receptor antagonist, TXA2 receptor antagonist, and TXA2 synthetase inhibitor on bronchoprovocation test (BPT) in patients with mild-to-moderate atopic asthma. METHODS: BPT was performed four times in each of six asthmatics. Development of the immediate asthmatic reaction (IAR) and late asthmatic reaction (LAR) was confirmed on the first BPT (BPT1). After a 7-day washout period, an LT receptor antagonist (pranlukast, 450 mg/d), TXA2 receptor antagonist (seratrodast, 80 mg/d), or TXA2 synthetase inhibitor (ozagrel, 800 mg/d) was administered orally over 7 days at random using a cross-over method (BPT2-4). Blood levels of LTB4, LTC4, LTD4, 11-dehydrothromboxane B2, eosinophil cationic protein, and histamine were measured at reaction phases of pre-BPT, IAR, and LAR. RESULTS: Administration of pranlukast suppressed IAR by 80.5% (p < 0.0001) and LAR by 54.6% (p = 0.0391). Ozagrel significantly suppressed IAR by 39.5% (p = 0.0413), but the fall in FEV1 was >20% (21.56+/-4.173%). Seratrodast did not suppress IAR or LAR. Blood levels of chemical mediators did not correlate with the suppressive effects of the tested drugs. CONCLUSIONS: The LT receptor antagonist was considered to be the most effective. LT might play a more important role in the pathogenesis of asthma than TXA2. Our data showed that measurement of blood levels of chemical mediators is not useful in identifying the pathogenic mechanisms of asthma.     

MiR-10a in Pancreatic Juice as a Biomarker for Invasive Intraductal Papillary Mucinous Neoplasm by miRNA Sequencing

New biomarkers are needed to further stratify the risk of malignancy in intraductal papillary mucinous neoplasm (IPMN). Although microRNAs (miRNAs) are expected to be stable biomarkers, they can vary owing to a lack of definite internal controls. To identify universal biomarkers for invasive IPMN, we performed miRNA sequencing using tumor-normal paired samples. A total of 19 resected tissues and 13 pancreatic juice samples from 32 IPMN patients were analyzed for miRNA expression by next-generation sequencing with a two-step normalization of miRNA sequence data. The miRNAs involved in IPMN associated with invasive carcinoma were identified from this tissue analysis and further verified with the pancreatic juice samples. From the tumor-normal paired tissue analysis of the expression levels of 2792 miRNAs, 20 upregulated and 17 downregulated miRNAs were identified. In IPMN associated with invasive carcinoma (INV), miR-10a-5p and miR-221-3p were upregulated and miR-148a-3p was downregulated when compared with noninvasive IPMN. When these findings were further validated with pancreatic juice samples, miR-10a-5p was found to be elevated in INV (p = 0.002). Therefore, three differentially expressed miRNAs were identified in tissues with INV, and the expression of miR-10a-5p was also elevated in pancreatic juice samples with INV. MiR-10a-5p is a promising additional biomarker for invasive IPMN.