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.     

Monomeric, monovalent derivative of Maackia amurensis leukoagglutinin. Preparation and application to the study of cell surface glycoconjugates by flow cytometry

A stable subunit of Maackia amurensis leukoagglutinin (MMAL) was prepared by the selective reduction of disulfide bridges between the subunits followed by alkylation with 4-vinylpyridine. MMAL failed to precipitate fetuin, whereas it retained its ability to bind to the same glycoprotein coated on a plastic plate, indicating the monovalency of this derivative. This binding to immobilized fetuin was inhibited by a haptenic sugar, Neu5Ac alpha 2-3lactose, with the same inhibitory potency as against the native M. amurensis leukoagglutinin. Microscopic observation as well as flow cytometric analyses showed that Chinese hamster ovary cells were clearly stained with fluorescein isothiocyanate-labeled MMAL without any detectable agglutination. This staining was inhibited by the addition of fetuin or by the sugar chains of fetuin. Differences in the types of sialylated glycoconjugates on the cell surface of several cell lines were detected by the combined use of fluorescein isothiocyanate-labeled MMAL and the monomeric derivative of elderberry bark lectin (specific for the Neu5Ac alpha 2-6Gal/GalNAc sequence) by flow cytometry. These results demonstrate the usefulness of these monovalent derivatives of sialylated oligosaccharide-specific lectins as probes for the analysis of cell surface glycoconjugates containing sialic acid by the technique of flow cytometry.     

Endogenous adenosine exerts inhibitory effects upon the development of spreading depression and glutamate release induced by microdialysis with high K+ in rat hippocampus

Spreading depression (SD) is known to be involved in the N-methyl-D-aspartate receptor-mediated neuronal damage. In urethane-anesthetized rats, we examined the release of adenosine and glutamate during SD induced by microdialysis of high K+ perfusate through the hippocampal CA1 area. The effects of endogenous adenosine upon SD were studied by applying an adenosine antagonist, theophylline (1 mM) and by a simultaneous application of adenosine uptake blockers, dipyridamole (DPR) (100 microM) and nitrobenzylthioinosine (NBI) (50 microM). The dialysates were sampled every 5 or 10 min and analyzed by HPLC. SD was identified by flattening of background EEg and disappearance of population spikes recorded from the pyramidal cell layer of CA1 area by a glass microelectrode. Adenosine and glutamate release was enhanced significantly in association with the occurrence of SD. Theophylline increased the release of glutamate and the incidence of SD and decreased the latency of the SD occurrence. DPR+NBI decreased the release of glutamate and the occurrence of SD, but increased extracellular adenosine concentration. The effects of DPR+NBI were blocked by application of a selective antagonist of adenosine A1 receptor, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, 0.1 microM). These findings suggest that endogenous adenosine exerts inhibitory influences upon the development of SD and the glutamate release through the A1 receptor in rat hippocampus.     

A novel technique for a DC brushless motor without position sensors

A dc brushless motor is a kind of synchronous motor driven by an inverter and requires sensors to detect the rotor position. As one of the methods, the induced voltages of a brushless motor have been utilized in practice. However, there are some problems in this method, e.g., the motor can obtain insufficient torque due to the low induced voltages in a low-speed range. This paper proposes a new method which controls the inverter angular frequency ω₁ by using inherent characteristics wherein the torque current i_r is almost proportional to the internal phase angle φ where the primary flux of a synchronous motor is controlled to be constant. If the parameters of a motor are given exactly, the speed regulation is quite small and the transient characteristics with high response and high starting torque are obtained. Furthermore, it is possible to operate a synchronous motor in the field-weakening range. Here, the principle of the control method and the performance characteristics of a dc brushless motor having no position sensors are discussed. The simulation and the experimental results of the tested machine show that the proposed method is very useful for practical applications.     

Variable neighbourhood simulated annealing algorithm for capacitated vehicle routing problems

This article presents the variable neighbourhood simulated annealing (VNSA) algorithm, a variant of the variable neighbourhood search (VNS) combined with simulated annealing (SA), for efficiently solving capacitated vehicle routing problems (CVRPs). In the new algorithm, the deterministic ‘Move or not’ criterion of the original VNS algorithm regarding the incumbent replacement is replaced by an SA probability, and the neighbourhood shifting of the original VNS (from near to far by k← k+1) is replaced by a neighbourhood shaking procedure following a specified rule. The geographical neighbourhood structure is introduced in constructing the neighbourhood structures for the CVRP of the string model. The proposed algorithm is tested against 39 well-known benchmark CVRP instances of different scales (small/middle, large, very large). The results show that the VNSA algorithm outperforms most existing algorithms in terms of computational effectiveness and efficiency, showing good performance in solving large and very large CVRPs.     

A third-generation SPARC V9 64-b microprocessor

This quad-issue processor achieves 1-GHz operation through improved dynamic circuit techniques in critical paths and a more extensive on-chip memory system which scales in both bandwidth and latency. Critical logic paths use domino, delayed clocked domino, and logic embedded in dynamic flip-flops for minimum delay. A 64-KB sum-addressed memory data cache combines the address offset add with the cache decode, allowing the average memory latency to scale by more than the clock ratio. Memory bandwidth is improved by using wave pipelined SRAM designs for on-chip caches and a write cache for store traffic. Memory power is controlled without increased latency by use of delayed-reset logic decoders. The chip operates at 1000 MHz and dissipates less than 80 W from a 1.6-V supply. It contains 23 million transistors (12 million in RAM cells) on a 244 mm² die     

Optimization of parts scheduling in multiple cells considering intercell move using scatter search approach

This paper addresses the problem of parts scheduling in a cellular manufacturing system (CMS) by considering exceptional parts processed on machines located in multiple cells. To optimize the scheduling of parts as well as to minimize material handling between cells, the practice has to develop processing sequences for the parts in cells. A commonly chosen objective is to find part sequences within cells which results in a minimum tardiness. This paper proposes a nonlinear mathematical programming model of the problem by minimizing the total weighted tardiness in a CMS. To solve the mathematical model, a scatter search approach is developed, in which the common components of scatter search are redefined and redesigned so as to better fit the problem. This scatter search approach considers two different methods to generate diverse initial solutions and two improvement methods, and adopts the roulette wheel selection in the combination method to further expand the conceptual framework and implementation of the scatter search. The proposed approach is compared with the commercial solver CPLEX on a set of test problems, some of which are large dimensions. Computational results have demonstrated the effectiveness of this scatter search approach.     

Transcollicular approach to intrinsic tectal lesions

OBJECTIVE: We used a paramedian, infratentorial-supracerebellar, transcollicular approach to resect 11 intrinsic tectal lesions, including 8 tumors and 3 hematomas, in 11 patients. The route of access to the lesions was designed to minimize the anatomic and functional damage to the surrounding structures. METHODS: Access was through one superior colliculus in each of seven patients, through one inferior colliculus in each of two patients, and through the superior and inferior colliculi of one side in each of two patients. RESULTS: Of the eight tumors, three were totally resected, four were nearly totally resected, and one was partially resected. The preoperative ocular symptoms did not change in six of these eight patients and worsened in two, and the neurological deficits, except ocular symptoms, improved in two. All three hematomas were completely removed, along with abnormal blood vessels in the wall of the hematoma cavity; all three of these patients experienced neurological improvement. CONCLUSION: We conclude that the paramedian, infratentorial-supracerebellar, transcollicular approach permits safe removal of intrinsic tectal lesions. Resection of the superior or inferior colliculus or both on one side seems to be neurologically well tolerated.