Annu Int Conf IEEE Eng Med Biol Soc
November 2021
This paper describes the application of a proposed spiral coil to the transformer of a transcutaneous energy transfer system for a totally implantable artificial heart. To reduce the number of rectifier components in the power receiving circuit, the shape of the power receiving transformer was reviewed. The results indicated that the power transmission efficiency between the transformers was almost the same as that of the receiving transformer with the same shape.
View Article and Find Full Text PDFThe discharged state affects the charge transfer resistance of lithium-ion secondary batteries (LIBs), which is referred to as the depth of discharge (DOD). To understand the intrinsic charge/discharge property of LIBs, the DOD-dependent charge transfer resistance at the solid-liquid interface is required. However, in a general composite electrode, the conductive additive and organic polymeric binder are unevenly distributed, resulting in a complicated electron conduction/ion conduction path.
View Article and Find Full Text PDFβ-Site amyloid precursor protein cleaving enzyme 1 (BACE1) has been pursued as a prime target for the treatment of Alzheimer's disease (AD). In this report, we describe the discovery of BACE1 inhibitors with a 1-amino-3,4-dihydro-2,6-naphthyridine scaffold. Leveraging known inhibitors 2a and 2b, we designed the naphthyridine-based compounds by removing a structurally labile moiety and incorporating pyridine rings, which showed increased biochemical and cellular potency, along with reduced basicity on the amidine moiety.
View Article and Find Full Text PDFBACE1 is an attractive target for disease-modifying treatment of Alzheimer's disease. BACE2, having high homology around the catalytic site, poses a critical challenge to identifying selective BACE1 inhibitors. Recent evidence indicated that BACE2 has various roles in peripheral tissues and the brain, and therefore, the chronic use of nonselective inhibitors may cause side effects derived from BACE2 inhibition.
View Article and Find Full Text PDFAccumulation of amyloid β peptides (Aβ) is thought to be one of the causal factors of Alzheimer's disease (AD). The aspartyl protease β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is the rate-limiting protease for Aβ production, and therefore, BACE1 inhibition is a promising therapeutic approach for the treatment of AD. Starting with a dihydro-1,3-thiazine-based lead, Compound J, we discovered atabecestat (JNJ-54861911) as a centrally efficacious BACE1 inhibitor that was advanced into the EARLY Phase 2b/3 clinical trial for the treatment of preclinical AD patients.
View Article and Find Full Text PDFThe β-site amyloid precursor protein cleaving enzyme 1 (BACE1, also known as β-secretase) is a promising target for the treatment of Alzheimer's disease. A pK lowering approach over the initial leads was adopted to mitigate hERG inhibition and P-gp efflux, leading to the design of 6-CF dihydrothiazine 8 (N-(3-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-thiazin-4-yl)-4-fluorophenyl)-5-cyanopicolinamide). Optimization of 8 led to the discovery of 15 (N-(3-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-thiazin-4-yl)-4-fluorophenyl)-5-(fluoromethoxy)pyrazine-2-carboxamide) with an excellent balance of potency, hERG inhibition, P-gp efflux, and metabolic stability.
View Article and Find Full Text PDFGenetic evidence points to deposition of amyloid-β (Aβ) as a causal factor for Alzheimer's disease. Aβ generation is initiated when β-secretase (BACE1) cleaves the amyloid precursor protein. Starting with an oxazine lead , we describe the discovery of a thiazine-based BACE1 inhibitor with robust Aβ reduction in vivo at low concentrations, leading to a low projected human dose of 14 mg/day where achieved sustained Aβ reduction of 80% at trough level.
View Article and Find Full Text PDFBACE1 inhibitors hold potential as agents in disease-modifying treatment for Alzheimer's disease. BACE2 cleaves the melanocyte protein PMEL in pigment cells of the skin and eye, generating melanin pigments. This role of BACE2 implies that nonselective and chronic inhibition of BACE1 may cause side effects derived from BACE2.
View Article and Find Full Text PDFβ-Secretase (BACE1) has an essential role in the production of amyloid β peptides that accumulate in patients with Alzheimer's disease (AD). Thus, inhibition of BACE1 is considered to be a disease-modifying approach for the treatment of AD. Our hit-to-lead efforts led to a cellular potent 1,3-dihydro-oxazine 6, which however inhibited hERG and showed high P-gp efflux.
View Article and Find Full Text PDFAccumulation of Aβ peptides is a hallmark of Alzheimer's disease (AD) and is considered a causal factor in the pathogenesis of AD. β-Secretase (BACE1) is a key enzyme responsible for producing Aβ peptides, and thus agents that inhibit BACE1 should be beneficial for disease-modifying treatment of AD. Here we describe the discovery and optimization of novel oxazine-based BACE1 inhibitors by lowering amidine basicity with the incorporation of a double bond to improve brain penetration.
View Article and Find Full Text PDFPurpose: Many forestry workers who use chain-saws suffer from low back pain. Previous studies have reported that low back pain is related to the working postures while felling a tree with a using chain-saws. However, no previous study has investigated trunk muscle activities during work.
View Article and Find Full Text PDFMps1, also known as TTK, is a dual-specificity kinase that regulates the spindle assembly check point. Increased expression levels of Mps1 are observed in cancer cells, and the expression levels correlate well with tumor grade. Such evidence points to selective inhibition of Mps1 as an attractive strategy for cancer therapeutics.
View Article and Find Full Text PDFMonopolar spindle 1 (Mps1) is an attractive oncology target due to its high expression level in cancer cells as well as the correlation of its expression levels with histological grades of cancers. An imidazo[1,2-a]pyrazine 10a was identified during an HTS campaign. Although 10a exhibited good biochemical activity, its moderate cellular as well as antiproliferative activities needed to be improved.
View Article and Find Full Text PDFThe electromagnetic compatibility of implantable or wearable medical devices has often been evaluated using human phantoms to electrically mimic biological tissues. However, no currently existing test fixture can measure the electrical characteristics of gel-like materials. In this paper, we report the development of a new test fixture that consists of a coaxial tube whose outer conductor is divided along the axial direction into two sections, which facilitates filling and removal of gel-like materials in order to measure their electrical characteristics.
View Article and Find Full Text PDFAnnu Int Conf IEEE Eng Med Biol Soc
August 2015
Human body communication (HBC) is a new communication technology that has presented potential applications in health care and elderly support systems in recent years. In this study, which is focused on a wearable transmitter and receiver for HBC in a body area network (BAN), we performed electromagnetic field analysis and simulation using the finite difference time domain (FDTD) method with various models of the human body. Further we redesigned a number of impedance-matched electrodes to allow transmission without stubs or transformers.
View Article and Find Full Text PDFAnnu Int Conf IEEE Eng Med Biol Soc
August 2015
Transcutaneous energy transmission is useful for improving patient quality of life and for supplying energy to implantable devices noninvasively. To supply highly efficient energy transmission through the skin, it is necessary to increase the coupling factor between the coils and increase the inductance of each coil. In this study, the optimal shape required for the coils to increase the coupling factor was investigated.
View Article and Find Full Text PDFFor further investigation of BACE1 inhibitors using conformational restriction with sp(3) hybridized carbon, we applied this approach to 6-substituted aminopyrimidone derivatives 3 to improve the inhibitory activity by reducing the entropic energy loss upon binding to BACE1. Among eight stereoisomers synthesized, [trans-(1'R,2'R),6S] isomer 6 exhibited the best BACE1 inhibitory activity, which was statistically superior to that of the corresponding ethylene linker compound (R)-3. Combinational examinations of the binding mode of 6 were performed, which included isothermal titration calorimetry (ITC), X-ray crystallographic structure analysis and theoretical calculations, to clarify the effect of our conformational restriction approach.
View Article and Find Full Text PDFMonopolar spindle 1 (Mps1) is essential for centrosome duplication, the spindle assembly check point, and the maintenance of chromosomal instability. Mps1 is highly expressed in cancer cells, and its expression levels correlate with the histological grades of cancers. Thus, selective Mps1 inhibitors offer an attractive opportunity for the development of novel cancer therapies.
View Article and Find Full Text PDFTo improve the efficacy of the conformationally restricted BACE1 inhibitors, structural modifications were investigated using two strategies: (a) modification of the terminal aromatic ring and (b) insertion of a spacer between the aromatic rings. In the latter approach, another type of inhibitor 17 bearing an ethylene spacer between two aromatic rings was found to exhibit good BACE1 inhibitory activity, while the corresponding conformationally unrestricted compound 25 showed no activity. This result revealed an interesting effect of a conformational restriction with a cyclopropane ring.
View Article and Find Full Text PDFImprovement of a drug's binding activity using the conformational restriction approach with sp³ hybridized carbon is becoming a key strategy in drug discovery. We applied this approach to BACE1 inhibitors and designed four stereoisomeric cyclopropane compounds in which the ethylene linker of a known amidine-type inhibitor 2 was replaced with chiral cyclopropane rings. The synthesis and biologic evaluation of these compounds revealed that the cis-(1S,2R) isomer 6 exhibited the most potent BACE1 inhibitory activity among them.
View Article and Find Full Text PDFMonopolar spindle 1 (Mps1) is an attractive cancer drug target due to the important role that it plays in centrosome duplication, the spindle assembly checkpoint, and the maintenance of chromosomal stability. A design based on JNK inhibitors with an aminopyridine scaffold and subsequent modifications identified diaminopyridine 9 with an IC50 of 37 nM. The X-ray structure of 9 revealed that the Cys604 carbonyl group of the hinge region flips to form a hydrogen bond with the aniline NH group in 9.
View Article and Find Full Text PDFWhen patients are fitted with a totally implantable artificial heart (TAH), they need to be implanted with two additional devices: one for the transmission of energy and one for information. However, this is a cumbersome process that affects the quality of life of the recipient. Therefore, we investigated the use of electromagnetic coupling for the transmission of energy and information and the possibility of unifying two transcutaneous transformers for the simultaneous transmission of energy and information.
View Article and Find Full Text PDFTranscutaneous energy transmission (TET) that uses electromagnetic induction between the external and internal coils of a transformer is the most promising method to supply driving energy to a totally implantable artificial heart without invasion. Induction-heating (IH) cookers generate magnetic flux, and if a cooker is operated near a transcutaneous transformer, the magnetic flux generated will link with the external and internal coils of the transcutaneous transformer. This will affect the performance of the TET and the artificial heart system.
View Article and Find Full Text PDFProc Natl Acad Sci U S A
April 2008
The oxidation of thiol groups in proteins is a common event in biochemical processes involving disulfide bond formation and in response to an increased level of reactive oxygen species. It has been widely accepted that the oxidation of a cysteine side chain is initiated by the formation of cysteine sulfenic acid (Cys-SOH). Here, we demonstrate a mechanism of thiol oxidation through a hypervalent sulfur intermediate by presenting crystallographic evidence from an archaeal peroxiredoxin (Prx), the thioredoxin peroxidase from Aeropyrum pernix K1 (ApTPx).
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