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111.
Based on the original spirodiketopiperazine design framework, further optimization of an orally available CCR5 antagonist was undertaken. Structural hybridization of the hydroxylated analog 4 derived from one of the oxidative metabolites and the new orally available non-hydroxylated benzoic acid analog 5 resulted in another potent orally available CCR5 antagonist 6a as a clinical candidate. Full details of a structure-activity relationship (SAR) study and ADME properties are presented.  相似文献   
112.
The calcium-sensing receptor antagonist (CaSR) has been recognized as a promising target of anabolic agents for treating osteoporosis. In the course of developing a new drug candidate for osteoporosis, we found tetrahydropyrazolopyrimidine derivative 1 to be an orally active CaSR antagonist that stimulated transient PTH secretion in rats. However, compound 1 showed poor physical and chemical stability. In order to work out this compound's chemical stability and further understand its in vivo efficacy, we focused on modifying the 2-position of the tetrahydropyrazolopyrimidine. As a result of chemical modification, we discovered (5R)-N-[1-ethyl-1-(4-ethylphenyl)propyl]-2,7,7-trimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide monotosylate 10m (TAK-075), which showed improved solubility, chemical stability, and in vivo efficacy. Furthermore, we describe that evaluating the active metabolite is important during repeated treatment with short-acting CaSR antagonists.  相似文献   
113.
114.
The host-selective toxin victorin is produced by Cochliobolus victoriae, the causal agent of victoria blight of oats. Victorin has been shown to bind to the P protein of the glycine decarboxylase complex (GDC) in mitochondria, and induce defense-related responses such as phytoalexin synthesis, extracellular alkalization and programmed cell death. However, evidence demonstrating that the GDC plays a critical role in the onset of cell death is still lacking, and the role of defense-like responses in the pathogenicity has yet to be elucidated. Here, cytofluorimetric analyses, using the fluorescein (VicFluor) or bovine serum albumin-fluorescein derivative of victorin (VicBSA), demonstrated that victorin-induced cell death occurs before these conjugates traverse the plasma membrane. As with native victorin, VicBSA clearly elicits apoptosis-like cell death, production of phytoalexin, extracellular alkalization, and generation of nitric oxide and reactive oxygen intermediates. These results suggest that the initial recognition of victorin takes place on the cell surface, not in mitochondria, and leads to the activation of a battery of victorin-induced responses. Pharmacological studies showed that extracellular alkalization is the essential regulator for both victorin- and VicBSA-induced cellular responses. We propose a model where victorin may kill the host cell by activating an HR-like response, independent of the binding to the GDC, through ion fluxes across the plasma membrane.  相似文献   
115.
Several strategies for mapping ventricular outflow tract tachycardia have been reported as useful indices for differentiating between those originating from the right and the left side. Recently, tissue tracking imaging (TTI) has been demonstrated as a novel non-invasive modality for identifying the origin of outflow tract tachycardias. Tissue tracking imaging is an ultrasonographic technique that measures the myocardial motion amplitude towards the transducer in each region during systole, identifying regional myocardial displacement on the basis of myocardial velocities using color Doppler myocardial imaging principles. In this technique, the origin of the arrhythmia could be recognized as the site where the earliest color-coded signal (ECCS) appeared on the myocardium at the onset of the systole. In preliminary studies this modality was found to be useful in differentiating outflow tract ventricular tachycardias. ECCS was always found below or at the level of the pulmonary valve in all arrhythmias which could be ablated from the right ventricular outflow tract, while in those where the ECCS was above and close to the pulmonary valve it could be ablated from the left sinus of valsalva. These results indicate that TTI can provide detailed and accurate information on the arrhythmia origin of outflow tract tachycardia and may be useful for differentiating between an outflow tract tachycardia originating from the LV epicardium remote from the LSV and that from the LSV. Newer advances in echocardiographic technologies like high resolution, high frame rate real time three dimensional echocardiography with speckle tracking may further improve the precise localization of arrhythmias in the future.  相似文献   
116.
Preparation of specific lineages at high purities from embryonic stem (ES) cells requires both selective culture conditions and markers to guide and monitor the differentiation. In this study, we distinguished definitive and visceral endoderm by using a mouse ES cell line that bears the gfp and human IL2R alpha (also known as CD25) marker genes in the goosecoid (Gsc) and Sox17 loci, respectively. This cell line allowed us to monitor the generation of Gsc+ Sox17+ definitive endoderm and Gsc- Sox17+ visceral endoderm and to define culture conditions that differentially induce definitive and visceral endoderm. By comparing the gene expression profiles of definitive and visceral endoderm, we identified seven surface molecules that are expressed differentially in the two populations. One of the seven markers, Cxcr4, to which a monoclonal antibody is available allowed us to monitor and purify the Gsc+ population from genetically unmanipulated ES cells under the condition that selects definitive endoderm.  相似文献   
117.
The infective third-stage larvae (L3s) of Strongyloides ratti, a parasitic nematode in rodents, showed two types of chemokinesis on a gradient of sodium chloride (NaCl) in an in vitro agarose tracking assay. The types were a consistent directional avoidance behavior under unfavorable environmental conditions and a reduced avoidance behavior under favorable conditions. We examined the effects of treatments with glycolytic enzymes and lectins by analyzing the avoidance behavior. L-Fucose dehydrogenase, hyaluronidase, beta-glucosidase, alpha-mannosidase, beta-galactosidase, concanavalin A, wheat germ agglutinin and soybean agglutinin exhibited inhibitory or enhancive effects on chemokinesis. We also confirmed the sites of the amphids of L3s aside from the mouth at the anterior end by scanning electron microscopy, and that concanavalin A-binding sites existed in the vicinity of the amphids using lectin-histochemistry. The carbohydrate moieties in the amphids of S. ratti L3s may play an important role as chemosensors in perceiving environmental cues.  相似文献   
118.
The effect of an inorganic additive on the methane production from NH(4+)-rich organic sludge during anaerobic digestion was investigated using different kinds of inorganic adsorbent zeolites (mordenite, clinoptilolite, zeolite 3A, zeolite 4A), clay mineral (vermiculite), and manganese oxides (hollandite, birnessite). The additions of inorganic materials resulted in significant NH4+ removals from the natural organic sludge ([NH4+]=1, 150 mg N/l), except for the H-type zeolite 3A and birnessite. However, an enhanced methane production was only achieved using natural mordenite. Natural mordenite also enhanced the methane production from the sludge with a markedly high NH4+ concentration (4500 mg N/l) during anaerobic digestion. Chemical analyses of the sludge after the digestion showed considerable increases in the Ca2+ and Mg2+ concentrations in the presence of natural mordenite, but not with synthetic zeolite 3A. The effect of Ca2+ or Mg2+ addition on the methane production was studied using Na(+)-exchanges mordenite and Ca2+ or Mg(2+)-enriched sludge. The simultaneous addition of Ca2+ ions and Na(+)-exchanged mordenite enhanced the methane production; the amount of produced methane was about three times greater than that using only the Na(+)-exchanged mordenite. In addition, comparing the methane production by the addition of natural mordenite or Ca2+ ions, the methane production with natural mordenite was about 1.7 times higher than that with only Ca2+ ions. The addition of 5% and 10% natural mordenite were suitable condition for obtaining a high methane production. These results indicated that the Ca2+ ions, which are released from natural mordenite by a Ca2+/NH4+ exchange, enhanced the methane production of the organic waste at a high NH4+ concentration. Natural mordenite has a synergistic effect on the Ca2+ supply as well on the NH4+ removal during anaerobic digestion, which is effective for the mitigation of NH4+ inhibition against methane production.  相似文献   
119.
A rat model for human minimal change nephropathy was obtained by the intravenous injection of adriamycin (ADR) at 5 mg/kg. By using an in vivo electron paramagnetic resonance (EPR) spectrometer operating at 700 MHz, the temporal changes in signal intensities of a nitroxide radical, 4-hydroxyl-2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPOL), in the kidneys of rats with ADR nephropathy were investigated. The decay rate of the EPR signal intensity obtained in the kidney is indicative of the renal reducing ability. It was found that the reducing ability in the kidney declined on the 7th day after ADR administration and recovered after the 14th day. Impairment of the reducing ability occurred before the appearance of continuous urinary protein. The in vitro EPR study showed that this impairment of in vivo renal reducing ability is related to impairment of the reducing ability in the mitochondria.  相似文献   
120.
Distribution of photosystem II (PSII) extrinsic proteins was examined using antibodies raised against various extrinsic proteins from different sources. The results showed that a glaucophyte (Cyanophora paradoxa) having the most primitive plastids contained the cyanobacterial-type extrinsic proteins (PsbO, PsbV, PsbU), and the primitive red algae (Cyanidium caldarium) contained the red algal-type extrinsic proteins (PsO, PsbQ', PsbV, PsbU), whereas a prasinophyte (Pyraminonas parkeae), which is one of the most primitive green algae, contained the green algal-type ones (PsbO, PsbP, PsbQ). These suggest that the extrinsic proteins had been diverged into cyanobacterial-, red algal- and green algal-types during early phases of evolution after a primary endosymbiosis. This study also showed that a haptophyte, diatoms and brown algae, which resulted from red algal secondary endosymbiosis, contained the red algal-type, whereas Euglena gracilis resulted from green algal secondary endosymbiosis contained the green algal-type extrinsic proteins, suggesting that the red algal- and green algal-type extrinsic proteins have been retained unchanged in the different lines of organisms following the secondary endosymbiosis. Based on these immunological analyses, together with the current genome data, the evolution of photosynthetic oxygen-evolving PSII was discussed from a view of distribution of the extrinsic proteins, and a new model for the evolution of the PSII extrinsic proteins was proposed.  相似文献   
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