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951.
Spiro-pyrazolidinedione derivatives without quaternary chiral center were discovered by structure-based drug design and characterized as potent acetyl-CoA carboxylase (ACC) inhibitors. The high metabolic stability of the spiro-pyrazolo[1,2-a]pyridazine scaffold and enhancement of the activity by incorporation of a 7-methoxy group on the benzothiophene core successfully led to the identification of compound 4c as an orally bioavailable and highly potent ACC inhibitor. Oral administration of 4c significantly decreased the values of the respiratory quotient in rats, indicating the stimulation of fatty acid oxidation.  相似文献   
952.
953.
Optimization starting with our lead compound 1 (IC50 = 4.9 nM) led to the identification of pyrrolidinyl phenylurea derivatives. Further modification toward improvement of the bioavailability provided (R)-1-(1-((6-fluoronaphthalen-2-yl)methyl)pyrrolidin-3-yl)-3-(2-(2-hydroxyethoxy)phenyl)urea 32 (IC50 = 1.7 nM), a potent and orally active CCR3 antagonist.  相似文献   
954.
Sakai A  Takasu K  Sawada M  Suzuki H 《PloS one》2012,7(2):e32268
The mammalian tachykinins, substance P (SP) and hemokinin-1 (HK-1), are widely distributed throughout the nervous system and/or peripheral organs, and function as neurotransmitters or chemical modulators by activating their cognate receptor NK(1). The TAC1 gene encoding SP is highly expressed in the nervous system, while the TAC4 gene encoding HK-1 is uniformly expressed throughout the body, including a variety of peripheral immune cells. Since TAC4 mRNA is also expressed in microglia, the resident immune cells in the central nervous system, HK-1 may be involved in the inflammatory processes mediated by these cells. In the present study, we found that TAC4, rather than TAC1, was the predominant tachykinin gene expressed in primary cultured microglia. TAC4 mRNA expression was upregulated in the microglia upon their activation by lipopolysaccharide, a well-characterized Toll-like receptor 4 agonist, while TAC1 mRNA expression was downregulated. Furthermore, both nuclear factor-κB and p38 mitogen-activated protein kinase intracellular signaling pathways were required for the upregulation of TAC4 mRNA expression, but not for the downregulation of TAC1 mRNA expression. These findings suggest that HK-1, rather than SP, plays dominant roles in the pathological conditions associated with microglial activation, such as neurodegenerative and neuroinflammatory disorders.  相似文献   
955.
Adopting an unusual posture can sometimes give rise to paradoxical experiences. For example, the subjective ordering of successive unseen tactile stimuli delivered to the two arms can be affected when people cross them. A growing body of evidence now highlights the role played by the parietal cortex in spatio-temporal information processing when sensory stimuli are delivered to the body or when actions are executed; however, little is known about the neural basis of such paradoxical feelings resulting from such unusual limb positions. Here, we demonstrate increased fMRI activation in the left posterior parietal cortex when human participants adopted a crossed hands posture with their eyes closed. Furthermore, by assessing tactile temporal order judgments (TOJs) in the same individuals, we observed a positive association between activity in this area and the degree of reversal in TOJs resulting from crossing arms. The strongest positive association was observed in the left intraparietal sulcus. This result implies that the left posterior parietal cortex may be critically involved in monitoring limb position and in spatio-temporal binding when serial events are delivered to the limbs.  相似文献   
956.
Timing of cell differentiation is strictly controlled and is crucial for normal development and stem cell differentiation. However, underlying mechanisms regulating differentiation timing are fully unknown. Here, we show a molecular mechanism determining differentiation timing from mouse embryonic stem cells (ESCs). Activation of protein kinase A (PKA) modulates differentiation timing to accelerate the appearance of mesoderm and other germ layer cells, reciprocally correlated with the earlier disappearance of pluripotent markers after ESC differentiation.?PKA activation increases protein expression of G9a, an H3K9 methyltransferase, along with earlier H3K9 dimethylation and DNA methylation in Oct3/4 and Nanog gene promoters. Deletion of G9a completely abolishes PKA-elicited acceleration of differentiation and epigenetic modification. Furthermore, G9a knockout mice show prolonged expressions of?Oct3/4 and Nanog at embryonic day 7.5 and delayed development. In this study, we demonstrate molecular machinery that regulates timing of multilineage differentiation by linking signaling with epigenetics.  相似文献   
957.
The family Cecidomyiidae (Diptera) including about 6100 described species displays diverse feeding habits. The tribe Asphondyliini is a well‐circumscribed monophyletic group of Cecidomyiidae and all species are known as gall inducers. Species belonging to this tribe exhibit fascinating ecological traits such as host alternation, polyphagy, extended diapause, induction of dimorphic galls and association with fungal symbionts. For these reasons, biogeographical and phylogenetic studies of Asphondyliini are of interest in elucidating the evolution of these traits, and particularly the processes of host‐range expansion, host‐plant shift and shifts in gall‐bearing organs. In order to facilitate further evolutionary studies of Asphondyliini, I review studies of systematics, biogeography, phylogeny, speciation, cytology, behavior, ecology, physiology, biological interaction and economic importance in this tribe.  相似文献   
958.
Tadpoles of Rana grylio were raised as edible frogs in fishponds of Guanqiao in Wuhan City, Hubei, China, during cyanobacterial blooms from June to October. The dominant cyanobacterial species was Microcystis, which was found to be lethally toxic by intraperitoneal (i.p.) mouse bioassay. Little is known about the effect of tadpoles on toxic cyanobacterial blooms. To evaluate the potential of the tadpoles to graze on cyanobacterial blooms, the tadpoles were fed on Microcystis collected from the field in the laboratory. The Microcystis cells decreased from 1.19 × 107 cells mL?1 to 3.23 × 106 cells mL?1, with a sharp reduction of 73% of the initial Microcystis population observed in the first 24 h after introduction of the tadpoles. The ponds containing tadpoles had a markedly lower density of Microcystis than those lacking tadpoles. Tadpoles exposed to either cultured Microcystis aeruginosa (NIES–90, 2.768 µg microcystins mg–1 dw–1) cells or lysed M. aeruginosa cells grew well, however, indicating that they were unaffected by Microcystis toxins. We found a significant increase in tadpole body weight after feeding on either field Microcystis or cultured M. aeruginosa. The mean increase in individual body weight was 20 mg day?1 when fed on Microcystis from the pond, and 7 mg day?1 when fed on M. aeruginosa from culture. Our study strongly suggested that there is a direct trophic relationship between R. grylio tadpoles and toxic Microcystis blooms and they possess the potential to graze on toxic Microcystis. The results imply that R. grylio tadpoles may play an important ecological role in reducing toxic cyanobacterial blooms caused by Microcystis.  相似文献   
959.
Red tides of Chattonella spp. have caused continuous damage to Japanese aquaculture, however, the life cycle of this organism remains incompletely understood. To further investigate this matter, we assessed genotypes at 14 microsatellite markers in three varieties of Chattonella marina, viz., C. marina var. antiqua, C. marina var. marina, and C. marina var. ovata, to establish whether Chattonella undergoes asexual diploidization or sexual reproduction. After genotyping 287 strains of C. marina, all but one of these strains was shown to be heterozygous for at least some loci, and thus, in the diploid state, suggesting that Chattonella strains undergo sexual reproduction. In addition, we performed single‐cell amplification on ‘small cells’ that are derived from vegetative cells under dark and low‐nutrient conditions. The results indicated the existence of two types of small cells. The ‘Small cell Type 1’ was found to be heterozygous, genotypically equivalent to the vegetative cells, and is therefore diploid. These small cells may change to resting cells (cysts) directly. The ‘Small cell Type 2’ was homozygous at all analyzed loci, suggesting that these small cells are haploid and may be derived by meiosis. As fusion between small cells has previously been observed, the ‘Small cell Type 2’ may be the gamete of Chattonella. We present a construct of the full life cycle of Chattonella marina based on our own and previous results.  相似文献   
960.
Cylindrospermopsis raciborskii is a common, bloom‐forming, planktonic, freshwater cyanobacterium. Toxic populations producing cylindrospermopsin can cause water‐safety problems. Although C. raciborskii is distributed worldwide, the presence of cylindrospermopsin‐producing strains of C. raciborskii was initially reported only in Australia and recently in Thailand. Here, we report the isolation of a toxic strain of C. raciborskii (ISG9) from a freshwater sample collected in Okinawa in 2008. This is the first report describing toxin expression in this species in Japan, detected from a subtropical area. The C. raciborskii species is known to produce cylindrospermopsin as a dominant toxin; however, in this new isolate, the dominant toxin expressed was deoxy‐cylindrospermopsin. The discovery of a toxic strain of C. raciborskii in southern Japan emphasizes the need for basic monitoring schemes for this species in water supplies located in the temperate regions of Japan because of its possible expansion and distribution to other geographic areas.  相似文献   
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