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271.
Yano S Kazuno H Sato T Suzuki N Emura T Wierzba K Yamashita J Tada Y Yamada Y Fukushima M Asao T 《Bioorganic & medicinal chemistry》2004,12(13):3443-3450
A series of novel 6-methylene-bridged uracil derivatives have been optimized for clinical use as the inhibitors of human thymidine phosphorylase (TP). We describe their synthesis and evaluation. Introduction of a guanidino or an amidino group enhanced the in vitro inhibitory activity of TP comparing with formerly reported inhibitor 1. Their selectivity for TP based on uridine phosphorylase inhibitory activity was also evaluated. Compound 2 (TPI) has been selected for clinical evaluation based on its strong TP inhibition and excellent modulation of 2'-deoxy-5-(trifluoromethyl)uridine (F(3)dThd) pharmacokinetics. As a result, TAS-102 (a combination of F(3)dThd and TPI) is currently in phase 1 clinical studies. 相似文献
272.
Genetic variation in levels of parasitism of hosts is an underlying assumption of studies of coevolution, but few such estimates are available from the field. We studied genetic variation in the abundance of the chewing louse Hirundoecus malleus on its barn swallow host Hirundo rustica. These parasites are directly transmitted and a test of genetic variation of parasite abundance would thus provide a particularly strong test. The prevalence and the abundance of the chewing lice did not differ significantly between adult male and female hosts. The resemblance in parasite intensity of H. malleus of offspring and their parents was positive and highly significant, and an analysis of extra-pair paternity in the host allowed partitioning of this resemblance between genetic and common environment effects. There was no significant resemblance in parasite intensity between extra-pair offspring and their foster parents, although the resemblance remained for within-pair offspring. This provides evidence for the abundance of directly transmitted parasites having an additive genetic component. We found no evidence of common environment effects as parents did not resemble each other with respect to lice abundance. 相似文献
273.
Chen J Anderson JB DeWeese-Scott C Fedorova ND Geer LY He S Hurwitz DI Jackson JD Jacobs AR Lanczycki CJ Liebert CA Liu C Madej T Marchler-Bauer A Marchler GH Mazumder R Nikolskaya AN Rao BS Panchenko AR Shoemaker BA Simonyan V Song JS Thiessen PA Vasudevan S Wang Y Yamashita RA Yin JJ Bryant SH 《Nucleic acids research》2003,31(1):474-477
Three-dimensional structures are now known within most protein families and it is likely, when searching a sequence database, that one will identify a homolog of known structure. The goal of Entrez's 3D-structure database is to make structure information and the functional annotation it can provide easily accessible to molecular biologists. To this end, Entrez's search engine provides several powerful features: (i) links between databases, for example between a protein's sequence and structure; (ii) pre-computed sequence and structure neighbors; and (iii) structure and sequence/structure alignment visualization. Here, we focus on a new feature of Entrez's Molecular Modeling Database (MMDB): Graphical summaries of the biological annotation available for each 3D structure, based on the results of automated comparative analysis. MMDB is available at: http://www.ncbi.nlm.nih.gov/Entrez/structure.html. 相似文献
274.
Di Lorenzo G Gangemi S Merendino RA Minciullo PL Cannavò SP Martinelli N Mansueto P Rini GB Corrocher R Pacor ML 《Mediators of inflammation》2003,12(2):123-125
The value of CD30 and the soluble circulating fragment of CD30 (sCD30) for atopic dermatitis (AD) remains unclear. In particular, little is known about the effects of age, duration of disease and Scoring Atopic Dermatitis index (SCORAD) on the levels of serum sCD30 in patients affected by AD. In the present study, we have analysed serum sCD30 levels of adult patients affected by AD. The study's population includes 18 non-smoking outpatients, with a diagnosis of AD. As a control group we studied 18 non-atopic subjects from laboratory staff, matched for sex and age. These subjects had no history of AD, urticaria or seasonal or perennial rhinitis or asthma, and had negative skin prick test to a panel of allergens. The sCD30 serum levels were clearly higher in patients affected by AD (14.2+/-9.0 IU/ml) than in healthy subjects (1.2+/-0.8 IU/ml) (p<0.001). No differences were observed between males and females affected by atopic dermatitis, regarding age, duration of disease and SCORAD. Significant correlations were found between serum levels of sCD30 levels and age (r=-0.55; 95% confidence interval (CI) for r (Fisher's z transformed)=-0.81 to -0.12; p=0.01), duration of the disease (months) (r=-0.64; 95% CI for r (Fisher's z transformed)=-0.85 to -0.24; p=0.004) and SCORAD (r=-0.74; 95% CI for r (Fisher's z transformed)=-0.89 to -0.42; p=0.004). As demonstrated by the close correlation with age, duration of disease and SCORAD, serum levels of sCD30 appear to be an additional marker for the follow-up of AD. 相似文献
275.
Sakai N Uchida Y Ohashi K Hibuse T Saika Y Tomari Y Kihara S Hiraoka H Nakamura T Ito S Yamashita S Matsuzawa Y 《Journal of lipid research》2003,44(6):1256-1262
The present study was designed to evaluate the metabolism of chylomicron and chylomicron remnants by measuring serum apolipoprotein B-48 (apoB-48) levels in 335 normolipidemic and 253 hyperlipidemic subjects using a novel ELISA system. The distribution of fasting serum apoB-48 levels in normolipidemic subjects varied widely, ranging from <1 to >24 microgram/ml (mean, 5.2 +/- 3.8 microgram/ml; median, 3.9 microgram/ml). Serum apoB-48 levels correlated with serum triglyceride (TG) concentrations (r = 0.45, P < 0.001), but not with total cholesterol levels. Serum apoB-48 levels were 7 to 18 times higher in patients with Type I, Type V, and Type III hyperlipidemia, and only slightly higher in patients with Type IIa, Type IIb, and Type IV hyperlipidemia, compared with normolipidemic subjects. The calculated apoB-48/TG ratio was elevated only in patients with dysbetalipoproteinemia (apoE2/2 phenotype). In normolipidemic subjects, oral fat loading resulted in about 2-fold increase in serum apoB-48 levels, with a peak level recorded at 3-4 h postloading, and then returned to the baseline level within 6 h. On the other hand, in patients with dysbetalipoproteinemia, serum apoB-48 levels did not change considerably. Our results indicate that serum apoB-48 is a very useful parameter for evaluating lipoprotein metabolism in exogenous pathways. 相似文献
276.
We study the optimal conservation effort for a population in a fluctuating environment. The survivorship of a population is affected by unpredictable environmental fluctuation (noise) and can be improved by conservation effort accompanied by a cost. The optimal effort level is the one that minimizes the total cost, defined as the weighted sum of the population extinction risk and the economic cost of conservation effort. The optimal effort depends on the variance and the probability distribution of the noise, the relative importance of the population's survival vs. the economic cost, the effectiveness of conservation effort, and the time scope over which we optimize. The analysis of dynamic programming illustrates that the choice of extinction risk function greatly affects the optimal effort level. The conservation effort level that is the best solution of a multiple-year optimization may be higher than that for the corresponding single-year optimization, if the population is relatively safe. However, the conservation level for the multiple-year optimization becomes lower than for the single-year optimization if the population is endangered. In a similar manner, the optimal conservation effort level for the problem with a short time scope is either higher or lower than that for the problem with a long time scope, depending on the extinction risk of the population. Next, for each parameter of the model, we define five different sensitivities of extinction probability or of the total cost. We then study the mean increase in the total cost caused by the uncertainty of parameters. To achieve the best conservation result, we need to invest the limited research effort to the parameter with the largest effect to the optimal effort level, rather than to those with large impacts on the extinction probability or on the total cost. The recommended policy should depend critically on the choice of the criterion to optimize, which shows the importance of theoretical study of the relationship in performing proper decision making in conservation practice. 相似文献
277.
Aspolin, a novel extremely aspartic acid-rich protein in fish muscle, promotes iron-mediated demethylation of trimethylamine-N-oxide 总被引:2,自引:0,他引:2
Takeuchi K Hatanaka A Kimura M Seki N Kimura I Yamada S Yamashita S 《The Journal of biological chemistry》2003,278(48):47416-47422
Trimethylamine-N-oxide (TMAO) is abundant in marine fish. Formaldehyde synthesis by TMAO demethylation during storage markedly deteriorates fish meat. In the present work, we cloned the extremely aspartic acid-rich proteins from skeletal muscle of a commercially important species, walleye pollack, in the course of molecular identification of trimethylamine-N-oxide demethylase (TMAOase). One of the cDNAs, designated as aspolin1, encodes an extremely aspartic acid-rich protein of 228 amino acids which is converted to the TMAOase after processing between Ala42 and Asp43. Mature aspolin1/TMAOase protein contains 179 Asp in 186 total amino acids. The other cDNA, designated as aspolin2, has a common nucleotide sequence with aspolin1 in the 5' part and encodes a protein which has an additional Asp polymer and a C-terminal cysteine-rich region. The amino acid sequence of the C-terminal cysteine-rich region of aspolin2 is highly homologous to the mammalian histidine-rich Ca2+-binding protein. Aspolin1/TMAOase and aspolin2 mRNA was most abundant in the skeletal muscle. A lower level of the mRNA was also detected in kidney, heart, spleen, and brain. Synthetic Asp polymer showed marked TMAOase activity in the presence of Fe2+, whereas a monomer and oligomers did not. Purified TMAOase protein bound to Fe2+ with low affinity, which may be responsible for the catalytic activity. Poly aspartic acid-Fe2+ complex generated after death would be involved in formaldehyde synthesis by the demethylation of TMAO during the storage of fish meat. 相似文献
278.
279.
The marine colonial hydroid Tubularia mesembryanthemum produces a morphologically unique dispersive stage, the actinula larva. Detailed observations were made on the behaviors and nematocyte dynamics of actinula larvae during attachment and morphogenesis by employing microscopic and time lapse video techniques. These observations produced four primary results. (1) Actinula larvae demonstrated two forms of attachment: temporary attachment by atrichous isorhiza (AI)-nematocysts discharged from the aboral tentacle (AT) tips-and permanent settlement by cement secretion from the columnar gland cells of the basal protrusion. (2) During larval settlement, numerous AIs were discharged from the AT tips with sinuous movement and rubbing of the tentacles onto the substrata, leading to "nematocyte-printing" around the settlement site. (3) Simultaneous with the discharge of the AIs, migration of stenoteles, desmonemes, and microbasic mastigophores occurred, resulting in a dramatic change of nematocyte composition in the ATs after larval settlement. This was in parallel with changes in larval behavior and the tentacle function. (4) Nematocyte-printing behavior during settlement could be recognized as metamorphic behavior responsible for irreversible changes in AT function, from attachment to feeding and defense. 相似文献
280.
Higuchi H Yamashita T Yoshikawa H Tohyama M 《Biochemical and biophysical research communications》2003,301(3):804-809
The neurotrophin receptor p75(NTR) mediates a wide variety of biological effects. Consistent with the function in controlling the survival and neurite formation, p75(NTR) is expressed during the developmental stages of the nervous system. Importantly, p75(NTR) is re-expressed in various pathological conditions and is suggested to contribute to the inhibition of neuronal regeneration and the death of the neurons. Here we develop a tool to knock down the expression of p75(NTR) by employing a small interfering RNA (siRNA). The siRNA for p75(NTR) effectively reduces the expression of endogenous p75(NTR) both in Schwann cells and dorsal root ganglion neurons in vitro. NGF-induced cell death in Schwann cells and the neurite retraction in DRG neurons induced by myelin-associated glycoprotein are attenuated by the siRNA. Inhibition of p75(NTR) in specific pathological conditions by the siRNA may provide a potential therapeutic agent. 相似文献