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51.
Hamish S. Sutherland Amy S.T. Tong Peter J. Choi Daniel Conole Adrian Blaser Scott G. Franzblau Christopher B. Cooper Anna M. Upton Manisha U. Lotlikar William A. Denny Brian D. Palmer 《Bioorganic & medicinal chemistry》2018,26(8):1797-1809
Replacing the naphthalene C-unit of the anti-tuberculosis drug bedaquiline with a range of bicyclic heterocycles of widely differing lipophilicity gave analogs with a 4.5-fold range in clogP values. The biological results for these compounds indicate on average a lower clogP limit of about 5.0 in this series for retention of potent inhibitory activity (MIC90s) against M.tb in culture. Some of the compounds also showed a significant reduction in inhibition of hERG channel potassium current compared with bedaquiline, but there was no common structural feature that distinguished these. 相似文献
52.
Geoffrey J. Hayton Colin K. Pearson Jeremy R. Scaife Hamish M. Keir 《The Biochemical journal》1973,131(3):499-508
Newly synthesized (3)H-labelled DNA was extracted from baby hamster kidney cells (BHK-21/C13 cells) and was shown to possess single-stranded properties when examined by column chromatography on benzoylated naphthoylated DEAE-cellulose, hydroxyapatite and methylated albumin on kieselguhr, and by its affinity for nitrocellulose filters. Some of the newly synthesized DNA was shown to be of lower molecular weight than the bulk of the DNA when examined by alkaline sucrose-density-gradient centrifugation. The properties observed were not affected by treatment of the DNA with ribonuclease, Pronase or amylase. The effect of the size of the DNA on its observed properties was examined and is discussed. It is concluded that DNA synthesis in BHK-21/C13 cells proceeds according to the discontinuous-mechanism model in at least one of the strands. 相似文献
53.
Studies on the skin of plaice (Pleuronectes platessa L.) 总被引:1,自引:0,他引:1
Histological and ultrastructural examinations were carried out on the integuments of larval plaice from hatching to 60 days. The skin of the newly hatched larva consisted of a delicate epidermis overlying a fluid filled dermal space. As the fish matured this became thicker, the fibrous dermis developed and the mitochondrion rich 'chloride cells' degenerated. Around the 42nd day the eosinophil granule cell appeared in the basal layers of the epidermis and by the sixtieth day the epidermis could be considered fully developed. 相似文献
54.
Studies on the skin of plaice (Pleuronectes platessa L.) 总被引:1,自引:0,他引:1
Eighty-nine O-group plaice from a natural population were exposed at 15°C to heavy infection by Cryptocotyle lingua cercariae. Subsequently 45 fish were retained at 15°C, whilst 44 were held at 5°C. Both groups were sampled by killing individual fish at intervals of 6,18,42 h and daily thereafter up to 710 h. Entire fish were fixed immediately in formol saline, transversely sectioned and stained by H & E, PAS, PAS-diastase, JSDB 109, Picro-Mallory, Masson's trichrome, Gram-Weigert and Alcian blue. Histopathological observations showed: (a) epidermal lesions associated with encysted metacercariae in adjacent tissues; (b) myofibrillar necrosis associated with bacteria possibly introduced by the parasite; and (c) a reactive swelling of the intermuscular septa. The progressive development of the parasite cyst and host capsule is described. Development of both was markedly inhibited at the lower temperature, but the inflammatory response at either temperature was slight. This may be evidence of a long-standing host-parasite relationship which has evolved to an advanced state of adaptation on the part of the parasite and tolerance on the part of the host. 相似文献
55.
56.
In this study, adaptive immune response was investigated in farmed southern bluefin tuna, Thunnus maccoyii, infected with a sanguinicolid Cardicola forsteri. A cohort (Cohort2005) of southern bluefin tuna was sampled between March 2005 and August 2006. Samples were taken at the transfer of wild caught tuna to sea cages and then at regular intervals. Parasite intensity, abundance and prevalence data were recorded. An ELISA was developed to detect and quantify an antibody response against the blood fluke in southern bluefin tuna serum. Intensity and prevalence of the blood fluke were shown to peak in May 2005 at 10.9 flukes per infected fish (SE = 1.72) and 97.5% prevalence and then decreased to low prevalence (10%) and intensity (1.0). There were no significant changes in prevalence or intensity in 2006. Antibody titres and seroprevalence increased from 1.37 U μl−1 and 10% at transfer in March 2005 to reach a peak in December 2005 of 25.86 U μl−1 (SE = 6.26 U μl−1) and 66.66%. No significant changes were observed in antibody titres for the same cohort of fish during 2006. Parasitological and serological values from Cohort2005 were compared to a 2006 cohort (Cohort2006) in March 2006 and August 2006 to determine if prior infection in Cohort2005 elicited any protection against infection in 2006. Although significant differences were not observed in intensities between cohorts it was shown that Cohort2005 had significantly lower abundances and prevalences of blood fluke infection than Cohort2006. Although there was no significant difference in mean antibody titres between cohorts in March 2006, the mean antibody titre of Cohort2006 was significantly greater than that of Cohort2005 in August 2006. No significant differences were observed in seroprevalence. This is one of the few studies to demonstrate the development of acquired resistance in fish against a parasite in an aquaculture environment under natural infection conditions. 相似文献
57.
The acyclic CB1R inverse agonist taranabant mediates weight loss by increasing energy expenditure and decreasing caloric intake 总被引:6,自引:0,他引:6
Addy C Wright H Van Laere K Gantz I Erondu N Musser BJ Lu K Yuan J Sanabria-Bohórquez SM Stoch A Stevens C Fong TM De Lepeleire I Cilissen C Cote J Rosko K Gendrano IN Nguyen AM Gumbiner B Rothenberg P de Hoon J Bormans G Depré M Eng WS Ravussin E Klein S Blundell J Herman GA Burns HD Hargreaves RJ Wagner J Gottesdiener K Amatruda JM Heymsfield SB 《Cell metabolism》2008,7(1):68-78
Cannabinoid 1 receptor (CB1R) inverse agonists are emerging as a potential obesity therapy. However, the physiological mechanisms by which these agents modulate human energy balance are incompletely elucidated. Here, we describe a comprehensive clinical research study of taranabant, a structurally novel acyclic CB1R inverse agonist. Positron emission tomography imaging using the selective CB1R tracer [(18)F]MK-9470 confirmed central nervous system receptor occupancy levels ( approximately 10%-40%) associated with energy balance/weight-loss effects in animals. In a 12-week weight-loss study, taranabant induced statistically significant weight loss compared to placebo in obese subjects over the entire range of evaluated doses (0.5, 2, 4, and 6 mg once per day) (p < 0.001). Taranabant treatment was associated with dose-related increased incidence of clinical adverse events, including mild to moderate gastrointestinal and psychiatric effects. Mechanism-of-action studies suggest that engagement of the CB1R by taranabant leads to weight loss by reducing food intake and increasing energy expenditure and fat oxidation. 相似文献
58.
Shen L Zhang Y Wang A Sieber-McMaster E Chen X Pelton P Xu JZ Yang M Zhu P Zhou L Reuman M Hu Z Russell R Gibbs AC Ross H Demarest K Murray WV Kuo GH 《Bioorganic & medicinal chemistry》2008,16(6):3321-3341
Replacement of the methyl-thiazole moiety of GW501516 (a PPARdelta selective agonist) with [1,2,4]thiadiazole gave compound 21 which unexpectedly displayed submicromolar potency as a partial agonist at PPARalpha in addition to the high potency at PPARdelta. A structure-activity relationships study of 21 resulted in the identification of 40 as a potent and selective PPARalpha/delta dual agonist. Compound 40 and its close analogs represent a new series of PPARalpha/delta dual agonists. The high potency, high selectivity, significant gene induction, excellent PK profiles, low P450 inhibition or induction, and good in vivo efficacy in four animal models support 40 being selected as a pre-clinical study candidate, and may render 40 as a valuable pharmacological tool in elucidating the complex roles of PPARalpha/delta dual agonists, and the potential usage for the treatment of metabolic syndrome. 相似文献
59.
Evolution of fitnesses in structured populations with correlated environments 总被引:1,自引:0,他引:1
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The outcome of selection in structured populations with spatially varying selection pressures depends on the interaction of two factors: the level of gene flow and the amount of heterogeneity among the demes. Here we investigate the effect of three different levels of spatial heterogeneity on the levels of genetic polymorphisms for different levels of gene flow, using a construction approach in which a population is constantly bombarded with new mutations. We further compare the relative importance of two kinds of balancing selection (heterozygote advantage and selection arising from spatial heterogeneity), the level of adaptation and the stability of the resulting polymorphic equilibria. The different levels of environmental heterogeneity and gene flow have a large influence on the final level of polymorphism. Both factors also influence the relative importance of the two kinds of balancing selection in the maintenance of variation. In particular, selection arising from spatial heterogeneity does not appear to be an important form of balancing selection for the most homogeneous scenario. The level of adaptation is highest for low levels of gene flow and, at those levels, remarkably similar for the different levels of spatial heterogeneity, whereas for higher levels of gene flow the level of adaptation is substantially reduced. 相似文献
60.
The generation and maintenance of genetic variation by frequency-dependent selection: constructing polymorphisms under the pairwise interaction model
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Frequency-dependent selection remains the most commonly invoked heuristic explanation for the maintenance of genetic variation. For polymorphism to exist, new alleles must be both generated and maintained in the population. Here we use a construction approach to model frequency-dependent selection with mutation under the pairwise interaction model. The pairwise interaction model is a general model of frequency-dependent selection at the genotypic level. We find that frequency-dependent selection is able to generate a large number of alleles at a single locus. The construction process generates multiallelic polymorphisms with a wide range of allele-frequency distributions and genotypic fitness relationships. Levels of polymorphism and mean fitness are uncoupled, so constructed polymorphisms remain permanently invasible to new mutants; thus the model never settles down to an equilibrium state. Analysis of constructed fitness sets reveals signatures of heterozygote advantage and positive frequency dependence. 相似文献