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971.
Clapham KM Bardos J Finlay MR Golding BT Griffen EJ Griffin RJ Hardcastle IR Menear KA Ting A Turner P Young GL Cano C 《Bioorganic & medicinal chemistry letters》2011,21(3):966-970
Introduction of an O-alkoxyphenyl substituent at the 8-position of the 2-morpholino-4H-chromen-4-one pharmacophore enabled regions of the ATP-binding site of DNA-dependent protein kinase (DNA-PK) to be probed further. Structure-activity relationships have been elucidated for inhibition of DNA-PK and PI3K (p110α), with N-(2-(cyclopropylmethoxy)-4-(2-morpholino-4-oxo-4H-chromen-8-yl)phenyl)-2-morpholinoacetamide 11a being identified as a potent and selective DNA-PK inhibitor (IC50 = 8 nM). 相似文献
972.
Rougeron V Bañuls AL Carme B Simon S Couppié P Nacher M Hide M De Meeûs T 《Molecular ecology》2011,20(15):3116-3127
Leishmania species of the subgenus Viannia and especially Leishmania Viannia guyanensis are responsible for a large proportion of New World leishmaniasis cases. Since a recent publication on Leishmania Viannia braziliensis, the debate on the mode of reproduction of Leishmania parasites has been reopened. A predominant endogamic reproductive mode (mating with relatives), together with strong Wahlund effects (sampling of strains from heterogeneous subpopulations), was indeed evidenced. To determine whether this hypothesis can be generalized to other Leishmania Viannia species, we performed a population genetic study on 153 human strains of L. (V.) guyanensis from French Guiana based on 12 microsatellite loci. The results revealed important homozygosity and very modest linkage disequilibrium, which is in agreement with a high level of sexual recombination and substantial endogamy. These results also revealed a significant isolation by distance with relatively small neighbourhoods and hence substantial viscosity of Leishmania populations in French Guiana. These results are of epidemiological relevance and suggest a major role for natural hosts and/or vectors in parasite strain diffusion across the country as compared to human hosts. 相似文献
973.
Most studies of behaviour examine traits whose proximate causes include sensory input and neural decision-making, but conflict and collaboration in biological systems began long before brains or sensory systems evolved. Many behaviours result from non-neural mechanisms such as direct physical contact between recognition proteins or modifications of development that coincide with altered behaviour. These simple molecular mechanisms form the basis of important biological functions and can enact organismal interactions that are as subtle, strategic and interesting as any. The genetic changes that underlie divergent molecular behaviours are often targets of selection, indicating that their functional variation has important fitness consequences. These behaviours evolve by discrete units of quantifiable phenotypic effect (amino acid and regulatory mutations, often by successive mutations of the same gene), so the role of selection in shaping evolutionary change can be evaluated on the scale at which heritable phenotypic variation originates. We describe experimental strategies for finding genes that underlie biochemical and developmental alterations of behaviour, survey the existing literature highlighting cases where the simplicity of molecular behaviours has allowed insight to the evolutionary process and discuss the utility of a genetic knowledge of the sources and spectrum of phenotypic variation for a deeper understanding of how genetic and phenotypic architectures evolve. 相似文献
974.
Crespi B 《Proceedings. Biological sciences / The Royal Society》2011,278(1711):1441-1449
I apply evolutionary perspectives and conceptual tools to analyse central issues underlying child health, with emphases on the roles of human-specific adaptations and genomic conflicts in physical growth and development. Evidence from comparative primatology, anthropology, physiology and human disorders indicates that child health risks have evolved in the context of evolutionary changes, along the human lineage, affecting the timing, growth-differentiation phenotypes and adaptive significance of prenatal stages, infancy, childhood, juvenility and adolescence. The most striking evolutionary changes in humans are earlier weaning and prolonged subsequent pre-adult stages, which have structured and potentiated maladaptations related to growth and development. Data from human genetic and epigenetic studies, and mouse models, indicate that growth, development and behaviour during pre-adult stages are mediated to a notable degree by effects from genomic conflicts and imprinted genes. The incidence of cancer, the primary cause of non-infectious childhood mortality, mirrors child growth rates from birth to adolescence, with paediatric cancer development impacted by imprinted genes that control aspects of growth. Understanding the adaptive significance of child growth and development phenotypes, in the context of human-evolutionary changes and genomic conflicts, provides novel insights into the causes of disease in childhood. 相似文献
975.
Wang GZ Haile PA Daniel T Belot B Viet AQ Goodman KB Sha D Dowdell SE Varga N Hong X Chakravorty S Webb C Cornejo C Olzinski A Bernard R Evans C Emmons A Briand J Chung CW Quek R Lee D Gough PJ Sehon CA 《Bioorganic & medicinal chemistry letters》2011,21(24):7291-7294
A series of biarylsulfonamides was identified as hCCR2 receptor antagonist but suffered from high plasma protein binding resulting in a >100 fold shift in activity in a functional GTPγS assay run in tandem in the presence and absence of human serum albumin. Introduction of an aryl amide with ethylenediamine linker led to compounds with reduced shifts and improved activity in whole blood. 相似文献
976.
Bello C Dal Bello G Cea M Nahimana A Aubry D Garuti A Motta G Moran E Fruscione F Pronzato P Grossi F Patrone F Ballestrero A Dupuis M Sordat B Zimmermann K Loretan J Wartmann M Duchosal MA Nencioni A Vogel P 《Bioorganic & medicinal chemistry》2011,19(24):7720-7727
New derivatives of 1,4-dideoxy-1,4-imino-d-ribitol have been prepared and evaluated for their cytotoxicity on solid and haematological malignancies. 1,4-Dideoxy-5-O-[(9Z)-octadec-9-en-1-yl]-1,4-imino-d-ribitol (13, IC50 ∼2 μM) and its C18-analogues (IC50 <10 μM) are cytotoxic toward SKBR3 (breast cancer) cells. 13 also inhibits (IC50 ∼8 μM) growth of JURKAT cells. 相似文献
977.
M. Simaei R. A. Khavarinejad S. Saadatmand F. Bernard H. Fahimi 《Russian Journal of Plant Physiology》2011,58(5):783-790
The effects of salicylic acid (SA), sodium nitroprusside (SNP), a nitric oxide donor, and their combination (SA+SNP) on some physiological parameters of 23-day-old soybean seedlings grown under saline and nonsaline conditions were studied. The changes in the leaf area, shoot fresh and dry weights, contents of chlorophylls and carotenoids, amounts of MDA and hydrogen peroxide showed that the addition of 100 μM SA and/or 100 μM SNP markedly declined the oxidative damage to soybean plants induced by 50 and 100 μM NaCl. Our results proved that combined action of SA and nitric oxide donor significantly activated catalase (CAT), ascorbate peroxidase (APX), and guaiacol peroxidase (GPX), which contributed to the decay of H2O2 in soybean leaves under NaCl toxicity. The protective action of (SA+SNP) against saltinduced oxidative damage was often more efficient than effects of SA and SNP alone. We also observed that the accumulation of proline was apparently accelerated by these substances under salt stress. As well, it was observed that the interaction between SA and nitric oxide had synergistic effects in decreasing of the damages induced by NaCl salinity. 相似文献
978.
Dietzel L Bräutigam K Steiner S Schüffler K Lepetit B Grimm B Schöttler MA Pfannschmidt T 《The Plant cell》2011,23(8):2964-2977
Within dense plant populations, strong light quality gradients cause unbalanced excitation of the two photosystems resulting in reduced photosynthetic efficiency. Plants redirect such imbalances by structural rearrangements of the photosynthetic apparatus via state transitions and photosystem stoichiometry adjustments. However, less is known about the function of photosystem II (PSII) supercomplexes in this context. Here, we show in Arabidopsis thaliana that PSII supercomplex remodeling precedes and facilitates state transitions. Intriguingly, the remodeling occurs in the short term, paralleling state transitions, but is also present in a state transition-deficient mutant, indicating that PSII supercomplex generation is independently regulated and does not require light-harvesting complex phosphorylation and movement. Instead, PSII supercomplex remodeling involves reversible phosphorylation of PSII core subunits (preferentially of CP43) and requires the luminal PSII subunit Psb27 for general formation and structural stabilization. Arabidopsis knockout mutants lacking Psb27 display highly accelerated state transitions, indicating that release of PSII supercomplexes is required for phosphorylation and subsequent movement of the antenna. Downregulation of PSII supercomplex number by physiological light treatments also results in acceleration of state transitions confirming the genetic analyses. Thus, supercomplex remodeling is a prerequisite and an important kinetic determinant of state transitions. 相似文献
979.
Brown algae are multicellular marine organisms evolutionarily distant from both metazoans and land plants. The molecular or cellular mechanisms that govern the developmental patterning in brown algae are poorly characterized. Here, we report the first morphogenetic mutant, étoile (etl), produced in the brown algal model Ectocarpus siliculosus. Genetic, cellular, and morphometric analyses showed that a single recessive locus, ETL, regulates cell differentiation: etl cells display thickening of the extracellular matrix (ECM), and the elongated, apical, and actively dividing E cells are underrepresented. As a result of this defect, the overrepresentation of round, branch-initiating R cells in the etl mutant leads to the rapid induction of the branching process at the expense of the uniaxial growth in the primary filament. Computational modeling allowed the simulation of the etl mutant phenotype by including a modified response to the neighborhood information in the division rules used to specify wild-type development. Microarray experiments supported the hypothesis of a defect in cell-cell communication, as primarily Lin-Notch-domain transmembrane proteins, which share similarities with metazoan Notch proteins involved in binary cell differentiation were repressed in etl. Thus, our study highlights the role of the ECM and of novel transmembrane proteins in cell-cell communication during the establishment of the developmental pattern in this brown alga. 相似文献
980.
Panavas T Lu J Liu X Winkis AM Powers G Naso MF Amegadzie B 《Protein expression and purification》2011,79(1):7-15
Expressed protein libraries are becoming a critical tool for new target discovery in the pharmaceutical industry. In order to get the most meaningful and comprehensive results from protein library screens, it is essential to have library proteins in their native conformation with proper post-translation modifications. This goal is achieved by expressing untagged human proteins in a human cell background. We optimized the transfection and cell culture conditions to maximize protein expression in a 96-well format so that the expression levels were comparable with the levels observed in shake flasks. For detection purposes, we engineered a 'tag after stop codon' system. Depending on the expression conditions, it was possible to express either native or tagged proteins from the same expression vector set. We created a human secretion protein library of 1432 candidates and a small plasma membrane protein set of about 500 candidates. Utilizing the optimized expression conditions, we expressed and analyzed both libraries by SDS-PAGE gel electrophoresis and Western blotting. Two thirds of secreted proteins could be detected by Western-blot analyses; almost half of them were visible on Coomassie stained gels. In this paper, we describe protein expression libraries that can be easily produced in mammalian expression systems in a 96-well format, with one protein expressed per well. The libraries and methods described allow for the development of robust, high-throughput functional screens designed to assay for protein specific functions associated with a relevant disease-specific activity. 相似文献