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Krenitsky VP Delgado M Nadolny L Sahasrabudhe K Ayala L Clareen SS Hilgraf R Albers R Kois A Hughes K Wright J Nowakowski J Sudbeck E Ghosh S Bahmanyar S Chamberlain P Muir J Cathers BE Giegel D Xu L Celeridad M Moghaddam M Khatsenko O Omholt P Katz J Pai S Fan R Tang Y Shirley MA Benish B Blease K Raymon H Bhagwat S Henderson I Cole AG Bennett B Satoh Y 《Bioorganic & medicinal chemistry letters》2012,22(3):1427-1432
In this Letter we describe the optimization of an aminopurine lead (1) with modest potency and poor overall kinase selectivity which led to the identification of a series of potent, selective JNK inhibitors. Improvement in kinase selectivity was enabled by introduction of an aliphatic side chain at the C-2 position. CC-359 (2) was selected as a potential clinical candidate for diseases manifested by ischemia reperfusion injury. 相似文献
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Zörgö E Gjuvsland A Cubillos FA Louis EJ Liti G Blomberg A Omholt SW Warringer J 《Molecular biology and evolution》2012,29(7):1781-1789
A fundamental question in biology is whether variation in organisms primarily emerges as a function of adaptation or as a function of neutral genetic drift. Trait variation in the model organism baker's yeast follows population bottlenecks rather than environmental boundaries suggesting that it primarily results from genetic drift. Based on the yeast life history, we hypothesized that population-specific loss-of-function mutations emerging in genes recently released from selection is the predominant cause of trait variation within the species. As retention of one functional copy of a gene in diploid yeasts is typically sufficient to maintain completely unperturbed performance, we also conjectured that a crossing of natural yeasts from populations with different loss-of-function mutations would provide a further efficient test bed for this hypothesis. Charting the first species-wide map of trait inheritance in a eukaryotic organism, we found trait heredity to be strongly biased toward diploid hybrid performance exactly mimicking the performance of the best of the parents, as expected given a complete dominance of functional over nonfunctional alleles. Best parent heterosis, partial dominance, and negative nonadditivity were all rare phenomena. Nonadditive inheritance was observed primarily in crosses involving at least one very poor performing parent, most frequently of the West African population, and when molecularly dissected, loss-of-function alleles were identified as the underlying cause. These findings provide support for that population-specific loss-of-function mutations do have a strong impact on genotype-phenotype maps and underscores the role of neutral genetic drift as a driver for trait variation within species. 相似文献
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Cubillos FA Billi E Zörgö E Parts L Fargier P Omholt S Blomberg A Warringer J Louis EJ Liti G 《Molecular ecology》2011,20(7):1401-1413
Phenotypic variation arising from populations adapting to different niches has a complex underlying genetic architecture. A major challenge in modern biology is to identify the causative variants driving phenotypic variation. Recently, the baker's yeast, Saccharomyces cerevisiae has emerged as a powerful model for dissecting complex traits. However, past studies using a laboratory strain were unable to reveal the complete architecture of polygenic traits. Here, we present a linkage study using 576 recombinant strains obtained from crosses of isolates representative of the major lineages. The meiotic recombinational landscape appears largely conserved between populations; however, strain-specific hotspots were also detected. Quantitative measurements of growth in 23 distinct ecologically relevant environments show that our recombinant population recapitulates most of the standing phenotypic variation described in the species. Linkage analysis detected an average of 6.3 distinct QTLs for each condition tested in all crosses, explaining on average 39% of the phenotypic variation. The QTLs detected are not constrained to a small number of loci, and the majority are specific to a single cross-combination and to a specific environment. Moreover, crosses between strains of similar phenotypes generate greater variation in the offspring, suggesting the presence of many antagonistic alleles and epistatic interactions. We found that subtelomeric regions play a key role in defining individual quantitative variation, emphasizing the importance of the adaptive nature of these regions in natural populations. This set of recombinant strains is a powerful tool for investigating the complex architecture of polygenic traits. 相似文献
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In quantitative genetics, the degree of resemblance between parents and offspring is described in terms of the additive variance (V(A)) relative to genetic (V(G)) and phenotypic (V(P)) variance. For populations with extreme allele frequencies, high V(A)/V(G) can be explained without considering properties of the genotype-phenotype (GP) map. We show that randomly generated GP maps in populations with intermediate allele frequencies generate far lower V(A)/V(G) values than empirically observed. The main reason is that order-breaking behaviour is ubiquitous in random GP maps. Rearrangement of genotypic values to introduce order-preservation for one or more loci causes a dramatic increase in V(A)/V(G). This suggests the existence of order-preserving design principles in the regulatory machinery underlying GP maps. We illustrate this feature by showing how the ubiquitously observed monotonicity of dose-response relationships gives much higher V(A)/V(G) values than a unimodal dose-response relationship in simple gene network models. 相似文献
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Øyehaug L Østby I Lloyd CM Omholt SW Einevoll GT 《Journal of computational neuroscience》2012,32(1):147-165
Exposed to a sufficiently high extracellular potassium concentration ([K?+?]o), the neuron can fire spontaneous discharges or even become inactivated due to membrane depolarisation (??depolarisation block??). Since these phenomena likely are related to the maintenance and propagation of seizure discharges, it is of considerable importance to understand the conditions under which excess [K?+?]o causes them. To address the putative effect of glial buffering on neuronal activity under elevated [K?+?]o conditions, we combined a recently developed dynamical model of glial membrane ion and water transport with a Hodgkin?CHuxley type neuron model. In this interconnected glia-neuron model we investigated the effects of natural heterogeneity or pathological changes in glial membrane transporter density by considering a large set of models with different, yet empirically plausible, sets of model parameters. We observed both the high [K?+?]o-induced duration of spontaneous neuronal firing and the prevalence of depolarisation block to increase when reducing the magnitudes of the glial transport mechanisms. Further, in some parameter regions an oscillatory bursting spiking pattern due to the dynamical coupling of neurons and glia was observed. Bifurcation analyses of the neuron model and of a simplified version of the neuron-glia model revealed further insights about the underlying mechanism behind these phenomena. The above insights emphasise the importance of combining neuron models with detailed astroglial models when addressing phenomena suspected to be influenced by the astroglia-neuron interaction. To facilitate the use of our neuron-glia model, a CellML version of it is made publicly available. 相似文献
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Kristin Tøndel Ulf G Indahl Arne B Gjuvsland Stig W Omholt Harald Martens 《BMC systems biology》2012,6(1):1-21
Background
The physical periphery of a biological cell is mainly described by signaling pathways which are triggered by transmembrane proteins and receptors that are sentinels to control the whole gene regulatory network of a cell. However, our current knowledge about the gene regulatory mechanisms that are governed by extracellular signals is severely limited.Results
The purpose of this paper is three fold. First, we infer a gene regulatory network from a large-scale B-cell lymphoma expression data set using the C3NET algorithm. Second, we provide a functional and structural analysis of the largest connected component of this network, revealing that this network component corresponds to the peripheral region of a cell. Third, we analyze the hierarchical organization of network components of the whole inferred B-cell gene regulatory network by introducing a new approach which exploits the variability within the data as well as the inferential characteristics of C3NET. As a result, we find a functional bisection of the network corresponding to different cellular components.Conclusions
Overall, our study allows to highlight the peripheral gene regulatory network of B-cells and shows that it is centered around hub transmembrane proteins located at the physical periphery of the cell. In addition, we identify a variety of novel pathological transmembrane proteins such as ion channel complexes and signaling receptors in B-cell lymphoma. 相似文献48.
Background
Cytokines are small proteins that regulate immunity in vertebrate species. Marsupial and eutherian mammals last shared a common ancestor more than 180 million years ago, so it is not surprising that attempts to isolate many key marsupial cytokines using traditional laboratory techniques have been unsuccessful. This paucity of molecular data has led some authors to suggest that the marsupial immune system is 'primitive' and not on par with the sophisticated immune system of eutherian (placental) mammals.Results
The sequencing of the first marsupial genome has allowed us to identify highly divergent immune genes. We used gene prediction methods that incorporate the identification of gene location using BLAST, SYNTENY + BLAST and HMMER to identify 23 key marsupial immune genes, including IFN-γ, IL-2, IL-4, IL-6, IL-12 and IL-13, in the genome of the grey short-tailed opossum (Monodelphis domestica). Many of these genes were not predicted in the publicly available automated annotations.Conclusion
The power of this approach was demonstrated by the identification of orthologous cytokines between marsupials and eutherians that share only 30% identity at the amino acid level. Furthermore, the presence of key immunological genes suggests that marsupials do indeed possess a sophisticated immune system, whose function may parallel that of eutherian mammals. 相似文献49.
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