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851.
Shoujun Chen Lijun Sun Keizo Koya Noriaki Tatsuta Zhiqiang Xia Timothy Korbut Zhenjian Du Jim Wu Guiqing Liang Jun Jiang Mitsunori Ono Dan Zhou Andrew Sonderfan 《Bioorganic & medicinal chemistry letters》2013,23(18):5070-5076
A series of N′1,N′3-dialkyl-N′1,N′3-di(alkylcarbonothioyl) malonohydrazides have been designed and synthesized as anticancer agents by targeting oxidative stress and Hsp70 induction. Structure–activity relationship (SAR) studies lead to the discovery of STA-4783 (elesclomol), a novel small molecule that has been evaluated in a number of clinical trials as an anticancer agent in combination with Taxol. 相似文献
852.
Colin A. Lowery Michael Adler Andrew Borrell Kim D. Janda 《Bioorganic & medicinal chemistry letters》2013,23(24):6743-6746
The botulinum neurotoxins, characterized by their neuromuscular paralytic effects, are the most toxic proteins known to man. Due to their extreme potency, ease of production, and duration of activity, the BoNT proteins have been classified by the Centers for Disease Control as high threat agents for bioterrorism. In an attempt to discover effective BoNT therapeutics, we have pursued a strategy in which we leverage the blockade of K+ channels that ultimately results in the reversal of neuromuscular paralysis. Towards this end, we utilized peptides derived from scorpion venom that are highly potent K+ channel blockers. Herein, we report the synthesis of charybdotoxin, a 37 amino acid peptide, and detail its activity, along with iberiotoxin and margatoxin, in a mouse phrenic nerve hemidiaphragm assay in the absence and the presence of BoNT/A. 相似文献
853.
Xiaojun Han Rita L. Civiello Charles M. Conway Deborah A. Cook Carl D. Davis Andrew P. Degnan Xiang-Jun Jiang Robert Macci Neil R. Mathias Paul Moench Sokhom S. Pin Richard Schartman Laura J. Signor George Thalody George Tora Valerie Whiterock Cen Xu John E. Macor Gene M. Dubowchik 《Bioorganic & medicinal chemistry letters》2013,23(12):3674
854.
Compelling data supports the hypothesis that Pin1 inhibitors will be useful for the therapy of cancer: Pin1 deficient mice resist the induction of breast cancers normally evoked by expression of MMTV-driven Ras or Erb2 alleles. While Pin1 poses challenges for drug discovery, several groups have identified potent antagonists by structure based drug design, significant progress has been made designing peptidic inhibitors and a number of natural products have been found that blockade Pin1, notably epigallocatchechin gallate (EGCG), a major flavonoid in green tea. Here we critically discuss the modes of action and likely specificity of these compounds, concluding that a suitable chemical biology tool for probing the function of Pin1 has yet to be found. We conclude by outlining some open questions regarding the target validation of Pin1 and the prospects for identification of improved inhibitors in the future. 相似文献
855.
Daryl R. Trumbo Stephen F. Spear Jason Baumsteiger Andrew Storfer 《Molecular ecology》2013,22(5):1250-1266
A species' genetic structure often varies in response to ecological and landscape processes that differ throughout the species' geographic range, yet landscape genetics studies are rarely spatially replicated. The Cope's giant salamander (Dicamptodon copei) is a neotenic, dispersal‐limited amphibian with a restricted geographic range in the Pacific northwestern USA. We investigated which landscape factors affect D. copei gene flow in three regions spanning the species' range, which vary in climate, landcover and degree of anthropogenic disturbance. Least cost paths and Circuitscape resistance analyses revealed that gene flow patterns vary across the species' range, with unique combinations of landscape variables affecting gene flow in different regions. Populations in the northern coastal portions of the range had relatively high gene flow, largely facilitated by stream and river networks. Near the southeastern edge of the species' range, gene flow was more restricted overall, with relatively less facilitation by streams and more limitation by heat load index and fragmented forest cover. These results suggested that the landscape is more difficult for individuals to disperse through at the southeastern edge of the species' range, with terrestrial habitat desiccation factors becoming more limiting to gene flow. We suggest that caution be used when attempting to extrapolate landscape genetic models and conservation measures from one portion of a species' range to another. 相似文献
856.
Female Drosophila melanogaster frequently mate with multiple males, and the success of a given male depends not only on his genotype but also on the genotype of his competitor. Here, we assess how natural genetic variation affects male–male interactions for traits influencing pre‐ and postcopulatory sexual selection. Males from a set of 66 chromosome substitution lines were competed against each other in a ‘round‐robin’ design, and paternity was scored using bulk genotyping. We observed significant effects of the genotype of the first male to mate, the second male to mate and an interaction between the males for measures of male mating rate and sperm utilization. We also identified specific combinations of males who show nontransitive patterns of reproductive success and engage in ‘rock‐paper‐scissors’ games. We then tested for associations between 245 polymorphisms in 32 candidate male reproductive genes and male reproductive success. We identified eight polymorphisms in six reproductive genes that associate with male reproductive success independent of the competitor (experimentwise P < 0.05). We also identified four SNPs in four different genes where the relative reproductive success of the alternative alleles changes depending on the competing males' genetic background (experimentwise P < 0.05); two of these associations include premature stop codons. This may be the first study that identifies the genes contributing to nontransitivity among males and further highlights that ‘rock‐paper‐scissors’ games could be an important evolutionary force maintaining genetic variation in natural populations. 相似文献
857.
Andrew D. Foote Jason Newton María C. ávila-Arcos Marie-Louise Kampmann Jose A. Samaniego Klaas Post Aqqalu Rosing-Asvid Mikkel-Holger S. Sinding M. Thomas P. Gilbert 《Proceedings. Biological sciences / The Royal Society》2013,280(1768)
Niche variation owing to individual differences in ecology has been hypothesized to be an early stage of sympatric speciation. Yet to date, no study has tracked niche width over more than a few generations. In this study, we show the presence of isotopic niche variation over millennial timescales and investigate the evolutionary outcomes. Isotopic ratios were measured from tissue samples of sympatric killer whale Orcinus orca lineages from the North Sea, spanning over 10 000 years. Isotopic ratios spanned a range similar to the difference in isotopic values of two known prey items, herring Clupea harengus and harbour seal Phoca vitulina. Two proxies of the stage of speciation, lineage sorting of mitogenomes and genotypic clustering, were both weak to intermediate indicating that speciation has made little progress. Thus, our study confirms that even with the necessary ecological conditions, i.e. among-individual variation in ecology, it is difficult for sympatric speciation to progress in the face of gene flow. In contrast to some theoretical models, our empirical results suggest that sympatric speciation driven by among-individual differences in ecological niche is a slow process and may not reach completion. We argue that sympatric speciation is constrained in this system owing to the plastic nature of the behavioural traits under selection when hunting either mammals or fish. 相似文献
858.
The accumulation of body mass, as growth, is fundamental to all organisms. Being able to understand which model(s) best describe this growth trajectory, both empirically and ultimately mechanistically, is an important challenge. A variety of equations have been proposed to describe growth during ontogeny. Recently, the West Brown Enquist (WBE) equation, formulated as part of the metabolic theory of ecology, has been proposed as a universal model of growth. This equation has the advantage of having a biological basis, but its ability to describe invertebrate growth patterns has not been well tested against other, more simple models. In this study, we collected data for 58 species of marine invertebrate from 15 different taxa. The data were fitted to three growth models (power, exponential and WBE), and their abilities were examined using an information theoretic approach. Using Akaike information criteria, we found changes in mass through time to fit an exponential equation form best (in approx. 73% of cases). The WBE model predominantly overestimates body size in early ontogeny and underestimates it in later ontogeny; it was the best fit in approximately 14% of cases. The exponential model described growth well in nine taxa, whereas the WBE described growth well in one of the 15 taxa, the Amphipoda. Although the WBE has the advantage of being developed with an underlying proximate mechanism, it provides a poor fit to the majority of marine invertebrates examined here, including species with determinate and indeterminate growth types. In the original formulation of the WBE model, it was tested almost exclusively against vertebrates, to which it fitted well; the model does not however appear to be universal given its poor ability to describe growth in benthic or pelagic marine invertebrates. 相似文献
859.
Darren S. Baldwin Matthew J. Colloff Gavin N. Rees Anthony A. Chariton Garth O. Watson Leon N. Court Diana M. Hartley Matthew j. Morgan Andrew J. King Jessica S. Wilson Michael Hodda Christopher M. Hardy 《Molecular ecology》2013,22(6):1746-1758
Floodplain ecosystems are characterized by alternating wet and dry phases and periodic inundation defines their ecological character. Climate change, river regulation and the construction of levees have substantially altered natural flooding and drying regimes worldwide with uncertain effects on key biotic groups. In southern Australia, we hypothesized that soil eukaryotic communities in climate change affected areas of a semi‐arid floodplain would transition towards comprising mainly dry‐soil specialist species with increasing drought severity. Here, we used 18S rRNA amplicon pyrosequencing to measure the eukaryote community composition in soils that had been depleted of water to varying degrees to confirm that reproducible transitional changes occur in eukaryotic biodiversity on this floodplain. Interflood community structures (3 years post‐flood) were dominated by persistent rather than either aquatic or dry‐specialist organisms. Only 2% of taxa were unique to dry locations by 8 years post‐flood, and 10% were restricted to wet locations (inundated a year to 2 weeks post‐flood). Almost half (48%) of the total soil biota were detected in both these environments. The discovery of a large suite of organisms able to survive nearly a decade of drought, and up to a year submerged supports the concept of inherent resilience of Australian semi‐arid floodplain soil communities under increasing pressure from climatic induced changes in water availability. 相似文献
860.
Martin C. Fischer Christian Rellstab Andrew Tedder Stefan Zoller Felix Gugerli Kentaro K. Shimizu Rolf Holderegger Alex Widmer 《Molecular ecology》2013,22(22):5594-5607
Natural genetic variation is essential for the adaptation of organisms to their local environment and to changing environmental conditions. Here, we examine genomewide patterns of nucleotide variation in natural populations of the outcrossing herb Arabidopsis halleri and associations with climatic variation among populations in the Alps. Using a pooled population sequencing (Pool‐Seq) approach, we discovered more than two million SNPs in five natural populations and identified highly differentiated genomic regions and SNPs using FST‐based analyses. We tested only the most strongly differentiated SNPs for associations with a nonredundant set of environmental factors using partial Mantel tests to identify topo‐climatic factors that may underlie the observed footprints of selection. Possible functions of genes showing signatures of selection were identified by Gene Ontology analysis. We found 175 genes to be highly associated with one or more of the five tested topo‐climatic factors. Of these, 23.4% had unknown functions. Genetic variation in four candidate genes was strongly associated with site water balance and solar radiation, and functional annotations were congruent with these environmental factors. Our results provide a genomewide perspective on the distribution of adaptive genetic variation in natural plant populations from a highly diverse and heterogeneous alpine environment. 相似文献