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811.
Alexis Kaushansky Albert S. Ye Laura S. Austin Sebastian A. Mikolajczak Ashley M. Vaughan Nelly Camargo Peter G. Metzger Alyse N. Douglass Gavin MacBeath Stefan H.I. Kappe 《Cell reports》2013,3(3):630-637
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812.
813.
Austin E. Smith Mohona Sarkar Gregory B. Young Gary J. Pielak 《Protein science : a publication of the Protein Society》2013,22(10):1313-1319
Intrinsic rates of exchange are essential parameters for obtaining protein stabilities from amide 1H exchange data. To understand the influence of the intracellular environment on stability, one must know the effect of the cytoplasm on these rates. We probed exchange rates in buffer and in Escherichia coli lysates for the dynamic loop in the small globular protein chymotrypsin inhibitor 2 using a modified form of the nuclear magnetic resonance experiment, SOLEXSY. No significant changes were observed, even in 100 g dry weight L−1 lysate. Our results suggest that intrinsic rates from studies conducted in buffers are applicable to studies conducted under cellular conditions. 相似文献
814.
Ying-zi Xu Jenifer L. Smith Christopher M. Semko Kassandra I. Rossiter Juri Y. Fukuda Michael S. Dappen David A. Quincy Andrei W. Konradi Wenxian Mao Brent Welch Mark L. Dreyer Bhushan Samant Hongbin Zhang Judevin Lugar Zhenmei Liao Carrol Henschel Eric Petersen Christopher Vandevert Ted A. Yednock 《Bioorganic & medicinal chemistry letters》2013,23(15):4370-4373
A series of potent α4β1/α4β7 integrin inhibitors is reported, including an inhibitor 12d with remarkable oral exposure and efficacy in rat models of rheumatoid arthritis and Crohn’s disease. 相似文献
815.
816.
Christopher P. Kozakiewicz Lauren Ricci Austin H. Patton Amanda R. Stahlke Sarah A. Hendricks Mark J. Margres Manuel Ruiz‐Aravena David G. Hamilton Rodrigo Hamede Hamish McCallum Menna E. Jones Paul A. Hohenlohe Andrew Storfer 《Molecular ecology》2020,29(17):3217-3233
Genetic structure in host species is often used to predict disease spread. However, host and pathogen genetic variation may be incongruent. Understanding landscape factors that have either concordant or divergent influence on host and pathogen genetic structure is crucial for wildlife disease management. Devil facial tumour disease (DFTD) was first observed in 1996 and has spread throughout almost the entire Tasmanian devil geographic range, causing dramatic population declines. Whereas DFTD is predominantly spread via biting among adults, devils typically disperse as juveniles, which experience low DFTD prevalence. Thus, we predicted little association between devil and tumour population structure and that environmental factors influencing gene flow differ between devils and tumours. We employed a comparative landscape genetics framework to test the influence of environmental factors on patterns of isolation by resistance (IBR) and isolation by environment (IBE) in devils and DFTD. Although we found evidence for broad‐scale costructuring between devils and tumours, we found no relationship between host and tumour individual genetic distances. Further, the factors driving the spatial distribution of genetic variation differed for each. Devils exhibited a strong IBR pattern driven by major roads, with no evidence of IBE. By contrast, tumours showed little evidence for IBR and a weak IBE pattern with respect to elevation in one of two tumour clusters we identify herein. Our results warrant caution when inferring pathogen spread using host population genetic structure and suggest that reliance on environmental barriers to host connectivity may be ineffective for managing the spread of wildlife diseases. Our findings demonstrate the utility of comparative landscape genetics for identifying differential factors driving host dispersal and pathogen transmission. 相似文献
817.
Xia M Guo V Huang R Shahane SA Austin CP Nirenberg M Sharma SK 《Cellular and molecular neurobiology》2011,31(6):901-907
Opiates are not only potent analgesics but also drugs of abuse mainly because they produce euphoria. Chronic use of opiates
results in the development of tolerance and dependence. Dr Marshall Nirenberg’s group at the National Institutes of Health
(NIH) was the first to use a cellular model system of Neuroblastoma × Glioma hybrid cells (NG108-15) to study morphine addiction.
They showed that opiates affect adenylyl cyclase (AC) by two opposing mechanisms mediated by the opiate receptor. Although
the cellular mechanisms that cause addiction are not yet completely understood, the most observed correlative biochemical
adaptation is the upregulation of AC. This model also provides the opportunity to look for compounds which could dissociate
the acute effect of opiates from the delayed response, upregulation of AC, and thus lead to the discovery of non-addictive
drugs. To identify small molecule compounds that can inhibit morphine-induced cAMP overshoot, we have validated and optimized
a cell-based assay in a high throughput format that measures cellular cAMP production after morphine withdrawal. The assay
performed well in the 1536-well plate format. The LOPAC library of 1,280 compounds was screened in this assay on a quantitative
high-throughput screening (qHTS) platform. A group of compounds that can inhibit morphine-induced cAMP overshoot were identified.
The most potent compounds are eight naloxone-related compounds, including levallorphan tartrate, naloxonazine dihydrochloride,
naloxone hydrochloride, naltrexone hydrochloride, and naltriben methanesulfonate. The qHTS approach we used in this study
will be useful in identifying novel inhibitors of morphine induced addiction from a larger scale screening. 相似文献
818.
Improving species distribution models for climate change studies: variable selection and scale 总被引:1,自引:0,他引:1
Statistical species distribution models (SDMs) are widely used to predict the potential changes in species distributions under climate change scenarios. We suggest that we need to revisit the conceptual framework and ecological assumptions on which the relationship between species distributions and environment is based. We present a simple conceptual framework to examine the selection of environmental predictors and data resolution scales. These vary widely in recent papers, with light inconsistently included in the models. Focusing on light as a necessary component of plant SDMs, we briefly review its dependence on aspect and slope and existing knowledge of its influence on plant distribution. Differences in light regimes between north‐ and south‐facing aspects in temperate latitudes can produce differences in temperature equivalent to moves 200 km polewards. Local topography may create refugia that are not recognized in many climate change SDMs using coarse‐scale data. We argue that current assumptions about the selection of predictors and data resolution need further testing. Application of these ideas can clarify many issues of scale, extent and choice of predictors, and potentially improve the use of SDMs for climate change modelling of biodiversity. 相似文献
819.
In Diptera (Insecta), alternatively spliced male-specific and female-specific products of the doublesex (dsx) gene play a key role in regulating development of the adult genital structures from the genital disc. Analysis of the pattern of nucleotide substitution of different domains of the dsx gene in 29 dipteran species showed that, over short evolutionary times, purifying selection predominated on the domain common to both sexes, the female-specific exons, and the and male-specific exon. However, over longer the evolutionary time frames represented by between-family comparisons, the male-specific exon accumulated nonsynonymous substitutions at a much more rapid rate than either the common domain or the female-specific exon. Overall, the accumulation of nonsynonymous substitutions in the male-specific exon occurred at a significantly greater than linear rate relative to the common domain, whereas the accumulation of nonsynonymous substitutions in the female-specific exon occurred at less than linear rate relative to the common domain. The evolution of the male-specific exon of dsx thus shows a pattern reminiscent of that seen in the "runaway" evolution of male secondary sexual characters at the morphological level, consistent with the hypothesis that female choice is an important factor in the morphological diversification of insect male genitalia. 相似文献
820.
Austin RS Vidaurre D Stamatiou G Breit R Provart NJ Bonetta D Zhang J Fung P Gong Y Wang PW McCourt P Guttman DS 《The Plant journal : for cell and molecular biology》2011,67(4):715-725
Next‐generation genomic sequencing technologies have made it possible to directly map mutations responsible for phenotypes of interest via direct sequencing. However, most mapping strategies proposed to date require some prior genetic analysis, which can be very time‐consuming even in genetically tractable organisms. Here we present a de novo method for rapidly and robustly mapping the physical location of EMS mutations by sequencing a small pooled F2 population. This method, called Next Generation Mapping (NGM), uses a chastity statistic to quantify the relative contribution of the parental mutant and mapping lines to each SNP in the pooled F2 population. It then uses this information to objectively localize the candidate mutation based on its exclusive segregation with the mutant parental line. A user‐friendly, web‐based tool for performing NGM analysis is available at http://bar.utoronto.ca/NGM . We used NGM to identify three genes involved in cell‐wall biology in Arabidopsis thaliana, and, in a power analysis, demonstrate success in test mappings using as few as ten F2 lines and a single channel of Illumina Genome Analyzer data. This strategy can easily be applied to other model organisms, and we expect that it will also have utility in crops and any other eukaryote with a completed genome sequence. 相似文献