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961.
962.
William Engen Terrence E. O’Brien Brendan Kelly Jacinda Do Liezel Rillera Lance K. Stapleton Jack F. Youngren Marc O. Anderson 《Bioorganic & medicinal chemistry》2010,18(16):5995-6005
The insulin-like growth factor receptor (IGF-1R) is a receptor tyrosine kinase (RTK) involved in all stages of the development and propagation of breast and other cancers. The inhibition of IGF-1R by small molecules remains a promising strategy to treat cancer. Herein, we explore SAR around previously characterized lead compound (1), which is an aryl-heteroaryl urea (AHU) consisting of 4-aminoquinaldine and a substituted aromatic ring system. A library of novel AHU compounds was prepared based on derivatives of the 4-aminoquinoline heterocycle (including various 2-substituted derivatives, and naphthyridines). The compounds were screened for in vitro inhibitory activity against IGF-1R, and several compounds with improved activity (3–5 μM) were identified. Furthermore, a computational docking study was performed, which identifies a fairly consistent lowest energy mode of binding for the more-active set of inhibitors in this series, while the less-active inhibitors do not adopt a consistent mode of binding. 相似文献
963.
Cyanobacteria are able to survive in various extreme environments via the production of organic compounds known as compatible
solutes. In particular, cyanobacteria are capable of inhabiting hypersaline environments such as those found in intertidal
regions. Cyanobacteria in these environments must possess regulatory mechanisms for surviving the changing osmotic pressure
as a result of desiccation, rainfall and tidal fluxes. The objective of this study was to determine the compatible solutes
that are accumulated by cyanobacteria from hypersaline regions, and specifically, the stromatolite ecosystems of Shark Bay,
Western Australia. Previously, the cyanobacterial populations associated with these stromatolites were characterized in two
separate studies. Compatible solutes were extracted from isolated cyanobacteria here and identified by nuclear magnetic resonance.
As the media of isolation contained no complex carbon source, the solutes accumulated were likely synthesized by the cyanobacteria.
The data indicate that from this one habitat taxonomically distinct cyanobacteria exposed to varying salinities accumulate
a range of known compatible solutes. In addition, taxonomically similar cyanobacteria do not necessarily accumulate the same
compatible solutes. Glucosylglycerol, a compatible solute unique to marine cyanobacteria was not detected; however, various
saccharides, glycine betaine, and trimethylamine-N-oxide were identified as the predominant solutes. We conclude that the cyanobacterial communities from these hypersaline
stromatolites are likely to possess more complex mechanisms of adaptation to osmotic stress than previously thought. The characterization
of osmoregulatory properties of stromatolite microorganisms provides further insight into how life can thrive in such extreme
environments. 相似文献
964.
Brendan Mackey Sandy Gilmore Hugh Pringle Paul Foreman Linda Van Bommel Sandra Berry Murray Haseler 《Ecological Management & Restoration》2010,11(1):51-60
Summary A framework is presented for terrestrial conservation assessment that has been developed for Bush Heritage, an Australian non-profit organisation that manages land of outstanding conservation value through acquisition or working in partnership with other landowners. The framework is called Biodiversity Prediction using Ecological Processes and comprises seven conservation goals, with a set of candidate criteria and indicators for each goal. Particular emphasis is given to criteria that relate to habitat quality in addition to the more conventional focus on land quantity. The MCAS-S graphic user interface is used to help analyse the indicators and visualise the results in a transparent way that assists the decision-making process. The interface also allows indicators to be weighted differently, which among other things, allows analyses to reflect inter-regional differences in what represents high quality land. The framework was tested in a case study region (the Woodland region of south-eastern Australia), and the results reveal land that is potentially a priority for conservation investments. While the framework and case study results are indicative, and further analyses are required before they can be considered operational, the approach has potential application to other organisations in the private conservation sector. 相似文献
965.
Peter E Chen Christopher Cook Andrew C Stewart Niranjan Nagarajan Dan D Sommer Mihai Pop Brendan Thomason Maureen P Kiley Thomason Shannon Lentz Nichole Nolan Shanmuga Sozhamannan Alexander Sulakvelidze Alfred Mateczun Lei Du Michael E Zwick Timothy D Read 《Genome biology》2010,11(1):1-18
Background
New DNA sequencing technologies have enabled detailed comparative genomic analyses of entire genera of bacterial pathogens. Prior to this study, three species of the enterobacterial genus Yersinia that cause invasive human diseases (Yersinia pestis, Yersinia pseudotuberculosis, and Yersinia enterocolitica) had been sequenced. However, there were no genomic data on the Yersinia species with more limited virulence potential, frequently found in soil and water environments.Results
We used high-throughput sequencing-by-synthesis instruments to obtain 25- to 42-fold average redundancy, whole-genome shotgun data from the type strains of eight species: Y. aldovae, Y. bercovieri, Y. frederiksenii, Y. kristensenii, Y. intermedia, Y. mollaretii, Y. rohdei, and Y. ruckeri. The deepest branching species in the genus, Y. ruckeri, causative agent of red mouth disease in fish, has the smallest genome (3.7 Mb), although it shares the same core set of approximately 2,500 genes as the other members of the species, whose genomes range in size from 4.3 to 4.8 Mb. Yersinia genomes had a similar global partition of protein functions, as measured by the distribution of Cluster of Orthologous Groups families. Genome to genome variation in islands with genes encoding functions such as ureases, hydrogeneases and B-12 cofactor metabolite reactions may reflect adaptations to colonizing specific host habitats.Conclusions
Rapid high-quality draft sequencing was used successfully to compare pathogenic and non-pathogenic members of the Yersinia genus. This work underscores the importance of the acquisition of horizontally transferred genes in the evolution of Y. pestis and points to virulence determinants that have been gained and lost on multiple occasions in the history of the genus. 相似文献966.
967.
Mandalia S Mandalia R Lo G Chadborn T Sharott P Youle M Anderson J Baily G Brettle R Fisher M Gompels M Kinghorn G Johnson M McCarron B Pozniak A Tang A Walsh J White D Williams I Gazzard B Beck EJ;NPMS-HHC Steering Group 《PloS one》2010,5(12):e15677
Background
The number of people living with HIV (PLHIV) is increasing in the UK. This study estimated the annual population cost of providing HIV services in the UK, 1997–2006 and projected them 2007–2013.Methods
Annual cost of HIV treatment for PLHIV by stage of HIV infection and type of ART was calculated (UK pounds, 2006 prices). Population costs were derived by multiplying the number of PLHIV by their annual cost for 1997–2006 and projected 2007–2013.Results
Average annual treatment costs across all stages of HIV infection ranged from £17,034 in 1997 to £18,087 in 2006 for PLHIV on mono-therapy and from £27,649 in 1997 to £32,322 in 2006 for those on quadruple-or-more ART. The number of PLHIV using NHS services rose from 16,075 to 52,083 in 2006 and was projected to increase to 78,370 by 2013. Annual population cost rose from £104 million in 1997 to £483 million in 2006, with a projected annual cost between £721 and £758 million by 2013. When including community care costs, costs increased from £164 million in 1997, to £683 million in 2006 and between £1,019 and £1,065 million in 2013.Conclusions
Increased number of PLHIV using NHS services resulted in rising UK population costs. Population costs are expected to continue to increase, partly due to PLHIV''s longer survival on ART and the relative lack of success of HIV preventing programs. Where possible, the cost of HIV treatment and care needs to be reduced without reducing the quality of services, and prevention programs need to become more effective. While high income countries are struggling to meet these increasing costs, middle- and lower-income countries with larger epidemics are likely to find it even more difficult to meet these increasing demands, given that they have fewer resources. 相似文献968.
Regional management units for marine turtles: a novel framework for prioritizing conservation and research across multiple scales 总被引:2,自引:0,他引:2
Wallace BP DiMatteo AD Hurley BJ Finkbeiner EM Bolten AB Chaloupka MY Hutchinson BJ Abreu-Grobois FA Amorocho D Bjorndal KA Bourjea J Bowen BW Dueñas RB Casale P Choudhury BC Costa A Dutton PH Fallabrino A Girard A Girondot M Godfrey MH Hamann M López-Mendilaharsu M Marcovaldi MA Mortimer JA Musick JA Nel R Pilcher NJ Seminoff JA Troëng S Witherington B Mast RB 《PloS one》2010,5(12):e15465
Background
Resolving threats to widely distributed marine megafauna requires definition of the geographic distributions of both the threats as well as the population unit(s) of interest. In turn, because individual threats can operate on varying spatial scales, their impacts can affect different segments of a population of the same species. Therefore, integration of multiple tools and techniques — including site-based monitoring, genetic analyses, mark-recapture studies and telemetry — can facilitate robust definitions of population segments at multiple biological and spatial scales to address different management and research challenges.Methodology/Principal Findings
To address these issues for marine turtles, we collated all available studies on marine turtle biogeography, including nesting sites, population abundances and trends, population genetics, and satellite telemetry. We georeferenced this information to generate separate layers for nesting sites, genetic stocks, and core distributions of population segments of all marine turtle species. We then spatially integrated this information from fine- to coarse-spatial scales to develop nested envelope models, or Regional Management Units (RMUs), for marine turtles globally.Conclusions/Significance
The RMU framework is a solution to the challenge of how to organize marine turtles into units of protection above the level of nesting populations, but below the level of species, within regional entities that might be on independent evolutionary trajectories. Among many potential applications, RMUs provide a framework for identifying data gaps, assessing high diversity areas for multiple species and genetic stocks, and evaluating conservation status of marine turtles. Furthermore, RMUs allow for identification of geographic barriers to gene flow, and can provide valuable guidance to marine spatial planning initiatives that integrate spatial distributions of protected species and human activities. In addition, the RMU framework — including maps and supporting metadata — will be an iterative, user-driven tool made publicly available in an online application for comments, improvements, download and analysis. 相似文献969.
Polymer hydrogels containing positively charged functional groups were used to investigate the critical material and biological components of FVII activation and subsequent fibrin formation in citrated plasma. A FVIIa ELISA confirmed the ability of the polymer to induce FVII activation and provided insight into the material parameters which were influential in this activation. Experiments utilizing coagulation factor depleted and inhibited plasmas indicated that FVII, FX, FII, and FI are all vital to the process outlining the general mechanism of fibrin formation from the onset of FVII activation. Dynamic mechanical analysis and swelling experiments were used to establish a critical correlation between polymer microstructure and FVII activation. 相似文献
970.
Jokinen R Marttinen P Sandell HK Manninen T Teerenhovi H Wai T Teoli D Loredo-Osti JC Shoubridge EA Battersby BJ 《PLoS genetics》2010,6(10):e1001161
Mitochondrial DNA (mtDNA) sequence variants segregate in mutation and tissue-specific manners, but the mechanisms remain unknown. The segregation pattern of pathogenic mtDNA mutations is a major determinant of the onset and severity of disease. Using a heteroplasmic mouse model, we demonstrate that Gimap3, an outer mitochondrial membrane GTPase, is a critical regulator of this process in leukocytes. Gimap3 is important for T cell development and survival, suggesting that leukocyte survival may be a key factor in the genetic regulation of mtDNA sequence variants and in modulating human mitochondrial diseases. 相似文献