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131.
Cannabinoid type-1 (CB(1)) receptor ligands, derived from the 1,5-diarylpyrazole core template of rimonabant (Acomplia), have been the focus of several studies aimed at examining structure-activity relationships (SARs). The purpose of this study was to design and synthesize a set of compounds based on the 1,5-diarylpyrazole template while focusing on the potential for discovery of CB(1) receptor radioligands that might be used as probes with in vivo molecular imaging. Each synthesized ligand was evaluated for potency as an antagonist at CB(1) and cannabinoid type-2 (CB(2)) receptors in vitro using a GTPgamma(35)S-binding assay. clog P values were calculated with Pallas 3.0. The antagonist binding affinities (K(B)) at CB(1) receptors ranged from 11 to >16,000 nM, CB(1) versus CB(2) selectivities from 0.6 to 773, and clog Ps from 3.61 to 6.25. An interesting new ligand, namely N-(piperidin-1-yl)-1-(2-bromophenyl)-5-(4-methoxyphenyl)-4-methyl-1H-pyrazole-3-carboxamide (9j), emerged from the synthesized set with appealing properties (K(B)=11 nM; CB(1) selectivity>773; clog P=5.85), for labeling with carbon-11 and development as a radioligand for imaging brain CB(1) receptors in vivo with positron emission tomography (PET). 相似文献
132.
Litter decay controlled by temperature,not soil properties,affecting future soil carbon 总被引:3,自引:0,他引:3
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Edward G. Gregorich Henry Janzen Benjamin H. Ellert Bobbi L. Helgason Budong Qian Bernie J. Zebarth Denis A. Angers Ronald P. Beyaert Craig F. Drury Scott D. Duguid William E. May Brian G. McConkey Miles F. Dyck 《Global Change Biology》2017,23(4):1725-1734
Widespread global changes, including rising atmospheric CO2 concentrations, climate warming and loss of biodiversity, are predicted for this century; all of these will affect terrestrial ecosystem processes like plant litter decomposition. Conversely, increased plant litter decomposition can have potential carbon‐cycle feedbacks on atmospheric CO2 levels, climate warming and biodiversity. But predicting litter decomposition is difficult because of many interacting factors related to the chemical, physical and biological properties of soil, as well as to climate and agricultural management practices. We applied 13C‐labelled plant litter to soil at ten sites spanning a 3500‐km transect across the agricultural regions of Canada and measured its decomposition over five years. Despite large differences in soil type and climatic conditions, we found that the kinetics of litter decomposition were similar once the effect of temperature had been removed, indicating no measurable effect of soil properties. A two‐pool exponential decay model expressing undecomposed carbon simply as a function of thermal time accurately described kinetics of decomposition. (R2 = 0.94; RMSE = 0.0508). Soil properties such as texture, cation exchange capacity, pH and moisture, although very different among sites, had minimal discernible influence on decomposition kinetics. Using this kinetic model under different climate change scenarios, we projected that the time required to decompose 50% of the litter (i.e. the labile fractions) would be reduced by 1–4 months, whereas time required to decompose 90% of the litter (including recalcitrant fractions) would be reduced by 1 year in cooler sites to as much as 2 years in warmer sites. These findings confirm quantitatively the sensitivity of litter decomposition to temperature increases and demonstrate how climate change may constrain future soil carbon storage, an effect apparently not influenced by soil properties. 相似文献
133.
Climate change and nesting behaviour in vertebrates: a review of the ecological threats and potential for adaptive responses
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Mark C. Mainwaring Iain Barber Denis C. Deeming David A. Pike Elizabeth A. Roznik Ian R. Hartley 《Biological reviews of the Cambridge Philosophical Society》2017,92(4):1991-2002
Nest building is a taxonomically widespread and diverse trait that allows animals to alter local environments to create optimal conditions for offspring development. However, there is growing evidence that climate change is adversely affecting nest‐building in animals directly, for example via sea‐level rises that flood nests, reduced availability of building materials, and suboptimal sex allocation in species exhibiting temperature‐dependent sex determination. Climate change is also affecting nesting species indirectly, via range shifts into suboptimal nesting areas, reduced quality of nest‐building environments, and changes in interactions with nest predators and parasites. The ability of animals to adapt to sustained and rapid environmental change is crucial for the long‐term persistence of many species. Many animals are known to be capable of adjusting nesting behaviour adaptively across environmental gradients and in line with seasonal changes, and this existing plasticity potentially facilitates adaptation to anthropogenic climate change. However, whilst alterations in nesting phenology, site selection and design may facilitate short‐term adaptations, the ability of nest‐building animals to adapt over longer timescales is likely to be influenced by the heritable basis of such behaviour. We urgently need to understand how the behaviour and ecology of nest‐building in animals is affected by climate change, and particularly how altered patterns of nesting behaviour affect individual fitness and population persistence. We begin our review by summarising how predictable variation in environmental conditions influences nest‐building animals, before highlighting the ecological threats facing nest‐building animals experiencing anthropogenic climate change and examining the potential for changes in nest location and/or design to provide adaptive short‐ and long‐term responses to changing environmental conditions. We end by identifying areas that we believe warrant the most urgent attention for further research. 相似文献
134.
Normal differentiated cells rely primarily on mitochondrial oxidative phosphorylation to produce adenosine triphosphate (ATP) to maintain their viability and functions by using three major bioenergetic fuels: glucose, glutamine and fatty acids. Many cancer cells, however, rely on aerobic glycolysis for their growth and survival, and recent studies indicate that some cancer cells depend on glutamine as well. This altered metabolism in cancers occurs through oncogene activation or loss of tumor suppressor genes in multiple signaling pathways, including the phosphoinositide 3-kinase and Myc pathways. Relatively little is known, however, about the role of fatty acids as a bioenergetic fuel in growth and survival of cancer cells. Here, we report that human glioblastoma SF188 cells oxidize fatty acids and that inhibition of fatty acid β-oxidation by etomoxir, a carnitine palmitoyltransferase 1 inhibitor, markedly reduces cellular ATP levels and viability. We also found that inhibition of fatty acid oxidation controls the NADPH level. In the presence of reactive oxygen species scavenger tiron, however, ATP depletion is prevented without restoring fatty acid oxidation. This suggests that oxidative stress may lead to bioenergetic failure and cell death. Our work provides evidence that mitochondrial fatty acid oxidation may provide NADPH for defense against oxidative stress and prevent ATP loss and cell death. 相似文献
135.
Adak S Yang KS Macdonald-Obermann J Pike LJ 《The Journal of biological chemistry》2011,286(52):45146-45155
The binding of EGF induces dimerization of its receptor, leading to the stimulation of its intracellular tyrosine kinase activity. Kinase activation occurs within the context of an asymmetric dimer in which one kinase domain serves as the activator for the other kinase domain but is not itself activated. How ligand binding is related to the formation and dynamics of this asymmetric dimer is not known. The binding of EGF to its receptor is negatively cooperative--that is, EGF binds with lower affinity to the second site on the dimer than to the first site on the dimer. In this study, we analyzed the binding of (125)I-EGF to a series of EGF receptor mutants in the intracellular juxtamembrane domain and demonstrate that the most membrane-proximal portion of this region plays a significant role in the genesis of negative cooperativity in the EGF receptor. The data are consistent with a model in which the binding of EGF to the first site on the dimer induces the formation of one asymmetric kinase dimer. The binding of EGF to the second site is required to disrupt the initial asymmetric dimer and allow the formation of the reciprocal asymmetric dimer. Thus, some of the energy of binding to the second site is used to reorient the first asymmetric dimer, leading to a lower binding affinity and the observed negative cooperativity. 相似文献
136.
Fei Gao Ru Dai Sharon M. Pike Wenping Qiu Walter Gassmann 《Plant molecular biology》2014,86(4-5):381-393
The molecular interactions between grapevine and the obligate biotrophic fungus Erysiphe necator are not understood in depth. One reason for this is the recalcitrance of grapevine to genetic modifications. Using defense-related Arabidopsis mutants that are susceptible to pathogens, we were able to analyze key components in grapevine defense responses. We have examined the functions of defense genes associated with the salicylic acid (SA) pathway, including ENHANCED DISEASE SUSCEPTIBILITY 1 (EDS1), EDS1-LIKE 2 (EDL2), EDL5 and PHYTOALEXIN DEFICIENT 4 (PAD4) of two grapevine species, Vitis vinifera cv. Cabernet Sauvignon, which is susceptible to E. necator, and V. aestivalis cv. Norton, which is resistant. Both VaEDS1 and VvEDS1 were previously found to functionally complement the Arabidopsis eds1-1 mutant. Here we show that the promoters of both VaEDS1 and VvEDS1 were induced by SA, indicating that the heightened defense of Norton is related to its high SA level. Other than Va/VvEDS1, only VaEDL2 complemented Arabidopsis eds1-1, whereas Va/VvPAD4 did not complement Arabidopsis pad4-1. Bimolecular fluorescence complementation results indicated that Vitis EDS1 and EDL2 proteins interact with Vitis PAD4 and AtPAD4, suggesting that Vitis EDS1/EDL2 forms a complex with PAD4 to confer resistance, as is known from Arabidopsis. However, Vitis EDL5 and PAD4 did not interact with Arabidopsis EDS1 or PAD4, correlating with their inability to function in Arabidopsis. Together, our study suggests a more complicated EDS1/PAD4 module in grapevine and provides insight into molecular mechanisms that determine disease resistance levels in Vitis species native to the North American continent. 相似文献
137.
Tianzhi Yang Tracy Bantegui Kaitlynn Pike Raymond Bloom Roger Phipps 《Journal of liposome research》2014,24(4):270-279
One of the biggest challenges for small interfering RNAs (siRNAs) as therapeutic agents is their insufficient cellular delivery efficiency. We developed long circulating and cationic liposomes to improve the cell uptake and inhibitory effectiveness of siRNA on the expression of vascular endothelial growth factor (VEGF) in cancer cells. SiRNA liposomes were obtained by polyelectrolyte complexation between negatively charged siRNA and positively charged liposome prepared by a hydration method. Gel electrophoresis was used to evaluate the loading efficiency of siRNA on the cationic liposome. The optimized siRNA liposomes were observed to be spherical in shape and had smooth surfaces with particle sizes of 167.7?±?2.0?nm and zeta potentials of 4.03?±?0.69?mV, which had no significant change when stored at 4?°C for three months. Fluorescence-activated cell sorting studies and confocal laser scanning images indicated that the cationic liposomes significantly increased the uptake of fluorescence-labeled siRNA in cancer cells. Effects of the siRNA on the inhibition of VEGF were tested by measuring concentrations of VEGF in cell culture media via an enzyme-linked immunosorbent assay and intracellular VEGF levels using a western blotting method. The liposomal siRNA was significantly effective at inhibiting the expression of VEGF in lung, liver and breast cancer cells. Optimal liposomes could effectively deliver siRNA into cancer cells and inhibit VEGF as a therapy agent. 相似文献
138.
The cytoplasmic domain of Ig alpha is necessary and sufficient to support efficient early B cell development 总被引:3,自引:0,他引:3
Pike KA Iacampo S Friedmann JE Ratcliffe MJ 《Journal of immunology (Baltimore, Md. : 1950)》2004,172(4):2210-2218
The B cell receptor complex (BcR) is essential for normal B lymphocyte function, and surface BcR expression is a crucial checkpoint in B cell development. However, functional requirements for chains of the BcR during development remain controversial. We have used retroviral gene transfer to introduce components of the BcR into chicken B cell precursors during embryonic development. A chimeric heterodimer, in which the cytoplasmic domains of chicken Igalpha and Igbeta are expressed by fusion with the extracellular and transmembrane domains of murine CD8alpha and CD8beta, respectively, targeted the cytoplasmic domains of the BcR to the cell surface in the absence of extracellular BcR domains. Expression of this chimeric heterodimer supported all early stages of embryo B cell development: bursal colonization, clonal expansion, and induction of repertoire diversification by gene conversion. Expression of the cytoplasmic domain of Igalpha, in the absence of the cytoplasmic domain of Igbeta, was not only necessary, but sufficient to support B cell development as efficiently as the endogenous BcR. In contrast, expression of the cytoplasmic domain of Igbeta in the absence of the cytoplasmic domain of Igalpha failed to support B cell development. The ability of the cytoplasmic domain of Igalpha to support early B cell development required a functional Igalpha immunoreceptor tyrosine-based activation motif. These results support a model in which expression of surface IgM following productive V(D)J recombination in developing B cell precursors serves to chaperone the cytoplasmic domain of Igalpha to the B cell surface, thereby initiating subsequent stages of development. 相似文献
139.
For endangered species that persist as apparently isolated populations within a previously more extensive range, the degree of genetic exchange between those populations is critical to conservation and management. A lack of gene flow can exacerbate impacts of threatening processes and delay or prevent colonization of sites after local extirpation. The broad-headed snake, Hoplocephalus bungaroides, is a small venomous species restricted to a handful of disjunct reserves near Sydney, Australia. Mark-recapture studies have indicated low vagility for this ambush predator, suggesting that gene flow also may be low. However, our analyses of 11 microsatellite loci from 163 snakes collected in Morton National Park, from six sites within a 10-km diameter, suggest relatively high rates of gene flow among sites. Most populations exchange genes with each other, with one large population serving as a source area and smaller populations apparently acting as sinks. About half of the juvenile snakes, for which we could reliably infer parentage, were collected from populations other than those in which we collected their putative parents. As expected from the snakes' reliance on rocky outcrops during cooler months of the year, most gene flow appears to be along sandstone plateaux rather than across the densely forested valleys that separate plateaux. The unexpectedly high rates of gene flow on a landscape scale are encouraging for future conservation of this endangered taxon. For example, wildlife managers could conserve broad-headed snakes by restoring habitats near extant source populations in areas predicted to be least affected by future climate change. 相似文献
140.
Russell H. Messing Michelle N. Tremblay Edward B. Mondor Robert G. Foottit Keith S. Pike 《Biological invasions》2007,9(5):601-607
Invasive species have had devastating impacts on the fauna and flora of the Hawaiian Islands. While the negative effects of
some invasive species are obvious, other species are less visible, though no less important. Aphids (Homoptera: Aphididae)
are not native to Hawai’i but have thoroughly invaded the Island chain, largely as a result of anthropogenic influences. As
aphids cause both direct plant feeding damage and transmit numerous pathogenic viruses, it is important to document aphid
distributions and ranges throughout the archipelago. On the basis of an extensive survey of aphid diversity on the five largest
Hawaiian Islands (Hawai’i, Kaua’i, O’ahu, Maui, and Moloka’i), we provide the first evidence that invasive aphids feed not
just on agricultural crops, but also on native Hawaiian plants. To date, aphids have been observed feeding and reproducing
on 64 native Hawaiian plants (16 indigenous species and 48 endemic species) in 32 families. As the majority of these plants
are endangered, invasive aphids may have profound impacts on the island flora. To help protect unique island ecosystems, we
propose that border vigilance be enhanced to prevent the incursion of new aphids, and that biological control efforts be renewed
to mitigate the impact of existing species. 相似文献