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961.
Daniel P. Mould Ulf Bremberg Allan M. Jordan Matthis Geitmann Alba Maiques-Diaz Alison E. McGonagle Helen F. Small Tim C.P. Somervaille Donald Ogilvie 《Bioorganic & medicinal chemistry letters》2017,27(14):3190-3195
A series of reversible inhibitors of lysine specific demethylase 1 (LSD1) with a 5-hydroxypyrazole scaffold have been developed from compound 7, which was identified from the patent literature. Surface plasmon resonance (SPR) and biochemical analysis showed it to be a reversible LSD1 inhibitor with an IC50 value of 0.23 µM. Optimisation of this compound by rational design afforded compounds with Kd values of <10 nM. In human THP-1 cells, these compounds were found to upregulate the expression of the surrogate cellular biomarker CD86. Compound 11p was found to have moderate oral bioavailability in mice suggesting its potential for use as an in vivo tool compound. 相似文献
962.
Joseph Tillotson Magdalena Kedzior Larissa Guimarães Alison B. Ross Tara L. Peters Andrew J. Ambrose Cody J. Schmidlin Donna D. Zhang Letícia V. Costa-Lotufo Abimael D. Rodríguez Jonathan H. Schatz Eli Chapman 《Bioorganic & medicinal chemistry letters》2017,27(17):4082-4085
Activation of translation initiation is a common trait of cancer cells. Formation of the heterotrimeric eukaryotic initiation factor F (eIF4F) complex is the rate-limiting step in 5′ m7GpppN cap-dependent translation. This trimeric complex includes the eIF4E cap binding protein, the eIF4G scaffolding protein, and the DEAD box RNA helicase eIF4A. eIF4A is an ATP-dependent helicase and because it is the only enzyme in the eIF4F complex, it has been shown to be a potential therapeutic target for a variety of malignancies. To this end, we have used a simple ATPase biochemical screen to survey several hundred marine and terrestrial derived natural products. Herein, we report the discovery of two natural products from marine sources, elisabatin A (1) and allolaurinterol (2), which show low µM inhibition of eIF4A ATPase activity. Enzymological analyses revealed 1 and 2 to be ATP-competitive, and cellular evaluations showed reasonable cytotoxicity against A549 (lung cancer) and MDA-MA-468 (breast cancer) cell lines. However, only compound 2 showed potent inhibition of helicase activity congruent with its ATPase inhibitory activity. 相似文献
963.
Daniel P. Mould Ulf Bremberg Allan M. Jordan Matthis Geitmann Alison E. McGonagle Tim C.P. Somervaille Gary J. Spencer Donald J. Ogilvie 《Bioorganic & medicinal chemistry letters》2017,27(20):4755-4759
As part of our ongoing efforts to develop reversible inhibitors of LSD1, we identified a series of 4-(pyrrolidin-3-yl)benzonitrile derivatives that act as successful scaffold-hops of the literature inhibitor GSK-690. The most active compound, 21g, demonstrated a Kd value of 22 nM and a biochemical IC50 of 57 nM. In addition, this compound displayed improved selectivity over the hERG ion channel compared to GSK-690, and no activity against the related enzymes MAO-A and B. In human THP-1 acute myeloid leukaemia cells, 21g was found to increase the expression of the surrogate cellular biomarker CD86. This work further demonstrates the versatility of scaffold-hopping as a method to develop structurally diverse, potent inhibitors of LSD1. 相似文献
964.
Local genes for local bacteria: Evidence of allopatry in the genomes of transatlantic Campylobacter populations
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Ben Pascoe Guillaume Méric Koji Yahara Helen Wimalarathna Susan Murray Matthew D. Hitchings Emma L. Sproston Catherine D. Carrillo Eduardo N. Taboada Kerry K. Cooper Steven Huynh Alison J. Cody Keith A. Jolley Martin C. J. Maiden Noel D. McCarthy Xavier Didelot Craig T. Parker Samuel K. Sheppard 《Molecular ecology》2017,26(17):4497-4508
The genetic structure of bacterial populations can be related to geographical locations of isolation. In some species, there is a strong correlation between geographical distance and genetic distance, which can be caused by different evolutionary mechanisms. Patterns of ancient admixture in Helicobacter pylori can be reconstructed in concordance with past human migration, whereas in Mycobacterium tuberculosis it is the lack of recombination that causes allopatric clusters. In Campylobacter, analyses of genomic data and molecular typing have been successful in determining the reservoir host species, but not geographical origin. We investigated biogeographical variation in highly recombining genes to determine the extent of clustering between genomes from geographically distinct Campylobacter populations. Whole‐genome sequences from 294 Campylobacter isolates from North America and the UK were analysed. Isolates from within the same country shared more recently recombined DNA than isolates from different countries. Using 15 UK/American closely matched pairs of isolates that shared ancestors, we identify regions that have frequently and recently recombined to test their correlation with geographical origin. The seven genes that demonstrated the greatest clustering by geography were used in an attribution model to infer geographical origin which was tested using a further 383 UK clinical isolates to detect signatures of recent foreign travel. Patient records indicated that in 46 cases, travel abroad had occurred <2 weeks prior to sampling, and genomic analysis identified that 34 (74%) of these isolates were of a non‐UK origin. Identification of biogeographical markers in Campylobacter genomes will contribute to improved source attribution of clinical Campylobacter infection and inform intervention strategies to reduce campylobacteriosis. 相似文献
965.
Colony‐level behavioural variation correlates with differences in expression of the foraging gene in red imported fire ants
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Among social insects, colony‐level variation is likely to be widespread and has significant ecological consequences. Very few studies, however, have documented how genetic factors relate to behaviour at the colony level. Differences in expression of the foraging gene have been associated with differences in foraging and activity of a wide variety of organisms. We quantified expression of the red imported fire ant foraging gene (sifor) in workers from 21 colonies collected across the natural range of Texas fire ant populations, but maintained under standardized, environmentally controlled conditions. Colonies varied significantly in their behaviour. The most active colonies had up to 10 times more active foragers than the least active colony and more than 16 times as many workers outside the nest. Expression differences among colonies correlated with this colony‐level behavioural variation. Colonies with higher sifor expression in foragers had, on average, significantly higher foraging activity, exploratory activity and recruitment to nectar than colonies with lower expression. Expression of sifor was also strongly correlated with worker task (foraging vs. working in the interior of the nest). These results provide insight into the genetic and physiological processes underlying collective differences in social behaviour. Quantifying variation in expression of the foraging gene may provide an important tool for understanding and predicting the ecological consequences of colony‐level behavioural variation. 相似文献
966.
967.
Louis Bernatchez Maren Wellenreuther Cristián Araneda David T. Ashton Julia M.I. Barth Terry D. Beacham Gregory E. Maes Jann T. Martinsohn Kristina M. Miller Kerry A. Naish Jennifer R. Ovenden Craig R. Primmer Ho Young Suk Nina O. Therkildsen Ruth E. Withler 《Trends in ecology & evolution》2017,32(9):665-680
968.
Rebecca M. Trapp Alison M. Bell 《Ethology : formerly Zeitschrift fur Tierpsychologie》2017,123(3):213-220
Social learning is an important process in the spread of information, especially in changing environments where inherited behaviors may not remain relevant. In many species, the decision of whom to trust to have reliable information depends on the relationship between individuals. Many fish species, including three‐spined sticklebacks, preferentially associate with familiar individuals. Previous studies in three‐spined sticklebacks have provided mixed evidence about the effect of familiarity on social learning in this species. Therefore, this study further explores familiarity and social learning in sticklebacks, specifically from a demonstrator‐focused perspective. We found that in a food patch discrimination task, individuals with unfamiliar demonstrators performed significantly better than those with familiar demonstrators. In a problem‐solving task, we found that focal fish attended to the behavior of demonstrators, but we did not detect an effect of familiarity on performance, and indeed the proportion of individuals to solve the task after observing demonstrators was low. These results suggest that sticklebacks have a preference for unfamiliar demonstrators, but that the use of social information varies depending on context. 相似文献
969.
970.
Intraspecific adaptive radiation: Competition,ecological opportunity,and phenotypic diversification within species
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Nicholas A. Levis Ryan A. Martin Kerry A. O'Donnell David W. Pfennig 《Evolution; international journal of organic evolution》2017,71(10):2496-2509
Intraspecific variation in resource‐use traits can have profound ecological and evolutionary implications. Among the most striking examples are resource polymorphisms, where alternative morphs that utilize different resources evolve within a population. An underappreciated aspect of their evolution is that the same conditions that favor resource polymorphism—competition and ecological opportunity—might foster additional rounds of diversification within already existing morphs. We examined these issues in spadefoot toad tadpoles that develop into either a generalist "omnivore" or a specialist "carnivore" morph. Specifically, we assessed the morphological diversity of tadpoles from natural ponds and experimentally induced carnivores reared on alternative diets. We also surveyed natural ponds to determine if the strength of intramorph competition and the diversity and abundance of dietary resources (measures of ecological opportunity) influenced the diversity of within‐morph variation. We found that five omnivore and four carnivore types were present in natural ponds; alternative diets led to shape differences, some of which mirrored variation in the wild; and both competition and ecological opportunity were associated with enhanced morphological diversity in natural ponds. Such fine‐scale intraspecific variation might represent an underappreciated form of biodiversity and might constitute a crucible of evolutionary innovation and diversification. 相似文献