125 research outputs found

    Ligand modulation of sidechain dynamics in a wild-type human GPCR

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    GPCRs regulate all aspects of human physiology, and biophysical studies have deepened our understanding of GPCR conformational regulation by different ligands. Yet there is no experimental evidence for how sidechain dynamics control allosteric transitions between GPCR conformations. To address this deficit, we generated samples of a wild-type GPCR (A2AR) that are deuterated apart from 1H/13C NMR probes at isoleucine d1 methyl groups, which facilitated 1H/13C methyl TROSY NMR measurements with opposing ligands. Our data indicate that low [Na+] is required to allow large agonist-induced structural changes in A2AR, and that patterns of sidechain dynamics substantially differ between agonist (NECA) and inverse agonist (ZM241385) bound receptors, with the inverse agonist suppressing fast ps-ns timescale motions at the G protein binding site. Our approach to GPCR NMR creates a framework for exploring how different regions of a receptor respond to different ligands or signaling proteins through modulation of fast ps-ns sidechain dynamics

    Body mass index and age at natural menopause: an international pooled analysis of 11 prospective studies

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    Current evidence on the association between body mass index (BMI) and age at menopause remains unclear. We investigated the relationship between BMI and age at menopause using data from 11 prospective studies. A total of 24,196 women who experienced menopause after recruitment was included. Baseline BMI was categorised according to the WHO criteria. Age at menopause, confirmed by natural cessation of menses for ≥ 12 months, was categorised as < 45 years (early menopause), 45–49, 50–51 (reference category), 52–53, 54–55, and ≥ 56 years (late age at menopause). We used multinomial logistic regression models to estimate multivariable relative risk ratios (RRRs) and 95% confidence intervals (CI) for the associations between BMI and age at menopause. The mean (standard deviation) age at menopause was 51.4 (3.3) years, with 2.5% of the women having early and 8.1% late menopause. Compared with those with normal BMI (18.5–24.9 kg/m2), underweight women were at a higher risk of early menopause (RRR 2.15, 95% CI 1.50–3.06), while overweight (1.52, 1.31–1.77) and obese women (1.54, 1.18–2.01) were at increased risk of late menopause. Overweight and obesity were also significantly associated with around 20% increased risk of menopause at ages 52–53 and 54–55 years. We observed no association between underweight and late menopause. The risk of early menopause was higher among obese women albeit not significant (1.23, 0.89–1.71). Underweight women had over twice the risk of experiencing early menopause, while overweight and obese women had over 50% higher risk of experiencing late menopause

    Key steps for effective breast cancer prevention

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    EPIGEAL INSECT COMMUNITIES AND NOVEL PEST MANAGEMENT STRATEGIES IN PACIFIC NORTHWEST HYBRID POPLAR PLANTATIONS

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    Hybrid poplars are a short rotation woody crop grown for a variety of target markets including paper pulp, saw timber, and biofuels in the Pacific Northwest. Development of pest control strategies within hybrid poplar plantations over the last several decades has focused on controlling foliar feeding herbivores and wood boring pests, and has overlooked the epigeal arthropod community. Understanding this unstudied suite of organisms would allow pest managers to better evaluate the impact their management strategies have on the poplar agroecosystem. Qualitative surveys of the arthropod communities in hybrid poplar plantations and nearby native habitats demonstrated that a greater arthropod diversity persists in the surrounding native areas. Additionally, the poplar plantation's epigeal arthropod community was composed of species found within sampled native areas.Historically poplar research focused on protecting trees in the years following establishment through harvest from emerging pests while discounting cutting mortality by replanting areas of failure. Describing unrooted cutting transplant morality and distribution within newly established planting block could provide a risk assessment tool that growers could utilize to evaluate their potential crop loss. It was determined through the examination of damaged cuttings that several pests were responsible for diminishing establishment success. Identification of these risks led to the development of a management strategy to reduce mortality in newly planted areas. Soaking cuttings in imidacloprid for 48 hrs provided superior herbivore protection for unrooted cuttings until root formation allowed for uptake from chemigation treatments.An additional study was motivated by the increased concern in growing `clear wood' as poplar has migrated from pulp to saw timber. The accompanying renewed interest in reducing insect galleries in mature trees led to the exploration of deploying a mass trapping, or trap out, effort to reduce populations of Prionoxystus robiniae (Lepidoptera Cossidae) in specific areas of a hybrid poplar plantation. We show that a trap out effort of roughly 5 pheromone-baited traps/ha decimated P. robiniae populations in treated areas throughout the trap out effort and three years post application

    James Cather

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    Full length studio portrait of Willa Cather's brother James Cather as a child. Wearing a suit, he stands beside a table made of twigs with his hand on an open publication

    Epigeal insect communities & novel pest management strategies in Pacific Northwest hybrid poplar plantations

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    Hybrid poplars are a short rotation woody crop grown for a variety of target markets including paper pulp, saw timber, and biofuels in the Pacific Northwest. Development of pest control strategies within hybrid poplar plantations over the last several decades has focused on controlling foliar feeding herbivores and wood boring pests, and has overlooked the epigeal arthropod community. Understanding this unstudied suite of organisms would allow pest managers to better evaluate the impact their management strategies have on the poplar agroecosystem. Qualitative surveys of the arthropod communities in hybrid poplar plantations and nearby native habitats demonstrated that a greater arthropod diversity persists in the surrounding native areas. Additionally, the poplar plantation's epigeal arthropod community was composed of species found within sampled native areas. Historically poplar research focused on protecting trees in the years following establishment through harvest from emerging pests while discounting cutting mortality by replanting areas of failure. Describing unrooted cutting transplant morality and distribution within newly established planting block could provide a risk assessment tool that growers could utilize to evaluate their potential crop loss. It was determined through the examination of damaged cuttings that several pests were responsible for diminishing establishment success. Identification of these risks led to the development of a management strategy to reduce mortality in newly planted areas. Soaking cuttings in imidacloprid for 48 hrs provided superior herbivore protection for unrooted cuttings until root formation allowed for uptake from chemigation treatments. An additional study was motivated by the increased concern in growing `clear wood' as poplar has migrated from pulp to saw timber. The accompanying renewed interest in reducing insect galleries in mature trees led to the exploration of deploying a mass trapping, or trap out, effort to reduce populations of Prionoxystus robiniae (Lepidoptera Cossidae) in specific areas of a hybrid poplar plantation. We show that a trap out effort of roughly 5 pheromone-baited traps/ha decimated P. robiniae populations in treated areas throughout the trap out effort and three years post application
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