1,053 research outputs found

    Nuclear-receptor–mediated regulation of drug– and bile-acid–transporter proteins in gut and liver

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    This is an Accepted Manuscript of an article published by Taylor & Francis in Drug Metabolism Reviews on 2015 Sep 2, available online: http://www.tandfonline.com/10.3109/03602532.2012.748793.Adverse drug events (ADEs) are a common cause of patient morbidity and mortality and are classically thought to result, in part, from variation in expression and activity of hepatic enzymes of drug metabolism. It is now known that alterations in the expression of genes that encode drug- and bile-acid–transporter proteins in both the gut and liver play a previously unrecognized role in determining patient drug response and eventual clinical outcome. Four nuclear receptor (NR) superfamily members, including pregnane X receptor (PXR, NR1I2), constitutive androstane receptor (NR1I3), farnesoid X receptor (NR1H4), and vitamin D receptor (NR1I1), play pivotal roles in drug- and bile-acid– activated programs of gene expression to coordinately regulate drug- and bile-acid transport activity in the intestine and liver. This review focuses on the NR-mediated gene activation of drug and bile-acid transporters in these tissues as well as the possible underlying molecular mechanisms

    Activation of the JAK-STAT pathway is necessary for desensitization of 5-HT2A receptor-stimulated phospholipase C signalling by olanzapine, clozapine and MDL 100907

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    This is the publisher's version, also available electronically from http://journals.cambridge.org/action/displayAbstract?fromPage=online&aid=5564880&fileId=S1461145708009590We have previously demonstrated that olanzapine-induced desensitization of 5-HT2A receptor-stimulated phospholipase C (PLC) activity is associated with increases in RGS7 protein levels both in vivo and in cells in culture, and the increase in RGS7 is dependent on activation of the JAK-STAT pathway in cells in culture. In the present study, we found that desensitization of 5-HT2A receptor-stimulated PLC activity induced by olanzapine is dependent on activation of the JAK-STAT pathway. Similar to olanzapine, clozapine-induced desensitization of 5-HT2A receptor signalling is accompanied by increases in RGS7 and activation of JAK2. Treatment with the selective 5-HT2A receptor antagonist MDL 100907 also increased RGS7 protein levels and JAK2 activation. Using a JAK2 inhibitor AG490, we found that clozapine and MDL 100907-induced increases in RGS7 are dependent on activation of the JAK-STAT pathway. Olanzapine, clozapine, and MDL 100907 treatment increased mRNA levels of RGS7. Using a chromatin immunoprecipitation assay we found STAT3 binding to the putative RGS7 promoter region. Taken together, olanzapine-induced activation of the JAK-STAT pathway, and STAT3 binding to the RGS7 gene could underlie the increase in RGS7 mRNA which could subsequently increase protein expression. Furthermore, the increase in RGS7 protein could play a role in the desensitization of 5-HT2A receptor signalling by terminating the activated Gαq/11 proteins more rapidly. Overall, our data suggest that the complete desensitization of 5-HT2A receptor-stimulated PLC activity by olanzapine, clozapine and MDL 100907 requires activation of the JAK-STAT pathway, which in turn increases RGS7 expression probably by direct transcriptional activity of STAT3

    Canine presumed glial brain tumours treated with radiotherapy: Is there an inferior outcome in tumours contacting the subventricular zone?

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    Post-treatment outcome in canine glial tumours is described with a broad range of survival times between 2 and 28 months. After surgery or radiation therapy, the tumours may progress locally or spread within the central nervous system. It is unknown if tumour- or patient-specific factors influence prognosis. In humans, glioblastoma involving the subventricular zone has been found to recur distantly, with shortened time to progression and overall survival. We included 32 dogs irradiated for a presumptive primary glial brain tumour in this retrospective cohort study. Tumours were grouped relative to subventricular zone contact and overt ventricular invasion assessing pre-treatment magnetic resonance images. Median time to progression (TTP) for all cases was 534 days (95%CI, 310–758), with a significantly shorter TTP in dogs with lesions at the subventricular zone (median TTP, 260 vs. 687 days; p =.049). Tumours at the subventricular zone progressed more often (p =.001), and more likely as CNS-metastasis (52.9% vs. 13.3%, p =.028). Median overall survival (OS) was 489 days (95%CI, 147–831) and median tumour-specific survival 609 days (95%CI, 382–835). Involvement of the subventricular zone was significantly associated with a shorter tumour-specific survival (median, 306 vs. 719 days; p =.044). Glial tumours contacting the subventricular zone in dogs have a shorter tumour-specific survival and a higher rate of progression and CNS-metastasis. Despite local tumour control, metastasis must be considered and should prompt further treatment approaches

    Counteracting Green Alder Shrub Expansion by Low-Input Grazing

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    In the past decades, the decline of traditional agriculture has caused an abandonment of marginal pastures in many mountain areas of Europe. In the Swiss Alps, green alder (Alnus viridis) is the most abundant successional shrub. A survey of 24 pasture-shrub gradients showed that the encroachment by green alder, in contrast to other shrubs, is associated with a substantial decline in plant species richness. The understorey of alder is primarily populated by very few, broad-leaved herbaceous species benefitting from the atmospheric nitrogen fixed by actinomycetes in symbiosis with green alder. However, the understory vegetation also provides an underestimated forage, rich in protein and comparable in productivity and digestibility to nearby open pastures. A two-year grazing experiment with cattle (Dexter), sheep (local Engadine sheep) and mixed-breed goats in the Eastern Swiss Alps demonstrated that robust breeds were able to exploit these resources as they readily penetrated the thickets. The Engadine sheep and the goats consumed green alder bark and thus actively counteracted shrub encroachment. Dexter cattle did not forage on alder bark but on leaves and opened the thickets by their movement through them. Since goats preferred other woody species to green alder and depleted them before the alder, they may impair the regeneration of late-successional forest. Dexter heifers and Engadine lambs performed equally well on pastures with high shrub cover and on open pastures in terms of average daily weight gain, carcass and meat quality. This was facilitated by the comparatively low productivity of these breeds. In this way, low-input grazing systems utilizing adapted breeds, especially sheep, can add to conservation goals and sustain a viable meat production in marginal areas

    2007-2010), the Mid-Atlantic Bight (MAB; 2009-2010) and the South Atlantic Bight (SAB; 2010-2011)

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    a b s t r a c t Large pelagic predators were used as biological samplers to gain information on cephalopod diversity, abundance, distribution, and their role as prey in the Northwest Atlantic Ocean. Fish predators were caught by recreational anglers in offshore waters of New Englan

    The role of sand lances (Ammodytes sp.) in the Northwest Atlantic ecosystem: a synthesis of current knowledge with implications for conservation and management

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    © The Author(s), 2020. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Staudinger, M. D., Goyert, H., Suca, J. J., Coleman, K., Welch, L., Llopiz, J. K., Wiley, D., Altman, I., Applegate, A., Auster, P., Baumann, H., Beaty, J., Boelke, D., Kaufman, L., Loring, P., Moxley, J., Paton, S., Powers, K., Richardson, D., Robbins, J., Runge, J., Smith, B., Spiegel, C., & Steinmetz, H. The role of sand lances (Ammodytes sp.) in the Northwest Atlantic ecosystem: a synthesis of current knowledge with implications for conservation and management. Fish and Fisheries, 00, (2020): 1-34, doi:10.1111/faf.12445.The American sand lance (Ammodytes americanus, Ammodytidae) and the Northern sand lance (A. dubius, Ammodytidae) are small forage fishes that play an important functional role in the Northwest Atlantic Ocean (NWA). The NWA is a highly dynamic ecosystem currently facing increased risks from climate change, fishing and energy development. We need a better understanding of the biology, population dynamics and ecosystem role of Ammodytes to inform relevant management, climate adaptation and conservation efforts. To meet this need, we synthesized available data on the (a) life history, behaviour and distribution; (b) trophic ecology; (c) threats and vulnerabilities; and (d) ecosystem services role of Ammodytes in the NWA. Overall, 72 regional predators including 45 species of fishes, two squids, 16 seabirds and nine marine mammals were found to consume Ammodytes. Priority research needs identified during this effort include basic information on the patterns and drivers in abundance and distribution of Ammodytes, improved assessments of reproductive biology schedules and investigations of regional sensitivity and resilience to climate change, fishing and habitat disturbance. Food web studies are also needed to evaluate trophic linkages and to assess the consequences of inconsistent zooplankton prey and predator fields on energy flow within the NWA ecosystem. Synthesis results represent the first comprehensive assessment of Ammodytes in the NWA and are intended to inform new research and support regional ecosystem‐based management approaches.This manuscript is the result of follow‐up work stemming from a working group formed at a two‐day multidisciplinary and international workshop held at the Parker River National Wildlife Refuge, Massachusetts in May 2017, which convened 55 experts scientists, natural resource managers and conservation practitioners from 15 state, federal, academic and non‐governmental organizations with interest and expertise in Ammodytes ecology. Support for this effort was provided by USFWS, NOAA Stellwagen Bank National Marine Sanctuary, U.S. Department of the Interior, U.S. Geological Survey, Northeast Climate Adaptation Science Center (Award # G16AC00237), an NSF Graduate Research Fellowship to J.J.S., a CINAR Fellow Award to J.K.L. under Cooperative Agreement NA14OAR4320158, NSF award OCE‐1325451 to J.K.L., NSF award OCE‐1459087 to J.A.R, a Regional Sea Grant award to H.B. (RNE16‐CTHCE‐l), a National Marine Sanctuary Foundation award to P.J.A. (18‐08‐B‐196) and grants from the Mudge Foundation. The contents of this paper are the responsibility of the authors and do not necessarily represent the views of the National Oceanographic and Atmospheric Administration, U.S. Fish and Wildlife Service, New England Fishery Management Council and Mid‐Atlantic Fishery Management Council. This manuscript is submitted for publication with the understanding that the United States Government is authorized to reproduce and distribute reprints for Governmental purposes. Any use of trade, firm or product names is for descriptive purposes only and does not imply endorsement by the U.S. Government

    Different effects of dual task demands on the speech of young and older adults

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    This is an electronic version of an article published in Kemper, S., Herman, R. E., Nartowicz, J.(2005). Different effects of dual task demands on the speech of young and older adults. Aging, Neuropsychology, and Cognition, 12, 340-358. PM#1410812. Aging, Neuropsychology, and Cognition is available online at www.taylorandfrancis.comYoung and older adults provided language samples in response to elicitation questions while concurrently performing 3 different tasks. The language samples were scored on three dimensions: fluency, grammatical complexity, and content. Previous research has shown that older adults use a restricted speech register that is grammatically less complex than young adults’ and has suggested that this restricted speech register is buffered from the costs of dual task demands. This hypothesis was tested by comparing language samples collected during a baseline condition with those produced while the participants were performing the concurrent tasks. The results indicate that young and older adults adopt different strategies when confronted with dual task demands. Young adults shift to a restricted speech register when confronted with dual task demands. Older adults, who were already using a restricted speech register, became less fluent although the grammatical complexity and informational content of their speech was preserved. Hence, some but not all aspects of older adults’ speech are buffered from dual task demands
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