1,843 research outputs found

    Identifying and modeling the contribution of nuclear receptors to environmental obesogen-induced toxicity in bone

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    Bone is a dynamic tissue, where bone forming osteoblasts and bone resorbing osteoclasts maintain homeostasis. Research into bone toxicology has largely focused on pharmaceutical side effects adversely affecting bone development. However, many environmental toxicants can regulate bone homeostasis. Recently, the nuclear receptor peroxisome proliferator activated receptor gamma (PPARĪ³) has emerged as an important target of environmental toxicants. PPARĪ³ dimerizes with the retinoid-X receptor alpha (RXRĪ±), is a central transcription factor in adipogenesis, and in bone can transdifferentiate osteoblasts into adipocytes by suppressing osteogenic pathways. The central hypothesis of this dissertation is that environmental chemicals can adversely affect bone homeostasis by activating nuclear receptors in bone cells ā€“ particularly osteoblasts and osteoclasts ā€“ to perturb cellular differentiation and function. Three study aims were developed to test and refine this hypothesis. First, a set of structurally diverse environmental PPARĪ³ agonists were individually applied to mouse primary bone marrow mesenchymal stromal cell cultures undergoing osteogenic differentiation. In vitro PPARĪ³ ligand treatment suppressed osteogenesis and stimulated adipogenesis. Organotin compounds (tributyltin, triphenyltin) in particular more efficaciously suppressed osteogenesis. The second aim characterized the effects of in vivo tributyltin exposure on bone microarchitecture in female C57Bl/6 mice. Tributyltin exposure resulted in a thinner cortical bone, but significantly increased trabecular mineralization. Further analyses suggested that tributyltin did not suppress osteoclast numbers but rather changed osteoclast function, minimally attenuating the resorptive function and enhancing their ability to generate osteogenesis-stimulating factors. Furthermore, tributyltin activated not only PPARĪ³, but also RXR and liver X receptors. The third aim established the utility of Generalized Concentration Addition in modeling PPARĪ³ activation by mixtures of full and partial PPARĪ³ agonists. A complex mixture of multiple phthalate compounds activated an in vitro PPARĪ³ reporter assay, and the individual dose-responses of each compound were used to construct modeled responses. The comparisons of empirical data and model predictions supported the use of Generalized Concentration Addition in modeling a complex mixture of environmental PPARĪ³ agonists. Together, these studies support and establish important toxicological mechanisms related to PPARĪ³ and RXRĪ± activation in different aspects of bone biology and provide a basis for studying mixture effects of PPARĪ³ agonists

    Characterisation of a gene trap integration marking hepatic specification

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    Experienees of a Packer in the Washington Territory Mining Camps During the Sixties

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    "William S. Lewis, Historian, through interviews and conferences with James W. Watt during the past two years, has secured this illuminating and helpful narrative of forceful and dramatic experiences during the placer mining days in Washington Territory, including...

    The Land of Saddle-bags: A Study of the Mountain People of Appalachia

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    This charming account of life in Appalachia at the turn of the century is one of the three most important books from the early twentieth century that, as Dwight Billings writes in his foreword, have ā€œhad a profound and lasting impact on how we think about Appalachia and, indeed, on the fact that we commonly believe that such a place and people can be readily identified.ā€ Originally published in 1924, it was advertised as a ā€œracy book, full of the thrill of mountain adventure and the delicious humor of vigorously human people.ā€ James Watt Raine, professor of English literature and later head of the English and drama departments at Berea College from 1906 until his retirement in 1939, provides eyewitness accounts of mountain speech and folksinging, education, religion, community, politics, and farming. In a conscious effort to dispel the negative stereotype of the drunken, slothful, gun-toting hillbilly prone to violence, Raine presents positive examples from his own experiences among the region\u27s native inhabitants. A lively, first-hand account of a Berea College professor\u27s favorable experience with mountain people. -- Now & Then Will enable modern readers to experience how early-twentieth-century writers viewed the Appalachian region and its people. The foreword, penned by Dwight Billings, is especially outstanding as a modern critique of the work. -- Register of the Kentucky Historical Society First published in 1924, The Land of the Saddle-Bags provides a unique and timeless study of Appalachia and its people. -- The Bourbon Timeshttps://uknowledge.uky.edu/upk_united_states_history/1014/thumbnail.jp

    In defence of democracy: the criminalisation of impersonation

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    This article offers a philosophical justification for the criminalisation of voting as another person (impersonation or, in English law, personation) in public elections by arguing that it involves wrongdoing in the form of anti-democratic behaviour and that the failure to criminalise it will harm the public good of electoral integrity. With regard to harm, the article argues that the failure to criminalise impersonation will eventually result in widespread impersonation, such widespread impersonation undermining electoral integrity, itself instrumental to a number of public goods reflecting the democratic character of any given polity. Finally, the article completes the case for criminalisation by arguing that, in any given jurisdiction, it may be neither effective nor desirable for the entire burden of preventing impersonation to fall onto the civil law, with the result that the criminalisation of impersonation can serve a useful complementary role to the civil law in maintaining electoral integrity
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