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"Nicholas, Sarah"
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Ethics and integrity in British politics : how citizens judge their politicians' conduct and why it matters
\"Public perceptions of political ethics are at the heart of current political debate. Drawing on original data, this book is the first general account of popular understandings of political ethics in contemporary British politics. It offers new insights into how citizens understand political ethics and integrity and how they form judgments of their leaders. By locating these insights against the backdrop of contemporary British political ethics, the book shows how current institutional preoccupations with standards of conduct all too often miss the mark. While the use of official resources is the primary focus of much regulation, politicians' consistency, frankness and sincerity, which citizens tend to see in terms of right and wrong, are treated as 'normal politics'. The authors suggest that new approaches may need to be adopted if public confidence in politicians' integrity is to be restored\"-- Provided by publisher.
Book
Activin-dependent signaling in fibro/adipogenic progenitors causes fibrodysplasia ossificans progressiva
Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal-dominant disorder characterized by progressive and profoundly disabling heterotopic ossification (HO). Here we show that fibro/adipogenic progenitors (FAPs) are a major cell-of-origin of HO in an accurate genetic mouse model of FOP (
Acvr1
tnR206H
). Targeted expression of the disease-causing type I bone morphogenetic protein (BMP) receptor, ACVR1(R206H), to FAPs recapitulates the full spectrum of HO observed in FOP patients. ACVR1(R206H)-expressing FAPs, but not wild-type FAPs, activate osteogenic signaling in response to activin ligands. Conditional loss of the wild-type
Acvr1
allele dramatically exacerbates FAP-directed HO, suggesting that mutant and wild-type ACVR1 receptor complexes compete for activin ligands or type II BMP receptor binding partners. Finally, systemic inhibition of activin A completely blocks HO and restores wild-type-like behavior to transplanted
Acvr1
R206H/+
FAPs. Understanding the cells that drive HO may facilitate the development of cell-specific therapeutic approaches to inhibit catastrophic bone formation in FOP.
Fibrodysplasia ossificans progressiva is a severe disorder characterized by heterotopic ossification, and is caused by mutations in ACVR1. Here, the authors show that expression of mutant ACVR1 in fibro/adipogenic progenitors recapitulates disease progression, and that this can be halted by systemic inhibition of activin A in mice.
Journal Article
Dictionary of environmental and climate change law
This dictionary defines terms employed in international agreements, national legislation and scholarly legal studies related to comparative and international environmental law and the emerging law of climate change. Each term also includes its pinyin translation in order to facilitate accessing the Mandarin variants of each term.
Book
Iron persistence in a distal hydrothermal plume supported by dissolved–particulate exchange
Hydrothermally sourced dissolved metals have been recorded in all ocean basins. In the oceans’ largest known hydrothermal plume, extending westwards across the Pacific from the Southern East Pacific Rise, dissolved iron and manganese were shown by the GEOTRACES program to be transported halfway across the Pacific. Here, we report that particulate iron and manganese in the same plume also exceed background concentrations, even 4,000 km from the vent source. Both dissolved and particulate iron deepen by more than 350 m relative to
3
He—a non-reactive tracer of hydrothermal input—crossing isopycnals. Manganese shows no similar descent. Individual plume particle analyses indicate that particulate iron occurs within low-density organic matrices, consistent with its slow sinking rate of 5–10 m yr
−1
. Chemical speciation and isotopic composition analyses reveal that particulate iron consists of Fe(
III
) oxyhydroxides, whereas dissolved iron consists of nanoparticulate Fe(
III
) oxyhydroxides and an organically complexed iron phase. The descent of plume-dissolved iron is best explained by reversible exchange onto slowly sinking particles, probably mediated by organic compounds binding iron. We suggest that in ocean regimes with high particulate iron loadings, dissolved iron fluxes may depend on the balance between stabilization in the dissolved phase and the reversibility of exchange onto sinking particles.
The largest known hydrothermal plume moves dissolved iron halfway across the Pacific.
In situ
measurements show that dissolved and particulate iron transport is facilitated by reversible exchange of dissolved iron onto organic compounds.
Journal Article
Classic concepts in anthropology
The late anthropologist Valerio Valeri (1944-98) was best known for his substantial writings on societies of Polynesia and eastern Indonesia. This volume, however, presents a lesser-known side of Valeri's genius through a dazzlingly erudite set of comparative essays on core topics in the history of anthropological theory. Offering masterly discussions of anthropological thought about ritual, fetishism, cosmogonic myth, belief, caste, kingship, mourning, play, feasting, ceremony, and cultural relativism, Classic Concepts in Anthropology, presented here with a critical foreword by Rupert Stasch and Giovanni da Col, will be an eye-opening, essential resource for students and researchers not only in anthropology but throughout the humanities.
Book
Palovarotene reduces heterotopic ossification in juvenile FOP mice but exhibits pronounced skeletal toxicity
Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder characterized by debilitating heterotopic ossification (HO). The retinoic acid receptor gamma agonist, palovarotene, and antibody-mediated activin A blockade have entered human clinical trials, but how these therapeutic modalities affect the behavior of pathogenic fibro/adipogenic progenitors (FAPs) is unclear. Using live-animal luminescence imaging, we show that transplanted pathogenic FAPs undergo rapid initial expansion, with peak number strongly correlating with HO severity. Palovarotene significantly reduced expansion of pathogenic FAPs, but was less effective than activin A inhibition, which restored wild-type population growth dynamics to FAPs. Palovarotene pretreatment did not reduce FAPs’ skeletogenic potential, indicating that efficacy requires chronic administration. Although palovarotene inhibited chondrogenic differentiation in vitro and reduced HO in juvenile FOP mice, daily dosing resulted in aggressive synovial joint overgrowth and long bone growth plate ablation. These results highlight the challenge of inhibiting pathological bone formation prior to skeletal maturation.
Journal Article
Chaos theory
\"After living his life with clockwork precision, a man throws any and all caution to the wind in this freewheeling comedy drama. Frank Allen (Ryan Reynolds) is a successful motivational speaker and author whose book \"The Five-Minute Efficiency Trainer\" advises readers that strict organization and avoiding impulsive behavior is the key to success. Frank is married to Susan (Emily Mortimer), who has been his sweetheart since college, but while he's happy, she's beginning to have second thoughts -- she chose to be with Frank rather than his best friend, Buddy (Stuart Townsend), because of his sweet and gentle nature, but his new habit of carefully budgeting every moment of the day has squeezed most of the fun out of their lives. After a quarrel with Susan leaves Frank in a troubled state of mind, he's enthusiastically propositioned by a sexy woman at a self-help seminar (Sarah Chalke), and has to take a pregnant woman (Jocelyne Loewen) to the hospital when he nearly runs her over on the street. Susan learns about Frank's day and comes to the mistaken conclusion that he's been unfaithful to her with both women. Susan leaves him and Frank decides that his hyper-organized life is to blame for the collapse of his marriage. Suddenly, Frank figures it's time to give his id full reign -- he buys a motorcycle, starts fist fights in bars, sleeps with strange women, takes up streaking, and does nearly everything the old Frank would warn him against\"--Allmovie.com, viewed January 5, 2018.
DVD
Splice factor polypyrimidine tract-binding protein 1 (Ptbp1) primes endothelial inflammation in atherogenic disturbed flow conditions
NF-κB–mediated endothelial activation drives leukocyte recruitment and atherosclerosis, in part through adhesion molecules Icam1 and Vcam1. The endothelium is primed for cytokine activation of NF-κB by exposure to low and disturbed blood flow (LDF)but the molecular underpinnings are not fully understood. In an experimental in vivo model of LDF, platelets were required for the increased expression of several RNA-binding splice factors, including polypyrimidine tract binding protein (Ptbp1). This was coordinated with changes in RNA splicing in the NF-κB pathway in primed cells, leading us to examine splice factors as mediators of priming. Using Icam1 and Vcam1 induction by tumor necrosis factor (TNF)-α stimulation as a readout, we performed a CRISPR Cas9 knockout screen and identified a requirement for Ptbp1 in priming. Deletion of Ptbp1 had no effect on cell growth or response to apoptotic stimuli, but reversed LDF splicing patterns and inhibited NF-κB nuclear translocation and transcriptional activation of downstream targets, including Icam1 and Vcam1. In human coronary arteries, elevated PTBP1 correlates with expression of TNF pathway genes and plaque. In vivo, endothelial-specific deletion of Ptbp1 reduced Icam1 expression and myeloid cell infiltration at regions of LDF in atherosclerotic mice, limiting atherosclerosis. This may be mediated, in part, by allowing inclusion of a conserved alternative exon in Ripk1 leading to a reduction in Ripk1 protein. Our data show that Ptbp1, which is induced in a subset of the endothelium by platelet recruitment at regions of LDF, is required for priming of the endothelium for subsequent NF-κB activation, myeloid cell recruitment and atherosclerosis.
Journal Article
A method for rapid flow-cytometric isolation of endothelial nuclei and RNA from archived frozen brain tissue
Endothelial cells are important contributors to brain development, physiology, and disease. Although RNA sequencing has contributed to the understanding of brain endothelial cell diversity, bulk analysis and single-cell approaches have relied on fresh tissue digestion protocols for the isolation of single endothelial cells and flow cytometry-based sorting on surface markers or transgene expression. These approaches are limited in the analysis of the endothelium in human brain tissues, where fresh samples are difficult to obtain. Here, we developed an approach to examine endothelial RNA expression by using an endothelial-specific marker to isolate nuclei from abundant archived frozen brain tissues. We show that this approach rapidly and reliably extracts endothelial nuclei from frozen mouse brain samples, and importantly, from archived frozen human brain tissues. Furthermore, isolated RNA transcript levels are closely correlated with expression in whole cells from tissue digestion protocols and are enriched in endothelial markers and depleted of markers of other brain cell types. As high-quality RNA transcripts could be obtained from as few as 100 nuclei in archived frozen human brain tissues, we predict that this approach should be useful for both bulk analysis of endothelial RNA transcripts in human brain tissues as well as single-cell analysis of endothelial sub-populations.
Understanding of endothelial functions would be accelerated by methods for the specific isolation of these cells from archived human specimens. Here, the authors use the endothelial transcription factor Erg to isolate nuclei from mouse and human tissues, paving the way for high-throughput characterization of the function of endothelium in homeostasis and disease.
Journal Article
Copa Syndrome: a Novel Autosomal Dominant Immune Dysregulatory Disease
Inherently defective immunity typically results in either ineffective host defense, immune regulation, or both. As a category of primary immunodeficiency diseases, those that impair immune regulation can lead to autoimmunity and/or autoinflammation. In this review we focus on one of the most recently discovered primary immunodeficiencies that leads to immune dysregulation: “Copa syndrome”. Copa syndrome is named for the gene mutated in the disease, which encodes the alpha subunit of the coatomer complex-I that, in aggregate, is devoted to transiting molecular cargo from the Golgi complex to the endoplasmic reticulum (ER). Copa syndrome is autosomal dominant with variable expressivity and results from mutations affecting a narrow amino acid stretch in the
COPA
gene-encoding COPα protein. Patients with these mutations typically develop arthritis and interstitial lung disease with pulmonary hemorrhage representing a striking feature. Immunologically Copa syndrome is associated with autoantibody development, increased Th17 cells and pro-inflammatory cytokine expression including IL-1β and IL-6. Insights have also been gained into the underlying mechanism of Copa syndrome, which include excessive ER stress owing to the impaired return of proteins from the Golgi, and presumably resulting aberrant cellular autophagy. As such it represents a novel cellular disorder of intracellular trafficking associated with a specific clinical presentation and phenotype.
Journal Article