The unblemished concubine: Representations of Anne Boleyn in the English written word, 2000-2012

Anne Boleyn, the second wife of Henry VIII, has been the subject of fictional and nonfictional historical narratives since her execution in 1536. Although already a contentious figure for her role in Henry VIII’s annulment of his first marriage and England’s ensuing break from the Roman Catholic Church, the nature of her death ensured that she would become a focus of examination, intrigue and scrutiny. This fascination is, in part, fuelled by limited primary source materials, particularly from Boleyn’s perspective; there is an accepted, familiar narrative of her life that is defined by landmark events, however we cannot know precisely how she experienced these events. The reasons for her death are unclear because conclusive evidence confirming either her guilt or her innocence is yet to be uncovered. This combination of fascination and ambiguity means that Anne Boleyn is an apt case study for a consideration of the tensions between history and fiction that appear in all historical narratives. In recent decades, postmodern historiography has highlighted the literary qualities of histories, and scholars such as Hayden White have drawn attention to the narrativisation, emplotment and characterisation that occur in both fictional and non-fictional histories. The role of the historian as author—rather than as objective observer—has been integral to such scholarship. This study examines ten twenty-firstcentury historical narratives, encompassing a range of historical writing, including academic histories, popular biographies, historiographic metafiction and historical fiction. In spite of variations in style, audience, genre and veracity, each of the focus texts constructs both a characterisation of Boleyn and a narrative of her life. A close textual analysis of these narratives reveals that there are representational techniques and practices that are shared by the authors, regardless of their claims to authenticity and accuracy. Thus, the thesis rejects the apparent disjuncture between fictional and non-fictional histories on the basis of their capacity to relate truth, and argues that these texts should each be considered examples of historical writing

Retail promotions and perceptions of R.J. Reynolds' novel dissolvable tobacco in a US test market

<p>Abstract</p> <p>Background</p> <p>With declining cigarette sales, tobacco manufacturers have been developing and marketing new smokeless products, such as R. J. Reynolds' dissolvable tobacco, Camel Sticks, Strips and Orbs. This study assessed the availability, price and point-of-purchase promotional strategies for Camel Dissolvables, and investigated consumer awareness, interest and perception of these products in the Indiana test market.</p> <p>Methods</p> <p>An exploratory retail audit of point-of-purchase promotions was conducted in a random sample of retailers from 6 store categories (n = 81) in the test market area. Data included: store type, location, product placement, forms/flavors carried, price, types and locations of advertisements and promotions, and ad messages. An Awareness-Attitude-Usage (AAU) survey was used to gauge consumer awareness and knowledge of tobacco products including Camel Dissolvables. Respondents were shown promotional materials from a package onsert and perceptions and interest in the Camel Dissolvables were assessed. An Intended Target Survey (ITS) compared subjects' perceptions of ad targets for several non-tobacco products, as well as Camel Snus, Camel No. 9 and Camel Dissolvables. Respondents were asked to identify each ad's intended target category, perceived targetedness, and purchase intent.</p> <p>Results</p> <p>The products were carried by 46% of stores, most frequently gas stations (100%) and convenience stores (75%). They were shelved near smokeless tobacco (70%), cigarettes (25%) or candy (5%). Prices ranged from $3.59 -$4.19 per package; most stores carried at least 1 promotional item. Ad messages included: "Dissolvable Tobacco" (60%). "Free Trial" (24%), "Special Price" (24%), "What's Your Style?" (22%). At 14% of stores, free trial packs of Camel Dissolvables were offered with another Camel purchase. Awareness was reported by 42% of respondents (n = 243), and trial by 3%. Consumer interest was very low, but younger respondents (< 40 years) were more familiar with Camel Dissolvables (60% vs. 45% for those > 40 years, p < .01). Males, as well as current and former smokers had higher rates of interest and trial; only 1% of never smokers reported trial. In the ITS, only for the 3 tobacco product ads, was perceived targetedness for smokers significantly higher than for non-smokers. Smokers and nonsmokers perceived that the ads targeted smokers.</p> <p>Conclusions</p> <p>Current retail promotional strategies for Camel Sticks, Strips & Orbs appear to be targeting a select audience, primarily current smokers. Overall, consumer awareness, interest and trial were low.</p

Sestrin2 is a leucine sensor for the mTORC1 pathway

Leucine is a proteogenic amino acid that also regulates many aspects of mammalian physiology, in large part by activating the mTOR complex 1 (mTORC1) protein kinase, a master growth controller. Amino acids signal to mTORC1 through the Rag guanosine triphosphatases (GTPases). Several factors regulate the Rags, including GATOR1, aGTPase-activating protein; GATOR2, a positive regulator of unknown function; and Sestrin2, a GATOR2-interacting protein that inhibits mTORC1 signaling. We find that leucine, but not arginine, disrupts the Sestrin2-GATOR2 interaction by binding to Sestrin2 with a dissociation constant of 20 micromolar, which is the leucine concentration that half-maximally activates mTORC1. The leucine-binding capacity of Sestrin2 is required for leucine to activate mTORC1 in cells. These results indicate that Sestrin2 is a leucine sensor for the mTORC1 pathway.United States. National Institutes of Health (R01CA103866)United States. National Institutes of Health (AI47389)United States. Department of Defense (W81XWH-07-0448)United States. National Institutes of Health (T32 GM007753)United States. National Institutes of Health (F30 CA189333)United States. National Institutes of Health (F31 CA180271

Structural basis for leucine sensing by the Sestrin2-mTORC1 pathway

Eukaryotic cells coordinate growth with the availability of nutrients through the mechanistic target of rapamycin complex 1 (mTORC1), a master growth regulator. Leucine is of particular importance and activates mTORC1 via the Rag guanosine triphosphatases and their regulators GATOR1 and GATOR2. Sestrin2 interacts with GATOR2 and is a leucine sensor. Here we present the 2.7 angstrom crystal structure of Sestrin2 in complex with leucine. Leucine binds through a single pocket that coordinates its charged functional groups and confers specificity for the hydrophobic side chain. A loop encloses leucine and forms a lid-latch mechanism required for binding. A structure-guided mutation in Sestrin2 that decreases its affinity for leucine leads to a concomitant increase in the leucine concentration required for mTORC1 activation in cells. These results provide a structural mechanism of amino acid sensing by the mTORC1 pathway.United States. Department of Defense (W81XWH-07- 0448)Damon Runyon Cancer Research Foundation (DRG-112-12)National Institutes of Health (U.S.) (Predoctoral Training Grant T32GM007287)National Institutes of Health (U.S.) (Grants R01CA103866, AI47389, T32 GM007753, F30 CA189333, F31 CA180271, and F31 CA189437)United States. Dept. of Defense. Breast Cancer Research Program (Postdoctoral Fellowship BC120208)Massachusetts Institute of Technology. Office of the Dean for Graduate Education (Whitaker Health Sciences Fund Fellowship)Damon Runyon Cancer Research Foundation (Sally Gordon Fellowship DRG-112-12

The phosphatase calcineurin regulates pathological TDP-43 phosphorylation

Detergent insoluble inclusions of TDP-43 protein are hallmarks of the neuropathology in over 90% of amyotrophic lateral sclerosis (ALS) cases and approximately half of frontotemporal dementia (FTLD-TDP) cases. In TDP-43 proteinopathy disorders, lesions containing aggregated TDP-43 protein are extensively post-translationally modified, with phosphorylated TDP-43 (pTDP) being the most consistent and robust marker of pathological TDP-43 deposition. Abnormally phosphorylated TDP-43 has been hypothesized to mediate TDP-43 toxicity in many neurodegenerative disease models. To date several different kinases have been implicated in the genesis of pTDP, but no phosphatases have been shown to reverse pathological TDP-43 phosphorylation. We have identified the phosphatase calcineurin as an enzyme binding to and catalyzing the removal of pathological C-terminal phosphorylation of TDP-43 in vitro. In C. elegans models of TDP-43 proteinopathy, genetic elimination of calcineurin results in accumulation of excess pTDP, exacerbated motor dysfunction, and accelerated neurodegenerative changes. In cultured human cells, treatment with FK506 (tacrolimus), a calcineurin inhibitor, results in accumulation of pTDP species. Lastly, calcineurin co-localizes with pTDP in degenerating areas of the central nervous system in subjects with FTLD-TDP and ALS. Taken together these findings suggest calcineurin acts on pTDP as a phosphatase in neurons. Furthermore, patient treatment with calcineurin inhibitors may have unappreciated adverse neuropathological consequences

Transcultural engagement with Polish memory of the Holocaust while watching Leszek Wosiewicz's Kornblumenblau

Kornblumenblau (Leszek Wosiewicz 1989) is a film that explores the experience of a Polish political prisoner interned at Auschwitz I. It particularly foregrounds issues related to Polish-Jewish relations during the Holocaust in its diegesis. Holocaust films are often discussed in relation to representation and the cultural specificity of their production context. However, this paper suggests thinking about film and topographies, the theme of this issue, not in relation to where a work is produced but in regards to the spectatorial space. It adopts a phenomenological approach to consider how, despite Kornblumenblau's particularly Polish themes, it might address the transcultural spectator and draw attention to the broader difficulties one faces when attempting to remember the Holocaust. Influenced particularly by the writing of Jennifer M. Barker and Laura U. Marks, this paper suggests that film possesses a body ¬¬- a display of intentionality, beyond those presented within the diegesis, which engages in dialogue with the spectator. During the experience of viewing Kornblumenblau, this filmic corporeality draws attention to the difficulties of confronting the Holocaust in particularly haptic ways, as the film points to the unreliability of visual historical sources, relates abject sensations to concentrationary spaces and breaks down as it confronts the scene of the gas chamber

How could different obesity scenarios alter the burden of type 2 diabetes and liver disease in Saudi Arabia?

Introduction Obesity is a major risk factor for type 2 diabetes (T2DM) and liver disease, and obesity-attributable liver disease is a common indication for liver transplant. Obesity prevalence in Saudi Arabia (SA) has increased in recent decades. SA has committed to the WHO ‘halt obesity’ target to shift prevalence to 2010 levels by 2025. We estimated the future benefits of reducing obesity in SA on incidence and costs of T2DM and liver disease under two policy scenarios: 1) SA meets the ‘halt obesity’ target; 2) population body mass index (BMI) is reduced by 1% annually from 2020 to 2040. Methods We developed a dynamic microsimulation of working-age people (20-59 years) in SA between 2010 and 2040. Model inputs included population demographic, disease and healthcare cost data, and relative risks of diseases associated with obesity. In our two policy scenarios, we manipulated population BMI and compared predicted disease incidence and associated healthcare costs to a baseline ‘no change’ scenario. Results Adults 1.15 million combined cases of T2DM, liver disease and liver cancer could be avoided by 2040. Healthcare cost savings for the ‘halt obesity’ and 1% reduction scenarios are 46.7 and 32.8 billion USD, respectively. Discussion/Conclusion SA’s younger working-age population is set to meet the ‘halt obesity’ target, but those aged 35-59 are off-track. Even a modest annual 1% BMI reduction could result in substantial future health and economic benefits. Our findings strongly support universal initiatives to reduce population-level obesity, with targeted initiatives for working-age people ≥35 years of age

Airborne dust and high temperatures are risk factors for invasive bacterial disease

Background The Sahel region of West Africa has the highest bacterial meningitis attack and case fatality rate in the world. The effect of climatic factors on patterns of invasive respiratory bacterial disease is not well documented. Objective We aimed to assess the link between climatic factors and occurrence of invasive respiratory bacterial disease in a Sahel region of Niger. Methods We conducted daily disease surveillance and climatic monitoring over an 8-year period between January 1, 2003, and December 31, 2010, in Niamey, Niger, to determine risk factors for bacterial meningitis and invasive bacterial disease. We investigated the mechanistic effects of these factors on Streptococcus pneumoniae infection in mice. Results High temperatures and low visibility (resulting from high concentrations of airborne dust) were identified as significant risk factors for bacterial meningitis. Dust inhalation or exposure to high temperatures promoted progression of stable asymptomatic pneumococcal nasopharyngeal carriage to pneumonia and invasive disease. Dust exposure significantly reduced phagocyte-mediated bacterial killing, and exposure to high temperatures increased release of the key pneumococcal toxin pneumolysin through increased bacterial autolysis. Conclusion Our findings show that climatic factors can have a substantial influence on infectious disease patterns, altering density of pneumococcal nasopharyngeal carriage, reducing phagocytic killing, and resulting in increased inflammation and tissue damage and consequent invasiveness. Climatic surveillance should be used to forecast invasive bacterial disease epidemics, and simple control measures to reduce particulate inhalation might reduce the incidence of invasive bacterial disease in regions of the world exposed to high temperatures and increased airborne dust

BiCyCLE NMES—neuromuscular electrical stimulation in the perioperative treatment of sarcopenia and myosteatosis in advanced rectal cancer patients: design and methodology of a phase II randomised controlled trial

Abstract: Background: Colorectal cancer is associated with secondary sarcopenia (muscle loss) and myosteatosis (fatty infiltration of muscle) and patients who exhibit these host characteristics have poorer outcomes following surgery. Furthermore, patients, who undergo curative advanced rectal cancer surgery such as pelvic exenteration, are at risk of skeletal muscle loss due to immobility, malnutrition and a post-surgical catabolic state. Neuromuscular electrical stimulation (NMES) may be a feasible adjunctive treatment to help ameliorate these adverse side-effects. Hence, the purpose of this study is to investigate NMES as an adjunctive pre- and post-operative treatment for rectal cancer patients in the radical pelvic surgery setting and to provide early indicative evidence of efficacy in relation to key health outcomes. Method: In a phase II, double-blind, randomised controlled study, 58 patients will be recruited and randomised (1:1) to either a treatment (NMES plus standard care) or placebo (sham-NMES plus standard care) group. The intervention will begin 2 weeks pre-operatively and continue for 8 weeks after exenterative surgery. The primary outcome will be change in mean skeletal muscle attenuation, a surrogate marker of myosteatosis. Sarcopenia, quality of life, inflammatory status and cancer specific outcomes will also be assessed. Discussion: This phase II randomised controlled trial will provide important preliminary evidence of the potential for this adjunctive treatment. It will provide guidance on subsequent development of phase 3 studies on the clinical benefit of NMES for rectal cancer patients in the radical pelvic surgery setting. Trial registration: Protocol version 6.0; 05/06/20. ClinicalTrials.gov NCT04065984. Registered on 22 August 2019; recruiting