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Background Individuals on the autism spectrum have been long described to process sensory information differently than neurotypical individuals. While much effort has been leveraged towards characterizing and investigating the neurobiology underlying the sensory differences of autism, there has been a notable lack of consistency in the terms being used to describe the nature of those differences. Main body We argue that inconsistent and interchangeable terminology-use when describing the sensory differences of autism has become problematic beyond mere pedantry and inconvenience. We begin by highlighting popular terms that are currently being used to describe the sensory differences of autism (e.g. “sensitivity”, “reactivity” and “responsivity”) and discuss why poor nomenclature may hamper efforts towards understanding the aetiology of sensory differences in autism. We then provide a solution to poor terminology-use by proposing a hierarchical taxonomy for describing and referring to various sensory features. Conclusion Inconsistent terminology-use when describing the sensory features of autism has stifled discussion and scientific understanding of the sensory differences of autism. The hierarchical taxonomy proposed was developed to help resolve lack of clarity when discussing the sensory differences of autism and to place future research targets at appropriate levels of analysis.

A wealth of evidence shows that exposure to the natural environment and nature-based learning can benefit children’s physical, mental, social, and emotional health. Despite this, children are spend...

This article argues that Michel Houellebecq is an écrivain médiatique, a media author, and examines how and why he engages in a type of authorial strategy that relies on more than the text and presents the author as a multimedia, visible and culturally relevant figure. It will address how Houellebecq attempts to situate and justify this media-focused and author-centric strategy, showing how this reflects a broader sociocultural shift. The article will first deal with the concept of media authorship, defining and situating it, to show how Houellebecq can productively be understood as an écrivain médiatique. The type of authorship that Houellebecq represents through use of more than the text but media activities and opportunities for visibility presents us with an epistemological need to reassess literary authorship in the media age. This article engages with critical tools that are able to address new authorial strategies. Firstly, this article will address Jérôme Meizoz’s concept of posturing (2007) as a productive lens through which to understand Houellebecq's polemical public persona as it oscillates in and out of his novels. In doing so, the article considers how his posturing indicates a reliance on visibility for success in the contemporary sociocultural context. Secondly, the article examines the range of Houellebecq’s multimedia activities and creations beyond the text, including adaptations, albums, exhibitions, films, photography, and media appearances, decentring the text as part of a broader transmedial whole, using Richard Saint-Gelais’ concept of transmediality (2011). This will show how Houellebecq is producing a multimedia world beyond the text and constructing himself as more than an author. Finally, this article discusses the evocation of social discourse, to use Marc Angenot’s term (1989), in Houellebecq’s works as a means to present a digital and mass media orientated cultural context in order to justify and rationalise his media-focused acts. These tools provide a framework that enables us to better evidence and understand Houellebecq’s focus beyond the text. This strategy for successful authorship, reliant on mediatisation and multimedia, reflects the challenges of the cultural domination of mass media and new technologies of the Digital Age and indicates that the autonomy of the literary field is diminishing as it comes under the increased influence of industry, and other media forms and cultural fields. This article will show how a superficially transgressive engagement with the media and multimedia in fact reflects consent to the dynamics and values of the contemporary sociocultural context.

With benefits to patient outcomes, provider burden, and health system costs, the goal of reducing hospital readmissions for patients with diabetes mellitus (DM) is multifaceted. Current studies have neither elucidated a clear approach to accurately identify at-risk patients nor implemented reliable interventions to significantly reduce readmissions. We trialed a Quality Improvement project utilizing a diabetes Nurse Practitioner (NP)/Certified Diabetes Care and Education Specialist (CDCES) to see at-risk patients during initial hospitalization and in close clinic follow-up after discharge with an endpoint of reducing future readmissions. Over 21 months, 79 hospitalized patients with DM were identified as high-risk for readmission. Identifying factors included previous admission, DKA/HHS, new DM diagnosis, new to insulin, high-dose steroid use, or provider discretion. The NP/CDCES provided DM management, education, and coordinated discharge. Patients were called shortly after discharge and had a 2-4 week clinic follow-up with the NP/CDCES. The primary endpoint was number of readmissions 180 days post-discharge after NP/CDCES intervention versus number of previous readmissions pre-intervention. Change in hemoglobin A1C, time to post-hospital phone call, and time to outpatient follow-up were also evaluated. Pre- and post-intervention readmission rates remained unchanged; average pre-intervention readmissions per patient was 1.7 versus 1.88 post-intervention readmissions (p=0.74). However, a secondary endpoint of reduction in A1C was statistically significant, with a mean decrease in A1C of 0.97% per patient (p=0.0025). Time to post-hospital phone call and early follow-up did not affect readmission rates. While targeted inpatient-to-outpatient intervention for high-risk patients with DM did not reduce readmission rates, our data suggests coordinated inpatient intervention with close hospital follow-up may improve A1C in high-risk patients with diabetes. Disclosure A. Harris: None. K. Grdinovac: None.

To mitigate the harmful effects of stormwater runoff, many cities in the United States are constructing green stormwater infrastructure (GSI), yet the varied perceptions of GSI by local municipal m...

Abstract. Anabolic Androgenic Steroids (AAS) usage has been repeatedly linked with a body image disorder called Muscle Dysmorphia (MD). However, evidence for how this relationship manifests is currently inconclusive. This study focused on the extent to which MD may precipitate or perpetuate the use of AAS. Utilizing a cross-sectional design, the sample consisted of 57 users (current and lifetime) and 51 non-using (never used AAS) bodybuilders recruited from two bodybuilding dedicated gymnasiums located in Wales, UK. Significantly higher levels of MD were found in users compared to non-users across training experience duration (0–2, 3–5, and 6+ years). MD levels irrespective of AAS usage (users vs. non-users) were consistent between 0–2 and 3–5 years of training declining however between those of 6+ years training experience. No differences were reported in symptoms of MD between users of AAS with varying lengths of AAS use exposure. This provides preliminary evidence suggesting MD may influence both initiation and maintenance of AAS use; however, neither regular gym attendance nor prolonged AAS usage may exacerbate MD symptoms.

Fetal stroke is an important cause of cerebral palsy but is difficult to diagnose unless imaging is undertaken in pregnancies at risk because of known maternal or fetal disorders. Fetal ultrasound or magnetic resonance imaging may show haemorrhage or ischaemic lesions including multicystic encephalomalacia and focal porencephaly. Serial imaging has shown the development of malformations including schizencephaly and polymicrogyra after ischaemic and haemorrhagic stroke. Recognised causes of haemorrhagic fetal stroke include alloimmune and autoimmune thrombocytopaenia, maternal and fetal clotting disorders and trauma but these are relatively rare. It is likely that a significant proportion of periventricular and intraventricular haemorrhages are of venous origin. Recent evidence highlights the importance of arterial endothelial dysfunction, rather than thrombocytopaenia, in the intraparenchymal haemorrhage of alloimmune thrombocytopaenia. In the context of placental anastomoses, monochorionic diamniotic twins are at risk of twin twin transfusion syndrome (TTTS), or partial forms including Twin Oligohydramnios Polyhydramnios Sequence (TOPS), differences in estimated weight (selective Intrauterine growth Retardation; sIUGR), or in fetal haemoglobin (Twin Anaemia Polycythaemia Sequence; TAPS). There is a very wide range of ischaemic and haemorrhagic injury in a focal as well as a global distribution. Acute twin twin transfusion may account for intraventricular haemorrhage in recipients and periventricular leukomalacia in donors but there are additional risk factors for focal embolism and cerebrovascular disease. The recipient has circulatory overload, with effects on systemic and pulmonary circulations which probably lead to systemic and pulmonary hypertension and even right ventricular outflow tract obstruction as well as the polycythaemia which is a risk factor for thrombosis and vasculopathy. The donor is hypovolaemic and has a reticulocytosis in response to the anaemia while maternal hypertension and diabetes may influence stroke risk. Understanding of the mechanisms, including the role of vasculopathy, in well studied conditions such as alloimmune thrombocytopaenia and monochorionic diamniotic twinning may lead to reduction of the burden of antenatally sustained cerebral palsy.

Mame-Fatou Niang’s Identites francaises: Banlieues, feminites et universalisme discusses contemporary notions of identity, belonging and marginalization in order to ‘interroger l’ecart entre les pe...

Findings – The chapter argues that in some situations there are good and perhaps compelling moral reasons for researchers to take action when they observe certain problematic drinking behaviour. Researchers who fail to notice and/or act may be morally blameworthy and culpable in other ways, e.g. in breach of contract or code of conduct.

There is a plethora of published research reporting the wealth and breadth of biopsychosocial benefits of physical activity; however, a recent Cochrane systematic review concluded insufficient evidence for current population level physical activity interventions, citing scalability as a major contributory factor, with many of the interventions failing to reach a substantial proportion of the community. The current study aimed to conduct a pilot evaluation of a technology-enabled, gamification-based intervention called Beat the Street and sought to examine the impact of the Beat the Street intervention on self-reported physical activity.In total, n = 329 people completed the International Physical Activity Questionnaire Short Form (I-PAQ-SF) in full at baseline (before the intervention) and follow-up (immediately following the 7-week intervention).Overall, participants increased their weekly walking by +180 minutes per week (P 0.001) and their weekly physical activity by +335 minutes per week (P 0001). Vigorous activity increased by +48 minutes per week (P = 0.004) and moderate activity increased by +60 minutes per week (P 0.001).The findings provide preliminary evidence that the Beat the Street intervention may be a promising approach to increasing physical activity at a community-wide level and warrants further investigation.

Introduction Active travel (i.e., walking, cycling, scooting, or wheeling to/from school or work) positively impacts the physical activity and health of individuals and can help reduce congestion, air pollution and climate change. In recent years, evidence has emerged which suggests gamification may be a promising approach to encourage people to be more physically active. However, evidence in this area still remains sparse and little is known about the extent to which these programs encourage active travel, or leisure time activity. Methods This study used a range of complimentary methods (including self-report, observational and objective measures), to identify the extent to which a gamification based intervention ‘Beat the Street’ increased active travel. Results Throughout intervention, 53% of all activity undertaken was during typical travel to/from school and work periods. Following the intervention, the proportion of players reporting low levels of activity (less than 30 min per week) decreased by 7%, whereas the proportion reporting high levels of activity (150 or more minutes per week) increased by 13%. Finally, between pre- and post-intervention 53% fewer cars and vans were monitored travelling along a target road during morning commute times, and 33% fewer cars and 20% fewer vans were monitored during afternoon commute times. Conclusions This study provides evidence that gamification can increase activite travel, although more research is needed into the precise gamification components (i.e., leader boards, points, badges) which are most important for stimulating behaviour change.

IntroductionTourette’s syndrome (TS) affects approximately 1% of children. This study will determine the efficacy and safety of paired comprehensive behavioural intervention for tics (CBIT) plus repetitive transcranial magnetic stimulation (rTMS) treatment in children with Tourette’s syndrome. We hypothesise that CBIT and active rTMS to the supplementary motor area (SMA) will (1) decrease tic severity, and (2) be associated with changes indicative of enhanced neuroplasticity (eg, changes in in vivo metabolite concentrations and TMS neurophysiology measures).Methods and analysisThis study will recruit 50 youth with TS, aged 6–18 for a phase II, double-blind, block randomised, sham-controlled trial comparing active rTMS plus CBIT to sham rTMS plus CBIT in a 1:1 ratio. The CBIT protocol is eight sessions over 10 weeks, once a week for 6 weeks and then biweekly. The rTMS protocol is 20 sessions of functional MRI-guided, low-frequency (1 Hz) rTMS targeted to the bilateral SMA over 5 weeks (weeks 2–6). MRI, clinical and motor assessments and neurophysiological evaluations including motor mapping will be performed 1 week before CBIT start, 1 week after rTMS treatment and 1 week after CBIT completion. The primary outcome measure is Tourette’s symptom change from baseline to post-CBIT treatment, as measured by the Yale Global Tic Severity Scale. Secondary outcomes include changes in imaging, neurophysiological and behavioural markers.Ethics and disseminationEthical approval by the Conjoint Health Research Ethics Board (REB18-0220). The results of this study will be published in peer-reviewed scientific journals, on ClinicalTrials.gov and shared with the Tourette and OCD Alberta Network. The results will also be disseminated through the Alberta Addictions and Mental Health Research Hub.Trial registrationNCT03844919.

Background The CTOT-11 (Prevention of Cardiac Allograft Vasculopathy Using Rituximab Therapy in Cardiac Transplantation [Clinical Trials in Organ Transplantation-11]) study was a randomized, placebo-controlled, multicenter, double-blinded clinical trial in nonsensitized primary heart transplant (HTX) recipients. Objectives The study sought to determine whether B cell depletion therapy would attenuate the development of cardiac allograft vasculopathy. Methods A total of 163 HTX recipients were randomized to rituximab 1,000 mg intravenous or placebo on days 0 and 12 post-transplant. Primary outcome was change in percent atheroma volume (PAV) from baseline to 1 year measured by intravascular ultrasound. Secondary outcomes included treated episodes of acute rejection, de novo anti-HLA antibodies (including donor-specific antibodies), and phenotypic differentiation of B cells. Results There were no significant differences at study entry between the rituximab and placebo groups. Paired intravascular ultrasound measures were available at baseline and 1 year in 86 subjects (49 rituximab, 37 placebo). The mean ± SD change in PAV at 12 months was +6.8 ± 8.2% rituximab versus +1.9 ± 4.4% placebo (p = 0.0019). Mortality at 12 months was 3.4% rituximab versus 6.8% placebo (p = 0.47); there were no retransplants or post-transplant lymphoproliferative disorder. The rate of treated rejection was 24.7% rituximab versus 32.4% placebo (p = 0.28). Rituximab therapy effectively eliminated CD20+/CD19+ B cells followed by a gradual expansion of a CD19– cell population in the rituximab-treated group. Conclusions A marked, unexpected increase in coronary artery PAV with rituximab was observed during the first year in HTX recipients. One-year mortality was not impacted; however, longer-term follow-up and mechanistic explanations are required. (Prevention of Cardiac Allograft Vasculopathy Using Rituximab [Rituxan] Therapy in Cardiac Transplantation; NCT01278745)

Programme card In the UK, total adult physical activity has fallen from 216 Metabolic Equivalent of Task (MET)-hours per week in 1961 to 173 MET-hours per week in 2005 (a 20% decline).1 If current …

Fetal stroke is an important cause of cerebral palsy but is difficult to diagnose unless imaging is undertaken in pregnancies at risk because of known maternal or fetal disorders. Fetal ultrasound or magnetic resonance imaging may show haemorrhage or ischaemic lesions including multicystic encephalomalacia and focal porencephaly. Serial imaging has shown the development of malformations including schizencephaly and polymicrogyra after ischaemic and haemorrhagic stroke. Recognised causes of haemorrhagic fetal stroke include alloimmune and autoimmune thrombocytopaenia, maternal and fetal clotting disorders and trauma but these are relatively rare. It is likely that a significant proportion of periventricular and intraventricular haemorrhages are of venous origin. Recent evidence highlights the importance of arterial endothelial dysfunction, rather than thrombocytopaenia, in the intraparenchymal haemorrhage of alloimmune thrombocytopaenia. In the context of placental anastomoses, monochorionic diamniotic twins are at risk of twin twin transfusion syndrome (TTTS), or partial forms including Twin Oligohydramnios Polyhydramnios Sequence (TOPS), differences in estimated weight (selective Intrauterine growth Retardation; sIUGR), or in fetal haemoglobin (Twin Anaemia Polycythaemia Sequence; TAPS). There is a very wide range of ischaemic and haemorrhagic injury in a focal as well as a global distribution. Acute twin twin transfusion may account for intraventricular haemorrhage in recipients and periventricular leukomalacia in donors but there are additional risk factors for focal embolism and cerebrovascular disease. The recipient has circulatory overload, with effects on systemic and pulmonary circulations which probably lead to systemic and pulmonary hypertension and even right ventricular outflow tract obstruction as well as the polycythaemia which is a risk factor for thrombosis and vasculopathy. The donor is hypovolaemic and has a reticulocytosis in response to the anaemia while maternal hypertension and diabetes may influence stroke risk. Understanding of the mechanisms, including the role of vasculopathy, in well studied conditions such as alloimmune thrombocytopaenia and monochorionic diamniotic twinning may lead to reduction of the burden of antenatally sustained cerebral palsy.

Gamification refers to the use of game mechanics (e.g. competition, point scoring, progress visualisation and task setting) to engage and motivate people to achieve an end goal. Public health programs that incorporate gamification-based approaches which aim to improve the public's health have grown in popularity, however most commonplace are individualistic, smartphone-based applications and few studies have been conducted on community-wide interventions. Furthermore, the few studies which have been conducted have relied on small sample sizes with short-term follow-up. In view of this gap in current understanding, this study explored the impact of a community-wide gamified intervention, called ‘Beat the Street’ (in Reading UK) on levels of physical activity at 1 and 2-years post-intervention (between 2014 and 2016). Data were available for N = 1567 participants at one-year post-intervention and N = 723 participants at 2-years post-intervention. A Pretest-Posttest analysis revealed a 11% and 13% decrease in levels of inactivity at 1 and 2-years post-intervention respectively. Furthermore, participants who were inactive at baseline reported undertaking 3.4 and 3.8 days of activity at 1 and 2-years post-intervention, respectively. These findings provide promising preliminary evidence that gamification may be effective for decreasing physical inactivity and game-design mechanisms which may support behaviour change are discussed., Highlights • This study explored behaviour change 1 and 2 year’s following a community-wide gamified physical activity intervention • 61% and 72% of inactive participants had become active at 1 and 2-years following the intervention, respectively. • Inactive participants were undertaking an average of 3.4 and 3.8 days of activity at 1 and 2-years, respectively

Purpose To evaluate the effect of premolar axial wall height on the retention of adhesive, full-coverage, computer-aided design/computer-assisted manufacture (CAD/CAM) restorations. Materials and methods A total of 48 premolar teeth randomized into four groups (n = 12 per group) received all-ceramic CAD/CAM restorations with axial wall heights (AWH) of 3, 2, 1, and 0 mm and 16-degree total occlusal convergence (TOC). Specimens were restored with lithium disilicate material and cemented with self-adhesive resin cement. Specimens were loaded to failure after 24 hours. Results The 3- and 2-mm AWH specimens demonstrated significantly greater failure load. Failure analysis suggests a 2-mm minimum AWH for premolars with a TOC of 16 degrees. Conclusion Adhesive technology may compensate for compromised AWH.

To evaluate bicuspid axial wall height effect on the fracture mode of adhesively luted, all-ceramic CAD/CAM crowns with a 20° total occlusal convergence (TOC).Recently extracted premolars were randomly divided into 4 groups (n = 12) with all-ceramic crown preparations accomplished using a high-speed handpiece inserted into a milling device. Specimens were prepared containing occlusogingival axial wall heights of 3, 2, and 1 mm as well as a group containing a flat preparation surface with no axial wall height. All preparations contained a 20° TOC. Completed preparation surface area was determined, and preparation features confirmed using a digital measuring microscope. Scanned preparations (CEREC) were fitted with milled and crystallized lithium disilicate full coverage restorations and luted with a self-etching adhesive resin cement after hydrofluoric acid etching and silanation. All manufacturer recommendations were followed. Specimens were stored at 37°C/98% humidity for 24 hours. Specimens were tested to failure at a 45° angle to the long axis of the tooth root on a universal testing machine. Failure load was converted to MPa using the available bonding surface area with mean data analyzed using Kruskal-Wallis/Dunn's (p = 0.05) RESULTS: The 3 mm preparation height specimens were similar to the 2 mm specimens, and both demonstrated significantly stronger failure load than the 1 mm axial wall height and flat preparation specimens. The flat preparation and 1 mm axial wall height specimens all failed adhesively, while the 2 mm and 3 mm specimens failed largely due to tooth fracture.Further evidence is provided that CAD/CAM adhesive techniques may compensate for less than ideal preparation features. Under the conditions of this study, bicuspid preparations with a 20° TOC restored with adhesively luted, CAD/CAM e.max CAD crowns require at least 2 mm of axial wall height, but further planned fatigue studies are necessary before definitive recommendations can be made.

An estimated 293,000 people living in the United Kingdom have used anabolic-androgenic steroids. However, there is currently no intervention to reduce usage available in practice or academic circulation throughout the United Kingdom. This study aimed to test a novel hypothesis that increased levels of intrasexual competition may play an important influential role in the use of anabolic-androgenic steroids. Significantly higher levels of intrasexual competition were evident in users compared to non-users but only in the novice group (0–2 years of experience). The research provides evidence for intrasexual competition potentially influencing anabolic-androgenic steroid use but only during the initial stages of usage.

Each night all the houses on Mahogany Tree Street but one were warmed by the soft glow of newly installed electric lights. The dark home was called a “nail house” because its inhabitants refused to...

BMI1 is a core component of the polycomb repressive complex 1 (PRC1) and emerging data support a role of BMI1 in cancer. The central domain of BMI1 is involved in protein–protein interactions and is essential for its oncogenic activity. Here, we present the structure of BMI1 bound to the polyhomeotic protein PHC2 illustrating that the central domain of BMI1 adopts an ubiquitin-like (UBL) fold and binds PHC2 in a β-hairpin conformation. Unexpectedly, we find that the UBL domain is involved in homo-oligomerization of BMI1. We demonstrate that both the interaction of BMI1 with polyhomeotic proteins and homo-oligomerization via UBL domain are necessary for H2A ubiquitination activity of PRC1 and for clonogenic potential of U2OS cells. Here, we also emphasize need for joint application of NMR spectroscopy and X-ray crystallography to determine the overall structure of the BMI1–PHC2 complex., BMI1, a core element of the polycomb repressive complex 1, is suggested to have oncogenic activity in a variety of cancers. Here, the authors report the structure of BMI1 bound to the protein PHC2, identify BMI1 homo-oligomerization interfaces, and analyse the role of BMI1 protein-protein interactions in PRC1 function.

SummaryThe retinal pigment epithelium (RPE) is a monolayer of cells underlying and supporting the neural retina. It begins as a plastic tissue, capable, in some species, of generating lens and retina, but differentiates early in development and remains normally nonproliferative throughout life. Here we show that a subpopulation of adult human RPE cells can be activated in vitro to a self-renewing cell, the retinal pigment epithelial stem cell (RPESC) that loses RPE markers, proliferates extensively, and can redifferentiate into stable cobblestone RPE monolayers. Clonal studies demonstrate that RPESCs are multipotent and in defined conditions can generate both neural and mesenchymal progeny. This plasticity may explain human pathologies in which mesenchymal fates are seen in the eye, for example in proliferative vitroretinopathy (PVR) and phthisis bulbi. This study establishes the RPESC as an accessible, human CNS-derived multipotent stem cell, useful for the study of fate choice, replacement therapy, and disease modeling.

wilson d.m., harris a., hollis v. & mohankumar d. (2010) Upstream thinking and health promotion planning for older adults at risk of social isolation. International Journal of Older People Nursing6, 282–288 doi: 10.1111/j.1748-3743.2010.00259.x Aims and objectives. To raise awareness of social isolation, and provide an approach to first conceptualise and then prevent social isolation among older community-dwelling persons. Background. Older adults comprise a vulnerable population for social isolation and its associated health risks. Design. Literature review. Methods. Canada’s Population Health Promotion Model was chosen as a comprehensive tool to understand and prevent social isolation. Research studies were sought to identify key health determinants and evidence-based options for preventing social isolation. Results. Around 1 out of 6 older persons are socially isolated and three health determinants are of prime importance: (i) income and social status; (ii) personal health practices and coping skills and (iii) social support networks. Evidence-based interventions targeted to these health determinants are suggested. Conclusion. Nurses are a key group to advocate for actions needed to prevent social isolation. Implications for practice. Nurses can play a vital role in minimising social isolation through a variety of educational, prevention and political lobbying activities.

Mental ill health accounts for 13 per cent of total global disease burden with predictions that depression alone will be the leading cause of disease burden globally by 2030. Poor mental health is consistently associated with deprivation, low income, unemployment, poor education, poorer physical health and increased health-risk behaviour. A plethora of research has examined the relationship between physical activity and mental wellbeing; however, the influence of community-wide gamification-based physical activity interventions on mental wellbeing, to the authors’ knowledge, is yet to be explored. In view of this paucity of attention, the current study examined the relationship between physical activity and mental wellbeing pre/post a community-wide, gamification-based intervention. The findings revealed that increases in mental wellbeing were significantly greater for the least active prior to the intervention, and a strong, positive correlation between increase in physical activity and increase in mental wellbeing was observed.

An interaction between the B2 subunit of vacuolar H(+)-ATPase (V-ATPase) and microfilaments is required for osteoclast bone resorption. An atomic homology model of the actin binding site on B2 was generated and molecular docking simulations were performed. Enoxacin, a fluoroquinolone antibiotic, was identified and in vitro testing demonstrated that enoxacin blocked binding between purified B2 and microfilaments. Enoxacin dose dependently reduced the number of osteoclasts differentiating in mouse marrow cultures stimulated with 1,25-dihydroxyvitamin D(3), as well as markers of osteoclast activity, and the number of resorption lacunae formed on bone slices. Enoxacin inhibited osteoclast formation at concentrations where osteoblast formation was not altered. In summary, enoxacin is a novel small molecule inhibitor of osteoclast bone resorption that acts by an unique mechanism and is therefore an attractive lead molecule for the development of a new class of antiosteoclastic agents.

The polycomb proteins BMI-1 and EZH2 are highly overexpressed by Ewing sarcoma (ES), a tumor of stem cell origin that is driven by EWS-ETS fusion oncogenes, most commonly EWS-FLI1. In the current study we analyzed expression of transcription programs that are controlled by polycomb proteins during embryonic development to determine if they are abnormal in ES. Our results show that polycomb target gene expression in ES deviates from normal tissues and stem cells and that, as expected, most targets are relatively repressed. However, we also discovered a paradoxical up regulation of numerous polycomb targets and these were highly enriched for homeobox (HOX) genes. Comparison of HOX profiles between malignant and non-malignant tissues revealed a distinctive HOX profile in ES, which was characterized by overexpression of posterior HOXD genes. In addition, ectopic expression of EWS-FLI1 during stem cell differentiation led to aberrant up regulation of posterior HOXD genes. Mechanistically, this up regulation was associated with altered epigenetic regulation. Specifically, ES and EWS-FLI1+ stem cells displayed a relative loss of polycomb-dependent H3K27me3 and gain of trithorax-dependent H3K4me3 at the promoters of posterior HOXD genes and also at the HOXD11.12 polycomb response element. In addition, a striking correlation was evident between HOXD13 and other genes whose regulation is coordinately regulated during embryonic development by distal enhancer elements. Together, these studies demonstrate that epigenetic regulation of polycomb target genes, in particular HOXD genes, is altered in ES and that these changes are mediated downstream of EWS-FLI1.

Epidemic levels of obesity represent a growing public health problem associated with a variety of negative health outcomes. Population level interventions that aim to moderate obesigenic environments have been proposed but remain largely unimplemented. Standard individual level interventions that focus on dietary restraint have been ineffective and in some cases harmful. Intuitive eating, an anti-dieting strategy that relies on recognizing and responding to internal hunger and satiation cues, has been proposed as an alternative approach to healthy weight management at the individual level—but it remains largely untested. This study evaluated the relationship between intuitive eating and various health indicators among female college students. As measured by the Intuitive Eating Scale (IES), it was found that intuitive eating was significantly correlated with lower body mass index (r = -.576), lower triglyceride levels (r = -.408), higher levels of high density lipoproteins (.437), and improved ca...

Ewing sarcoma is driven by the oncogenic fusion protein, EWS-FLI1, and arises via de-regulation of developmental transcriptional programs. Control of normal developmental transcription programs is governed by epigenetic regulation which, in the case of HOX programs, is dependent on coordinated and reciprocal actions of polycomb (PcG) and trithorax (TrxG) proteins. We recently reported that in Ewing sarcoma posterior HOX genes, in particular HOXD13, are abnormally over-expressed and that the promoters of these genes are marked with the TrxG-dependent activating histone modification, H3K4me3. H3K4me3 is deposited by the MLL methyltransferase, a key enzyme that is frequently mutated in leukemia, largely as a result of chromosomal translocations that induce the creation of oncogenic MLL fusion-proteins. In leukemia, MLL fusion-proteins cooperate with wild-type MLL and the scaffolding protein menin to induce malignant transformation via deregulation of HOXA genes. The purpose of this study was to test the hypothesis that MLL and menin contribute to tumorigenesis and to posterior HOX gene deregulation in Ewing sarcoma. Gene and protein expression were determined by microarray, qRT-PCR, western blot and immunohistochemistry. Loss of function was achieved by lentiviral shRNAs and by exposing cells to MI-503, a small molecule inhibitor of menin-MLL protein-protein interactions. Changes in gene and protein expression after MI-503 treatment were assessed by qRT-PCR and western blot. Chromatin immunoprecipitation (ChIP) was used to assess binding of MLL and menin at gene promoters. Our results confirm that MLL, menin and HOXD13 are all highly expressed by Ewing sarcoma tumors and cell lines relative to non-malignant tissues and stem cells, and loss of function studies implicate each as a tumor promoting oncogene. Specifically, knockdown of MLL, menin or HOXD13 resulted in reduced cell proliferation, increased death and/or reduced tumorigenic capacity, as determined by anchorage-independent growth in soft agar and subcutaneous tumor formation in vivo. At a molecular level, knockdown of MLL and menin led to reduced expression of HOXD13, implicating these proteins as key mediators of HOXD13 over-expression. Exposure of Ewing sarcoma cells to MI-503 inhibited proliferation and colony formation in soft agar, and resulted in reduced expression of HOXD13 as well as other posterior HOX genes. In contrast, MI-NC, a control compound with similar structure that lacks affinity for the menin-MLL interaction had no effect on cell growth, viability or HOX gene expression. Significantly, MI-503-treated cells also showed a marked reduction in EWS-FLI1 and wild-type EWSR1 expression, both of which are regulated by the EWSR1 promoter, and of EZH2, a well-established oncogene in Ewing sarcoma. ChIP studies of the EWSR1 and EZH2 promoters demonstrated reduced binding of MLL and menin in MI-503-treated cells. These data demonstrate a key role for MLL and menin in Ewing sarcoma pathogenesis and directly implicate the TrxG complex in regulation of EWS-FLI1, thus highlighting a novel opportunity for therapeutic intervention. Citation Format: Laurie K. Svoboda, Natashay Bailey, Melanie Krook, Raelene Van Noord, Ashley Harris, Rajiv M. Patel, Dafydd Thomas, Tomek Cierpicki, Jolanta Grembecka, Elizabeth R. Lawlor. Tumorigenicity of Ewing sarcoma is critically dependent on the trithorax proteins MLL and menin. [abstract]. In: Proceedings of the AACR Special Conference: Developmental Biology and Cancer; Nov 30-Dec 3, 2015; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(4_Suppl):Abstract nr A20.

Normal development is governed by covalent modifications to chromatin that are mediated by the reciprocal actions of Polycomb group (PcG) and Trithorax (TrxG) proteins, which promote gene repression and activation, respectively. We recently reported that HOX genes, key developmental transcription factors that are regulated by PcG and TrxG during embryogenesis, are abnormally expressed in Ewing sarcoma (ES). In particular, we found that the posterior HOXD genes, including HOXD13, are markedly overexpressed, and that the promoters of these genes are aberrantly marked with the TrxG-dependent histone mark, H3K4me3. The TrxG proteins MLL and menin cooperate to drive HOX gene expression and promote tumorigenesis in leukemia. We therefore hypothesized that MLL and menin might also contribute to ES pathogenesis. Gene and protein expression were determined by microarray, q-RT-PCR and western blot of ES cell lines and tumors. Lentiviral shRNA constructs were used to knock down HOXD13, menin and MLL. Proliferation, survival, and tumorigenicity of genetically modified cells were assessed in vitro and in vivo. Inhibition of TrxG function was achieved by exposing cells to MI-503, a small molecule inhibitor of menin-MLL interactions. Our results confirm that menin, MLL and HOXD13 are all highly expressed by ES relative to non-malignant tissues and stem cells. Moreover, loss of function studies implicate each as a tumor promoting oncogene. Specifically, knockdown of HOXD13, menin or MLL inhibited cell proliferation and cell death was also induced by loss of either MLL or HOXD13. Colony formation in soft agar was likewise inhibited by MLL and HOXD13 knockdown and tumor formation in vivo was significantly delayed in ES cells with reduced expression of HOXD13. Importantly, knockdown of MLL led to reduced expression of HOXD13 further implicating MLL as a key mediator of HOXD13 over-expression in ES and supporting the hypothesis that, like MLL-fusion-dependent leukemias, HOX deregulation and tumorigenicity in ES are dependent on the TrxG complex. To further test this hypothesis we exposed ES cells to MI-503, an inhibitor of menin-MLL protein-protein interaction that disrupts the TrxG complex. Exposure of ES cells to MI-503 resulted in a dose-dependent inhibition of cell proliferation and marked inhibition of colony formation in soft agar. In contrast, MI-NC, a control compound with similar structure that lacks affinity for the menin-MLL interaction had no effect on ES cell growth or viability. Together these data for the first time demonstrate a key role for menin and MLL in ES pathogenesis and highlight a novel opportunity for therapeutic intervention in these aggressive tumors. Citation Format: Laurie K. Svoboda, Cassondra Cramer, Ashley Harris, Natashay Bailey, Tomek Cierpicki, Jolanta Grembecka, Elizabeth Lawlor. The Trithorax proteins menin and MLL promote Ewing sarcoma tumorigenicity. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 490. doi:10.1158/1538-7445.AM2015-490

IDA is a not-for-profit organization that manages DoD-sponsored FFRDCs. Founded in 1947 as the Weapons Systems Evaluation Group, IDA was incorporated in 1956 and has its headquarters in Alexandria, Virginia, with sites in Norfolk, Virginia; Princeton, New Jersey; San Diego, California; and Bowie, Maryland. IDA employees specialize in national security issues, computer software and engineering, strategy and force assessments, operational test and evaluation, research in civil space, expert systems for criminal investigation, and energy and environmental issues. The PwC office in Washington, D.C., has provided audit services to IDA since the early 1960s. The DCAA office in Columbia, Maryland, has provided 0MB Circular A-133 audit services to IDA since FY 1998. PwC and DCAA coordinated and accepted certain audit responsibilities for the FY 2001 single audit of IDA Details on the division of audit responsibilities for the single audit are discussed in Appendix B. As the cognizant Federal agency for IDA, the Office of the inspector General of the Department of Defense (OIG DoD) performed a Quality Control Review (QcR) of the single audit report and supporting audit documentation for the FY 2001 IDA single audit. The objectives of the review were to determine whether the audit was conducted according to generally accepted auditing standards, Government Auditing Standards (GAS), and the auditing and reporting requirements of 0MB Circular A-133. We also reviewed corrective actions taken by PwC as a result of a QCR performed on the FY 1998 single audit of IDA (see OIG DoD Report Number D2OOO-6-OO8, Quality Control Review of PricewaterhouseCoopers LLP, for 0MB Circular A-133 Audit Report for Institute for Defense Analyses, Fiscal Year Ended September 25, 1998," August 14, 2000).