ApplBuilder: An Object-Oriented Application Generator Supporting Rapid Prototyping

This paper describes an object-oriented application generator, APPLBUILDER, currently being developed in the Mjølner BETA programming environment. APPLBUILDER supports several rapid prototyping styles as well as final development of BETA applications. User interface objects such as dialogs, menus, and windows are designed using direct manipulation graphical editors. Actions behind buttons and menu items are programmed as ''scripts'' in textual editors activated from within a graphical editor. The editors reflect changes in the code directly in an underlying Abstract Syntax Tree (AST) thus saving compilation time. Moreover, generated applications are modularized so that editing, for instance the script for a button, only requires re-compilation of the script itself. An advantage of APPLBUILDER compared to other user-interface design tools such as HyperCard is that APPLBUILDER's scripts are embedded in a general purpose programming language making it possible to avoid calls to external routines written in another language. In addition, APPLBUILDER's ability to work with ASTs instead of textual code skeletons supports reverse engineering

OPEN-ENDED INTERACTION IN COOPERATIVE PROTOTYPING: A Video-Based Analysis

Cooperative Prototyping can be characterized as the use and development of prototypes as catalysts during discussions between designers and potential users - the overall intention being one of mutual learning. On the one hand, the designers learn more about the work practices of the users in ways that are tied concretely to some current version of the prototype. On the other hand, the users learn more about the potential for change in their work practice, whether computer-based or otherwise. This paper presents the results of a field study of the cooperative prototyping process. The study is based on a fine-grained video-based analysis of a single prototyping session, and focuses on the effects of an open-ended style of interaction between users and designers around a prototype. An analysis of focus shifts, initiative and storytelling during the session is brought to bear on the question of whether and how cooperative prototyping can be successful with users who are reluctant to \u27play in the future.\u27 The paper also discusses issues in applying video analysis to system design

Amenability of algebras of approximable operators

We give a necessary and sufficient condition for amenability of the Banach algebra of approximable operators on a Banach space. We further investigate the relationship between amenability of this algebra and factorization of operators, strengthening known results and developing new techniques to determine whether or not a given Banach space carries an amenable algebra of approximable operators. Using these techniques, we are able to show, among other things, the non-amenability of the algebra of approximable operators on Tsirelson's space.Comment: 20 pages, to appear in Israel Journal of Mathematic

miR-449 inhibits cell proliferation and is down-regulated in gastric cancer

<p>Abstract</p> <p>Background</p> <p>Gastric cancer is the fourth most common cancer in the world and the second most prevalent cause of cancer related death. The development of gastric cancer is mainly associated with <it>H. Pylori </it>infection leading to a focus in pathology studies on bacterial and environmental factors, and to a lesser extent on the mechanistic development of the tumour. MicroRNAs are small non-coding RNA molecules involved in post-transcriptional gene regulation. They are found to regulate genes involved in diverse biological functions and alterations in microRNA expression have been linked to the pathogenesis of many malignancies. The current study is focused on identifying microRNAs involved in gastric carcinogenesis and to explore their mechanistic relevance by characterizing their targets.</p> <p>Results</p> <p>Invitrogen NCode miRNA microarrays identified miR-449 to be decreased in 1-year-old <it>Gastrin </it>KO mice and in <it>H. Pylori </it>infected gastric tissues compared to tissues from wild type animals. Growth rate of gastric cell lines over-expressing miR-449 was inhibited by 60% compared to controls. FACS cell cycle analysis of miR-449 over-expressing cells showed a significant increase in the sub-G₁fraction indicative of apoptosis. ß-Gal assays indicated a senescent phenotype of gastric cell lines over-expressing miR-449. Affymetrix 133v2 arrays identified <it>GMNN</it>, <it>MET, CCNE2, SIRT1 </it>and <it>CDK6 </it>as miR-449 targets. Luciferase assays were used to confirm <it>GMNN</it>, <it>MET</it>, <it>CCNE2 </it>and <it>SIRT1 </it>as direct targets. We also show that miR-449 over-expression activated p53 and its downstream target p21 as well as the apoptosis markers cleaved CASP3 and PARP. Importantly, qPCR analyses showed a loss of miR-449 expression in human clinical gastric tumours compared to normal tissues.</p> <p>Conclusions</p> <p>In this study, we document a diminished expression of miR-449 in <it>Gastrin </it>KO mice and further confirmed its loss in human gastric tumours. We investigated the function of miR-449 by identifying its direct targets. Furthermore we show that miR-449 induces senescence and apoptosis by activating the p53 pathway.</p

Urea cycle dysregulation in non-alcoholic fatty liver disease

Background: In non-alcoholic steatohepatitis (NASH), function of urea cycle enzymes (UCEs) may be affected and result in hyperammonemia with risk of disease progression. We aimed to determine whether expression and function of UCEs are altered in a NASH animal model and in non-alcoholic fatty liver disease (NAFLD) patients and whether this is reversible. / Methods: Rats were fed a high-fat, high-cholesterol diet for 10 months to induce NASH and then changed to normal chow to recover. In humans, we obtained liver biopsies from 20 patients with steatosis and 15 NASH patients. Primary rat hepatocytes were isolated and cultured with free fatty acids. We measured the gene and protein expression, the activity of ornithine transcarbamylase (OTC) and ammonia concentrations. Moreover, we assessed the promoter methylation status of OTC and carbamoyl phosphate synthetase (CPS1) in rats, humans and in steatotic hepatocytes. / Results: In NASH animals, gene and protein expression of OTC and CPS1 and activity of OTC were reversibly reduced and hypermethylation of OTC promotor genes was observed. Also in NAFLD patients, OTC enzyme concentration and activity were reduced and ammonia concentrations were increased and more so in NASH. Furthermore, OTC and CPS1 promoter regions were hypermethylated. In primary hepatocytes induction of steatosis was associated with OTC promoter hypermethylation, reduction in the gene expression of OTC and CPS1 and an increase in ammonia concentration in the supernatant. / Conclusion: NASH is associated with a reduction in gene and protein expression, and activity of UCEs resulting in hyperammonemia, possibly through hypermethylation of UCE genes and impairment of urea synthesis. Our investigations describe for the first time a link between NASH, function of UCEs and hyperammonemia providing a novel therapeutic target. / Lay summary: In patients with fatty liver disease, the enzymes that convert nitrogen waste into urea may be affected leading to the accumulation of the toxic substance, ammonia. This accumulation of ammonia can lead to development of scar tissue and risk of progression of disease. In this study, we show that fat accumulation in the liver produces a reversible reduction in the function of these enzymes that are involved in detoxification of ammonia. These data provide potential new targets for therapy of fatty liver disease

The Citrullinated and MMP-degraded Vimentin Biomarker (VICM) Predicts Early Response to Anti-TNF alpha Treatment in Crohn's Disease

Background: In Crohn's disease (CD), 10% to 40% of patients do not respond to anti-tumor necrosis factor- (TNF) treatment. Currently, there are no biomarkers with adequate sensitivity to separate responders from nonresponders at an early stage. Aim: The aim of this study was to investigated whether early changes in the VICM (citrullinated and matrix metalloproteinase-degraded vimentin) biomarker were associated with response to anti-TNF treatment in patients with CD. Methods: Serum VICM levels were measured by ELISA in 2 independent cohorts of CD patients (n=42) treated with anti-TNF (infliximab or adalimumab). Response was determined by achieving clinical remission (Harvey Bradshaw Index<5). Results: Compared with baseline, VICM serum levels were reduced by anti-TNF in the infliximab cohort (week 6 and 14) and in the adalimumab cohort (week 8). VICM was lower in the responders compared with the nonresponders [infliximab: Week 6, P<0.05; area under the curve (AUC)=0.90; adalimumab: Week 1, P<0.01 (AUC=0.91), and week 8, P<0.05 (AUC=0.86)], and were able to predict response to treatment after 1 week of treatment with an odds ratio of 42.5. Conclusions: The VICM biomarker was time dependently reduced in CD patients responding to anti-TNF treatment. We suggest that VICM may be used as a marker for monitoring early response to anti-TNF in patients with CD

Limited clinical efficacy of azacitidine in transfusion-dependent, growth factor-resistant, low- and Int-1-risk MDS:Results from the nordic NMDSG08A phase II trial

This prospective phase II study evaluated the efficacy of azacitidine (Aza) + erythropoietin (Epo) in transfusion-dependent patients with lower-risk myelodysplastic syndrome (MDS). Patients ineligible for or refractory to full-dose Epo + granulocyte colony stimulation factors for 48 weeks and a transfusion need of ≥ 4 units over 8 weeks were included. Aza 75mgm -2 d-1, 5/28 days, was given for six cycles; non-responding patients received another three cycles combined with Epo 60 000 units per week. Primary end point was transfusion independence (TI). All patients underwent targeted mutational screen for 42 candidate genes. Thirty enrolled patients received ≥ one cycle of Aza. Ten patients discontinued the study early, 7 due to adverse events including 2 deaths. Thirty-eight serious adverse events were reported, the most common being infection. Five patients achieved TI after six cycles and one after Aza + Epo, giving a total response rate of 20%. Mutational screening revealed a high frequency of recurrent mutations. Although no single mutation predicted for response, SF3A1 (n = 3) and DNMT3A (n = 4) were only observed in nonresponders. We conclude that Aza can induce TI in severely anemic MDS patients, but efficacy is limited, toxicity substantial and most responses of short duration. This treatment cannot be generally recommended in lower-risk MDS. Mutational screening revealed a high frequency of mutations

Exposure to revised drinking guidelines and 'COM-B' determinants of behaviour change: descriptive analysis of a monthly cross-sectional survey in England

BACKGROUND: January 2016 saw the publication of proposed revisions to the UK's lower risk drinking guidelines but no sustained promotional activity. This paper aims to explore the impact of publishing guidelines without sustained promotional activity on reported guideline exposure and determinants of behaviour (capability, opportunity and motivation) proposed by the COM-B model. METHODS: Data were collected by a monthly repeat cross-sectional survey of adults (18+) resident in England over 15 months between November 2015 and January 2017 from a total of 16,779 drinkers, as part of the Alcohol Toolkit Study. Trends and associated 95% confidence intervals were described in the proportion of reported exposure to guidelines in the past month and measures of the capability, opportunity and motivation to consume alcohol within drinking guidelines. RESULTS: There was a rise in reported exposure to drinking guidelines in January 2016 (57.6-80.6%) which did not reoccur in January 2017. Following the increase in January 2016, reported exposure reduced slowly but remained significantly higher than in December 2015. In February 2016, there was an increase in measures of capability (31.1% reported tracking units of alcohol consumption and 87.8% considered it easier to drink safely) and opportunity (84.0% perceived their lifestyle as conducive to drinking within guidelines). This change was not maintained in subsequent months. Other measures showed marginal changes between January and February 2016 with no evidence of change in subsequent months. CONCLUSIONS: Following the publication of revised drinking guideline in January 2016, there was a transient increase in exposure to guidelines, and capability and opportunity to drink within the guidelines that diminished over time. The transience and size of the changes indicate that behaviour change is unlikely. Well-designed, theory-based promotional campaigns may be required for drinking guidelines to be an effective public health intervention