Entinostat prevents leukemia maintenance in a collaborating oncogene-dependent model of CN-AML.

The incidence of refractory acute myeloid leukemia (AML) is on the increase due in part to an aging population that fails to respond to traditional therapies. High throughput genomic analysis promises better diagnosis, prognosis and therapeutic intervention based on improved patient stratification. Relevant pre-clinical models are urgently required to advance drug development in this area. The collaborating oncogenes, HOXA9 and MEIS1, are frequently co-overexpressed in cytogenetically normal AML (CN-AML) and a conditional transplantation mouse model was developed that demonstrated oncogene-dependency and expression levels comparable to CN-AML patients. Integration of gene signatures obtained from the mouse model and a cohort of CN-AML patients using statistically significant connectivity Map (sscMap) analysis identified Entinostat as a drug with the potential to alter the leukemic condition towards the normal state. Ex vivo treatment of leukemic cells, but not age-matched normal bone marrow controls, with Entinostat validated the gene signature and resulted in reduced viability in liquid culture, impaired colony formation and loss of the leukemia initiating cell. Furthermore, in vivo treatment with Entinostat resulted in prolonged survival of leukemic mice. This study demonstrates that the HDAC inhibitor Entinostat inhibits disease maintenance and prolongs survival in a clinically relevant murine model of cytogenetically normal AML. © 2013 AlphaMed Press

Online Multiperson Tracking With Occlusion Reasoning and Unsupervised Track Motion Model

We address the problem of multi-target tracking in realistic crowded conditions by introducing a novel dual-stage online tracking algorithm. The problem of data-association between tracks and detections, based on appearance, is often complicated by partial occlusion. In the first stage, we address the issue of occlusion with a novel method of robust data-association, that can be used to compute the appearance similarity between tracks and detections without the need for explicit knowledge of the occluded regions. In the second stage, broken tracks are linked based on motion and appearance, using an online-learned linking model. The online-learned motion-model for track linking uses the confident tracks from the first stage tracker as training examples. The new approach has been tested on the town centre dataset and has performance comparable with the present state-of-the-art

State Estimation for Anaerobic Digesters using the ADM1

The optimization of full-scale biogas plant operation is of great importance to make biomass a competitive source of renewable energy. The implementation of innovative control and optimization algorithms, such as Nonlinear Model Predictive Control, requires an online estimation of operating states of biogas plants. This state estimation allows for optimal control and operating decisions according to the actual state of a plant. In this paper such a state estimator is developed using a calibrated simulation model of a full-scale biogas plant, which is based on the Anaerobic Digestion Model No.1. The use of advanced pattern recognition methods shows that model states can be predicted from basic online measurements such as biogas production, CH4 and CO2 content in the biogas, pH value and substrate feed volume of known substrates. The machine learning methods used are trained and evaluated using synthetic data created with the biogas plant model simulating over a wide range of possible plant operating regions. Results show that the operating state vector of the modelled anaerobic digestion process can be predicted with an overall accuracy of about 90%. This facilitates the application of state-based optimization and control algorithms on full-scale biogas plants and therefore fosters the production of eco-friendly energy from biomass.

Compromising Spatial Quality: Modernity in the Era of National State Building in Cairo

The paper examines the imposition of western ideals of urbanism within colonial Cairo between1882-1952. It looks at the ideologies of capitalism, state control, and utopian idealism, which were vital tools to create modern built environments in the city. The argument is that principles of Western urbanism were at work and deeply influenced the institutional and professional practices of the Egyptian planners, who were mostly educated in Europe; however the outcomes revealed a major shift towards more inflexible solutions described as more open to compromise with the existing conditions. The paper analyses the case of a re-planning scheme drafted in the 1920s by the first Egyptian director of the Ministry of Town Planning under the British occupation. The scheme represented the superimposition of a western-style neighbourhood model on a historically rooted traditional quarter in Cairo. The paper largely relies on original archival materials, maps, documents and accounts to support the historical narrative of urban planning in Cairo. It reports that westernization approaches for planning Cairo were introduced to offer a new imagery representation, which remained central to the development of planning practices in postcolonial Egypt through different practical applications.

AGWAN: A Generative Model for Labelled, Weighted Graphs

Real-world graphs or networks tend to exhibit a well-known set of properties, such as heavy-tailed degree distributions, clustering and community formation. Much effort has been directed into creating realistic and tractable models for unlabelled graphs, which has yielded insights into graph structure and evolution. Recently, attention has moved to creating models for labelled graphs: many real-world graphs are labelled with both discrete and numeric attributes. In this paper, we present AGWAN (Attribute Graphs: Weighted and Numeric), a generative model for random graphs with discrete labels and weighted edges. The model is easily generalised to edges labelled with an arbitrary number of numeric attributes. We include algorithms for fitting the parameters of the AGWAN model to real-world graphs and for generating random graphs from the model. Using the Enron “who communicates with whom” social graph, we compare our approach to state-of-the-art random labelled graph generators and draw conclusions about the contribution of discrete vertex labels and edge weights to the structure of real-world graphs.

Community Engagement in Ireland's Developmental Welfare State: a study of the life cycle approach

The idea that people matter in modern democracies, often referred to as 'civic engagement' is recognised at the highest international level (United Nations 2008: 9). Civic or community engagement is essential to how budgets are decided, policy is developed and public services delivered. Significantly, community engagement is crucial in developing policy for sustained economic and social development. In Ireland the idea of the Developmental Welfare State (DWS) is based on the premise that the social policy system should support citizens so as to reach their full potential. Such a system comprises three overlapping elements: tax and welfare transfer, the provision of services and activist initiatives (National Economic and Social Council, 2005: ix-xviii). Civil Society Organisations have been challenged to 'operationalise the DWS' using a 'life cycle framework' as part of Ireland's corporatist partnership model (Department of Taoiseach, 2006: 40).

Criticality, factorization, and long-range correlations in the anisotropic XY model

We study the long-range quantum correlations in the anisotropic XY model. By first examining the thermodynamic limit, we show that employing the quantum discord as a figure of merit allows one to capture the main features of the model at zero temperature. Furthermore, by considering suitably large site separations we find that these correlations obey a simple scaling behavior for finite temperatures, allowing for efficient estimation of the critical point. We also address ground-state factorization of this model by explicitly considering finite-size systems, showing its relation to the energy spectrum and explaining the persistence of the phenomenon at finite temperatures. Finally, we compute the fidelity between finite and infinite systems in order to show that remarkably small system sizes can closely approximate the thermodynamic limit.

Effect of the crown design and interface lute parameters on the stress-state of a machined crown-tooth system: A finite element analysis

The effect of preparation design and the physical properties of the interface lute on the restored machined ceramic crown-tooth complex are poorly understood. The aim of this work was to determine, by means of three-dimensional finite element analysis (3D FEA) the effect of the tooth preparation design and the elastic modulus of the cement on the stress state of the cemented machined ceramic crown-tooth complex. The three-dimensional structure of human premolar teeth, restored with adhesively cemented machined ceramic crowns, was digitized with a micro-CT scanner. An accurate, high resolution, digital replica model of a restored tooth was created. Two preparation designs, with different occlusal morphologies, were modeled with cements of 3 different elastic moduli. Interactive medical image processing software (mimics and professional CAD modeling software) was used to create sophisticated digital models that included the supporting structures; periodontal ligament and alveolar bone. The generated models were imported into an FEA software program (hypermesh version 10.0, Altair Engineering Inc.) with all degrees of freedom constrained at the outer surface of the supporting cortical bone of the crown-tooth complex. Five different elastic moduli values were given to the adhesive cement interface 1.8 GPa, 4 GPa, 8 GPa, 18.3 GPa and 40 GPa; the four lower values are representative of currently used cementing lutes and 40 GPa is set as an extreme high value. The stress distribution under simulated applied loads was determined. The preparation design demonstrated an effect on the stress state of the restored tooth system. The cement elastic modulus affected the stress state in the cement and dentin structures but not in the crown, the pulp, the periodontal ligament or the cancellous and cortical bone. The results of this study suggest that both the choice of the preparation design and the cement elastic modulus can affect the stress state within the restored crown-tooth complex.

The changing university business model: a stakeholder perspective

Universities are in a current state of transition, whereby they are expected to develop a wide range of relationships with stakeholders in order to enhance regional innovation systems. However, despite external environmental pressures commonly regarded as one of the main drivers of business model evolution, there is a lack of studies that explore business model innovation as a result of multiple stakeholder influences. Accordingly, the aim of this paper is to examine the changing university business model within a region of the United Kingdom, using a stakeholder perspective that will aid theoretical development and refinement in both the business model and stakeholder fields. This examination is aided by consideration of the university business model as an activity system. Repeat interviews, combined with stakeholder theory, have been used to show how the changing university business model–stakeholder relationship has progressed through different stakeholder stages with resultant changes in content, structure and governance. Furthermore, conflicting objectives between each of the stakeholder groups (i.e. academics, industry liaison staff, technology transfer office staff and government support agency representatives) have led to the university business model evolving not as a process of co-creation but rather in a series of transitions whereby multiple stakeholders are continually shaping the university business model through strategies that are dependent upon their salience. Finally, this paper contributes to the development and refinement of business model innovation research, in that the use of stakeholder constructs can illustrate the impact of multiple stakeholders' power and influence on business model innovation.

The nucleus of Comet 67P/Churyumov-Gerasimenko. A new shape model and thermophysical analysis

Context. Comet 67P/Churyumov-Gerasimenko is the target of the European Space Agency Rosetta spacecraft rendez-vous mission. Detailed physical characteristation of the comet before arrival is important for mission planning as well as providing a test bed for ground-based observing and data-analysis methods. Aims: To conduct a long-term observational programme to characterize the physical properties of the nucleus of the comet, via ground-based optical photometry, and to combine our new data with all available nucleus data from the literature. Methods: We applied aperture photometry techniques on our imaging data and combined the extracted rotational lightcurves with data from the literature. Optical lightcurve inversion techniques were applied to constrain the spin state of the nucleus and its broad shape. We performed a detailed surface thermal analysis with the shape model and optical photometry by incorporating both into the new Advanced Thermophysical Model (ATPM), along with all available Spitzer 8-24 μm thermal-IR flux measurements from the literature. Results: A convex triangular-facet shape model was determined with axial ratios b/a = 1.239 and c/a = 0.819. These values can vary by as much as 7% in each axis and still result in a statistically significant fit to the observational data. Our best spin state solution has Psid = 12.76137 ± 0.00006 h, and a rotational pole orientated at Ecliptic coordinates λ = 78°(±10°), β = + 58°(±10°). The nucleus phase darkening behaviour was measured and best characterized using the IAU HG system. Best fit parameters are: G = 0.11 ± 0.12 and HR(1,1,0) = 15.31 ± 0.07. Our shape model combined with the ATPM can satisfactorily reconcile all optical and thermal-IR data, with the fit to the Spitzer 24 μm data taken in February 2004 being exceptionally good. We derive a range of mutually-consistent physical parameters for each thermal-IR data set, including effective radius, geometric albedo, surface thermal inertia and roughness fraction. Conclusions: The overall nucleus dimensions are well constrained and strongly imply a broad nucleus shape more akin to comet 9P/Tempel 1, rather than the highly elongated or "bi-lobed" nuclei seen for comets 103P/Hartley 2 or 8P/Tuttle. The derived low thermal inertia of

Universal tight binding model for chemical reactions in solution and at surfaces. III. Stoichiometric and reduced surfaces of titania and the adsorption of water

We demonstrate a model for stoichiometric and reduced titanium dioxide intended for use in molecular dynamics and other atomistic simulations and based in the polarizable ion tight binding theory. This extends the model introduced in two previous papers from molecular and liquid applications into the solid state, thus completing the task of providing a comprehensive and unified scheme for studying chemical reactions, particularly aimed at problems in catalysis and electrochemistry. As before, experimental results are given priority over theoretical ones in selecting targets for model fitting, for which we used crystal parameters and band gaps of titania bulk polymorphs, rutile and anatase. The model is applied to six low index titania surfaces, with and without oxygen vacancies and adsorbed water molecules, both in dissociated and non-dissociated states. Finally, we present the results of molecular dynamics simulation of an anatase cluster with a number of adsorbed water molecules and discuss the role of edge and corner atoms of the cluster. (C) 2014 AIP Publishing LLC.

Evidence for a glassy state in strongly driven carbon

Here, we report results of an experiment creating a transient, highly correlated carbon state using a combination of optical and x-ray lasers. Scattered x-rays reveal a highly ordered state with an electrostatic energy significantly exceeding the thermal energy of the ions. Strong Coulomb forces are predicted to induce nucleation into a crystalline ion structure within a few picoseconds. However, we observe no evidence of such phase transition after several tens of picoseconds but strong indications for an over-correlated fluid state. The experiment suggests a much slower nucleation and points to an intermediate glassy state where the ions are frozen close to their original positions in the fluid.

Proportionality in Age Discrimination Cases - a Model Suitable for Socially Embedded Rights

This chapter discusses the use of proportionality in age discrimination cases before the Court of Justice of the European Union. It argues that the Court does not use this concept systematically - indeed it exposes some contradiction that make the case law seem arbitrary - and proposes a more fruitful use of the principle, which is in line with a modern conception of human rights. The chapter argues that the principle of proportionality stems from the time when human rights served the recently liberated burgeois elite in guarding their rights to property and liberty against the state. Today, states not only respect human rights (which is fully sufficient for this elite, who can rely on their inherited wealth to fend for themselves). They also protect and promote human rights, and these activities are a precondition for human rights to be practically relevant for the whole population. This also means that state activity, which is experienced as a limitation of rights to property and liberty by some, may constitute a measure to promote and protect human rights of others. In employment law - the only field where the EU ban on age discrimination is applied - this is a typical situation. If such a situation occurs, the principle of proportionality must be applied in a bifurcated way.It is not sufficient that the limitation of property rights is proportionate for the achievement of a public policy aim. If the aim of public policy is to enable the effective use of human rights, the limitation of the state action must be proportionate to the protection and promotion of those human rights. It is argued that the principle of proportionality is superior to less structures balancing acts (e.g. the Wednesbury principle), if it is applied both ways. Going over to the field of age discrimination, the chapter identifies a number of potentially colliding aims pursued in this field. Banning age discrimination may relate to genuine aims of anti-discrimination law if bias against older or very young workers is addressed. However, the EU ban of discrimination against all ages also serves to restructure employment law and policy to the age of flexibilisation, replacing the synchronisation principle that has been predominant for the welfare states of the 20th century. The former aim is related to human rights protection, while the latter aim is not (at least not always). This has consequences for applying the proportionality test. The chapter proposes different ways to argue the most difficult age discrimination cases, where anti-discrimination rationales and flexibilisation rationales clash

Polymorphism in Sulfadimidine/4-Aminosalicylic Acid Cocrystals: Solid-State Characterization and Physicochemical Properties

Polymorphism of crystalline drugs is a common phenomenon. However, the number of reported polymorphic cocrystals is very limited. In this work, the synthesis and solid-state characterization of a polymorphic cocrystal composed of sulfadimidine (SD) and 4-aminosalicylic acid (4-ASA) is reported for the first time. By liquid-assisted milling, the SD:4-ASA 1:1 form I cocrystal, the structure of which has been previously reported, was formed. By spray drying, a new polymorphic form (form II) of the SD:4-ASA 1:1 cocrystal was discovered which could also be obtained by solvent evaporation from ethanol and acetone. Structure determination of the form II cocrystal was calculated using high-resolution X-ray powder diffraction. The solubility of the SD:4-ASA 1:1 cocrystal was dependent on the pH and predicted by a model established for a two amphoteric component cocrystal. The form I cocrystal was found to be thermodynamically more stable in aqueous solution than form II, which showed transformation to form I. Dissolution studies revealed that the dissolution rate of SD from both cocrystals was enhanced when compared with a physical equimolar mixture and pure SD.

Evaluation of infilled frames: an updated in-plane-stiffness macro-model considering the effects of vertical loads

The influence of masonry infills on the in-plane behaviour of RC framed structures is a central topic in the seismic evaluation and retrofitting of existing buildings. Many models in the literature use an equivalent strut member in order to represent the infill but, among the parameters influencing the equivalent strut behaviour, the effect of vertical loads acting on the frames is recognized but not quantified. Nevertheless a vertical load causes a non-negligible variation in the in-plane behaviour of infilled frames by influencing the effective volume of the infill. This results in a change in the stiffness and strength of the system. This paper presents an equivalent diagonal pin-jointed strut model taking into account the stiffening effect of vertical loads on the infill in the initial state. The in-plane stiffness of a range of infilled frames was evaluated using a finite element model of the frame-infill system and the cross-section of the strut equivalent to the infill was obtained for different levels of vertical loading by imposing the equivalence between the frame containing the infill and the frame containing the diagonal strut. In this way a law for identifying the equivalent strut width depending on the geometrical and mechanical characteristics of the infilled frame was generalized to consider the influence of vertical loads for use in the practical applications. The strategy presented, limited to the initial stiffness of infilled frames, is preparatory to the definition of complete non-linear cyclic laws for the equivalent strut.