Increased diversity of libraries from libraries: chemoinformatic analysis of bis-diazacyclic libraries

Combinatorial libraries continue to play a key role in drug discovery. To increase structural diversity, several experimental methods have been developed. However, limited efforts have been performed so far to quantify the diversity of the broadly used diversity-oriented synthetic (DOS) libraries. Herein we report a comprehensive characterization of 15 bis-diazacyclic combinatorial libraries obtained through libraries from libraries, which is a DOS approach. Using MACCS keys, radial and different pharmacophoric fingerprints as well as six molecular properties, it was demonstrated the increased structural and property diversity of the libraries from libraries over the individual libraries. Comparison of the libraries to existing drugs, NCI Diversity and the Molecular Libraries Small Molecule Repository revealed the structural uniqueness of the combinatorial libraries (mean similarity < 0.5 for any fingerprint representation). In particular, bis-cyclic thiourea libraries were the most structurally dissimilar to drugs retaining drug-like character in property space. This study represents the first comprehensive quantification of the diversity of libraries from libraries providing a solid quantitative approach to compare and contrast the diversity of DOS libraries with existing drugs or any other compound collection.

Uncertainty and topographic visualisations

This thesis is a study of low-dimensional visualisation methods for data visualisation under certainty of the input data. It focuses on the two main feed-forward neural network algorithms which are NeuroScale and Generative Topographic Mapping (GTM) by trying to make both algorithms able to accommodate the uncertainty. The two models are shown not to work well under high levels of noise within the data and need to be modified. The modification of both models, NeuroScale and GTM, are verified by using synthetic data to show their ability to accommodate the noise. The thesis is interested in the controversy surrounding the non-uniqueness of predictive gene lists (PGL) of predicting prognosis outcome of breast cancer patients as available in DNA microarray experiments. Many of these studies have ignored the uncertainty issue resulting in random correlations of sparse model selection in high dimensional spaces. The visualisation techniques are used to confirm that the patients involved in such medical studies are intrinsically unclassifiable on the basis of provided PGL evidence. This additional category of ‘unclassifiable’ should be accommodated within medical decision support systems if serious errors and unnecessary adjuvant therapy are to be avoided.

Predictive gene lists for breast cancer prognosis: a topographic visualisation study

Background: The controversy surrounding the non-uniqueness of predictive gene lists (PGL) of small selected subsets of genes from very large potential candidates as available in DNA microarray experiments is now widely acknowledged 1. Many of these studies have focused on constructing discriminative semi-parametric models and as such are also subject to the issue of random correlations of sparse model selection in high dimensional spaces. In this work we outline a different approach based around an unsupervised patient-specific nonlinear topographic projection in predictive gene lists. Methods: We construct nonlinear topographic projection maps based on inter-patient gene-list relative dissimilarities. The Neuroscale, the Stochastic Neighbor Embedding(SNE) and the Locally Linear Embedding(LLE) techniques have been used to construct two-dimensional projective visualisation plots of 70 dimensional PGLs per patient, classifiers are also constructed to identify the prognosis indicator of each patient using the resulting projections from those visualisation techniques and investigate whether a-posteriori two prognosis groups are separable on the evidence of the gene lists. A literature-proposed predictive gene list for breast cancer is benchmarked against a separate gene list using the above methods. Generalisation ability is investigated by using the mapping capability of Neuroscale to visualise the follow-up study, but based on the projections derived from the original dataset. Results: The results indicate that small subsets of patient-specific PGLs have insufficient prognostic dissimilarity to permit a distinction between two prognosis patients. Uncertainty and diversity across multiple gene expressions prevents unambiguous or even confident patient grouping. Comparative projections across different PGLs provide similar results. Conclusion: The random correlation effect to an arbitrary outcome induced by small subset selection from very high dimensional interrelated gene expression profiles leads to an outcome with associated uncertainty. This continuum and uncertainty precludes any attempts at constructing discriminative classifiers. However a patient's gene expression profile could possibly be used in treatment planning, based on knowledge of other patients' responses. We conclude that many of the patients involved in such medical studies are intrinsically unclassifiable on the basis of provided PGL evidence. This additional category of 'unclassifiable' should be accommodated within medical decision support systems if serious errors and unnecessary adjuvant therapy are to be avoided.

Market orientation of hotels and travel services in China

China is unique both politically and economically. How this uniqueness impacts on firms'' adoption of market orientation and the impact of market orientation on business performance, however, remain unclear. This book reports a study by Dr Riliang Qu who aims to address the above knowledge void. The study employs a two-stage research strategy including interviews and a survey of 1000 hotels and travel services. The study found that government regulations restricting the firm rivalry and the shortage of competent managerial talents are among the most serious constraints to the firms'' development of market orientation along with such factors as inadequacy of government regulation on product quality and consumer protection. The findings suggest that in transitional like China, government actions could be a major force behind firms'' aspiration of being market-oriented. The study also found that the benefits of market orientation are multi-fold in that it not only improves company''s business performance but also has positive effects on customer satisfaction/retention, power in distribution channel, and corporate social responsibility.

Effective electromagnetic noise cancellation with beamformers and synthetic gradiometry in shielded and partly shielded environments

The major challenge of MEG, the inverse problem, is to estimate the very weak primary neuronal currents from the measurements of extracranial magnetic fields. The non-uniqueness of this inverse solution is compounded by the fact that MEG signals contain large environmental and physiological noise that further complicates the problem. In this paper, we evaluate the effectiveness of magnetic noise cancellation by synthetic gradiometers and the beamformer analysis method of synthetic aperture magnetometry (SAM) for source localisation in the presence of large stimulus-generated noise. We demonstrate that activation of primary somatosensory cortex can be accurately identified using SAM despite the presence of significant stimulus-related magnetic interference. This interference was generated by a contact heat evoked potential stimulator (CHEPS), recently developed for thermal pain research, but which to date has not been used in a MEG environment. We also show that in a reduced shielding environment the use of higher order synthetic gradiometry is sufficient to obtain signal-to-noise ratios (SNRs) that allow for accurate localisation of cortical sensory function.

Engineering education for the 21st century:scholarship, synergy and student success

Starting with the question “How can University level Engineering Education be developed in such a way so as to enhance the quality of the student learning experience?”, this discussion paper proposes an approach to engineering education developed by a senior engineering educator working alongside a pedagogical researcher in an attempt to engage colleagues in contemporary debates about the issues currently faced across the Sector. Such issues include difficulties with recruiting students onto programmes as well as high levels of student attrition and failure. Underpinned by three distinctive concepts: Synergy, Variety & Relationships (S+V+R), the approach brings together pedagogic and engineering epistemologies in an empirically grounded framework in such a way so as to provide an accessible and relevant learning approach that, if followed, engenders student success [S2]. Specifically developed with the intention of increasing retention and positively impacting student success [S2], the S+V+R=S2 approach provides a scholarly and Synergetic (S) approach to engineering education that is both innovative and exciting. Building on the argument that Variety (V) in education is pivotal to promoting originality and creativity in learning and teaching, this paper shows how, by purposefully developing a range of learning and teaching approaches, student engagement and thus success can be increased. It also considers the importance of Relationships (R) in higher education, arguing that belonging and relationships are crucial factors impacting student experiences. When taken together (Synergy, Variety and Relationships) and applied within an Engineering Education context, students are provided with a unique learning environment – one that both promotes individual success and improves organisational effectiveness. The uniqueness of the approach is in the synthesis of these three concepts within an Engineering Education epistemology.

Determining planar multiple sound-soft obstacles from scattered acoustic fields

An inverse problem is considered where the structure of multiple sound-soft planar obstacles is to be determined given the direction of the incoming acoustic field and knowledge of the corresponding total field on a curve located outside the obstacles. A local uniqueness result is given for this inverse problem suggesting that the reconstruction can be achieved by a single incident wave. A numerical procedure based on the concept of the topological derivative of an associated cost functional is used to produce images of the obstacles. No a priori assumption about the number of obstacles present is needed. Numerical results are included showing that accurate reconstructions can be obtained and that the proposed method is capable of finding both the shapes and the number of obstacles with one or a few incident waves.

Null Condition for Semilinear Wave Equation with Variable Coefficients

∗The author was partially supported by M.U.R.S.T. Progr. Nazionale “Problemi Non Lineari...”

A Gradient-Type Optimization Technique for the Optimal Control for Schrodinger Equations

In this paper, we are considered with the optimal control of a schrodinger equation. Based on the formulation for the variation of the cost functional, a gradient-type optimization technique utilizing the finite difference method is then developed to solve the constrained optimization problem. Finally, a numerical example is given and the results show that the method of solution is robust.

Cauchy Problem for Differential Equation with Caputo Derivative

The paper is devoted to the study of the Cauchy problem for a nonlinear differential equation of complex order with the Caputo fractional derivative. The equivalence of this problem and a nonlinear Volterra integral equation in the space of continuously differentiable functions is established. On the basis of this result, the existence and uniqueness of the solution of the considered Cauchy problem is proved. The approximate-iterative method by Dzjadyk is used to obtain the approximate solution of this problem. Two numerical examples are given.

Inhomogeneous Fractional Diffusion Equations

2000 Mathematics Subject Classification: Primary 26A33; Secondary 35S10, 86A05

Nonlinear Waves: An Introduction

This book deals with equations of mathematical physics as the different modifications of the KdV equation, the Camassa-Holm type equations, several modifications of Burger's equation, the Hunter-Saxton equation, conservation laws equations and others. The equations originate from physics but are proposed here for their investigation via purely mathematical methods in the frames of university courses. More precisely, we propose classification theorems for the traveling wave solutions for a sufficiently large class of third order nonlinear PDE when the corresponding profiles develop different kind of singularities (cusps, peaks), existence and uniqueness results, etc. The orbital stability of the periodic solutions of traveling type for mKdV equations are also studied. Of great interest too is the interaction of peakon type solutions of the Camassa-Holm equation and the solvability of the classical and generalized Cauchy problem for the Hunter-Saxton equation. The Riemann problem for special systems of conservation laws and the corresponding -shocks are also considered. As it concerns numerical methods we apply the CNN approach. The book is addressed to a broader audience including graduate students, Ph.D. students, mathematicians, physicist, engineers and specialists in the domain of PDE.

An Analog of the Tricomi Problem for a Mixed Type Equation with a Partial Fractional Derivative

Mathematics Subject Classification 2010: 35M10, 35R11, 26A33, 33C05, 33E12, 33C20.

Impulsive Partial Hyperbolic Functional Differential Equations of Fractional Order with State-Dependent Delay

MSC 2010: 26A33, 34A37, 34K37, 34K40, 35R11

Maximum Principle and Its Application for the Time-Fractional Diffusion Equations

MSC 2010: 26A33, 33E12, 35B45, 35B50, 35K99, 45K05 Dedicated to Professor Rudolf Gorenflo on the occasion of his 80th anniversary