Predicting class II MHC-Peptide binding:a kernel based approach using similarity scores

Background - Modelling the interaction between potentially antigenic peptides and Major Histocompatibility Complex (MHC) molecules is a key step in identifying potential T-cell epitopes. For Class II MHC alleles, the binding groove is open at both ends, causing ambiguity in the positional alignment between the groove and peptide, as well as creating uncertainty as to what parts of the peptide interact with the MHC. Moreover, the antigenic peptides have variable lengths, making naive modelling methods difficult to apply. This paper introduces a kernel method that can handle variable length peptides effectively by quantifying similarities between peptide sequences and integrating these into the kernel. Results - The kernel approach presented here shows increased prediction accuracy with a significantly higher number of true positives and negatives on multiple MHC class II alleles, when testing data sets from MHCPEP [1], MCHBN [2], and MHCBench [3]. Evaluation by cross validation, when segregating binders and non-binders, produced an average of 0.824 AROC for the MHCBench data sets (up from 0.756), and an average of 0.96 AROC for multiple alleles of the MHCPEP database. Conclusion - The method improves performance over existing state-of-the-art methods of MHC class II peptide binding predictions by using a custom, knowledge-based representation of peptides. Similarity scores, in contrast to a fixed-length, pocket-specific representation of amino acids, provide a flexible and powerful way of modelling MHC binding, and can easily be applied to other dynamic sequence problems.

Hierarchical approach to project planning:the case of a petroleum pipeline construction

Projects exposed to an uncertain environment must be adapted to deal with the effective integration of various planning elements and the optimization of project parameters. Time, cost, and quality are the prime objectives of a project that need to be optimized to fulfill the owner's goal. In an uncertain environment, there exist many other conflicting objectives that may also need to be optimized. These objectives are characterized by varying degrees of conflict. Moreover, an uncertain environment also causes several changes in the project plan throughout its life, demanding that the project plan be totally flexible. Goal programming (GP), a multiple criteria decision making technique, offers a good solution for this project planning problem. There the planning problem is considered from the owner's perspective, which leads to classifying the project up to the activity level. GP is applied separately at each level, and the formulated models are integrated through information flow. The flexibility and adaptability of the models lies in the ease of updating the model parameters at the required level through changing priorities and/or constraints and transmitting the information to other levels. The hierarchical model automatically provides integration among various element of planning. The proposed methodology is applied in this paper to plan a petroleum pipeline construction project, and its effectiveness is demonstrated.

An investigation of management accounting control systems in the palm oil industry:a sociomaterial approach to practice change

The primary aim of this research is to understand what constitutes management accounting and control (MACs) practice and how these control processes are implicated in the day to day work practices and operations of the organisation. It also examines the changes that happen in MACs practices over time as multiple actors within organisational settings interact with each other. I adopt a distinctive practice theory approach (i.e. sociomateriality) and the concept of imbrication in this research to show that MACs practices emerge from the entanglement between human/social agency and material/technological agency within an organisation. Changes in the pattern of MACs practices happens in imbrication processes which are produced as the two agencies entangle. The theoretical approach employed in this research offers an interesting and valuable lens which seeks to reveal the depth of these interactions and uncover the way in which the social and material imbricate. The theoretical framework helps to reveal how these constructions impact on and produce modifications of MACs practices. The exploration of the control practices at different hierarchical levels (i.e. from the operational to middle management and senior level management) using the concept of imbrication process also maps the dynamic flow of controls from operational to top management and vice versa in the organisation. The empirical data which is the focus of this research has been gathered from a case study of an organisation involved in a large vertically integrated palm oil industry company in Malaysia specifically the refinery sector. The palm oil industry is a significant industry in Malaysia as it contributed an average of 4.5% of Malaysian Gross Domestic Product, over the period 1990 -2010. The Malaysian palm oil industry also has a significant presence in global food oil supply where it contributed 26% of the total oils and fats global trade in 2010. The case organisation is a significant contributor to the Malaysian palm oil industry. The research access has provided an interesting opportunity to explore the interactions between different groups of people and material/technology in a relatively heavy process food industry setting. My research examines how these interactions shape and are shaped by control practices in a dynamic cycle of imbrications over both short and medium time periods.

Multiple criteria optimization of contemporary logistics distribution network problems

In the contemporary customer-driven supply chain, maximization of customer service plays an equally important role as minimization of costs for a company to retain and increase its competitiveness. This article develops a multiple-criteria optimization approach, combining the analytic hierarchy process (AHP) and an integer linear programming (ILP) model, to aid the design of an optimal logistics distribution network. The proposed approach outperforms traditional cost-based optimization techniques because it considers both quantitative and qualitative factors and also aims at maximizing the benefits of deliverer and customers. In the approach, the AHP is used to determine the relative importance weightings or priorities of alternative warehouses with respect to some critical customer-oriented criteria. The results of AHP prioritization are utilized as the input of the ILP model, the objective of which is to select the best warehouses at the lowest possible cost. In this article, two commercial packages are used: including Expert Choice and LINDO.

Coupling in silico and in vitro analysis of peptide-MHC binding:a bioinformatic approach enabling prediction of superbinding peptides and anchorless epitopes

The ability to define and manipulate the interaction of peptides with MHC molecules has immense immunological utility, with applications in epitope identification, vaccine design, and immunomodulation. However, the methods currently available for prediction of peptide-MHC binding are far from ideal. We recently described the application of a bioinformatic prediction method based on quantitative structure-affinity relationship methods to peptide-MHC binding. In this study we demonstrate the predictivity and utility of this approach. We determined the binding affinities of a set of 90 nonamer peptides for the MHC class I allele HLA-A*0201 using an in-house, FACS-based, MHC stabilization assay, and from these data we derived an additive quantitative structure-affinity relationship model for peptide interaction with the HLA-A*0201 molecule. Using this model we then designed a series of high affinity HLA-A2-binding peptides. Experimental analysis revealed that all these peptides showed high binding affinities to the HLA-A*0201 molecule, significantly higher than the highest previously recorded. In addition, by the use of systematic substitution at principal anchor positions 2 and 9, we showed that high binding peptides are tolerant to a wide range of nonpreferred amino acids. Our results support a model in which the affinity of peptide binding to MHC is determined by the interactions of amino acids at multiple positions with the MHC molecule and may be enhanced by enthalpic cooperativity between these component interactions.

Development and psychometric evaluation of a new team effectiveness scale for all types of community adult mental health teams:a mixed-methods approach

Defining 'effectiveness' in the context of community mental health teams (CMHTs) has become increasingly difficult under the current pattern of provision required in National Health Service mental health services in England. The aim of this study was to establish the characteristics of multi-professional team working effectiveness in adult CMHTs to develop a new measure of CMHT effectiveness. The study was conducted between May and November 2010 and comprised two stages. Stage 1 used a formative evaluative approach based on the Productivity Measurement and Enhancement System to develop the scale with multiple stakeholder groups over a series of qualitative workshops held in various locations across England. Stage 2 analysed responses from a cross-sectional survey of 1500 members in 135 CMHTs from 11 Mental Health Trusts in England to determine the scale's psychometric properties. Based on an analysis of its structural validity and reliability, the resultant 20-item scale demonstrated good psychometric properties and captured one overall latent factor of CMHT effectiveness comprising seven dimensions: improved service user well-being, creative problem-solving, continuous care, inter-team working, respect between professionals, engagement with carers and therapeutic relationships with service users. The scale will be of significant value to CMHTs and healthcare commissioners both nationally and internationally for monitoring, evaluating and improving team functioning in practice.

Making hiring decisions:a grounded theory approach to a practise-based study of filtering in selection

This thesis objective is to discover “How are informal decisions reached by screeners when filtering out undesirable job applications?” Grounded theory techniques were employed in the field to observe and analyse informal decisions at the source by screeners in three distinct empirical studies. Whilst grounded theory provided the method for case and cross-case analysis, literature from academic and non-academic sources was evaluated and integrated to strengthen this research and create a foundation for understanding informal decisions. As informal decisions in early hiring processes have been under researched, this thesis contributes to current knowledge in several ways. First, it locates the Cycle of Employment which enhances Robertson and Smith’s (1993) Selection Paradigm through the integration of stages that individuals occupy whilst seeking employment. Secondly, a general depiction of the Workflow of General Hiring Processes provides a template for practitioners to map and further develop their organisational processes. Finally, it highlights the emergence of the Locality Effect, which is a geographically driven heuristic and bias that can significantly impact recruitment and informal decisions. Although screeners make informal decisions using multiple variables, informal decisions are made in stages as evidence in the Cycle of Employment. Moreover, informal decisions can be erroneous as a result of a majority and minority influence, the weighting of information, the injection of inappropriate information and criteria, and the influence of an assessor. This thesis considers these faults and develops a basic framework of understanding informal decisions to which future research can be launched.

Probabilistic multiple model neural network based leak detection system:experimental study

This paper presents an effective decision making system for leak detection based on multiple generalized linear models and clustering techniques. The training data for the proposed decision system is obtained by setting up an experimental pipeline fully operational distribution system. The system is also equipped with data logging for three variables; namely, inlet pressure, outlet pressure, and outlet flow. The experimental setup is designed such that multi-operational conditions of the distribution system, including multi pressure and multi flow can be obtained. We then statistically tested and showed that pressure and flow variables can be used as signature of leak under the designed multi-operational conditions. It is then shown that the detection of leakages based on the training and testing of the proposed multi model decision system with pre data clustering, under multi operational conditions produces better recognition rates in comparison to the training based on the single model approach. This decision system is then equipped with the estimation of confidence limits and a method is proposed for using these confidence limits for obtaining more robust leakage recognition results.

WDM sensor network approach:bridging the gap towards POF-based photonic sensing

In this work a self-referenced technique for fiberoptic intensity sensors using virtual lock-in amplifiers is proposed and discussed. The topology is compatible with WDM networks so multiple remote sensors can simultaneously be interrogated. A hybrid approach combining both silica fiber Bragg gratings and polymer optical fiber Bragg gratings is analyzed. The feasibility of the proposed solution for potential medical environments and biomedical applications is shown and tested using a selfreferenced configuration based on a power ratio parameter.

Agitation conditions for the culture and detachment of hMSCs from microcarriers in multiple bioreactor platforms

In our recent work in different bioreactors up to 2.5L in scale, we have successfully cultured hMSCs using the minimum agitator speed required for complete microcarrier suspension, N JS. In addition, we also reported a scaleable protocol for the detachment from microcarriers in spinner flasks of hMSCs from two donors. The essence of the protocol is the use of a short period of intense agitation in the presence of enzymes such that the cells are detached; but once detachment is achieved, the cells are smaller than the Kolmogorov scale of turbulence and hence not damaged. Here, the same approach has been effective for culture at N JS and detachment in-situ in 15mL ambr™ bioreactors, 100mL spinner flasks and 250mL Dasgip bioreactors. In these experiments, cells from four different donors were used along with two types of microcarrier with and without surface coatings (two types), four different enzymes and three different growth media (with and without serum), a total of 22 different combinations. In all cases after detachment, the cells were shown to retain their desired quality attributes and were able to proliferate. This agitation strategy with respect to culture and harvest therefore offers a sound basis for a wide range of scales of operation.

Entropy Based Approach to Finding Interacting Genes Responsible for Complex Human Disease

2000 Mathematics Subject Classification: 62P10, 92D10, 92D30, 94A17, 62L10.

A new VRPPD model and a hybrid heuristic solution approach for e-tailing

We analyze a business model for e-supermarkets to enable multi-product sourcing capacity through co-opetition (collaborative competition). The logistics aspect of our approach is to design and execute a network system where “premium” goods are acquired from vendors at multiple locations in the supply network and delivered to customers. Our specific goals are to: (i) investigate the role of premium product offerings in creating critical mass and profit; (ii) develop a model for the multiple-pickup single-delivery vehicle routing problem in the presence of multiple vendors; and (iii) propose a hybrid solution approach. To solve the problem introduced in this paper, we develop a hybrid metaheuristic approach that uses a Genetic Algorithm for vendor selection and allocation, and a modified savings algorithm for the capacitated VRP with multiple pickup, single delivery and time windows (CVRPMPDTW). The proposed Genetic Algorithm guides the search for optimal vendor pickup location decisions, and for each generated solution in the genetic population, a corresponding CVRPMPDTW is solved using the savings algorithm. We validate our solution approach against published VRPTW solutions and also test our algorithm with Solomon instances modified for CVRPMPDTW.

Optical fibre limits:an approach using ASE channel estimation

In this talk we investigate the usage of spectrally shaped amplified spontaneous emission (ASE) in order to emulate highly dispersed wavelength division multiplexed (WDM) signals in an optical transmission system. Such a technique offers various simplifications to large scale WDM experiments. Not only does it offer a reduction in transmitter complexity, removing the need for multiple source lasers, it potentially reduces the test and measurement complexity by requiring only the centre channel of a WDM system to be measured in order to estimate WDM worst case performance. The use of ASE as a test and measurement tool is well established in optical communication systems and several measurement techniques will be discussed [1, 2]. One of the most prevalent uses of ASE is in the measurement of receiver sensitivity where ASE is introduced in order to degrade the optical signal to noise ratio (OSNR) and measure the resulting bit error rate (BER) at the receiver. From an analytical point of view noise has been used to emulate system performance, the Gaussian Noise model is used as an estimate of highly dispersed signals and has had consider- able interest [3]. The work to be presented here extends the use of ASE by using it as a metric to emulate highly dispersed WDM signals and in the process reduce WDM transmitter complexity and receiver measurement time in a lab environment. Results thus far have indicated [2] that such a transmitter configuration is consistent with an AWGN model for transmission, with modulation format complexity and nonlinearities playing a key role in estimating the performance of systems utilising the ASE channel emulation technique. We conclude this work by investigating techniques capable of characterising the nonlinear and damage limits of optical fibres and the resultant information capacity limits. REFERENCES McCarthy, M. E., N. Mac Suibhne, S. T. Le, P. Harper, and A. D. Ellis, “High spectral efficiency transmission emulation for non-linear transmission performance estimation for high order modulation formats," 2014 European Conference on IEEE Optical Communication (ECOC), 2014. 2. Ellis, A., N. Mac Suibhne, F. Gunning, and S. Sygletos, “Expressions for the nonlinear trans- mission performance of multi-mode optical fiber," Opt. Express, Vol. 21, 22834{22846, 2013. Vacondio, F., O. Rival, C. Simonneau, E. Grellier, A. Bononi, L. Lorcy, J. Antona, and S. Bigo, “On nonlinear distortions of highly dispersive optical coherent systems," Opt. Express, Vol. 20, 1022-1032, 2012.

Diabetes in the very elderly:need for an individualised approach

Background: Intensive risk factor management is recommended for individuals with diabetes. However, it is not known if such an approach is appropriate in the elderly with multiple comorbidities and limited life expectancy. The aim of this study was to characterise a cohort of very elderly individuals with diabetes and assess the impact of known risk factors on mortality. Methods: This was a retrospective audit approved by the clinical audit lead. All patients aged >80 years who attended diabetes outpatient clinics 2 years prior to the date of the audit (April 2012) were identified from clinic records. A detailed history including demographics, comorbidities and treatment were collected. Blood pressure readings, HbA1c, cholesterol and renal function were extracted and the mean of these readings was recorded. Survival status at 2 years was recorded for all patients. Statistical analysis was performed using SPSS19. Results: Data were available for 864 (381 male, 483 female) patients. The majority (75%) lived in their own home. More than 60% had multiple comorbidities and 25% had a prior history of cardiovascular disease. Two-thirds of the patients had more than one hospital admission in 2 years and a third had more than three admissions. 60% were on either insulin or a sulfonylurea. Mean HbA1c was 7.6%, cholesterol 4.2mmol/l, systolic blood pressure 145mmHg and eGFR 53ml/min. Over 2 years, 174 (20%)had died. Age, creatinine and previous coronary heart disease were significant predictors of death. Conclusion: The benefits of intensive diabetes management appear to be uncertain in very elderly patients. The need for intensive treatment must therefore be individualised to each patient.

Multiple roles for executive control in belief-desire reasoning:distinct neural networks are recruited for self perspective inhibition and complexity of reasoning

Belief-desire reasoning is a core component of 'Theory of Mind' (ToM), which can be used to explain and predict the behaviour of agents. Neuroimaging studies reliably identify a network of brain regions comprising a 'standard' network for ToM, including temporoparietal junction and medial prefrontal cortex. Whilst considerable experimental evidence suggests that executive control (EC) may support a functioning ToM, co-ordination of neural systems for ToM and EC is poorly understood. We report here use of a novel task in which psychologically relevant ToM parameters (true versus false belief; approach versus avoidance desire) were manipulated orthogonally. The valence of these parameters not only modulated brain activity in the 'standard' ToM network but also in EC regions. Varying the valence of both beliefs and desires recruits anterior cingulate cortex, suggesting a shared inhibitory component associated with negatively valenced mental state concepts. Varying the valence of beliefs additionally draws on ventrolateral prefrontal cortex, reflecting the need to inhibit self perspective. These data provide the first evidence that separate functional and neural systems for EC may be recruited in the service of different aspects of ToM.