Agent-based modeling: a systematic assessment of use cases and requirements for enhancing pharmaceutical research and development productivity.

A crisis continues to brew within the pharmaceutical research and development (R&D) enterprise: productivity continues declining as costs rise, despite ongoing, often dramatic scientific and technical advances. To reverse this trend, we offer various suggestions for both the expansion and broader adoption of modeling and simulation (M&S) methods. We suggest strategies and scenarios intended to enable new M&S use cases that directly engage R&D knowledge generation and build actionable mechanistic insight, thereby opening the door to enhanced productivity. What M&S requirements must be satisfied to access and open the door, and begin reversing the productivity decline? Can current methods and tools fulfill the requirements, or are new methods necessary? We draw on the relevant, recent literature to provide and explore answers. In so doing, we identify essential, key roles for agent-based and other methods. We assemble a list of requirements necessary for M&S to meet the diverse needs distilled from a collection of research, review, and opinion articles. We argue that to realize its full potential, M&S should be actualized within a larger information technology framework--a dynamic knowledge repository--wherein models of various types execute, evolve, and increase in accuracy over time. We offer some details of the issues that must be addressed for such a repository to accrue the capabilities needed to reverse the productivity decline

Investigating patterns of deep sea coral and sponge diversity and abundance across multiple spatial scales in the Central Pacific

The deep sea is the largest ecosystem on the planet, comprising more than 90% of the volume that life can inhabit, yet it is the least explored biome in the world. The deep sea includes the benthos, which makes up 91.5 % of all the seafloor globally, and the water column deeper than 200 meters. It hosts a wealth of ecosystems including deep-sea vents, seamount coral gardens, abyssal plains, high-productivity whale falls, and life even in the deepest trenches. We now understand that all of these ecosystems host a variety of habitats, each with their own ecology and unique species. These ecosystems and habitats- and their associated biodiversity- provide essential ecosystem services such as carbon sequestration, nutrient regeneration, microbial processes detoxification, fisheries provisioning, and many others. However, despite the uniqueness of these ecosystems and the importance of the services they provide, we still know far less about them than we do about their shallow water and terrestrial counterparts. In this dissertation, I contribute new insights about the patterns of biodiversity in the Pacific Ocean across a large geographic area, and across a wide range of depths. To that end, in Chapter 1, I have used one of the largest ocean exploration datasets to look for patterns of the abundance and diversity across the most common benthic invertebrate families found on Pacific seamounts: Anthozoa, Porifera, and Echinodermata across the Central and Western Pacific. In addition to quantifying the diversity and abundance of known taxa, I also documented patterns of as-of-yet unidentified taxa by region, depth, and deepwater feature (seamount shape). Building on patterns associated with seamount shape that were described in Chapter 2, I focused on the effect of seamount shape on the diversity and abundance of deep-sea coral communities in Chapter 3. The analysis presented in Chapter 3 provides strong support for the novel hypothesis that gross seamount morphology is a significant driver of community composition. In Chapter 4, I focused on a single seamount to investigate biodiversity and abundance of coral and sponge taxa on a finer spatial scale, examining the role of direction (N, S, E, W) on different flanks of a single equatorial seamount. This analysis yielded interesting consistent patterns of zonation on all sides of the seamount in terms of depth, but with differences in abundance patterns on each flank for individual taxa. Finally, in Chapter 5, I took a global perspective to investigate gaps in deepwater data, with the goal of determining what regions need further exploration to conclusively determine patterns of deep-sea biodiversity, which will be critical for determining the health of deepwater ecosystems under climate change conditions with increased exploitation pressure and cooccuring with increased conservation efforts. Merging Ocean Biogeographic Information System (OBIS) records with the largest collection of deep submergence dive records ever collected, I used proposed biogeographic provinces schema to identify areas with the least supporting data. Additionally, I coupled records from OBIS with climate change projections to identify the areas with the fewest number of biodiversity records that are likely to change the fastest under different IPCC projections. These areas of low number of records and high likelihood of change by the end of the century should become priority targets for future exploration. Taken together, this dissertation provides valuable insights and generates new hypotheses about patterns and drivers of deep-sea biodiversity, and puts forth recommendations for future research and exploration efforts

Laser Generation of Narrow Band Ultrasound

Laser based sensor systems to replace conventional piezoelectric contact transducers for ultrasonic testing continue under development for applications where contact with the specimen surface is undesirable or impossible. To date, such systems are considerably less sensitive than their piezoelectric counterparts. As a result, a great deal of effort has contributed to the development of a number of interferoroetric transducer systems to detect ultrasound. Increasingly, however, researchers have begun looking at laser ultrasonic sources to see what improvements might be made to enhance overall system sensitivity for laser generation and detection of ultrasound

Robust Estimation for Linear Panel Data Models

In different fields of applications including, but not limited to, behavioral, environmental, medical sciences and econometrics, the use of panel data regression models has become increasingly popular as a general framework for making meaningful statistical inferences. However, when the ordinary least squares (OLS) method is used to estimate the model parameters, presence of outliers may significantly alter the adequacy of such models by producing biased and inefficient estimates. In this work we propose a new, weighted likelihood based robust estimation procedure for linear panel data models with fixed and random effects. The finite sample performances of the proposed estimators have been illustrated through an extensive simulation study as well as with an application to blood pressure data set. Our thorough study demonstrates that the proposed estimators show significantly better performances over the traditional methods in the presence of outliers and produce competitive results to the OLS based estimates when no outliers are present in the data set

Attitudes and barriers to exercise in adults with a recent diagnosis of type 1 diabetes: a qualitative study of participants in the Exercise for Type 1 Diabetes (EXTOD) study

This is the final published version. Available from BMJ Publishing via the DOI in this record.All data underlying the findings are fully available without restriction. All relevant data are within the paperObjectives To explore attitudes and barriers to exercise in adults with new-onset type 1 diabetes mellitus (T1DM). Design Qualitative methodology using focus group (n=1), individual face-to-face (n=4) and telephone interviews (n=8). Thematic analysis using the Framework Method. Setting Nineteen UK hospital sites. Participants Fifteen participants in the Exercise for Type 1 Diabetes study. We explored current and past levels of exercise, understanding of exercise and exercise guidelines, barriers to increasing exercise levels and preferences for monitoring of activity in a trial. Results Five main themes were identified: existing attitudes to exercise, feelings about diagnosis, perceptions about exercise consequences, barriers to increasing exercise and confidence in managing blood glucose. An important finding was that around half the participants reported a reduction in activity levels around diagnosis. Although exercise was felt to positively impact on health, some participants were not sure about the benefits or concerned about potential harms such as hypoglycaemia. Some participants reported being advised by healthcare practitioners (HCPs) not to exercise. Conclusions Exercise should be encouraged (not discouraged) from diagnosis, as patients may be more amenable to lifestyle change. Standard advice on exercise and T1DM needs to be made available to HCPs and patients with T1DM to improve patients’ confidence in managing their diabetes around exercise. Trial registration number ISRCTN91388505; ResultsNational Institute for Health Research (NIHR)National Institute for Health Research (NIHR

Does exercise improve glycaemic control in type 1 diabetes? A systematic review and meta-analysis.

This is the final published version. Available from PLoS via the DOI in this record.OBJECTIVE: Whilst regular exercise is advocated for people with type 1 diabetes, the benefits of this therapy are poorly delineated. Our objective was to review the evidence for a glycaemic benefit of exercise in type 1 diabetes. RESEARCH DESIGN AND METHODS: Electronic database searches were carried out in MEDLINE, Embase, Cochrane's Controlled Trials Register and SPORTDiscus. In addition, we searched for as yet unpublished but completed trials. Glycaemic benefit was defined as an improvement in glycosylated haemoglobin (HbA1c). Both randomised and non-randomised controlled trials were included. RESULTS: Thirteen studies were identified in the systematic review. Meta-analysis of twelve of these (including 452 patients) demonstrated an HbA1c reduction but this was not statistically significant (standardised mean difference (SMD) -0.25; 95% CI, -0.59 to 0.09). CONCLUSIONS: This meta-analysis does not reveal evidence for a glycaemic benefit of exercise as measured by HbA1c. Reasons for this finding could include increased calorie intake, insulin dose reductions around the time of exercise or lack of power. We also suggest that HbA1c may not be a sensitive indicator of glycaemic control, and that improvement in glycaemic variability may not be reflected in this measure. Exercise does however have other proven benefits in type 1 diabetes, and remains an important part of its management

Attitudes and barriers to exercise in adults with type 1 diabetes (T1DM) and how best to address them: a qualitative study

This is the final version. Available on open access from Public Library of Science via the DOI in this recordData Availability: The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper.BACKGROUND: Regular physical activity has recognised health benefits for people with T1DM. However a significant proportion of them do not undertake the recommended levels of activity. Whilst questionnaire-based studies have examined barriers to exercise in people with T1DM, a formal qualitative analysis of these barriers has not been undertaken. Our aims were to explore attitudes, barriers and facilitators to exercise in patients with T1DM. METHODOLOGY: A purposeful sample of long standing T1DM patients were invited to participate in this qualitative study. Twenty-six adults were interviewed using a semi-structured interview schedule to determine their level of exercise and barriers to initiation and maintenance of an exercise programme. PRINCIPAL FINDINGS: Six main barriers to exercise were identified: lack of time and work related factors; access to facilities; lack of motivation; embarrassment and body image; weather; and diabetes specific barriers (low levels of knowledge about managing diabetes and its complications around exercise). Four motivators to exercise were identified: physical benefits from exercise; improvements in body image; enjoyment and the social interaction of exercising at gym or in groups. Three facilitators to exercise were identified: free or reduced admission to gyms and pools, help with time management, and advice and encouragement around managing diabetes for exercise. SIGNIFICANCE: Many of the barriers to exercise in people with T1DM are shared with the non-diabetic population. The primary difference is the requirement for education about the effect of exercise on diabetes control and its complications. There was a preference for support to be given on a one to one basis rather than in a group environment. This suggests that with the addition of the above educational requirements, one to one techniques that have been successful in increasing activity in patients with other chronic disease and the general public should be successful in increasing activity in patients with T1DM.Insulin Dependent Diabetes Trus

An XML transfer schema for exchange of genomic and genetic mapping data: implementation as a web service in a Taverna workflow

<p>Abstract</p> <p>Background</p> <p>Genomic analysis, particularly for less well-characterized organisms, is greatly assisted by performing comparative analyses between different types of genome maps and across species boundaries. Various providers publish a plethora of on-line resources collating genome mapping data from a multitude of species. Datasources range in scale and scope from small bespoke resources for particular organisms, through larger web-resources containing data from multiple species, to large-scale bioinformatics resources providing access to data derived from genome projects for model and non-model organisms. The heterogeneity of information held in these resources reflects both the technologies used to generate the data and the target users of each resource. Currently there is no common information exchange standard or protocol to enable access and integration of these disparate resources. Consequently data integration and comparison must be performed in an <it>ad hoc </it>manner.</p> <p>Results</p> <p>We have developed a simple generic XML schema (GenomicMappingData.xsd – GMD) to allow export and exchange of mapping data in a common lightweight XML document format. This schema represents the various types of data objects commonly described across mapping datasources and provides a mechanism for recording relationships between data objects. The schema is sufficiently generic to allow representation of any map type (for example genetic linkage maps, radiation hybrid maps, sequence maps and physical maps). It also provides mechanisms for recording data provenance and for cross referencing external datasources (including for example ENSEMBL, PubMed and Genbank.). The schema is extensible via the inclusion of additional datatypes, which can be achieved by importing further schemas, e.g. a schema defining relationship types. We have built demonstration web services that export data from our ArkDB database according to the GMD schema, facilitating the integration of data retrieval into Taverna workflows.</p> <p>Conclusion</p> <p>The data exchange standard we present here provides a useful generic format for transfer and integration of genomic and genetic mapping data. The extensibility of our schema allows for inclusion of additional data and provides a mechanism for typing mapping objects via third party standards. Web services retrieving GMD-compliant mapping data demonstrate that use of this exchange standard provides a practical mechanism for achieving data integration, by facilitating syntactically and semantically-controlled access to the data.</p

VEGF promotes assembly of the p130Cas interactome to drive endothelial chemotactic signalling and angiogenesis

p130Cas is a polyvalent adapter protein essential for cardiovascular development, and with a key role in cell movement. In order to identify the pathways by which p130Cas exerts its biological functions in endothelial cells we mapped the p130Cas interactome and its dynamic changes in response to VEGF using high-resolution mass spectrometry and reconstruction of protein interaction (PPI) networks with the aid of multiple PPI databases. VEGF enriched the p130Cas interactome in proteins involved in actin cytoskeletal dynamics and cell movement, including actin-binding proteins, small GTPases and regulators or binders of GTPases. Detailed studies showed that p130Cas association of the GTPase-binding scaffold protein, IQGAP1, plays a key role in VEGF chemotactic signalling, endothelial polarisation, VEGF-induced cell migration, and endothelial tube formation. These findings indicate a cardinal role for assembly of the p130Cas interactome in mediating the cell migratory response to VEGF in angiogenesis, and provide a basis for further studies of p130Cas in cell movement

A Dynamic Model of Interactions of Ca^(2+), Calmodulin, and Catalytic Subunits of Ca^(2+)/Calmodulin-Dependent Protein Kinase II

During the acquisition of memories, influx of Ca^(2+) into the postsynaptic spine through the pores of activated N-methyl-D-aspartate-type glutamate receptors triggers processes that change the strength of excitatory synapses. The pattern of Ca^(2+) influx during the first few seconds of activity is interpreted within the Ca^(2+)-dependent signaling network such that synaptic strength is eventually either potentiated or depressed. Many of the critical signaling enzymes that control synaptic plasticity, including Ca^(2+)/calmodulin-dependent protein kinase II (CaMKII), are regulated by calmodulin, a small protein that can bind up to 4 Ca^(2+) ions. As a first step toward clarifying how the Ca^(2+)-signaling network decides between potentiation or depression, we have created a kinetic model of the interactions of Ca^(2+), calmodulin, and CaMKII that represents our best understanding of the dynamics of these interactions under conditions that resemble those in a postsynaptic spine. We constrained parameters of the model from data in the literature, or from our own measurements, and then predicted time courses of activation and autophosphorylation of CaMKII under a variety of conditions. Simulations showed that species of calmodulin with fewer than four bound Ca^(2+) play a significant role in activation of CaMKII in the physiological regime, supporting the notion that processing ofCa^(2+) signals in a spine involves competition among target enzymes for binding to unsaturated species of CaM in an environment in which the concentration of Ca^(2+) is fluctuating rapidly. Indeed, we showed that dependence of activation on the frequency of Ca^(2+) transients arises from the kinetics of interaction of fluctuating Ca^(2+) with calmodulin/CaMKII complexes. We used parameter sensitivity analysis to identify which parameters will be most beneficial to measure more carefully to improve the accuracy of predictions. This model provides a quantitative base from which to build more complex dynamic models of postsynaptic signal transduction during learning