Disruptive Strategies for Removing Drug Discovery Bottlenecks

Drug Discovery is shifting focus from the industry to outside partners and in the process creating new bottlenecks, suggesting the need for a more disruptive overhaul. Technologies like high throughput screening (HTS) have moved to a larger number of academic and institutional laboratories in the US, with little apparent coordination or consideration of the outputs and creating a translational gap. While there have been collaborative public private partnerships in Europe to share pharmaceutical data, the USA has lagged behind. Sharing precompetitive computational models may be the next frontier to provide more confidence in the quality of the leads produced and attract investment. We suggest there needs to be an awareness of what research is going on in the screening centers, more collaboration and coordination. These efforts will shift the focus to finding the best researchers to fund and require a rethink of how to reward their collaborative efforts

Spaces of Appearance: Writings on Contemporary Theatre and Performance

This thesis, a collection of previously published materials, reflects a plural and evolving engagement with theatre and performance over the past fifteen years or so: as researcher, writer, editor, teacher, practitioner, spectator. These have rarely been discreet categories for me, but rather different modalities of exploration and enquiry, interrelated spaces encouraging dynamic connectivities, flows and further questions. Section 1 offers critical accounts of the practices of four contemporary theatre directors: Jerzy Grotowski, Robert Wilson, Peter Brook and Ariane Mnouchkine. Section 2 draws on elements of contemporary philosophy and critical thinking to explore the mutable parameters of performance. lt proposes performative mappings of certain unpredictable, energetic events 'in proximity of performance', to borrow Matthew Goulish's phrase: contact, fire, animals, alterity, place. Section 3 contains examples of documentation of performance practices, including a thick description of a mise en scene of a major international theatre production, reflections on process, training and dramaturgy, a performance text with a framing dramaturgical statement, and personal perspectives on particular collaborations. The external Appendix comprises a recently published collection of edited and translated materials concerning five core collaborative projects realised by Ariane Mnouchkine and the Theatre du Soleil at their base in the Cartoucherie de Vincennes, Paris. The core concerns of this thesis include attempts to think through: • the working regimes, poetics and pedagogies of certain directors, usually in collaborative devising contexts within which the creative agency of performers is privileged; • the processes and micro-politics of collaboration, devising, and dramaturgical composition; the dramaturgical implications of trainings, narrative structures, spaces, mise en scene, and of images as multi-layered, dynamic 'fields'; • the predicament and agency of spectators in diverse performance contexts, and the ways in which spectatorial roles are posited or constructed by dramaturgies; • the imbrication of embodiment, movement and perception in performance, and the plurality of modes of perception; • the critical and political functions of theatre and theatre criticism as cultural/social practice and 'art of memory' (de Certeau), of dramaturgies as critical historiographies, and of theatre cultures (and identities) as plural, dynamic, and contested; • performance as concentrated space for inter-subjectivity and the flaring into appearance of the 'face-to-face' (Levinas); the possibility of ethical, 'response-able' encounter and exchange with another; identity as relational and in-process, alterity as productive event, the inter-personal as political; • the poetics and politics of what seems an unthinkable surplus (and constitutive 'outside') to the cognitive reach of many conventional frames and maps in theatre criticism and historiography; an exploration of acts of writing as performative propositions and provocations ('critical fictions') to think the event of meanings at/of the limits of knowledge and subjectivity. This partial listing of recurrent and evolving concerns within the thesis traces a trajectory in my evolution as a writer and thinker, a gradual displacement from the relatively 'solid ground' of theatre studies and theatre history towards more fluid and tentative articulations of the shifting 'lie of the land' in contemporary performance and philosophy. This trajectory reflects a growing fascination with present process, conditions, practices, perceptions 'in the middle', and ways of writing (about) performance as interactive and ephemeral event

Collaborative Systems Engineering in the Ascent Abort-2 Crew Module/Separation Ring Project

Generally speaking, systems engineering (SE) tool-sets face a dilemma balancing power and accessibility. High-powered SE tools (MagicDraw, Cradle, Core, etc.) tend to be specialized and are available only to highly trained Systems Engineers, and/or through the use of a 'back room' developer team making the output products available to the broader team. On the other hand, highly accessible tools (MS Word, Excel, etc.) do not have the power to implement SE in a rigorous manner. NASA has to test all aspects of the new human-rated Orion Multi-Purpose Crew Vehicle spacecraft prior to its first crewed mission. The test program includes uncrewed launch abort flight tests to demonstrate the capability to save the crew in the event that a launch failure occurs. Orion's second abort flight test will be a low-altitude flight test known as "Ascent Abort 2 (AA-2)." This test is currently scheduled to be carried out at Cape Canaveral Air Force Station's Space Launch Complex 46 (SLC-46) in Florida in 2019. NASA's in-house AA-2 Crew Module and Separation Ring (CSR) Team is producing the crew module and separation ring. Operating jointly as both an Advanced Exploration Systems (AES) Project and an Orion Project, the CSR project charter includes development of innovative, streamlined and generally more efficient practices for creation of flight hardware and software. One result of this tasking has been development of a collaborative and data-centric systems engineering environment within the team's shared web environment (Microsoft SharePoint). Through the use of built-in, 'out of the box capabilities' present in MS SharePoint, the CSR Systems Engineering team has created (with some limited developer support) a data-centric architecture for the project's SE implementation, including functional and interface analysis, requirements development and management, risk management, verification planning and management, test results, and end item management. Data elements are linked between data structures so as to define and control relationships between item types, link requirements to parents and children, and link tests to the requirements that they verify. The overall project team integration is increased by also linking SE content to project management content over the project life cycle, including team communication, action items, configuration management, decisional and meeting materials, and life cycle reviews. This presentation will provide an overview of the collaborative SE environment, showing how it provides the power for a number of SE tasks while still providing the accessibility and transparency to allow the full project team to collaborate and succeed. Given the project phase, we'll be able to present a nearly full lifecycle discussion, from concept through verification and approaching delivery

Individuals with low back pain: how do they view physical activity?

Background. Recent guidelines for those with acute low back pain have advocated early resumption of normal activity and increased physical activity. Little is known about the relationship between low back pain and physical activity, and on the impact of that relationship on the promotion of increased levels of physical activity within a general practice population. Objectives. We aimed to explore associations between factors that influence changes in physical activity and the way individuals perceive and behave with their low back pain, and the impact of those perceptions and behaviour on physical activity. Methods. Twenty-seven informants were chosen using a purposive sample from a larger group of individuals who, because of their low back trouble, had been referred by their GPs to a community-based, single-blind, randomized controlled trial (RCT) at the University of York, which is evaluating the effectiveness and cost-effectiveness of a progressive exercise programme. Fifty-four interviews were conducted with this subgroup of the RCT; four informants were interviewed once, 19 twice and four of them three times. Interviews were transcribed and analysed using manual and computer-aided approaches. Results. Physical activity was perceived as (i) activities of daily living, (ii) activities causing breathlessness that they went out of the way to do and (iii) more competitive-type activity. The avoidance of physical activity and fear of pain returning were the two main factors directly associated with informants' backs and changes in physical activity. These two factors hindered increases in physical activity, even though the majority of informants believed strongly that being physically active helped ease their low back pain. Conclusions. When advocating that individuals with acute low back pain return to or increase physical activity, it is important that clinicians identify avoidance of physical activity and/or fear of pain at the earliest stage in order to tailor advice and reassurance appropriately. If avoidance of activity and fear of pain is identified and clinicians want to encourage patients to take up and sustain increased physical activity, they should explore issues of fear of pain, and avoidance of and confidence to do physical activities, in addition to other factors influencing physical activity

Determination of kinetic parameters and thermodynamic properties for Ash (Fraxinus) wood sawdust slow pyrolysis by thermogravimetric analysis

Ash (Fraxinus) wood sawdust pyrolysis under nitrogen was conducted using 2, 5, 10, 15, and 20°C/min heating rates. Friedman and Starink methods were used for kinetic analysis while y(α) master plots were used for pyrolysis mechanisms prediction. The mean activation energy were 198 and 202 kJ/mol for Friedman and Starink, respectively. The master plots predicted that the pyrolysis process could be a combination of diffusion, geometrical contraction, nucleation, and reaction order models. The pre-exponential factors were in the range 1012 to 1019 s−1. Gibbs free energy was 180 −185 kJ/mol. The entropy values were negative up to α = 0.75 indicating high orderliness of products relative to reactants but changed to positive at higher conversions implying likely disorderliness of the products compared to reactants. The calorific value of Ash (Fraxinus) wood sawdust was 18.3 MJ/kg

Real time analysis of combustion emissions: a comparison of catalyst treated and untreated solid fuels

Carbon monoxide (CO) from combustion of solid fuels causes some deaths worldwide every year. This study has been undertaken to evaluate the amount of carbon monoxide, (and carbon dioxide, nitrogen oxide & methane) evolved from catalyst (Pd-Sn/alumina and Cu-Mn/graphite) treated charcoal briquettes, untreated charcoal briquettes, commercial charcoal and coal at non-isothermal temperatures between 50 to 800 oC attained at different heating rates of 20-40 (oC/min). Samples were heated in a thermal analysis instrument coupled with a multi-gas analyser under flowing air at different flow rates 20-100 (ml/min). Results showed a significant CO and NO reduction with catalyst treated charcoal compared to untreated charcoal briquettes and coal. There is also a strong dependence of CO emissions on heating rate and air flow. This study shows that catalyst treatment of solid fuels helps to minimise harmful combustion emissions

Mechanical impregnation of Pd-Sn/alumina and Cu-Mn/graphite on charcoal to minimise carbon monoxide emissions

This study investigated how to minimize carbon monoxide (CO) emissions from charcoal by impregnating with Pd-Sn/alumina and Cu-Mn/graphite. Samples were heated isothermally with continuous monitoring of residual CO using electrochemical and infra-red sensors. With 0.2wt% Pd-Sn/alumina, 26.9% and 44.4% were recorded as lowest and highest residual CO. On the other hand, when 2wt% Cu-Mn/graphite was used, 15.6%, and 25.3% were observed as lowest and highest residual CO. The activity of the catalysts decreased with temperature and increased with catalyst loading. This method could be used on briquettes, wood boiler chips and other solid carbonaceous materials to minimise CO emissions

The development of models to predict melting and pyrolysis point data associated with several hundred thousand compounds mined from PATENTS

BACKGROUND: Melting point (MP) is an important property in regards to the solubility of chemical compounds. Its prediction from chemical structure remains a highly challenging task for quantitative structure-activity relationship studies. Success in this area of research critically depends on the availability of high quality MP data as well as accurate chemical structure representations in order to develop models. Currently, available datasets for MP predictions have been limited to around 50k molecules while lots more data are routinely generated following the synthesis of novel materials. Significant amounts of MP data are freely available within the patent literature and, if it were available in the appropriate form, could potentially be used to develop predictive models. RESULTS: We have developed a pipeline for the automated extraction and annotation of chemical data from published PATENTS. Almost 300,000 data points have been collected and used to develop models to predict melting and pyrolysis (decomposition) points using tools available on the OCHEM modeling platform (http://ochem.eu). A number of technical challenges were simultaneously solved to develop models based on these data. These included the handing of sparse data matrices with >200,000,000,000 entries and parallel calculations using 32 × 6 cores per task using 13 descriptor sets totaling more than 700,000 descriptors. We showed that models developed using data collected from PATENTS had similar or better prediction accuracy compared to the highly curated data used in previous publications. The separation of data for chemicals that decomposed rather than melting, from compounds that did undergo a normal melting transition, was performed and models for both pyrolysis and MPs were developed. The accuracy of the consensus MP models for molecules from the drug-like region of chemical space was similar to their estimated experimental accuracy, 32 °C. Last but not least, important structural features related to the pyrolysis of chemicals were identified, and a model to predict whether a compound will decompose instead of melting was developed. CONCLUSIONS: We have shown that automated tools for the analysis of chemical information have reached a mature stage allowing for the extraction and collection of high quality data to enable the development of structure-activity relationship models. The developed models and data are publicly available at http://ochem.eu/article/99826