High throughput prediction of the long term stability of pharmaceutical macromolecules from short term multi-instrument spectroscopic data

The field of pharmaceutical chemistry is currently struggling with the question of how to relate changes in the physical form of a macromolecular biopharmaceutical, such as a therapeutic protein, to changes in the drug's efficacy, safety, and long term stability (ESS). A great number of experimental methods are typically utilized to investigate the differences between forms of a macromolecule, yet conclusions regarding changes in ESS are frequently tentative. An opportunity exists, however, to relate changes in form to changes in ESS. At least once during the development of a new drug, a study is undertaken (at great expense) of the ESS of the drug upon perturbation by multiple manufacturing, formulation, storage and transportation variables. The data acquired is then used to build a model that relates changes in ESS to manufacturing, formulation, storage and transportation variables. It is not common in the pharmaceutical industry, however, to relate changes in comprehensive ESS data sets to comprehensive measurements of changes in macromolecular form. We bridge the gap between physical measurements of a macromolecule's form and measurements of its long term stability, utilizing two data sets collected in a collaboration between our group at the University of Kansas and a group at the Ludwig Maximilians University in Munich, Germany. The long term stability data, collected by the team in Germany, contains measurements of the chemical and conformation stability of Granulocyte Colony Stimulating Factor (GCSF) over a period of two years in 16 different liquid formulations. The short term physical data, collected in our lab, is comprised of spectroscopic characterization of the response of GCSF to thermal unfolding. The same 16 liquid formulations of GCSF were used in each study, allowing us to fit models predicting the long term stability of GCSF from short term measurements. We first apply a novel data reduction method to the short term data. This method selects data in the neighborhood of thermal unfolding transitions, and automates traditional comparative analyses. We then model the long term stability measurements using a linear technique, least squares fits, and a nonlinear one, radial basis function networks (RBFN). Using a Pearson correlation coefficient permutation test, we find that many of the fitted results have less than a 1 percent probability of occurring by chance

NOVEL ALGORITHMS AND TOOLS FOR LIGAND-BASED DRUG DESIGN

Computer-aided drug design (CADD) has become an indispensible component in modern drug discovery projects. The prediction of physicochemical properties and pharmacological properties of candidate compounds effectively increases the probability for drug candidates to pass latter phases of clinic trials. Ligand-based virtual screening exhibits advantages over structure-based drug design, in terms of its wide applicability and high computational efficiency. The established chemical repositories and reported bioassays form a gigantic knowledgebase to derive quantitative structure-activity relationship (QSAR) and structure-property relationship (QSPR). In addition, the rapid advance of machine learning techniques suggests new solutions for data-mining huge compound databases. In this thesis, a novel ligand classification algorithm, Ligand Classifier of Adaptively Boosting Ensemble Decision Stumps (LiCABEDS), was reported for the prediction of diverse categorical pharmacological properties. LiCABEDS was successfully applied to model 5-HT1A ligand functionality, ligand selectivity of cannabinoid receptor subtypes, and blood-brain-barrier (BBB) passage. LiCABEDS was implemented and integrated with graphical user interface, data import/export, automated model training/ prediction, and project management. Besides, a non-linear ligand classifier was proposed, using a novel Topomer kernel function in support vector machine. With the emphasis on green high-performance computing, graphics processing units are alternative platforms for computationally expensive tasks. A novel GPU algorithm was designed and implemented in order to accelerate the calculation of chemical similarities with dense-format molecular fingerprints. Finally, a compound acquisition algorithm was reported to construct structurally diverse screening library in order to enhance hit rates in high-throughput screening

User Interfaces for Personal Knowledge Management with Semantic Technologies

This thesis describes iMapping and QuiKey, two novel user interface concepts for dealing with structured information. iMapping is a visual knowledge mapping technique based on zooming, which combines the advantages of several existing approaches and scales up to very large maps. QuiKey is a text-based tool to interact with graph-structured knowledge bases with very high interaction efficiency. Both tools have been implemented and positively evaluated in user studies

Analysis of Protistan Grazing on Bioremediative Bacteria Using IN WVO Fluorescent Protein Expression and Flow Cytometry

Protistan bacterivory can influence the size distribution, cell structure and composition of natural bacterial communities and is of significant concern for design of bioremediation efforts, yet adequate methods for observation and modeling are lacking. In this investigation, fluorescent protein expression and flow cytometry were used to study protistan grazing on genetically modified strains of several bacterial species that have been considered for use in bioremediation. Broad-host-range plasmids were constructed and used to introduce genes encoding GFP (green fluorescent protein) or RFP (red fluorescent protein) to prey species. A heterotrophic flagellate Paraphysomonas imperforata (Hflag) served as a model predator. Predator-prey interactions were observed and quantified using particle counts and individual optical signals recorded by FACScan flow cytometry. Result files were parsed by Windows Multiple-Document flow cytometry Interface (WinMDI v2.8) and analyzed by GR, a Per1 (Practical Extraction and Report Language) program described herein. Grazing preference of Hflag was influenced by prey type, size and predator culturing conditions. Hflag showed strong preference for bacterial cells over algal cells of a similar size, as well as for bacterial cells of different dimensions. However, size preferences were observed among cells within individual bacterial prey species. Significant preference was also observed for cells labeled by GFP and for unstained cells as compared to cells stained by a traditional DTAF-staining (5- (4,6-Dichloro-Triazin-2-y1)-Amino Fluorescein hydrochloride) method. No difference was observed between cells labeled by GFP and unstained cells. These results show that the methods described here provide a viable approach to observing protistan bacterivory that is superior in some respects to currently used methods

Structure evaluation of computer human animation quality

The University of Bedfordshire in partial fulfilment of the requirements for the degree of Doctor of PhilosophyThis work will give a wide survey for various techniques that are present in the field of character computer animation, which concentrates particularly on those techniques and problems involved in the production of realistic character synthesis and motion. A preliminary user study (including Questionnaire, online publishing such as flicker.com, interview, multiple choice questions, publishing on Android mobile phone, and questionnaire analysis, validation, statistical evaluation, design steps and Character Animation Observation) was conducted to explore design questions, identify users' needs, and obtain a "true story" of quality character animation and the effect of using animation as useful tools in Education. The first set of questionnaires were designed to accommodate the evaluation of animation from candidates from different walks of life, ranging from animators, gamers, teacher assistances (TA), students, teaches, professionals and researchers using and evaluating pre-prepared animated character videos scenarios, and the study outcomes has reviewed the recent advances techniques of character animation, motion editing that enable the control of complex animations by interactively blending, improving and tuning artificial or captured motions. The goal of this work was to augment the students learning intuition by providing ways to make education and learning more interesting, useful and fun objectively, in order to improve students’ respond and understanding to any subject area through the use of animation also by producing the required high quality motion, reaction, interaction and story board to viewers of the motion. We present a variety of different evaluation to the motion quality by measuring user sensitivity, observations to any noticeable artefact, usability, usefulness etc. to derive clear useful guidelines from the results, and discuss several interesting systematic trends we have uncovered in the experimental data. We also present an efficient technique for evaluating the capability of animation influence on education to fulfil the requirements of a given scenario, along with the advantages and the effect on those deficiencies of some methods commonly used to improve animation quality to serve the learning process. Finally, we propose a wide range of extensions and statistical calculation enabled by these evaluation tools, such as Wilcoxon, F-test, T-test, Wondershare Quiz creator (WQC), Chi square and many others explained with full details

Interactive multiview information visualization in tablet-sized touch devices for scientific data

In this thesis we describe an exploratory visualization system for scientific data using multiple views in tablet-sized touch devices. The increasing ubiquity of mobile devices and vast amount of data generation create a need for such exploration environment. We make the data analysis available anywhere at anytime with our approach. This thesis includes an interaction framework for scientific data and a spatial selection technique based on transfer functions. We then combine the interaction and selection with multiple information visualization views to make the data exploration possible. The proposed approach is one of the first multiview exploratory visualizations in tablet devices

Bringing the Physical to the Digital

This dissertation describes an exploration of digital tabletop interaction styles, with the ultimate goal of informing the design of a new model for tabletop interaction. In the context of this thesis the term digital tabletop refers to an emerging class of devices that afford many novel ways of interaction with the digital. Allowing users to directly touch information presented on large, horizontal displays. Being a relatively young field, many developments are in flux; hardware and software change at a fast pace and many interesting alternative approaches are available at the same time. In our research we are especially interested in systems that are capable of sensing multiple contacts (e.g., fingers) and richer information such as the outline of whole hands or other physical objects. New sensor hardware enable new ways to interact with the digital. When embarking into the research for this thesis, the question which interaction styles could be appropriate for this new class of devices was a open question, with many equally promising answers. Many everyday activities rely on our hands ability to skillfully control and manipulate physical objects. We seek to open up different possibilities to exploit our manual dexterity and provide users with richer interaction possibilities. This could be achieved through the use of physical objects as input mediators or through virtual interfaces that behave in a more realistic fashion. In order to gain a better understanding of the underlying design space we choose an approach organized into two phases. First, two different prototypes, each representing a specific interaction style – namely gesture-based interaction and tangible interaction – have been implemented. The flexibility of use afforded by the interface and the level of physicality afforded by the interface elements are introduced as criteria for evaluation. Each approaches’ suitability to support the highly dynamic and often unstructured interactions typical for digital tabletops is analyzed based on these criteria. In a second stage the learnings from these initial explorations are applied to inform the design of a novel model for digital tabletop interaction. This model is based on the combination of rich multi-touch sensing and a three dimensional environment enriched by a gaming physics simulation. The proposed approach enables users to interact with the virtual through richer quantities such as collision and friction. Enabling a variety of fine-grained interactions using multiple fingers, whole hands and physical objects. Our model makes digital tabletop interaction even more “natural”. However, because the interaction – the sensed input and the displayed output – is still bound to the surface, there is a fundamental limitation in manipulating objects using the third dimension. To address this issue, we present a technique that allows users to – conceptually – pick objects off the surface and control their position in 3D. Our goal has been to define a technique that completes our model for on-surface interaction and allows for “as-direct-as possible” interactions. We also present two hardware prototypes capable of sensing the users’ interactions beyond the table’s surface. Finally, we present visual feedback mechanisms to give the users the sense that they are actually lifting the objects off the surface. This thesis contributes on various levels. We present several novel prototypes that we built and evaluated. We use these prototypes to systematically explore the design space of digital tabletop interaction. The flexibility of use afforded by the interaction style is introduced as criterion alongside the user interface elements’ physicality. Each approaches’ suitability to support the highly dynamic and often unstructured interactions typical for digital tabletops are analyzed. We present a new model for tabletop interaction that increases the fidelity of interaction possible in such settings. Finally, we extend this model so to enable as direct as possible interactions with 3D data, interacting from above the table’s surface

A Software Engineered Voice-Enabled Job Recruitment Portal System

The inability of job seekers to get timely job information regarding the status of the application submitted via conventional job portal system which is usually dependent on accessibility to the Internet has made so many job applicants to lose their placements. Worse still, the epileptic services offered by Internet Service Providers and the poor infrastructures in most developing countries have greatly hindered the expected benefits from Internet usage. These have led to cases of online vacancies notifications unattended to simply because a job seeker is neither aware nor has access to the Internet. With an increasing patronage of mobile phones, a self-service job vacancy notification with audio functionality or an automated job vacancy notification to all qualified job seekers through mobile phones will simply provide a solution to these challenges. In this paper, we present a Voice-enabled Job Recruitment Portal (JRP) System. The system is accessed through two interfaces – the voice user’s interface (VUI) and web interface. The VUI was developed using VoiceXML and the web interface using PHP, and both interfaces integrated with Apache and MySQL as the middleware and back-end component respectively. The JRP proposed in this paper takes the hassle of job hunting from job seekers, provides job status information in real-time to the job seeker and offers other benefits such as, cost, effectiveness, speed, accuracy, ease of documentation, convenience and better logistics to the employer in seeking the right candidate for a job