I. The structure and properties of closed circular duplex DNA. II. Chemically interacting systems at equilibrium in a buoyant density gradient

I. The binding of the intercalating dye ethidium bromide to closed circular SV 40 DNA causes an unwinding of the duplex structure and a simultaneous and quantitatively equivalent unwinding of the superhelices. The buoyant densities and sedimentation velocities of both intact (I) and singly nicked (II) SV 40 DNAs were measured as a function of free dye concentration. The buoyant density data were used to determine the binding isotherms over a dye concentration range extending from 0 to 600 µg/m1 in 5.8 M CsCl. At high dye concentrations all of the binding sites in II, but not in I, are saturated. At free dye concentrations less than 5.4 µg/ml, I has a greater affinity for dye than II. At a critical amount of dye bound I and II have equal affinities, and at higher dye concentration I has a lower affinity than II. The number of superhelical turns, τ, present in I is calculated at each dye concentration using Fuller and Waring's (1964) estimate of the angle of duplex unwinding per intercalation. The results reveal that SV 40 DNA I contains about -13 superhelical turns in concentrated salt solutions.

The free energy of superhelix formation is calculated as a function of τ from a consideration of the effect of the superhelical turns upon the binding isotherm of ethidium bromide to SV 40 DNA I. The value of the free energy is about 100 kcal/mole DNA in the native molecule. The free energy estimates are used to calculate the pitch and radius of the superhelix as a function of the number of superhelical turns. The pitch and radius of the native I superhelix are 430 Å and 135 Å, respectively.

A buoyant density method for the isolation and detection of closed circular DNA is described. The method is based upon the reduced binding of the intercalating dye, ethidium bromide, by closed circular DNA. In an application of this method it is found that HeLa cells contain in addition to closed circular mitochondrial DNA of mean length 4.81 microns, a heterogeneous group of smaller DNA molecules which vary in size from 0.2 to 3.5 microns and a paucidisperse group of multiples of the mitochondrial length.

II. The general theory is presented for the sedimentation equilibrium of a macromolecule in a concentrated binary solvent in the presence of an additional reacting small molecule. Equations are derived for the calculation of the buoyant density of the complex and for the determination of the binding isotherm of the reagent to the macrospecies. The standard buoyant density, a thermodynamic function, is defined and the density gradients which characterize the four component system are derived. The theory is applied to the specific cases of the binding of ethidium bromide to SV 40 DNA and of the binding of mercury and silver to DNA.

Distributed Optimal Control of Cyber-Physical Systems: Controller Synthesis, Architecture Design and System Identification

The centralized paradigm of a single controller and a single plant upon which modern control theory is built is no longer applicable to modern cyber-physical systems of interest, such as the power-grid, software defined networks or automated highways systems, as these are all large-scale and spatially distributed. Both the scale and the distributed nature of these systems has motivated the decentralization of control schemes into local sub-controllers that measure, exchange and act on locally available subsets of the globally available system information. This decentralization of control logic leads to different decision makers acting on asymmetric information sets, introduces the need for coordination between them, and perhaps not surprisingly makes the resulting optimal control problem much harder to solve. In fact, shortly after such questions were posed, it was realized that seemingly simple decentralized optimal control problems are computationally intractable to solve, with the Wistenhausen counterexample being a famous instance of this phenomenon. Spurred on by this perhaps discouraging result, a concerted 40 year effort to identify tractable classes of distributed optimal control problems culminated in the notion of quadratic invariance, which loosely states that if sub-controllers can exchange information with each other at least as quickly as the effect of their control actions propagates through the plant, then the resulting distributed optimal control problem admits a convex formulation.

The identification of quadratic invariance as an appropriate means of "convexifying" distributed optimal control problems led to a renewed enthusiasm in the controller synthesis community, resulting in a rich set of results over the past decade. The contributions of this thesis can be seen as being a part of this broader family of results, with a particular focus on closing the gap between theory and practice by relaxing or removing assumptions made in the traditional distributed optimal control framework. Our contributions are to the foundational theory of distributed optimal control, and fall under three broad categories, namely controller synthesis, architecture design and system identification.

We begin by providing two novel controller synthesis algorithms. The first is a solution to the distributed H-infinity optimal control problem subject to delay constraints, and provides the only known exact characterization of delay-constrained distributed controllers satisfying an H-infinity norm bound. The second is an explicit dynamic programming solution to a two player LQR state-feedback problem with varying delays. Accommodating varying delays represents an important first step in combining distributed optimal control theory with the area of Networked Control Systems that considers lossy channels in the feedback loop. Our next set of results are concerned with controller architecture design. When designing controllers for large-scale systems, the architectural aspects of the controller such as the placement of actuators, sensors, and the communication links between them can no longer be taken as given -- indeed the task of designing this architecture is now as important as the design of the control laws themselves. To address this task, we formulate the Regularization for Design (RFD) framework, which is a unifying computationally tractable approach, based on the model matching framework and atomic norm regularization, for the simultaneous co-design of a structured optimal controller and the architecture needed to implement it. Our final result is a contribution to distributed system identification. Traditional system identification techniques such as subspace identification are not computationally scalable, and destroy rather than leverage any a priori information about the system's interconnection structure. We argue that in the context of system identification, an essential building block of any scalable algorithm is the ability to estimate local dynamics within a large interconnected system. To that end we propose a promising heuristic for identifying the dynamics of a subsystem that is still connected to a large system. We exploit the fact that the transfer function of the local dynamics is low-order, but full-rank, while the transfer function of the global dynamics is high-order, but low-rank, to formulate this separation task as a nuclear norm minimization problem. Finally, we conclude with a brief discussion of future research directions, with a particular emphasis on how to incorporate the results of this thesis, and those of optimal control theory in general, into a broader theory of dynamics, control and optimization in layered architectures.

Surface effects in simple molecular systems

This thesis examines two problems concerned with surface effects in simple molecular systems. The first is the problem associated with the interaction of a fluid with a solid boundary, and the second originates from the interaction of a liquid with its own vapor.

For a fluid in contact with a solid wall, two sets of integro-differential equations, involving the molecular distribution functions of the system, are derived. One of these is a particular form of the well-known Bogolyubov-Born-Green-Kirkwood-Yvon equations. For the second set, the derivation, in contrast with the formulation of the B.B.G.K.Y. hierarchy, is independent of the pair-potential assumption. The density of the fluid, expressed as a power series in the uniform fluid density, is obtained by solving these equations under the requirement that the wall be ideal.

The liquid-vapor interface is analyzed with the aid of equations that describe the density and pair-correlation function. These equations are simplified and then solved by employing the superposition and the low vapor density approximations. The solutions are substituted into formulas for the surface energy and surface tension, and numerical results are obtained for selected systems. Finally, the liquid-vapor system near the critical point is examined by means of the lowest order B.B.G.K.Y. equation.

Dynamic response of hysteretic systems with application to a system containing limited slip

A general class of single degree of freedom systems possessing rate-independent hysteresis is defined. The hysteretic behavior in a system belonging to this class is depicted as a sequence of single-valued functions; at any given time, the current function is determined by some set of mathematical rules concerning the entire previous response of the system. Existence and uniqueness of solutions are established and boundedness of solutions is examined.

An asymptotic solution procedure is used to derive an approximation to the response of viscously damped systems with a small hysteretic nonlinearity and trigonometric excitation. Two properties of the hysteresis loops associated with any given system completely determine this approximation to the response: the area enclosed by each loop, and the average of the ascending and descending branches of each loop.

The approximation, supplemented by numerical calculations, is applied to investigate the steady-state response of a system with limited slip. Such features as disconnected response curves and jumps in response exist for a certain range of system parameters for any finite amount of slip.

To further understand the response of this system, solutions of the initial-value problem are examined. The boundedness of solutions is investigated first. Then the relationship between initial conditions and resulting steady-state solution is examined when multiple steady-state solutions exist. Using the approximate analysis and numerical calculations, it is found that significant regions of initial conditions in the initial condition plane lead to the different asymptotically stable steady-state solutions.

Design and implementation of robust systems for secure malware detection

Malicious software (malware) have significantly increased in terms of number and effectiveness during the past years. Until 2006, such software were mostly used to disrupt network infrastructures or to show coders’ skills. Nowadays, malware constitute a very important source of economical profit, and are very difficult to detect. Thousands of novel variants are released every day, and modern obfuscation techniques are used to ensure that signature-based anti-malware systems are not able to detect such threats. This tendency has also appeared on mobile devices, with Android being the most targeted platform. To counteract this phenomenon, a lot of approaches have been developed by the scientific community that attempt to increase the resilience of anti-malware systems. Most of these approaches rely on machine learning, and have become very popular also in commercial applications. However, attackers are now knowledgeable about these systems, and have started preparing their countermeasures. This has lead to an arms race between attackers and developers. Novel systems are progressively built to tackle the attacks that get more and more sophisticated. For this reason, a necessity grows for the developers to anticipate the attackers’ moves. This means that defense systems should be built proactively, i.e., by introducing some security design principles in their development. The main goal of this work is showing that such proactive approach can be employed on a number of case studies. To do so, I adopted a global methodology that can be divided in two steps. First, understanding what are the vulnerabilities of current state-of-the-art systems (this anticipates the attacker’s moves). Then, developing novel systems that are robust to these attacks, or suggesting research guidelines with which current systems can be improved. This work presents two main case studies, concerning the detection of PDF and Android malware. The idea is showing that a proactive approach can be applied both on the X86 and mobile world. The contributions provided on this two case studies are multifolded. With respect to PDF files, I first develop novel attacks that can empirically and optimally evade current state-of-the-art detectors. Then, I propose possible solutions with which it is possible to increase the robustness of such detectors against known and novel attacks. With respect to the Android case study, I first show how current signature-based tools and academically developed systems are weak against empirical obfuscation attacks, which can be easily employed without particular knowledge of the targeted systems. Then, I examine a possible strategy to build a machine learning detector that is robust against both empirical obfuscation and optimal attacks. Finally, I will show how proactive approaches can be also employed to develop systems that are not aimed at detecting malware, such as mobile fingerprinting systems. In particular, I propose a methodology to build a powerful mobile fingerprinting system, and examine possible attacks with which users might be able to evade it, thus preserving their privacy. To provide the aforementioned contributions, I co-developed (with the cooperation of the researchers at PRALab and Ruhr-Universität Bochum) various systems: a library to perform optimal attacks against machine learning systems (AdversariaLib), a framework for automatically obfuscating Android applications, a system to the robust detection of Javascript malware inside PDF files (LuxOR), a robust machine learning system to the detection of Android malware, and a system to fingerprint mobile devices. I also contributed to develop Android PRAGuard, a dataset containing a lot of empirical obfuscation attacks against the Android platform. Finally, I entirely developed Slayer NEO, an evolution of a previous system to the detection of PDF malware. The results attained by using the aforementioned tools show that it is possible to proactively build systems that predict possible evasion attacks. This suggests that a proactive approach is crucial to build systems that provide concrete security against general and evasion attacks.

NHS Wales e-library portal evaluation (For Informing Healthcare Strategy implementation programme)

Thomas, R. & Urquhart, C. NHS Wales e-library portal evaluation. (For Informing Healthcare Strategy implementation programme). Aberystwyth: Department of Information Studies, University of Wales Aberystwyth Follow-on to NHS Wales User Needs study Sponsorship: Informing Healthcare, NHS Wales

Evaluation of the Specialist Libraries/Communities of Practice. Report for National Library for Health

Cooper, J., Spink, S., Thomas, R. & Urquhart, C. (2005). Evaluation of the Specialist Libraries/Communities of Practice. Report for National Library for Health. Aberystwyth: Department of Information Studies, University of Wales Aberystwyth. Sponsorship: National Library for Health (NLH)

The management of health library outreach services: evaluation and reflection on lessons learned on the VIVOS project

Yeoman, A. J., Cooper, J. M., Urquhart, C. J. & Tyler, A. (2003). The management of health library outreach services: evaluation and reflection on lessons learned on the VIVOS project. Journal of the Medical Library Association, 91(4), 426-433. Sponsorship: Resource

Moving Communities of Practice forward: the challenge for the National electronic Library for Health and its Virtual Branch Libraries

Yeoman, A., Urquhart, C. & Sharp, S. (2003). Moving Communities of Practice forward: the challenge for the National electronic Library for Health and its Virtual Branch Libraries. Health Informatics Journal, 9(4), 241-252. Previously appeared as a conference paper for the iSHIMR2003 conference (Proceedings of the Eighth International Symposium on Health Information Management Research, June 1-3, 2003, Boras, Sweden) Sponsorship: NHS Information Authority/National electronic Library for Health

Developing communities of practice in the NeLH (National electronic Library for Health)

Urquhart, C., Yeoman, A., Sharp, S. (2003). Developing communities of practice in the NeLH (National electronic Library for Health). In Proceedings of the UKAIS (UK Academy for Information Systems) annual conference, University of Warwick, April 2003. Sponsorship: NHS Information Authority/National electronic Library for Health

World Library Summit and visits to libraries in Singapore: a report

Tedd, L.A. (2002). World Library Summit and visits to libraries in Singapore: a report. Program:electronic library and information systems, 36(4), 253-260.

Developing a toolkit for assessing the impact of health library services on patient care

Urquhart,C., Spink, S., Thomas, R. & Weightman, A. (2007). Developing a toolkit for assessing the impact of health library services on patient care. Report to LKDN (Libraries and Knowledge Development Network). Aberystwyth: Department of Information Studies, Aberystwyth University. Sponsorship: Libraries and Knowledge Development Network/ NHS

Assessing the impact of a health library service. Best practice guidance

Urquhart, C. & Weightman, A. (2008). Assessing the impact of a health library service. Best Practice Guidance. Based on research originally funded by LKDN, now sponsored by National Library for Health. Aberystwyth: Department of Information Studies, Aberystwyth University. The guidance relates to a project report, Developing a toolkit for assessing the impact of health library services on patient care (also available in CADAIR). A version of this item is available as an online appendix to a paper in Health Information and Libraries Journal entitled: The value and impact of information provided through library services for patient care: developing guidance for best practice (Weightman, A., Urquhart, C. et al) available electronically prepublication Sponsorship: LKDN/NLH

Small angle scattering characterisation of micellar systems and templated architectures

The work described in this thesis reports the structural changes induced on micelles under a variety of conditions. The micelles of a liquid crystal film and dilute solutions of micelles were subjected to high pressure CO2 and selected hydrocarbon environments. Using small angle neutron scattering (SANS) techniques the spacing between liquid crystal micelles was measured in-situ. The liquid crystals studied were templated from different surfactants with varying structural characteristics. Micelles of a dilute surfactant solution were also subjected to elevated pressures of varying gas atmospheres. Detailed modelling of the in-situ SANS experiments revealed information of the size and shape of the micelles at a number of different pressures. Also reported in this thesis is the characterisation of mesoporous materials in the confined channels of larger porous materials. Periodic mesoporous organosilicas (PMOs) were synthesised within the channels of anodic alumina membranes (AAM) under different conditions, including drying rates and precursor concentrations. In-situ small angle x-ray scattering (SAXS) and transmission electron microscopy (TEM) was used to determine the pore morphology of the PMO within the AAM channels. PMO materials were also used as templates in the deposition of gold nanoparticles and subsequently used in the synthesis of germanium nanostructures. Polymer thin films were also employed as templates for the directed deposition of gold nanoparticles which were again used as seeds for the production of germanium nanostructures. A supercritical CO2 (sc-CO2) technique was successfully used during the production of the germanium nanostructures.

Studies on equine milk and comparative studies on equine and bovine milk systems

The composition of equine milk differs considerably from that of the milk of the principal dairying species, i.e., the cow, buffalo, goat and sheep. Because equine milk resembles human milk in many respects and is claimed to have special therapeutic properties, it is becoming increasingly popular in Western Europe, where it is produced on large farms in several countries. Equine milk is considered to be highly digestible, rich in essential nutrients and to possess an optimum whey protein:casein ratio, making it very suitable as a substitute for bovine milk in paediatric dietetics. There is some scientific basis for the special nutritional and health-giving properties of equine milk but this study provides a comprehensive analysis of the composition and physico-chemical properties of equine milk which is required to fully exploit its potential in human nutrition. Quantification and distribution of the nitrogenous components and principal salts of equine milk are reported. The effects of the high concentration of ionic calcium, large casein micelles (~ 260 nm), low protein, lack of a sulphydryl group in equine β-lactoglobulin and a very low level of κ-casein on the physico-chemical properties of equine milk are reported. This thesis provides an insight into the stability of equine casein micelles to heat, ethanol, high pressure, rennet or acid. Differences in rennet- and acid-induced coagulation between equine and bovine milk are attributed not only to the low casein content of equine milk but also to differences in the mechanism by which the respective micelles are stabilized. It has been reported that β-casein plays a role in the stabilization of equine casein micelles and proteomic techniques support this view. In this study, equine κ-casein appeared to be resistant to hydrolysis by calf chymosin but equine β-casein was readily hydrolysed. Resolution of equine milk proteins by urea-PAGE showed the multi-phosphorylated isoforms of equine αs- and β-caseins and capillary zone electrophoresis showed 3 to 7 phosphorylated residues in equine β-casein. In vitro digestion of equine β-casein by pepsin and Corolase PP™ did not produce casomorphins BCM-5 or BCM-7, believed to be harmful to human health. Electron microscopy provided very clear, detailed images of equine casein micelles in their native state and when renneted or acidified. Equine milk formed flocs rather then a gel when renneted or acidified which is supported by dynamic oscillatory analysis. The results presented in this thesis will assist in the development of new products from equine milk for human consumption which will retain some of its unique compositional and health-giving properties.