Improving T cell-induced response to subunit vaccines:opportunities for a proteomic systems approach

Prophylactic vaccines are an effective strategy to prevent development of many infectious diseases. With new and re-emerging infections posing increasing risks to food stocks and the health of the population in general, there is a need to improve the rationale of vaccine development. One key challenge lies in development of an effective T cell-induced response to subunit vaccines at specific sites and in different populations. Objectives: In this review, we consider how a proteomic systems-based approach can be used to identify putative novel vaccine targets, may be adopted to characterise subunit vaccines and adjuvants fully. Key findings: Despite the extensive potential for proteomics to aid our understanding of subunit vaccine nature, little work has been reported on identifying MHC 1-binding peptides for subunit vaccines generating T cell responses in the literature to date. Summary: In combination with predictive and structural biology approaches to mapping antigen presentation, proteomics offers a powerful and as yet un-tapped addition to the armoury of vaccine discovery to predict T-cell subset responses and improve vaccine design strategies.

An incentivized auction based group-selling approach for demand response management in V2G systems

Vehicle-to-Grid (V2G) system with efficient Demand Response Management (DRM) is critical to solve the problem of supplying electricity by utilizing surplus electricity available at EVs. An incentivilized DRM approach is studied to reduce the system cost and maintain the system stability. EVs are motivated with dynamic pricing determined by the group-selling based auction. In the proposed approach, a number of aggregators sit on the first level auction responsible to communicate with a group of EVs. EVs as bidders consider Quality of Energy (QoE) requirements and report interests and decisions on the bidding process coordinated by the associated aggregator. Auction winners are determined based on the bidding prices and the amount of electricity sold by the EV bidders. We investigate the impact of the proposed mechanism on the system performance with maximum feedback power constraints of aggregators. The designed mechanism is proven to have essential economic properties. Simulation results indicate the proposed mechanism can reduce the system cost and offer EVs significant incentives to participate in the V2G DRM operation.

Amplitude response of a unilaterally constrained nonlinear micromechanical resonator

Dynamical systems that involve impacts frequently arise in engineering. This Letter reports a study of such a system at microscale that consists of a nonlinear resonator operating with an unilateral impact. The microresonators were fabricated on silicon-on-insulator wafers by using a one-mask process and then characterised by using the capacitively driving and sensing method. Numerical results concerning the dynamics of this vibro-impact system were verified by the experiments. Bifurcation analysis was used to provide a qualitative scenario of the system steady-state solutions as a function of both the amplitude and the frequency of the external driving sinusoidal voltage. The results show that the amplitude of resonant peak is levelled off owing to the impact effect and that the bandwidth of impacting is dependent upon the nonlinearity and the operating conditions.

Liposomal vaccine delivery systems

INTRODUCTION: Liposomes remain at the forefront of drug and vaccine design owing to their well-documented abilities to act as delivery vehicles. Nevertheless, the concept of liposomes as delivery vehicles is not a new one, with most works focusing on their use for the delivery of genes and drugs. However, in the last 10 years a significant amount of research has focused on using liposomes as vaccine adjuvants, not only as an antigen delivery vehicle but also as a tool to increase the immunogenicity of peptide and protein antigens. AREAS COVERED: This paper reviews liposomal adjuvants now in vaccine development, with particular emphasis on their adjuvant mechanism and how specific physicochemical characteristics of liposomes affect the immune response. The inclusion of immunomodulators is also discussed, with prominence given to Toll-like receptor ligands. EXPERT OPINION: The use of liposomes as vaccine delivery systems is evolving rapidly owing to the combined increase in technological advances and understanding of the immune system. Liposomes that contain and deliver immunostimulators and antigens are now being developed to target diseases that require stimulation of both humoral and cell-mediated immune responses. The CAF liposomal system, described in detail in this review, is one liposomal model that shows such flexibility.

Response-based segmentation using Finite Mixture Partial Least Squares: theoretical foundations and an application to American Customer Satisfaction Index Data

When applying multivariate analysis techniques in information systems and social science disciplines, such as management information systems (MIS) and marketing, the assumption that the empirical data originate from a single homogeneous population is often unrealistic. When applying a causal modeling approach, such as partial least squares (PLS) path modeling, segmentation is a key issue in coping with the problem of heterogeneity in estimated cause-and-effect relationships. This chapter presents a new PLS path modeling approach which classifies units on the basis of the heterogeneity of the estimates in the inner model. If unobserved heterogeneity significantly affects the estimated path model relationships on the aggregate data level, the methodology will allow homogenous groups of observations to be created that exhibit distinctive path model estimates. The approach will, thus, provide differentiated analytical outcomes that permit more precise interpretations of each segment formed. An application on a large data set in an example of the American customer satisfaction index (ACSI) substantiates the methodology’s effectiveness in evaluating PLS path modeling results.

From national innovation systems to national innovation capacity:internationalisation and technology transfer perspectives

The last decade or so has witnessed the emergence of the national innovation system (NIS) phenomenon. Since then, many scholars have investigated NIS and its implementation in different countries. However, there are very few investigations into the relationship between the NIS of a country and its national innovation capacity. This paper aims to make a contribution in this area by examining the link that currently exists between these two topics. Whilst examining this relationship, we also explore internationalisation and technology transfer, being cognate areas that have been investigated during the same period. This follows our assertion that the link between NIS and national innovation capacity is the mechanism of internationalisation and technology transfer. The NIS approach was introduced in the late 1980s (see Freeman, 1987; Dosi et al., 1988) and further elaborated later (see Lundvall, 1992; Nelson, 1993; Edquist, 1997). In essence, a country?s NIS is a historically grown subsystem of the entire national economy consisting of organisations and institutions which play a major role in the innovative activity in the country. In the NIS approach, interactions within organisations as well as the interplay between organisations and institutions are of central importance. The NIS approach has been used to reveal the structure of the innovation processes and the main actors involved in them in industrialised and emerging countries. Although the national focus remains strong, it has been accompanied by studies seeking to analyse the notion of systems of innovation at an international level and at a sub-national scale (Archibugi et al., 1999). Dosi in the edition of Archibugi et al. (1999) argues that the general background of the discussion of national systems is the observation of non-random distributions across countries of: corporate capabilities; organisational forms; strategies; and ultimately revealed performances, in terms of production efficiency and inputs productivities, rates of innovation, rates of adoption/diffusion of innovation themselves, dynamics of market shares on the world markets, growth of income and employment. They also mention that there are several approaches to NIS. Nelson (1993) focuses upon the specificities of national institutions and policies supporting directly or indirectly innovation, diffusion and skills accumulation. Patel and Pavitt (1991) have stressed the links between the national patterns of technological accumulation and the competencies and innovative strategies of a few major national companies. Amable et al (1997) and Soskice (1993) and Zysman (1994) focus on the specifics of national institutions including, for example, the forms of organization, financial and labour markets, training institutions, forms of state intervention in the economy etc. However, the most common reference is by Lundvall (1992) who argues that the focus on the national level is associated with the fact that national economies vary according to their production system and their institutional framework and these differences are in turn strengthened by different historical experiences, language and culture. On the other hand, the national innovation capability consists of abilities to create and carry new technological possibilities through to economic practice. The term covers a wide range of activities from capability to invent to capability to innovate and to capability to improve existing technology beyond the original design parameters (Kim, 1997). The term innovation is often associated by many with technological change at international frontiers. However, technological capability is not the same as innovation capability. Technological capability refers to assimilation, use, adaptation, and change to existing technologies. It also enables the creation of new technologies and development of new products and processes in response to changing economic environments. It denotes operational command over knowledge (Kim, 1997). It is manifested not merely by the knowledge possessed, but, more important, by the uses to which that knowledge can be put and by the proficiency with which it is applied in the activities of investment and production and in the creation of new knowledge (Westphal et al., 1985). Therefore, the analytical framework that is used in this paper is based on the way a country derives from its NIS a national innovation capacity. There are two perspectives that are identified on this way. These are internationalisation and technology transfer. Even though NIS is not directly related to national innovation capacity, to achieve national innovation capacity from NIS, the country should have the ability for technology transfer. Technology transfer is a link between these two phenomena. On the other hand, internationalisation can be either the input or the output of the relationship between NIS and national innovation capability. If a company is investing in a country because of its national innovation capacity, this can be regarded as an input to the relationship between NIS and national innovation capacity. If this company is investigating the national innovation capacity of a country then, for its internationalisation, the national innovation capacity should be important, which in turn means this company is active in innovation and innovation is also an important success factor. The interrelationship between the investment of the company and the NIS of the country (assuming that the country is competent and competitive in technology transfer) will generate and improve that country?s national innovation capacity. This is the output of internationalisation from the relationship between NIS and national innovation capacity. When companies are evaluating whether to internationalise, they investigate certain factors in the countries in which they are considering to invest. The ability to transfer technology is dependent on ability to adopt a new technology and also on the learning derived from this technology. If countries wish to attract innovation related investment they need to show their ability to have a NIS and also the capability to transfer technology. Without the technology transfer capability, the NIS is not functioning. Therefore, companies that internationalise will investigate the factors common to NIS, technology transfer, and their business needs. Through this paper we will demonstrate this link though its mechanisms. Our research will be through extensive literature review and identifying relevant aspects of previous research carried out by the authors. It will investigate certain factors of different countries that are successful in attracting innovation related foreign direct investment. Through these, we will point out the factors that are important for the link and mechanisms of NIS and national innovation capability.

Types of task, types of audience, types of actor: interactions between mere presence and personality type in a simple mathematical task

Research into social facilitation effects reveals three factors affecting response performance: types of task, types of audience and type of actor. This study attempts to establish a minimal baseline for task and audience type in order to examine difference between personality types in the actors. Results indicate that performance in both extraverts and introverts increases in the minimal conditions of the mere presence of another person whilst carrying out a simple mathematical task. These results are interpreted through an analysis of Zajonc's (1965) drive theory with Eysenck's (1967) personality theory indicating that through further investigation performance curves might be devised for introverts and extraverts performing under a variety of task and audience conditions.

Manufacturing challenges in the new millenium:the Asia-Pacific response

Editorial

The design of robust protocols for distributed real-time systems

Modern distributed control systems comprise of a set of processors which are interconnected using a suitable communication network. For use in real-time control environments, such systems must be deterministic and generate specified responses within critical timing constraints. Also, they should be sufficiently robust to survive predictable events such as communication or processor faults. This thesis considers the problem of coordinating and synchronizing a distributed real-time control system under normal and abnormal conditions. Distributed control systems need to periodically coordinate the actions of several autonomous sites. Often the type of coordination required is the all or nothing property of an atomic action. Atomic commit protocols have been used to achieve this atomicity in distributed database systems which are not subject to deadlines. This thesis addresses the problem of applying time constraints to atomic commit protocols so that decisions can be made within a deadline. A modified protocol is proposed which is suitable for real-time applications. The thesis also addresses the problem of ensuring that atomicity is provided even if processor or communication failures occur. Previous work has considered the design of atomic commit protocols for use in non time critical distributed database systems. However, in a distributed real-time control system a fault must not allow stringent timing constraints to be violated. This thesis proposes commit protocols using synchronous communications which can be made resilient to a single processor or communication failure and still satisfy deadlines. Previous formal models used to design commit protocols have had adequate state coverability but have omitted timing properties. They also assumed that sites communicated asynchronously and omitted the communications from the model. Timed Petri nets are used in this thesis to specify and design the proposed protocols which are analysed for consistency and timeliness. Also the communication system is mcxielled within the Petri net specifications so that communication failures can be included in the analysis. Analysis of the Timed Petri net and the associated reachability tree is used to show the proposed protocols always terminate consistently and satisfy timing constraints. Finally the applications of this work are described. Two different types of applications are considered, real-time databases and real-time control systems. It is shown that it may be advantageous to use synchronous communications in distributed database systems, especially if predictable response times are required. Emphasis is given to the application of the developed commit protocols to real-time control systems. Using the same analysis techniques as those used for the design of the protocols it can be shown that the overall system performs as expected both functionally and temporally.

Dark solitons in optical communication systems

This thesis presents experimental and theoretical work on the use of dark optical solitons as data carriers in communications systems. The background chapters provide an introduction to nonlinear optics, and to dark solitons, described as intensity dips in a bright background, with an asymmetrical phase profile. The motivation for the work is explained, considering both the superior stability of dark solitons and the need for a soliton solution suitable for the normal, rather than the anomalous (bright soliton) dispersion regime. The first chapters present two generation techniques, producing packets of dark solitons via bright pulse interaction, and generating continuous trains of dark pulses using a fibre laser. The latter were not dark solitons, but were suitable for imposition of the required phase shift by virtue of their extreme stability. The later chapters focus on the propagation and control of dark solitons. Their response to periodic loss and gain is shown to result in the exponential growth of spectral sidebands. This may be suppressed by reducing the periodicity of the loss/gain cycle or using periodic filtering. A general study of the response of dark solitons to spectral filtering is undertaken, showing dramatic differences in the behaviour of black and 99.9% grey solitons. The importance of this result is highlighted by simulations of propagation in noisy systems, where the timing jitter resulting from random noise is actually enhanced by filtering. The results of using sinusoidal phase modulation to control pulse position are presented, showing that the control is at the expense of serious modulation of the bright background. It is concluded that in almost every case, dark and bright solitons have very different properties, and to continue to make comparisons would not be so productive as to develop a deeper understanding of the interactions between the dark soliton and its bright background.

A formal methodology for the verification of concurrent systems

There is an increasing emphasis on the use of software to control safety critical plants for a wide area of applications. The importance of ensuring the correct operation of such potentially hazardous systems points to an emphasis on the verification of the system relative to a suitably secure specification. However, the process of verification is often made more complex by the concurrency and real-time considerations which are inherent in many applications. A response to this is the use of formal methods for the specification and verification of safety critical control systems. These provide a mathematical representation of a system which permits reasoning about its properties. This thesis investigates the use of the formal method Communicating Sequential Processes (CSP) for the verification of a safety critical control application. CSP is a discrete event based process algebra which has a compositional axiomatic semantics that supports verification by formal proof. The application is an industrial case study which concerns the concurrent control of a real-time high speed mechanism. It is seen from the case study that the axiomatic verification method employed is complex. It requires the user to have a relatively comprehensive understanding of the nature of the proof system and the application. By making a series of observations the thesis notes that CSP possesses the scope to support a more procedural approach to verification in the form of testing. This thesis investigates the technique of testing and proposes the method of Ideal Test Sets. By exploiting the underlying structure of the CSP semantic model it is shown that for certain processes and specifications the obligation of verification can be reduced to that of testing the specification over a finite subset of the behaviours of the process.

Administration routes affect the quality of immune responses:a cross-sectional evaluation of particulate antigen-delivery systems

Particulate delivery systems such as liposomes and polymeric nano- and microparticles are attracting great interest for developing new vaccines. Materials and formulation properties essential for this purpose have been extensively studied, but relatively little is known about the influence of the administration route of such delivery systems on the type and strength of immune response elicited. Thus, the present study aimed at elucidating the influence on the immune response when of immunising mice by different routes, such as the subcutaneous, intradermal, intramuscular, and intralymphatic routes with ovalbumin-loaded liposomes, N-trimethyl chitosan (TMC) nanoparticles, and poly(lactide-co-glycolide) (PLGA) microparticles, all with and without specifically selected immune-response modifiers. The results showed that the route of administration caused only minor differences in inducing an antibody response of the IgG1 subclass, and any such differences were abolished upon booster immunisation with the various adjuvanted and non-adjuvanted delivery systems. In contrast, the administration route strongly affected both the kinetics and magnitude of the IgG2a response. A single intralymphatic administration of all evaluated delivery systems induced a robust IgG2a response, whereas subcutaneous administration failed to elicit a substantial IgG2a response even after boosting, except with the adjuvanted nanoparticles. The intradermal and intramuscular routes generated intermediate IgG2a titers. The benefit of the intralymphatic administration route for eliciting a Th1-type response was confirmed in terms of IFN-gamma production of isolated and re-stimulated splenocytes from animals previously immunised with adjuvanted and non-adjuvanted liposomes as well as with adjuvanted microparticles. Altogether the results show that the IgG2a associated with Th1-type immune responses are sensitive to the route of administration, whereas IgG1 response associated with Th2-type immune responses were relatively insensitive to the administration route of the particulate delivery systems. The route of administration should therefore be considered when planning and interpreting pre-clinical research or development on vaccine delivery systems.

Evaluation of the importance of astrocytes when screening for acute toxicity in neuronal cell systems

Reliable, high throughput, in vitro preliminary screening batteries have the potential to greatly accelerate the rate at which regulatory neurotoxicity data is generated. This study evaluated the importance of astrocytes when predicting acute toxic potential using a neuronal screening battery of pure neuronal (NT2.N) and astrocytic (NT2.A) and integrated neuronal/astrocytic (NT2.N/A) cell systems derived from the human NT2.D1 cell line, using biochemical endpoints (mitochondrial membrane potential (MMP) depolarisation and ATP and GSH depletion). Following exposure for 72 h, the known acute human neurotoxicants trimethyltin-chloride, chloroquine and 6-hydroxydopamine were frequently capable of disrupting biochemical processes in all of the cell systems at non-cytotoxic concentrations. Astrocytes provide key metabolic and protective support to neurons during toxic challenge in vivo and generally the astrocyte containing cell systems showed increased tolerance to toxicant insult compared with the NT2.N mono-culture in vitro. Whilst there was no consistent relationship between MMP, ATP and GSH log IC(50) values for the NT2.N/A and NT2.A cell systems, these data did provide preliminary evidence of modulation of the acute neuronal toxic response by astrocytes. In conclusion, the suitability of NT2 neurons and astrocytes as cell systems for acute toxicity screening deserves further investigation.

On the interaction between perceptual and response selection: neuropsychological evidence

We examined the relations between selection for perception and selection for action in a patient FK, with bilateral damage to his temporal and medial frontal cortices. The task required a simple grasp response to a common object (a cup) in the presence of a distractor (another cup). The target was cued by colour or location, and FK made manual responses. We examined the effects on performance of cued and uncued dimensions of both the target and the distractor. FK was impaired at perceptually selecting the target when cued by colour, when the target colour but not its location changed on successive trials. The effect was sensitive to the relative orientations of targets and distractors, indicating an effect of action selection on perceptual selection, when perceptual selection was weakly instantiated. The dimension-specific carry-over effect on reaching was enhanced when there was a temporal delay between a cue and the response, and it disappeared when there was a between-trial delay. The results indicate that perceptual and action selection systems interact to determine the efficiency with which actions are selected to particular objects.