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.

Collocations

J R Firth first gave prominence to collacation in linguistic theory. Halliday, Sinclair, Stubbs, and Hoey have all extended Firth's ideas. Palmer and Hornby recognized the pedagogical value of collocation, and incorporated it into their early EFL dictionaries. More recent EFL dictionaries, based on large, computerized language corpora, have used complex software and statistical measures to gain further insights into the way that collocational patterns are woven into language, and the results are visible in the dictionary entries of later editions. This has fed back into language pedagogy, and is also influencing translation and computational research. © 2006 Elsevier Ltd. All rights reserved.

The use of deterministic parsers on sublanguage for machine translation

For more than forty years, research has been on going in the use of the computer in the processing of natural language. During this period methods have evolved, with various parsing techniques and grammars coming to prominence. Problems still exist, not least in the field of Machine Translation. However, one of the successes in this field is the translation of sublanguage. The present work reports Deterministic Parsing, a relatively new parsing technique, and its application to the sublanguage of an aircraft maintenance manual for Machine Translation. The aim has been to investigate the practicability of using Deterministic Parsers in the analysis stage of a Machine Translation system. Machine Translation, Sublanguage and parsing are described in general terms with a review of Deterministic parsing systems, pertinent to this research, being presented in detail. The interaction between machine Translation, Sublanguage and Parsing, including Deterministic parsing, is also highlighted. Two types of Deterministic Parser have been investigated, a Marcus-type parser, based on the basic design of the original Deterministic parser (Marcus, 1980) and an LR-type Deterministic Parser for natural language, based on the LR parsing algorithm. In total, four Deterministic Parsers have been built and are described in the thesis. Two of the Deterministic Parsers are prototypes from which the remaining two parsers to be used on sublanguage have been developed. This thesis reports the results of parsing by the prototypes, a Marcus-type parser and an LR-type parser which have a similar grammatical and linguistic range to the original Marcus parser. The Marcus-type parser uses a grammar of production rules, whereas the LR-type parser employs a Definite Clause Grammar(DGC).

Diversity and the perceived barriers to participation in volunteer activity by older people

The first chapter introduces the subject from a psychological and sociological perspective emphasising the basic human activity of helping those in need. Governmental prominence for policies that assist this activity is briefly discussed with special mention of the programmes that encourage volunteering. Programmes particularly directed at older people, such as the Age Concern ‘Debate of the Age’ are considered briefly. An extensive review of the extant literature is the subject of the second chapter. The pervious research is explored to discover the formulae used to define a volunteer. A definition relative to this research is created. Volunteering issues aggravated by the demographic situation of older people are explored. Empirical volunteer survey research by mutual organisations is explored to ascertain the extent and nature of the already recorded volunteer population. The penultimate section of this chapter investigates the nature of old age and the strategies that older people adopt to enjoy the benefits and contain the problems. The issue of diversity arises from consideration of the literature suggesting that, although it is an essential voluntary sector strength, it is also a further barrier to recruitment. A model diversity is proposed. Chapter three reviews the theoretical processes, procedures and technologies used to collect and analyse the data required to discover the answer to the research problem. Analysis of the questionnaire survey data received is the subject of chapter four. The discovery of the agency uniqueness of volunteer profiles is the principle finding of this part of the research. The fifth chapter is the qualitative analysis of the oral and written statements received. A content analysis of the scripts and texts provided rich data covering motivational factors. Motivational factors were the same for volunteers in the same organisation, but differed between organisations. Finally, the analysed data is collated and discussed progressively toward a theory of diversity. The individuality of each branch of each agency is progressively described culminating in the creation of a model that infers that diversity is a barrier that aggravates all other barriers. The personal realisations of the researcher are described.

Early visual detection of oriented line targets: spatial characteristics,and reference frames of early visual orientation-processing

The orientations of lines and edges are important in defining the structure of the visual environment, and observers can detect differences in line orientation within the first few hundred milliseconds of scene viewing. The present work is a psychophysical investigation of the mechanisms of early visual orientation-processing. In experiments with briefly presented displays of line elements, observers indicated whether all the elements were uniformly oriented or whether a uniquely oriented target was present among uniformly oriented nontargets. The minimum difference between nontarget and target orientations that was required for effective target-detection (the orientation increment threshold) varied little with the number of elements and their spatial density, but the percentage of correct responses in detection of a large orientation-difference increased with increasing element density. The differing variations with element density of thresholds and percent-correct scores may indicate the operation of more than one mechanism in early visual orientation-processIng. Reducing element length caused threshold to increase with increasing number of elements, showing that the effectiveness of rapid, spatially parallel orientation-processing depends on element length. Orientational anisotropy in line-target detection has been reported previously: a coarse periodic variation and some finer variations in orientation increment threshold with nontarget orientation have been found. In the present work, the prominence of the coarse variation in relation to finer variations decreased with increasing effective viewing duration, as if the operation of coarse orientation-processing mechanisms precedes the operation of finer ones. Orientational anisotropy was prominent even when observers lay horizontally and viewed displays by looking upwards through a black cylinder that excluded all possible visual references for orientation. So, gravitational and visual cues are not essential to the definition of an orientational reference frame for early vision, and such a reference can be well defined by retinocentric neural coding, awareness of body-axis orientation, or both.

Organisational change and safety culture: the impact of communication

This research examines and explains the links between safety culture and communication. Safety culture is a concept that in recent years has gained prominence but there has been little applied research conducted to investigate the meaning of the concept in 'real life' settings. This research focused on a Train Operating Company undergoing change in a move towards privatisation. These changes were evident in the management of safety, the organisation of the industry and internally in their management. The Train Operating Company's management took steps to improve their safety culture and communications through the development of a cascade communication structure. The research framework employed a qualitative methodology in order to investigate the effect of the new system on safety culture. Findings of the research were that communications in the organisation failed to be effective for a number of reasons, including both cultural and logistical problems. The cultural problems related to a lack of trust in the organisation by the management and the workforce, the perception of communications as management propaganda, and asyntonic communications between those involved, whilst logistical problems related to the inherent difficulties of communicating over a geographically distributed network. An organisational learning framework was used to explain the results. It is postulated that one of the principal reasons why change, either to the safety culture or to communications, did not occur was because of the organisation's inability to learn. The research has also shown the crucial importance of trust between the members of the organisation, as this was one of the fundamental reasons why the safety culture did not change, and why safety management systems were not fully implemented. This is consistent with the notion of mutual trust in the HSC (1993) definition of safety culture. This research has highlighted its relevance to safety culture and its importance for organisational change.

West Midlands English:Birmingham and the Black Country

This volume focuses on the closely allied yet differing linguistic varieties of Birmingham and its immediate neighbour to the west, the industrial heartland of the Black Country. Both of these areas rose to economic prominence and success during the Industrial Revolution, and both have suffered economically and socially as a result of post-war industrial decline. The industrial heritage of both areas has meant that tight knit and socially homogeneous individual areas in each region have demonstrated in many respects little linguistic change over time, and have continued to exhibit linguistic features, especially morphological constructions, peculiar to these areas or now restricted to these areas. At the same time, immigration from other areas of the British Isles over time, from Commonwealth countries and later from EU member states, together with increased social mobility, have meant that newly developing structures and more widespread UK linguistic phenomena have spread into these varieties. This volume provides a clear description of the structure of the linguistic varieties spoken in the two areas. Following the structure of the Dialects of English volumes, it provides: •A comprehensive overview of the phonological, grammatical and lexical structure of both varieties, as well as similarities between the two varieties and distinguishing features •Thorough discussion of the historical and social factors behind the development of the varieties and the stigma attached to these varieties •Discussion of the unusual situation of the Black Country as an area undefined in geographical and administrative terms, existing only in the imagination •Examples of the variety from native speakers of differing ethnicities, ages and genders •An annotated bibliography for further consultation

Patient involvement in primary care mental health:a focus group study

Background: Patient involvement in health care is a strong political driver in the NHS. However in spite of policy prominence, there has been only limited previous work exploring patient involvement for people with serious mental illness. Aim: To describe the views on, potential for, and types of patient involvement in primary care from the perspectives of primary care health professionals and patients with serious mental illness. Design of study: Qualitative study consisting of six patient, six health professional and six combined focus groups between May 2002 and January 2003. Setting: Six primary care trusts in the West Midlands, England. Method: Forty-five patients with serious mental illness, 39 GPs, and eight practice nurses participated in a series of 18 focus groups. All focus groups were audiotaped and fully transcribed. Nvivo was used to manage data more effectively. Results: Most patients felt that only other people with lived experience of mental illness could understand what they were going through. This experience could be used to help others navigate the health- and social-care systems, give advice about medication, and offer support at times of crisis. Many patients also saw paid employment within primary care as a way of addressing issues of poverty and social exclusion. Health professionals were, however, more reluctant to see patients as partners, be it in the consultation or in service delivery. Conclusions: Meaningful change in patient involvement requires commitment and belief from primary care practitioners that the views and experiences of people with serious mental illness are valid and valuable.

Integrative bioinformatics for functional genorne annotation:trawling for G protein-coupled receptors

G protein-coupled receptors (GPCR) are amongst the best studied and most functionally diverse types of cell-surface protein. The importance of GPCRs as mediates or cell function and organismal developmental underlies their involvement in key physiological roles and their prominence as targets for pharmacological therapeutics. In this review, we highlight the requirement for integrated protocols which underline the different perspectives offered by different sequence analysis methods. BLAST and FastA offer broad brush strokes. Motif-based search methods add the fine detail. Structural modelling offers another perspective which allows us to elucidate the physicochemical properties that underlie ligand binding. Together, these different views provide a more informative and a more detailed picture of GPCR structure and function. Many GPCRs remain orphan receptors with no identified ligand, yet as computer-driven functional genomics starts to elaborate their functions, a new understanding of their roles in cell and developmental biology will follow.

Editorial overview:new protein production tools for structural biology

Full text: The idea of producing proteins from recombinant DNA hatched almost half a century ago. In his PhD thesis, Peter Lobban foresaw the prospect of inserting foreign DNA (from any source, including mammalian cells) into the genome of a λ phage in order to detect and recover protein products from Escherichia coli [ 1 and 2]. Only a few years later, in 1977, Herbert Boyer and his colleagues succeeded in the first ever expression of a peptide-coding gene in E. coli — they produced recombinant somatostatin [ 3] followed shortly after by human insulin. The field has advanced enormously since those early days and today recombinant proteins have become indispensable in advancing research and development in all fields of the life sciences. Structural biology, in particular, has benefitted tremendously from recombinant protein biotechnology, and an overwhelming proportion of the entries in the Protein Data Bank (PDB) are based on heterologously expressed proteins. Nonetheless, synthesizing, purifying and stabilizing recombinant proteins can still be thoroughly challenging. For example, the soluble proteome is organized to a large part into multicomponent complexes (in humans often comprising ten or more subunits), posing critical challenges for recombinant production. A third of all proteins in cells are located in the membrane, and pose special challenges that require a more bespoke approach. Recent advances may now mean that even these most recalcitrant of proteins could become tenable structural biology targets on a more routine basis. In this special issue, we examine progress in key areas that suggests this is indeed the case. Our first contribution examines the importance of understanding quality control in the host cell during recombinant protein production, and pays particular attention to the synthesis of recombinant membrane proteins. A major challenge faced by any host cell factory is the balance it must strike between its own requirements for growth and the fact that its cellular machinery has essentially been hijacked by an expression construct. In this context, Bill and von der Haar examine emerging insights into the role of the dependent pathways of translation and protein folding in defining high-yielding recombinant membrane protein production experiments for the common prokaryotic and eukaryotic expression hosts. Rather than acting as isolated entities, many membrane proteins form complexes to carry out their functions. To understand their biological mechanisms, it is essential to study the molecular structure of the intact membrane protein assemblies. Recombinant production of membrane protein complexes is still a formidable, at times insurmountable, challenge. In these cases, extraction from natural sources is the only option to prepare samples for structural and functional studies. Zorman and co-workers, in our second contribution, provide an overview of recent advances in the production of multi-subunit membrane protein complexes and highlight recent achievements in membrane protein structural research brought about by state-of-the-art near-atomic resolution cryo-electron microscopy techniques. E. coli has been the dominant host cell for recombinant protein production. Nonetheless, eukaryotic expression systems, including yeasts, insect cells and mammalian cells, are increasingly gaining prominence in the field. The yeast species Pichia pastoris, is a well-established recombinant expression system for a number of applications, including the production of a range of different membrane proteins. Byrne reviews high-resolution structures that have been determined using this methylotroph as an expression host. Although it is not yet clear why P. pastoris is suited to producing such a wide range of membrane proteins, its ease of use and the availability of diverse tools that can be readily implemented in standard bioscience laboratories mean that it is likely to become an increasingly popular option in structural biology pipelines. The contribution by Columbus concludes the membrane protein section of this volume. In her overview of post-expression strategies, Columbus surveys the four most common biochemical approaches for the structural investigation of membrane proteins. Limited proteolysis has successfully aided structure determination of membrane proteins in many cases. Deglycosylation of membrane proteins following production and purification analysis has also facilitated membrane protein structure analysis. Moreover, chemical modifications, such as lysine methylation and cysteine alkylation, have proven their worth to facilitate crystallization of membrane proteins, as well as NMR investigations of membrane protein conformational sampling. Together these approaches have greatly facilitated the structure determination of more than 40 membrane proteins to date. It may be an advantage to produce a target protein in mammalian cells, especially if authentic post-translational modifications such as glycosylation are required for proper activity. Chinese Hamster Ovary (CHO) cells and Human Embryonic Kidney (HEK) 293 cell lines have emerged as excellent hosts for heterologous production. The generation of stable cell-lines is often an aspiration for synthesizing proteins expressed in mammalian cells, in particular if high volumetric yields are to be achieved. In his report, Buessow surveys recent structures of proteins produced using stable mammalian cells and summarizes both well-established and novel approaches to facilitate stable cell-line generation for structural biology applications. The ambition of many biologists is to observe a protein's structure in the native environment of the cell itself. Until recently, this seemed to be more of a dream than a reality. Advances in nuclear magnetic resonance (NMR) spectroscopy techniques, however, have now made possible the observation of mechanistic events at the molecular level of protein structure. Smith and colleagues, in an exciting contribution, review emerging ‘in-cell NMR’ techniques that demonstrate the potential to monitor biological activities by NMR in real time in native physiological environments. A current drawback of NMR as a structure determination tool derives from size limitations of the molecule under investigation and the structures of large proteins and their complexes are therefore typically intractable by NMR. A solution to this challenge is the use of selective isotope labeling of the target protein, which results in a marked reduction of the complexity of NMR spectra and allows dynamic processes even in very large proteins and even ribosomes to be investigated. Kerfah and co-workers introduce methyl-specific isotopic labeling as a molecular tool-box, and review its applications to the solution NMR analysis of large proteins. Tyagi and Lemke next examine single-molecule FRET and crosslinking following the co-translational incorporation of non-canonical amino acids (ncAAs); the goal here is to move beyond static snap-shots of proteins and their complexes and to observe them as dynamic entities. The encoding of ncAAs through codon-suppression technology allows biomolecules to be investigated with diverse structural biology methods. In their article, Tyagi and Lemke discuss these approaches and speculate on the design of improved host organisms for ‘integrative structural biology research’. Our volume concludes with two contributions that resolve particular bottlenecks in the protein structure determination pipeline. The contribution by Crepin and co-workers introduces the concept of polyproteins in contemporary structural biology. Polyproteins are widespread in nature. They represent long polypeptide chains in which individual smaller proteins with different biological function are covalently linked together. Highly specific proteases then tailor the polyprotein into its constituent proteins. Many viruses use polyproteins as a means of organizing their proteome. The concept of polyproteins has now been exploited successfully to produce hitherto inaccessible recombinant protein complexes. For instance, by means of a self-processing synthetic polyprotein, the influenza polymerase, a high-value drug target that had remained elusive for decades, has been produced, and its high-resolution structure determined. In the contribution by Desmyter and co-workers, a further, often imposing, bottleneck in high-resolution protein structure determination is addressed: The requirement to form stable three-dimensional crystal lattices that diffract incident X-ray radiation to high resolution. Nanobodies have proven to be uniquely useful as crystallization chaperones, to coax challenging targets into suitable crystal lattices. Desmyter and co-workers review the generation of nanobodies by immunization, and highlight the application of this powerful technology to the crystallography of important protein specimens including G protein-coupled receptors (GPCRs). Recombinant protein production has come a long way since Peter Lobban's hypothesis in the late 1960s, with recombinant proteins now a dominant force in structural biology. The contributions in this volume showcase an impressive array of inventive approaches that are being developed and implemented, ever increasing the scope of recombinant technology to facilitate the determination of elusive protein structures. Powerful new methods from synthetic biology are further accelerating progress. Structure determination is now reaching into the living cell with the ultimate goal of observing functional molecular architectures in action in their native physiological environment. We anticipate that even the most challenging protein assemblies will be tackled by recombinant technology in the near future.

High performance liquid level monitoring system based on polymer fiber Bragg gratings embedded in silicone rubber diaphragm

Liquid-level sensing technologies have attracted great prominence, because such measurements are essential to industrial applications, such as fuel storage, flood warning and in the biochemical industry. Traditional liquid level sensors are based on electromechanical techniques; however they suffer from intrinsic safety concerns in explosive environments. In recent years, given that optical fiber sensors have lots of well-established advantages such as high accuracy, costeffectiveness, compact size, and ease of multiplexing, several optical fiber liquid level sensors have been investigated which are based on different operating principles such as side-polishing the cladding and a portion of core, using a spiral side-emitting optical fiber or using silica fiber gratings. The present work proposes a novel and highly sensitive liquid level sensor making use of polymer optical fiber Bragg gratings (POFBGs). The key elements of the system are a set of POFBGs embedded in silicone rubber diaphragms. This is a new development building on the idea of determining liquid level by measuring the pressure at the bottom of a liquid container, however it has a number of critical advantages. The system features several FBG-based pressure sensors as described above placed at different depths. Any sensor above the surface of the liquid will read the same ambient pressure. Sensors below the surface of the liquid will read pressures that increase linearly with depth. The position of the liquid surface can therefore be approximately identified as lying between the first sensor to read an above-ambient pressure and the next higher sensor. This level of precision would not in general be sufficient for most liquid level monitoring applications; however a much more precise determination of liquid level can be made by linear regression to the pressure readings from the sub-surface sensors. There are numerous advantages to this multi-sensor approach. First, the use of linear regression using multiple sensors is inherently more accurate than using a single pressure reading to estimate depth. Second, common mode temperature induced wavelength shifts in the individual sensors are automatically compensated. Thirdly, temperature induced changes in the sensor pressure sensitivity are also compensated. Fourthly, the approach provides the possibility to detect and compensate for malfunctioning sensors. Finally, the system is immune to changes in the density of the monitored fluid and even to changes in the effective force of gravity, as might be obtained in an aerospace application. The performance of an individual sensor was characterized and displays a sensitivity (54 pm/cm), enhanced by more than a factor of 2 when compared to a sensor head configuration based on a silica FBG published in the literature, resulting from the much lower elastic modulus of POF. Furthermore, the temperature/humidity behavior and measurement resolution were also studied in detail. The proposed configuration also displays a highly linear response, high resolution and good repeatability. The results suggest the new configuration can be a useful tool in many different applications, such as aircraft fuel monitoring, and biochemical and environmental sensing, where accuracy and stability are fundamental. © (2015) COPYRIGHT Society of Photo-Optical Instrumentation Engineers (SPIE). Downloading of the abstract is permitted for personal use only.

Charting new territory for organizational ethnography:insights from a team-based video ethnography of reinsurance trading in Lloyd’s of London

An increasing interest in “bringing actors back in” and gaining a nuanced understanding of their actions and interactions across a variety of strands in the management literature, has recently helped ethnography to unknown prominence in the field of organizational studies. Yet, calls remain that ethnography should “play a much more central role in the organization and management studies repertoire than it currently does” (Watson, 2011: 202). Ironically, those organizational realities that ethnographers are called to examine have at the same time become less and less amenable to ethnographic study. In this paper, we respond to these calls for innovative ethnographic methods in two ways. First, we report on the practices and ethnographic experiences of conducting a year-long team-based video ethnography of reinsurance trading in Lloyd’s of London. Second, drawing on these experiences, we propose an initial framework for systematizing new approaches to organizational ethnography and visualizing the ways in which they are ‘expanding’ ethnography as it was traditionally practiced.

Deconstruction-analysis-explanation:contextualization in professional digital discourse

It is already a truism that emerging communication technologies have changed the landscape of communication in every aspect of our lives, but this is specifically true for how we communicate at work. Advances in communication technologies have enabled a wide range of digital communication modes to be utilized for both internal and external business communication; including audio and visual communication and voice-over protocols, as well as text-based channels, such as email, forums, instant messaging and social media. In spite of the wide range of available audio-visual channels, and despite the ever-increasing popularity of email, real-time text-based communication technologies (instant messaging or IM) are also on the rise (see Mak, 2014; Pazos et al., 2013; Radicati & Levenstein, 2013; and Markman in this volume). The prominence of IM is evident in the rise of this mode of communication, not only as a tool for internal business communication, but as a front-stage channel, particularly for customer service encounters or professional-client conversations (Makarem et al., 2009; Pearce et al., 2013; L. Zhang et al., 2011).

The promotion of children's health and wellbeing:the contributions of England's charity sector

Background. Sports and arts based services for children have positive impacts on their mental and physical health. The charity sector provides such services, often set up in response to local communities expressing a need. The present study maps resilience promoting services provided by children's charities in England. Specifically, the prominence of sports and arts activities, and types of mental health provisions including telephone help-lines, are investigated. Findings. The study was a cross-sectional web-based survey of chief executives, senior mangers, directors and chairs of charities providing services for children under the age of 16. The aims, objectives and activities of participating children's charities and those providing mental health services were described overall. In total 167 chief executives, senior managers, directors and chairs of charities in England agreed to complete the survey. From our sample of charities, arts activities were the most frequently provided services (58/167, 35%), followed by counselling (55/167, 33%) and sports activities (36/167, 22%). Only 13% (22/167) of charities expected their work to contribute to the health legacy of the 2012 London Olympics. Telephone help lines were provided by 16% of the charities that promote mental health. Conclusions. Counselling and arts activities were relatively common. Sports activities were limited despite the evidence base that sport and physical activity are effective interventions for well-being and health gain. Few of the charities we surveyed expected a health legacy from the 2012 London Olympics. © 2010 Bhui et al; licensee BioMed Central Ltd.

Unity in Christ or Pan-Europeanism?:Nathan Söderblom and the ecumenical peace movement in the interwar period

In the summer of 2014 the Swedish Church is celebrating the 100th anniversary of the appointment of Nathan Söderblom as archbishop of Uppsala, and thus head of the Swedish church organisation. As a Lutheran with an enormously broad-minded and broad-reaching approach to ecumenical understanding and community-building, Söderblom shot to prominence in the interwar period not only because of his ecumenical engagement, calling for an evangelical catholicity so stand side by side with the Roman catholic and Orthodox catholic traditions, but also because of his comprehensive secular engagement for peace and understanding between peoples. In the latter context he also acquired a solid reputation as a perhaps less prominent but still noteworthy figure in the history of European integration. This article investigates how, why and to what extent Söderblom’s ecumenical and secular engagements were intertwined. The first part discusses how his biographical and academic background led to such staunch ecumenical positions, while the second part focuses on the secular engagement, which was perceived by Söderblom as necessary to make progress on the ecumenical front in the practical political realities of the 1920s. The final part, comparing and contrasting Söderblom’s views with those of Count Richard von Coudenhove-Calergi and the Pan-European Union, demonstrates why Söderblom’s engagement for Europe had to be limited: unity in Christ is by definition global in nature and therefore cannot be continent-specific.