Identifying Novel Leads Using Combinatorial Libraries: Issues and Successes

Chemically generated libraries of small, non-oligomeric compounds are being widely embraced by researchers in both industry and academia. There has been a steady development of new chemistries and equipment applied to library generation so it is now possible to synthesize almost any desired class of compound. However, there are still important issues to consider that range from what specific types of compounds should be made to concerns such as sample resynthesis, structural confirmation of the hit identified, and how to best integrate this technology into a pharmaceutical drug discovery operation. This paper illustrates our approach to new lead discovery (individual, diverse, drug-like molecules of known structural identity using a simple, spatially addressable parallel synthesis approach to prepare Multiple Diverse as well as Universal Libraries) and describes some representative examples of chemistries we had developed within these approaches (preparation of bis-benzamide phenols, thiophenes, pyrrolidines, and highly substituted biphenyls). Finally, the manuscript concludes by addressing some the present concerns that still must be considered in this field

A Nuclear Localization Signal in Herpesvirus Protein VP1-2 Is Essential for Infection via Capsid Routing to the Nuclear Pore

To initiate infection, herpesviruses must navigate to and transport their genomes across the nuclear pore. VP1-2 is a large structural protein of the virion that is conserved in all herpesviruses and plays multiple essential roles in virus replication, including roles in early entry. VP1-2 contains an N-terminal basic motif which functions as an efficient nuclear localization signal (NLS). In this study, we constructed a mutant HSV strain, K.VP1-2ΔNLS, which contains a 7-residue deletion of the core NLS at position 475. This mutant fails to spread in normal cells but can be propagated in complementing cell lines. Electron microscopy (EM) analysis of infection in noncomplementing cells demonstrated capsid assembly, cytoplasmic envelopment, and the formation of extracellular enveloped virions. Furthermore, extracellular virions isolated from noncomplementing cells had similar profiles and abundances of structural proteins. Virions containing VP1-2ΔNLS were able to enter and be transported within cells. However, further progress of infection was prevented, with at least a 500- to 1,000-fold reduction in the efficiency of initiating gene expression compared to that in the revertant. Ultrastructural and immunofluorescence analyses revealed that the K.VP1-2ΔNLS mutant was blocked at the microtubule organizing center or immediately upstream of nuclear pore docking and prior to gene expression. These results indicate that the VP1-2 NLS is not required for the known assembly functions of the protein but is a key requirement for the early routing to the nuclear pore that is necessary for successful infection. Given its conservation, we propose that this motif may also be critical for entry of other classes of herpesviruses

Performing heritage: the use of live 'actors' in heritage presentations

This paper investigates the phenomenon of 'living history' presentations of heritage, using live 'actors' to portray historical characters. Its aim is to discuss these presentations in the context of what may be understood as 'heritage', and of the nature of 'performance'. Four case studies of heritage sites, each important as a tourist attraction, have been selected for detailed study, together with a number of other examples of heritage performance. It is clear from the empirical work that different performance strategies are employed within the heritage industry and by individual 'actors'. Most of the performers take part as a leisure activity, and many do not consider themselves to be 'performing' at all. The greatest concern of participants lies in the degree of authenticity of the performance. Through 'living history', the 'actors' are drawn into an experience of heritage which has real meaning for them, and which may contribute both to a sense of identity and to an enhanced understanding of society, past and present. The popularity of such presentations with visitors also indicates that similar benefits are perceived by the 'audience'

A carboxyl-terminal interaction of lamin B1 is dependent on the CAAX endoprotease Rce1 and carboxymethylation

The mammalian nuclear lamina protein lamin B1 is posttranslationally modified by farnesylation, endoproteolysis, and carboxymethylation at a carboxyl-terminal CAAX motif. In this work, we demonstrate that the CAAX endoprotease Rce1 is required for lamin B1 endoproteolysis, demonstrate an independent pool of proteolyzed but nonmethylated lamin B1, as well as fully processed lamin B1, in interphase nuclei, and show a role for methylation in the organization of lamin B1 into domains of the nuclear lamina. Deficiency in the endoproteolysis or methylation of lamin B1 results in loss of integrity and deformity of the nuclear lamina. These data show that the organization of the nuclear envelope and lamina is dependent on a mechanism involving the methylation of lamin B1, and they identify a potential mechanism of laminopathy involving a B-type lamin

Implementing an integrated approach to self-management support in an acute major trauma therapy team: an improvement project.

More patients now survive multiple trauma injuries, but the level of long-term unmet needs is high. Evidence shows self-management support can improve patients ' confidence to manage these needs but traditionally this support starts post-hospital. Starting self-management support early could prepare patients and families for successful transitions from hospital. The skills and commitment of clinicians have been shown to contribute to the success or failure of self-management approaches. The aim of this project was to explore the feasibility of integrating self-management support in an acute major trauma setting by evaluating the impact of an educational intervention on clinicians' knowledge, attitudes and behaviours regarding self-management support and identifying any barriers and facilitators to integrating self-management into daily practice. Two improvement cycles were carried out over a 1-year period involving 18 allied health professionals (AHPs) in an acute major trauma centre in London, UK. An educational intervention, 'Bridges Self-Management Programme' was modified for the setting. The impact was evaluated using (1) a clinician questionnaire to evaluate knowledge and attitudes; (2) case reflection forms and (3) peer review to observe interactions to integrate self-management support. Questionnaire data were summarised and pre-training and post-training scores compared; the qualitative data from written case reflections, verbal and written feedback from training and group discussions was described and analysed thematically. The result of two improvement cycles has shown it was feasible to improve AHP's knowledge, attitudes and change behaviours regarding self-management support in the acute trauma setting, but difficult to sustain change beyond 6 months. Key barriers such as the pressure to discharge patients and support within the wider multidisciplinary team (MDT) were identified. Facilitators included the introduction of a new key-worker, to enable shared team approaches and paperwork to involve patients and families in goal setting and treatment planning. The main learning was to ensure sustainability mechanisms from the outset, engage the wider MDT in training, and integrate self-management language and principles into team processes

Supporting self-management after traumatic brain injury : codesign and evaluation of a new intervention across a trauma pathway

Background Supported self‐management (SSM) is a recognized approach for people with long‐term conditions but, despite the prevalence of unmet needs, little is known about its role for people with traumatic brain injury (TBI). Objectives To codesign an SSM intervention with people with TBI and evaluate feasibility of implementation through multidisciplinary staff across a trauma pathway. Setting and participants People who had previously been admitted to a Major Trauma Centre following TBI and family members participated in a series of codesign activities. Staff attended SSM workshops and used the intervention with patients in acute and rehabilitation settings. Methods We used Normalization Process Theory constructs to guide and interpret implementation. Knowledge, beliefs and confidence of staff in SSM were assessed through pre‐ and post‐training questionnaires, and staff, patients' and families' experiences were explored through semi‐structured interviews. Qualitative data were analysed thematically, and clinical measures were mapped against a matched sample. Results Codesigned resources were created and used within an SSM approach for which 110 staff participated in training. Evaluation demonstrated significant differences in staff SSM confidence and skills, following training. Qualitative evaluation revealed adoption by staff, and patients' and families' experiences of using the resources. Challenges included reaching staff across complex pathways to achieve collective implementation. Conclusion This is the first project to demonstrate feasibility of SSM for people after TBI starting in an acute trauma setting. Through an open approach to codesign with a marginalized group, the SSM resources were valued by them and held meaning and relevance for staff

Temporal dynamics of aquatic communities and implications for pond conservation

Conservation through the protection of particular habitats is predicated on the assumption that the conservation value of those habitats is stable. We test this assumption for ponds by investigating temporal variation in macroinvertebrate and macrophyte communities over a 10-year period in northwest England. We surveyed 51 ponds in northern England in 1995/6 and again in 2006, identifying all macrophytes (167 species) and all macroinvertebrates (221 species, excluding Diptera) to species. The alpha-diversity, beta-diversity and conservation value of these ponds were compared between surveys. We find that invertebrate species richness increased from an average of 29. 5 species to 39. 8 species between surveys. Invertebrate gamma-diversity also increased between the two surveys from 181 species to 201 species. However, this increase in diversity was accompanied by a decrease in beta-diversity. Plant alpha-, beta and gamma-diversity remained approximately constant between the two periods. However, increased proportions of grass species and a complete loss of charophytes suggests that the communities are undergoing succession. Conservation value was not correlated between sampling periods in either plants or invertebrates. This was confirmed by comparing ponds that had been disturbed with those that had no history of disturbance to demonstrate that levels of correlation between surveys were approximately equal in each group of ponds. This study has three important conservation implications: (i) a pond with high diversity or high conservation value may not remain that way and so it is unwise to base pond conservation measures upon protecting currently-speciose habitats; (ii) maximising pond gamma-diversity requires a combination of late and early succession ponds, especially for invertebrates; and (iii) invertebrate and plant communities in ponds may require different management strategies if succession occurs at varying rates in the two groups

Supporting self-management after traumatic brain injury: Codesign and evaluation of a new intervention across a trauma pathway.

BACKGROUND: Supported self-management (SSM) is a recognized approach for people with long-term conditions but, despite the prevalence of unmet needs, little is known about its role for people with traumatic brain injury (TBI). OBJECTIVES: To codesign an SSM intervention with people with TBI and evaluate feasibility of implementation through multidisciplinary staff across a trauma pathway. SETTING AND PARTICIPANTS: People who had previously been admitted to a Major Trauma Centre following TBI and family members participated in a series of codesign activities. Staff attended SSM workshops and used the intervention with patients in acute and rehabilitation settings. METHODS: We used Normalization Process Theory constructs to guide and interpret implementation. Knowledge, beliefs and confidence of staff in SSM were assessed through pre- and post-training questionnaires, and staff, patients' and families' experiences were explored through semi-structured interviews. Qualitative data were analysed thematically, and clinical measures were mapped against a matched sample. RESULTS: Codesigned resources were created and used within an SSM approach for which 110 staff participated in training. Evaluation demonstrated significant differences in staff SSM confidence and skills, following training. Qualitative evaluation revealed adoption by staff, and patients' and families' experiences of using the resources. Challenges included reaching staff across complex pathways to achieve collective implementation. CONCLUSION: This is the first project to demonstrate feasibility of SSM for people after TBI starting in an acute trauma setting. Through an open approach to codesign with a marginalized group, the SSM resources were valued by them and held meaning and relevance for staff

Crisis and change in industrial relations in Central and Eastern Europe

This article introduces the special issue on industrial relations in Central and Eastern Europe since the financial and economic crisis. Already dependent economically on funding from the west, and lacking the robust industrial relations institutions traditional in much of Western Europe, countries in the region were particularly vulnerable. However, there are important cross-national differences, and the strategies of key actors have significantly affected the outcomes