Interleukin-7 deficiency in rheumatoid arthritis: consequences for therapy-induced lymphopenia

We previously demonstrated prolonged, profound CD4+ T-lymphopenia in rheumatoid arthritis (RA) patients following lymphocyte-depleting therapy. Poor reconstitution could result either from reduced de novo T-cell production through the thymus or from poor peripheral expansion of residual T-cells. Interleukin-7 (IL-7) is known to stimulate the thymus to produce new T-cells and to allow circulating mature T-cells to expand, thereby playing a critical role in T-cell homeostasis. In the present study we demonstrated reduced levels of circulating IL-7 in a cross-section of RA patients. IL-7 production by bone marrow stromal cell cultures was also compromised in RA. To investigate whether such an IL-7 deficiency could account for the prolonged lymphopenia observed in RA following therapeutic lymphodepletion, we compared RA patients and patients with solid cancers treated with high-dose chemotherapy and autologous progenitor cell rescue. Chemotherapy rendered all patients similarly lymphopenic, but this was sustained in RA patients at 12 months, as compared with the reconstitution that occurred in cancer patients by 3–4 months. Both cohorts produced naïve T-cells containing T-cell receptor excision circles. The main distinguishing feature between the groups was a failure to expand peripheral T-cells in RA, particularly memory cells during the first 3 months after treatment. Most importantly, there was no increase in serum IL-7 levels in RA, as compared with a fourfold rise in non-RA control individuals at the time of lymphopenia. Our data therefore suggest that RA patients are relatively IL-7 deficient and that this deficiency is likely to be an important contributing factor to poor early T-cell reconstitution in RA following therapeutic lymphodepletion. Furthermore, in RA patients with stable, well controlled disease, IL-7 levels were positively correlated with the T-cell receptor excision circle content of CD4+ T-cells, demonstrating a direct effect of IL-7 on thymic activity in this cohort

Chain-length, flexibility and the glass transition of polymers

The glass-transition is a long-standing unsolved problem in materials science, and our understanding of how a material evolves from a fluid to an out-of-equilibrium solid glass is particularly poor for polymers. Here we study how the glass transition temperature Tg and the related structural (alpha) relaxation vary with molecular weight M and chain flexibility for polymers of varying chemistries; we complement our data with Monte-Carlo computer simulations of chain structure based on the Rotational Isomeric State model. We find that Tg(M) is controlled by a single chemistry-dependent parameter, the conformer, chosen as the average mass or volume per conformational degree of freedom. Moreover, we find that a molecular (gamma) relaxation, operating on the length-scale of a few conformers, acts as a fundamental excitation, which in turn is linked to slower beta and alpha relaxations, and thus Tg. We propose that dynamic facilitation, resulting in hierarchical relaxation dynamics, can explain our observations including logarithmic Tg(M) dependences. Our study provides a new route to understanding molecular relaxations and the glass-transition in polymers which paves the way for predictive design of polymers based on monomer-scale metrics

Search for the best indicators for the presence of a VPS13B gene mutation and confirmation of diagnostic criteria in a series of 34 patients genotyped for suspected Cohen syndrome

BACKGROUND: Cohen syndrome is a rare autosomal recessive inherited disorder that results from mutations of the VPS13B gene. Clinical features consist of a combination of mental retardation, facial dysmorphism, postnatal microcephaly, truncal obesity, slender extremities, joint hyperextensibility, myopia, progressive chorioretinal dystrophy, and intermittent neutropenia.PATIENTS AND METHODS: The aim of the study was to determine which of the above clinical features were the best indicators for the presence of VPS13B gene mutations in a series of 34 patients with suspected Cohen syndrome referred for molecular analysis of VPS13B. RESULTS: 14 VPS13B gene mutations were identified in 12 patients, and no mutation was found in 22 patients. The presence of chorioretinal dystrophy (92% vs 32%, p=0.0023), intermittent neutropenia (92% vs 5%, p<0.001), and postnatal microcephaly (100% vs 48%, p=0.0045) was significantly higher in the group of patients with a VPS13B gene mutation compared to the group of patients without a mutation. All patients with VPS13B mutations had chorioretinal dystrophy and/or intermittent neutropenia. The Kolehmainen diagnostic criteria provided 100% sensibility and 77% specificity when applied to this series. CONCLUSION: From this study and a review of more than 160 genotyped cases from the literature, it is concluded that, given the large size of the gene, VPS13B screening is not indicated in the absence of chorioretinal dystrophy or neutropenia in patients aged over 5 years. The follow-up of young patients could be a satisfactory alternative unless there are some reproductive issues

Antibody landscapes after influenza virus infection or vaccination.

We introduce the antibody landscape, a method for the quantitative analysis of antibody-mediated immunity to antigenically variable pathogens, achieved by accounting for antigenic variation among pathogen strains. We generated antibody landscapes to study immune profiles covering 43 years of influenza A/H3N2 virus evolution for 69 individuals monitored for infection over 6 years and for 225 individuals pre- and postvaccination. Upon infection and vaccination, titers increased broadly, including previously encountered viruses far beyond the extent of cross-reactivity observed after a primary infection. We explored implications for vaccination and found that the use of an antigenically advanced virus had the dual benefit of inducing antibodies against both advanced and previous antigenic clusters. These results indicate that preemptive vaccine updates may improve influenza vaccine efficacy in previously exposed individuals.This is the author’s version of the work. It will be under embargo for 6 months following publication. It is posted here by permission of the AAAS for personal use, not for redistribution. The final version is available from AAAS in Science at http://www.sciencemag.org/content/346/6212/996.long

Policy drivers of international entrepreneurship in Europe

The diversity of countries and cultures in Europe necessitates an international outlook for most businesses. This paper examines the internationalisation of business in Europe through a literature review on international entrepreneurship theory. The role of the individual business owner and of business and interorganisational activity in facilitating the internationalisation of businesses in Europe is discussed by utilising the theoretical framework of international entrepreneurship and by putting forward three main propositions. The main aim and intent of this paper is to understand how the policies of individual governments and institutions such as the European Union help businesses in Europe to internationalise, with particular emphasis on businesses in the Baltic region. The paper discusses policy implications and suggestions for future research, which highlight the importance for firms in Europe of focussing on international markets.<br /

Identifying Human Disease Genes through Cross-Species Gene Mapping of Evolutionary Conserved Processes

Understanding complex networks that modulate development in humans is hampered by genetic and phenotypic heterogeneity within and between populations. Here we present a method that exploits natural variation in highly diverse mouse genetic reference panels in which genetic and environmental factors can be tightly controlled. The aim of our study is to test a cross-species genetic mapping strategy, which compares data of gene mapping in human patients with functional data obtained by QTL mapping in recombinant inbred mouse strains in order to prioritize human disease candidate genes.We exploit evolutionary conservation of developmental phenotypes to discover gene variants that influence brain development in humans. We studied corpus callosum volume in a recombinant inbred mouse panel (C57BL/6J×DBA/2J, BXD strains) using high-field strength MRI technology. We aligned mouse mapping results for this neuro-anatomical phenotype with genetic data from patients with abnormal corpus callosum (ACC) development.).This approach that exploits highly diverse mouse strains provides an efficient and effective translational bridge to study the etiology of human developmental disorders, such as autism and schizophrenia

Supply chain sustainability performance measurement of small and medium sized enterprises using structural equation modeling

Sustainability of small and medium sized enterprises (SMEs) is significant as SMEs contribute to GDP substantially in every economy. This research develops an innovative sustainable supply chain performance measurement model for SMEs. Prior researches predominantly use balanced score card (BSC) approach that presume causal relationship of criteria and Data Envelopment Analysis (DEA), which derive efficiency of units from a few input and output criteria. While DEA is effective for policymakers, BSC is more suitable for individual SME. The proposed method that uses structural equation modeling (SEM) approach to derive the relationship of criteria and criteria weights formulates regression-type models for a specific region as well as for specific SME. The SEM-based supply chain sustainability performance measurement model is beneficial to policymakers as they can determine means for improvement at a regional level. The proposed method could also facilitate managers/owners of individual SMEs with measures for improving their supply chain sustainability performance. The method has been applied to three varied geographical locations in the UK, France and India in order to demonstrate its effectiveness

A Recombinant Influenza A Virus Expressing Domain III of West Nile Virus Induces Protective Immune Responses against Influenza and West Nile Virus

West Nile virus (WNV) continues to circulate in the USA and forms a threat to the rest of the Western hemisphere. Since methods for the treatment of WNV infections are not available, there is a need for the development of safe and effective vaccines. Here, we describe the construction of a recombinant influenza virus expressing domain III of the WNV glycoprotein E (Flu-NA-DIII) and its evaluation as a WNV vaccine candidate in a mouse model. FLU-NA-DIII-vaccinated mice were protected from severe body weight loss and mortality caused by WNV infection, whereas control mice succumbed to the infection. In addition, it was shown that one subcutaneous immunization with 105 TCID50 Flu-NA-DIII provided 100% protection against challenge. Adoptive transfer experiments demonstrated that protection was mediated by antibodies and CD4+T cells. Furthermore, mice vaccinated with FLU-NA-DIII developed protective influenza virus-specific antibody titers. It was concluded that this vector system might be an attractive platform for the development of bivalent WNV-influenza vaccines

The same but different: Understanding entrepreneurial behaviour in disadvantaged communities

While entrepreneurship is widely viewed as being equally accessible in all contexts, it could be questioned if potential or nascent entrepreneurs from minority and disadvantaged communities experience entrepreneurship in a similar manner to the mainstream population. This chapter examines immigrant, people with disability, youth, gay and unemployed communities to explore how their entrepreneurial behaviour might differ from the practices of mainstream entrepreneurs. What emerges is that marginalised communities can frequently find it difficult to divorce business from social living. This can have both positive and negative connotations for an entrepreneur, plus they face additional and distinctive challenges that mainstream entrepreneurs do not experience. The chapter concludes by proposing a novel ‘funnel approach’ that policymakers might adopt when seeking to introduce initiatives targeted at these disadvantaged communities