Complete analysis of the B-cell response to a protein antigen, from in vivo germinal centre formation to 3-D modelling of affinity maturation

Somatic hypermutation of immunoglobulin variable region genes occurs within germinal centres (GCs) and is the process responsible for affinity maturation of antibodies during an immune response. Previous studies have focused almost exclusively on the immune response to haptens, which may be unrepresentative of epitopes on protein antigens. In this study, we have exploited a model system that uses transgenic B and CD4<sup>+</sup> T cells specific for hen egg lysozyme (HEL) and a chicken ovalbumin peptide, respectively, to investigate a tightly synchronized immune response to protein antigens of widely differing affinities, thus allowing us to track many facets of the development of an antibody response at the antigen-specific B cell level in an integrated system <i>in</i> <i>vivo</i>. Somatic hypermutation of immunoglobulin variable genes was analysed in clones of transgenic B cells proliferating in individual GCs in response to HEL or the cross-reactive low-affinity antigen, duck egg lysozyme (DEL). Molecular modelling of the antibody–antigen interface demonstrates that recurring mutations in the antigen-binding site, selected in GCs, enhance interactions of the antibody with DEL. The effects of these mutations on affinity maturation are demonstrated by a shift of transgenic serum antibodies towards higher affinity for DEL in DEL-cOVA immunized mice. The results show that B cells with high affinity antigen receptors can revise their specificity by somatic hypermutation and antigen selection in response to a low-affinity, cross-reactive antigen. These observations shed further light on the nature of the immune response to pathogens and autoimmunity and demonstrate the utility of this novel model for studies of the mechanisms of somatic hypermutation

Pericyte FAK negatively regulates Gas6/Axl signalling to suppress tumour angiogenesis and tumour growth

The overexpression of the protein tyrosine kinase, Focal adhesion kinase (FAK), in endothelial cells has implicated its requirement in angiogenesis and tumour growth, but how pericyte FAK regulates tumour angiogenesis is unknown. We show that pericyte FAK regulates tumour growth and angiogenesis in multiple mouse models of melanoma, lung carcinoma and pancreatic B-cell insulinoma and provide evidence that loss of pericyte FAK enhances Gas6-stimulated phosphorylation of the receptor tyrosine kinase, Axl with an upregulation of Cyr61, driving enhanced tumour growth. We further show that pericyte derived Cyr61 instructs tumour cells to elevate expression of the proangiogenic/protumourigenic transmembrane receptor Tissue Factor. Finally, in human melanoma we show that when 50% or more tumour blood vessels are pericyte-FAK negative, melanoma patients are stratified into those with increased tumour size, enhanced blood vessel density and metastasis. Overall our data uncover a previously unknown mechanism of tumour growth by pericytes that is controlled by pericyte FAK

Multiple Imputation Ensembles (MIE) for dealing with missing data

Missing data is a significant issue in many real-world datasets, yet there are no robust methods for dealing with it appropriately. In this paper, we propose a robust approach to dealing with missing data in classification problems: Multiple Imputation Ensembles (MIE). Our method integrates two approaches: multiple imputation and ensemble methods and compares two types of ensembles: bagging and stacking. We also propose a robust experimental set-up using 20 benchmark datasets from the UCI machine learning repository. For each dataset, we introduce increasing amounts of data Missing Completely at Random. Firstly, we use a number of single/multiple imputation methods to recover the missing values and then ensemble a number of different classifiers built on the imputed data. We assess the quality of the imputation by using dissimilarity measures. We also evaluate the MIE performance by comparing classification accuracy on the complete and imputed data. Furthermore, we use the accuracy of simple imputation as a benchmark for comparison. We find that our proposed approach combining multiple imputation with ensemble techniques outperform others, particularly as missing data increases

Dimensional reduction at a quantum critical point

Competition between electronic ground states near a quantum critical point (QCP) - the location of a zero-temperature phase transition driven solely by quantum-mechanical fluctuations - is expected to lead to unconventional behaviour in low-dimensional systems. New electronic phases of matter have been predicted to occur in the vicinity of a QCP by two-dimensional theories, and explanations based on these ideas have been proposed for significant unsolved problems in condensed-matter physics, such as non-Fermi-liquid behaviour and high-temperature superconductivity. But the real materials to which these ideas have been applied are usually rendered three-dimensional by a finite electronic coupling between their component layers; a two-dimensional QCP has not been experimentally observed in any bulk three-dimensional system, and mechanisms for dimensional reduction have remained the subject of theoretical conjecture. Here we show evidence that the Bose-Einstein condensate of spin triplets in the three-dimensional Mott insulator BaCuSi2O6 provides an experimentally verifiable example of dimensional reduction at a QCP. The interplay of correlations on a geometrically frustrated lattice causes the individual two-dimensional layers of spin-1/2 Cu2+ pairs (spin dimers) to become decoupled at the QCP, giving rise to a two-dimensional QCP characterized by power law scaling distinctly different from that of its three-dimensional counterpart. Thus the very notion of dimensionality can be said to acquire an 'emergent' nature: although the individual particles move on a three-dimensional lattice, their collective behaviour occurs in lower-dimensional space.Comment: 14 pages, 4 figure

Presenteeism in hospital nurses

This quantitative, descriptive, cross-sectional research aimed to determine the estimated productivity of health-related limitations at work in 129 nurses working in direct care delivery to critical and potentially critical patients. Instruments were applied for socio-demographic and functional characterization and for the evaluation of presenteeism (Work Limitations Questionnaire). Statistical Package for the Social Sciences software was used for data analysis. In this study, 75% of nurses obtained a lost productivity index of up to 4.84%. The physical demand domain represented the major limitation for these professionals (25%). Presenteeism was directly correlated to health care, occurrence and number of absences, and indirectly related to work time at the unit. It was concluded that organizational or individual factors influence individuals' productivity, in view of the circumstances involving care delivery to critical and potentially critical patients.Estudio cuantitativo, descriptivo y transversal con el objetivo de determinar la productividad supuesta de las limitaciones en el trabajo relacionadas con la salud de 129 enfermeros que asisten a pacientes críticos y potencialmente críticos. Se utilizó un instrumento para la caracterización sociodemográfica y funcional y para la evaluación de la presencia. Se realizó un análisis estadístico de los datos con el software Statistical Package for the Social Sciences. En este estudio, 75 % de los enfermeros obtuvieron un índice de productividad perdida de hasta 4,84%. La demanda física fue el dominio que presentó mayor limitación (25%). La presencia se relacionó directamente a: realización de tratamiento de salud, ocurrencia y número de faltas, e indirectamente al tiempo en la unidad. Se concluye que existe influencia de factores organizacionales o individuales en la productividad del individuo frente a las circunstancias que involucran la asistencia al paciente crítico y potencialmente crítico.Este é um estudo quantitativo, descritivo e transversal com o objetivo de determinar a produtividade estimada das limitações no trabalho, relacionadas à saúde, em 129 enfermeiros atuantes na assistência direta a pacientes críticos e potencialmente críticos. Utilizou-se instrumento para caracterização sociodemográfica e funcional e para a avaliação do presenteísmo (questionário de limitações no trabalho). Procedeu-se à análise estatística dos dados com o software Statistical Package for the Social Sciences. Neste estudo, 75% dos enfermeiros obtiveram índice de produtividade perdida de até 4,84%. A demanda física foi o domínio que representou maior limitação para esses profissionais (25%). O presenteísmo correlacionou-se diretamente à realização de tratamento de saúde, ocorrência e número de faltas, e indiretamente ao tempo de trabalho na unidade. Conclui-se que existe influência de fatores organizacionais ou individuais na produtividade do indivíduo, frente às circunstâncias que envolvem a assistência ao paciente crítico e potencialmente crítico

Genome wide analysis of gene expression changes in skin from patients with type 2 diabetes

Non-healing chronic ulcers are a serious complication of diabetes and are a major healthcare problem. While a host of treatments have been explored to heal or prevent these ulcers from forming, these treatments have not been found to be consistently effective in clinical trials. An understanding of the changes in gene expression in the skin of diabetic patients may provide insight into the processes and mechanisms that precede the formation of non-healing ulcers. In this study, we investigated genome wide changes in gene expression in skin between patients with type 2 diabetes and non-diabetic patients using next generation sequencing. We compared the gene expression in skin samples taken from 27 patients (13 with type 2 diabetes and 14 non-diabetic). This information may be useful in identifying the causal factors and potential therapeutic targets for the prevention and treatment of diabetic related diseases