Computational prediction of human metabolic pathways from the complete human genome

BACKGROUND: We present a computational pathway analysis of the human genome that assigns enzymes encoded therein to predicted metabolic pathways. Pathway assignments place genes in their larger biological context, and are a necessary first step toward quantitative modeling of metabolism. RESULTS: Our analysis assigns 2,709 human enzymes to 896 bioreactions; 622 of the enzymes are assigned roles in 135 predicted metabolic pathways. The predicted pathways closely match the known nutritional requirements of humans. This analysis identifies probable omissions in the human genome annotation in the form of 203 pathway holes (missing enzymes within the predicted pathways). We have identified putative genes to fill 25 of these holes. The predicted human metabolic map is described by a Pathway/Genome Database called HumanCyc, which is available at . We describe the generation of HumanCyc, and present an analysis of the human metabolic map. For example, we compare the predicted human metabolic pathway complement to the pathways of Escherichia coli and Arabidopsis thaliana and identify 35 pathways that are shared among all three organisms. CONCLUSIONS: Our analysis elucidates a significant portion of the human metabolic map, and also indicates probable unidentified genes in the genome. HumanCyc provides a genome-based view of human nutrition that associates the essential dietary requirements of humans with a set of metabolic pathways whose existence is supported by the human genome. The database places many human genes in a pathway context, thereby facilitating analysis of gene expression, proteomics, and metabolomics datasets through a publicly available online tool called the Omics Viewer

Quantifying the limits of CAR T-cell delivery in mice and men

CAR (Chimeric Antigen Receptor) T cells have demonstrated clinical success for the treatment of multiple lymphomas and leukaemias, but not for various solid tumours, despite promising data from murine models. Lower effective CAR T-cell delivery rates to human solid tumours compared to haematological malignancies in humans and solid tumours in mice might partially explain these divergent outcomes. We used anatomical and physiological data for human and rodent circulatory systems to calculate the typical perfusion of healthy and tumour tissues, and estimated the upper limits of immune cell delivery rates across different organs, tumour types and species. Estimated maximum delivery rates were up to 10 000-fold greater in mice than humans yet reported CAR T-cell doses are typically only 10–100-fold lower in mice, suggesting that the effective delivery rates of CAR T cells into tumours in clinical trials are far lower than in corresponding mouse models. Estimated delivery rates were found to be consistent with published positron emission tomography data. Results suggest that higher effective human doses may be needed to drive efficacy comparable to mouse solid tumour models, and that lower doses should be tested in mice. We posit that quantitation of species and organ-specific delivery and homing of engineered T cells will be key to unlocking their potential for solid tumours

New directions in the arts and sport? Critiquing national strategies

Taking as its starting point the Fields of Vision initiative’s interest in promoting the potential benefits of bringing sports and arts closer together, this paper reviews how national (English) policy addresses that challenge. Four key strategic documents (the Government’s Sport Strategy and its Culture White Paper as well as the strategies of Arts Council England and Sport England) are examined. That is supplemented by the views of significant individuals from this interface, including the research network funded by the Arts and Humanities Research Council (AHRC). Noting the similar social remit ascribed to sport and the arts by the government, shortcomings in the current strategies are identified as barriers to integration. ‘Play’ and ‘movement’ are briefly discussed as integrating concepts alongside our assessment of the potential of the arts/sport nexus, in areas including aesthetic innovation, promoting health and wellbeing, and encouraging wider participation and engagement. Having challenged existing national policies the paper suggests possible future directions

‘Women can’t referee’: Exploring the experiences of female football officials within UK football culture

The purpose of this study was to explore the experiences of female (association) football officials who officiate in amateur men’s and boys’ football matches in two UK counties (Warwickshire and Somerset). The research presents a view of men’s football from a position that has hitherto been overlooked in the social exploration of football culture. Drawing upon ethnographic fieldwork collected between September and December 2012, the findings provide insight into some women’s experiences of sexism and marginalization in predominantly male football contexts. Participant observations, formal semi-structured interviews and a range of informal conversations with four female match officials demonstrated a wide range of abuse that could generally be construed as sexist. The women used various strategies to overcome the hostile attitudes that often greeted their presence on the football pitch. Moreover, they continuously negotiated their identities as females and football officials in a space where men and masculinity are prevalent

Long-lasting effects of land use history on soil fungal communities in second-growth tropical rain forests

Our understanding of the long-lasting effects of human land use on soil fungal communities in tropical forests is limited. Yet, over 70% of all remaining tropical forests are growing in former agricultural or logged areas. We investigated the relationship among land use history, biotic and abiotic factors, and soil fungal community composition and diversity in a second-growth tropical forest in Puerto Rico. We coupled high-throughput DNA sequencing with tree community and environmental data to determine whether land use history had an effect on soil fungal community descriptors. We also investigated the biotic and abiotic factors that underlie such differences and asked whether the relative importance of biotic (tree diversity, basal tree area, and litterfall biomass) and abiotic (soil type, pH, iron, and total carbon, water flow, and canopy openness) factors in structuring soil fungal communities differed according to land use history. We demonstrated long-lasting effects of land use history on soil fungal communities. At our research site, most of the explained variation in soil fungal composition (R2 = 18.6%), richness (R2 = 11.4%), and evenness (R2 = 10%) was associated with edaphic factors. Areas previously subject to both logging and farming had a soil fungal community with lower beta diversity and greater evenness of fungal operational taxonomic units (OTUs) than areas subject to light logging. Yet, fungal richness was similar between the two areas of historical land use. Together, these results suggest that fungal communities in disturbed areas are more homogeneous and diverse than in areas subject to light logging. Edaphic factors were the most strongly correlated with soil fungal composition, especially in areas subject to light logging, where soils are more heterogenous. High functional tree diversity in areas subject to both logging and farming led to stronger correlations between biotic factors and fungal composition than in areas subject to light logging. In contrast, fungal richness and evenness were more strongly correlated with biotic factors in areas of light logging, suggesting that these metrics might reflect long-term associations in old-growth forests. The large amount of unexplained variance in fungal composition suggests that these communities are structured by both stochastic and niche assemblage processes

Is urinary continence considered in the assessment of older people after a fall in England and Wales? Cross-sectional clinical audit results

OBJECTIVES: To investigate adherence to the urinary function assessments of the national falls guidelines for England and Wales. STUDY DESIGN: Secondary data analysis of the 2006 National Clinical Audit of Falls and Bone Health. SETTING: Acute hospitals in the UK. PARTICIPANTS: Patients aged 65 years and older with a fragility fracture as a result of a fall. MAIN OUTCOME MEASURES: Data were analysed to determine whether patients with fragility fractures received an assessment of urinary function including continence status; whether impairment was detected and if action was taken to prevent continence related falls. RESULTS: 63% (2009) of 3184 patients were assessed for urinary continence following a hip fracture and 41% (817) of these identified a problem. 21% (1187) of 5642 patients with nonhip fragility fractures were assessed and a problem was found in 27% (316). Hip fracture patients were more likely (p<0.0001) to receive a continence assessment and have problems detected. Only about half of those with problems had any intervention or a referral to a continence service. Admission to hospital for non-hip fracture patients was a strong predictor of being assessed (p<0.0001). CONCLUSION: Rates of assessment and action for those with who fall and have continence problems are low despite current national guidelines

Appendices from An <i>in silico</i> model of cytotoxic T-lymphocyte activation in the lymph node following short peptide vaccination

Additional data to support the main text, including A) a comparison of the model to previous work, B) Fitting of experimental velocity distributions for T-cells and dendritic cells, C) A discussion of probability distributions for T-cell activation success and D) The data tables for the sensitivity analysis presented graphically in the text