A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci

We conducted a multi-stage, genome-wide association study of bladder cancer with a primary scan of 591,637 SNPs in 3,532 affected individuals (cases) and 5,120 controls of European descent from five studies followed by a replication strategy, which included 8,382 cases and 48,275 controls from 16 studies. In a combined analysis, we identified three new regions associated with bladder cancer on chromosomes 22q13.1, 19q12 and 2q37.1: rs1014971, (P = 8 × 10?12) maps to a non-genic region of chromosome 22q13.1, rs8102137 (P = 2 × 10?11) on 19q12 maps to CCNE1 and rs11892031 (P = 1 × 10??) maps to the UGT1A cluster on 2q37.1. We confirmed four previously identified genome-wide associations on chromosomes 3q28, 4p16.3, 8q24.21 and 8q24.3, validated previous candidate associations for the GSTM1 deletion (P = 4 × 10?11) and a tag SNP for NAT2 acetylation status (P = 4 × 10?11), and found interactions with smoking in both regions. Our findings on common variants associated with bladder cancer risk should provide new insights into the mechanisms of carcinogenesis.     

Multimodal Systemic Metamethodology: An Application to Edgar Morin’s Doctrine

This paper intends to show how multimodal system methodology can be interpreted as a metamethodology that can house different specific methodologies to be used in action-research.

A Systemic Approach to Eliciting and Gathering the Expertise of a ‘Knowledge Guardian’: an Application of the Appreciative Inquiry Method to the Study of Classical Dressage

This paper reports on a study in which an interpretive systems-based approach to knowledge elicitation, the Appreciative Inquiry Method (AIM), is used to elicit and record the expertise of what is referred to as a ??knowledge guardian??. A ??knowledge guardian?? is an individual who is a current repository and representative of some culturally-embedded knowledge which, for generations, has been passed on through teaching and apprenticeship, and continues to be so. Such knowledge is rich, complex and precious and merits protection. The knowledge guardian in this study is a Portuguese rider and teacher of Classical Dressage. His expertise relies heavily upon the ability to ??feel?? and explain such feeling in his teaching. The view of Classical Dressage that emerges from the study emphasises the importance of the individual??s psychological development and motivation to participate in the art due to a desire to experience ??brilliance??. The paper describes the process undertaken during the elicitation sessions and provides the models developed and used to facilitate the discussion. These models (Root Definition and Conceptual Model) are of the type commonly associated with Soft Systems Methodology. The paper also provides comments on the use of AIM, the knowledge recorded about Classical Dressage and the reflections of the two collaborators involved in the study.     

Enterotypes of the human gut microbiome

Our knowledge of species and functional composition of the human gut microbiome is rapidly increasing, but it is still based on very few cohorts and little is known about variation across the world. By combining 22 newly sequenced faecal metagenomes of individuals from four countries with previously published data sets, here we identify three robust clusters (referred to as enterotypes hereafter) that are not nation or continent specific. We also confirmed the enterotypes in two published, larger cohorts, indicating that intestinal microbiota variation is generally stratified, not continuous. This indicates further the existence of a limited number of well-balanced host-microbial symbiotic states that might respond differently to diet and drug intake. The enterotypes are mostly driven by species composition, but abundant molecular functions are not necessarily provided by abundant species, highlighting the importance of a functional analysis to understand microbial communities. Although individual host properties such as body mass index, age, or gender cannot explain the observed enterotypes, data-driven marker genes or functional modules can be identified for each of these host properties. For example, twelve genes significantly correlate with age and three functional modules with the body mass index, hinting at a diagnostic potential of microbial markers.     

Mutant chromatin remodeling protein SMARCAL1 causes Schimke immuno-osseous dysplasia.

Schimke immuno-osseous dysplasia (SIOD, MIM 242900) is an autosomal-recessive pleiotropic disorder with the diagnostic features of spondyloepiphyseal dysplasia, renal dysfunction and T-cell immunodeficiency. Using genome-wide linkage mapping and a positional candidate approach, we determined that mutations in SMARCAL1 (SWI/SNF2-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1), are responsible for SIOD. Through analysis of data from persons with SIOD in 26 unrelated families, we observed that affected individuals from 13 of 23 families with severe disease had two alleles with nonsense, frameshift or splicing mutations, whereas affected individuals from 3 of 3 families with milder disease had a missense mutation on each allele. These observations indicate that some missense mutations allow retention of partial SMARCAL1 function and thus cause milder disease.     

Forecasting using targeted diffusion indexes

The simplicity of the standard diffusion index model of Stock and Watson has certainly contributed to its success among practitioners, resulting in a growing body of literature on factor‐augmented forecasts. However, as pointed out by Bai and Ng, the ranked factors considered in the forecasting equation depend neither on the variable to be forecast nor on the forecasting horizon. We propose a refinement of the standard approach that retains the computational simplicity while coping with this limitation. Our approach consists of generating a weighted average of all the principal components, the weights depending both on the eigenvalues of the sample correlation matrix and on the covariance between the estimated factor and the targeted variable at the relevant horizon. This ‘targeted diffusion index’ approach is applied to US data and the results show that it outperforms considerably the standard approach in forecasting several major macroeconomic series. Moreover, the improvement is more significant in the final part of the forecasting evaluation period. Copyright © 2009 John Wiley & Sons, Ltd.     

The Acceptance and Progress in Argentina of Multi-Modal Systems Thinking for Community Development

This article describes the acceptance and development of multi-modal systems thinking in Argentina in the last 5 years, both in theory and in practice. On the theoretical side, we show the efforts made to provide compatible epistemological doctrines for different modalities, starting with ethics and aesthetics. This took place first through the phenomenology of values and more recently in the context of Christian existentialism and continuing later on with the study of the relationship among other modalities. On the practical side, we describe the applications of this framework to study the so-called “crisis of the Argentine countryside”. This is a conflict between the community of farmers, the national government and the present situation with cattle producers. Other applications include a programme to teach action-research and projects related to abandoned children and education in indigenous communities.