Guts! Dietary modulation of innate defense

Necrotizing enterocolitis (NEC) is the most common gastro-intestinal emergency in the neonatal intensive care. The incidence of NEC ranges from 0.3 to 2.4 infants per 1000 live births, with nearly 70% of cases occurring in infants born at less than 36 weeks of gestation. The incidence of NEC varies, affecting 2-5% of all premature infants.[1] The overall mortality for NEC ranges from 10% to 50%.[2] Despite optimal medical and surgical management of NEC, infants that recover from the disease suffer from substantial morbidity, such as intestinal obstruction as a consequence of scarring, liver failure due to a prolonged requirement for total parenteral nutrition, short bowel syndrome with intestinal failure and associated nutritional deficiencies, and associated defects in growth and development.[3-4] Length of hospital stay in infants with surgical NEC and medically treated NEC exceeds those of controls by 60 days and 22 days respectively. Based on length of stay, the estimated total hospital charges for infants with surgical NEC in the USA averaged $186 200 in excess of those for controls and$73 700 more for infants with medical NEC. The yearly additional hospital charges for NEC were $216 666 per survivor.[5] Hence, NEC is a significant and growing health concern for prematurely born infants. The costs in the Netherlands are not exactly known, but will not be very different. As the number of preterm births has almost doubled over the past two decades in the Netherlands (Perinatale Registratie Nederland) and the United States (National Vital Statistics Report 2003), this burden will continue to increase. In addition, recently the national policy has changed into a more liberal approach to the lower limit of viability. More very immature infants (from a gestational age of 24 weeks onwards) will be given a chance to survive, with consequently more risk of developing NEC

Cloning, annotation and developmental expression of the chicken intestinal MUC2 gene

Intestinal mucin 2 (MUC2) encodes a heavily glycosylated, gel-forming mucin, which creates an important protective mucosal layer along the gastrointestinal tract in humans and other species. This first line of defense guards against attacks from microorganisms and is integral to the innate immune system. As a first step towards characterizing the innate immune response of MUC2 in different species, we report the cloning of a full-length, 11,359 bp chicken MUC2cDNA, and describe the genomic organization and functional annotation of this complex, 74.5 kb locus. MUC2 contains 64 exons and demonstrates distinct spatiotemporal expression profiles throughout development in the gastrointestinal tract; expression increases with gestational age and from anterior to posterior along the gut. The chicken protein has a similar domain organization as the human orthologue, with a signal peptide and several von Willebrand domains in the N-terminus and the characteristic cystine knot at the C-terminus. The PTS domain of the chicken MUC2 protein spans ~1600 amino acids and is interspersed with four CysD motifs. However, the PTS domain in the chicken diverges significantly from the human orthologue; although the chicken domain is shorter, the repetitive unit is 69 amino acids in length, which is three times longer than the human. The amino acid composition shows very little similarity to the human motif, which potentially contributes to differences in the innate immune response between species, as glycosylation across this rapidly evolving domain provides much of the musical barrier. Future studies of the function of MUC2 in the innate immune response system in chicken could provide an important model organism to increase our understanding of the biological significance of MUC2 in host defense and highlight the potential of the chicken for creating new immune-based therapies

High-level integration of murine intestinal transcriptomics data highlights the importance of the complement system in mucosal homeostasis.

BACKGROUND: The mammalian intestine is a complex biological system that exhibits functional plasticity in its response to diverse stimuli to maintain homeostasis. To improve our understanding of this plasticity, we performed a high-level data integration of 14 whole-genome transcriptomics datasets from samples of intestinal mouse mucosa. We used the tool Centrality based Pathway Analysis (CePa), along with information from the Reactome database. RESULTS: The results show an integrated response of the mouse intestinal mucosa to challenges with agents introduced orally that were expected to perturb homeostasis. We observed that a common set of pathways respond to different stimuli, of which the most reactive was the Regulation of Complement Cascade pathway. Altered expression of the Regulation of Complement Cascade pathway was verified in mouse organoids challenged with different stimuli in vitro. CONCLUSIONS: Results of the integrated transcriptomics analysis and data driven experiment suggest an important role of epithelial production of complement and host complement defence factors in the maintenance of homeostasis

Containment and Connectivity in Dutch Urban Systems: A Network‐Analytical Operationalisation of the Three‐Systems Model

This paper discusses key methodological issues with nodalising interaction data of urban networks to produce a state-of-the-art settlement geography of the Netherlands. We operationalise the threesystems model that analyses functional settlement geographies through the interaction between the daily urban system, the central place system and the export base system. We utilise theoreticallyinformed selections of spatial interactions derived from travel survey data at the finely-grained postcode level. After examining the methodological challenge of the node-inclusivity dilemma, we estimate the causal mechanisms that geographically structure each system and determine which spatial interactions should be assigned to nodes (containment) and edges (connectivity). The three systems produce different regionalisations that are neither mutually exclusive nor perfectly nested. Further analysis of the multiplexity of the three systems reveals the importance of the imbricated boundaries between the urban subsystems. We argue that these interplaces deserve more attention as they are particularly sensitive to changes in urbanisation trends