The Role of the Mucus Barrier in Digestion

Mucus forms a protective layer across a variety of epithelial surfaces. In the gastrointestinal (GI) tract, the barrier has to permit the uptake of nutrients, while excluding potential hazards, such as pathogenic bacteria. In this short review article, we look at recent literature on the structure, location, and properties of the mammalian intestinal secreted mucins and the mucus layer they form over a wide range of length scales. In particular, we look at the structure of the gel-forming glycoprotein MUC2, the primary intestinal secreted mucin, and the influence this has on the properties of the mucus layer. We show that, even at the level of the protein backbone, MUC2 is highly heterogeneous and that this is reflected in the networks it forms. It is evident that a combination of charge and pore size determines what can diffuse through the layer to the underlying gut epithelium. This information is important for the targeted delivery of bioactive molecules, including nutrients and pharmaceuticals, and for understanding how GI health is maintained

The Rat IgGFcγBP and Muc2 C-Terminal Domains and TFF3 in Two Intestinal Mucus Layers Bind Together by Covalent Interaction

The secreted proteins from goblet cells compose the intestinal mucus. The aims of this study were to determine how they exist in two intestinal mucus layers.The intestinal mucosa was fixed with Carnoy solution and immunostained. Mucus from the loose layer, the firm layer was gently suctioned or scraped, respectively, lysed in SDS sample buffer with or without DTT, then subjected to the western blotting of rTFF3, rIgGFcγBP or rMuc2. The non-reduced or reduced soluble mucus samples in RIPA buffer were co-immunoprecipitated to investigate their possible interactions. Polyclonal antibodies for rTFF3, the rIgGFcγBP C-terminal domain and the rMuc2 C-terminal domain confirmed their localization in the mucus layer and in the mucus collected from the rat intestinal loose layer or firm layer in both western blot and immunoprecipitation experiments. A complex of rTFF3, which was approximately 250 kDa, and a monomer of 6 kDa were present in both layers of the intestinal mucus; rIgGFcγBP was present in the complex (250-280 kDa) under non-reducing conditions, but shifted to 164 kDa under reducing conditions in both of the layers. rMuc2 was found mainly in a complex of 214-270 kDa under non-reducing conditions, but it shifted to 140 kDa under reducing conditions. The co-immunoprecipitation experiments showed that binding occurs among rTFF3, rIgGFcγBP and rMuc2 in the RIPA buffer soluble intestinal mucus. Blocking the covalent interaction by 100 mM DTT in the RIPA buffer soluble intestinal mucus disassociated their binding.Rat goblet cell-secreted TFF3, IgGFcγBP and Muc2, existing in the two intestinal mucus layers, are bound together by covalent interactions in the soluble fraction of intestinal mucus and form heteropolymers to be one of the biochemical mechanisms of composing the net-like structure of mucus

Altered innate defenses in the neonatal gastrointestinal tract in response to colonization by neuropathogenic Escherichia coli

Two-day-old (P2), but not nine-day-old (P9), rat pups are susceptible to systemic infection following gastrointestinal colonization by Escherichia coli K1. Age dependency reflects the capacity of colonizing K1 to translocate from gastrointestinal (GI) tract to blood. A complex GI microbiota developed by P2, showed little variation over P2-P9 and did not prevent stable K1 colonization. Substantial developmental expression was observed over P2-P9, including up-regulation of genes encoding components of the small intestinal (α-defensins Defa24 and Defa-rs1) and colonic (trefoil factor Tff2) mucus barrier. K1 colonization modulated expression of these peptides: developmental expression of Tff2 was dysregulated in P2 tissues and was accompanied by a decrease in mucin Muc2. Conversely, α-defensin genes were up-regulated in P9 tissues. We propose that incomplete development of the mucus barrier during early neonatal life and the capacity of colonizing K1 to interfere with mucus barrier maturation provide opportunities for neuropathogen translocation into the bloodstream

Microbial regulation of the L cell transcriptome.

L cells are an important class of enteroendocrine cells secreting hormones such as glucagon like peptide-1 and peptide YY that have several metabolic and physiological effects. The gut is home to trillions of bacteria affecting host physiology, but there has been limited understanding about how the microbiota affects gene expression in L cells. Thus, we rederived the reporter mouse strain, GLU-Venus expressing yellow fluorescent protein under the control of the proglucagon gene, as germ-free (GF). Lpos cells from ileum and colon of GF and conventionally raised (CONV-R) GLU-Venus mice were isolated and subjected to transcriptomic profiling. We observed that the microbiota exerted major effects on ileal L cells. Gene Ontology enrichment analysis revealed that microbiota suppressed biological processes related to vesicle localization and synaptic vesicle cycling in Lpos cells from ileum. This finding was corroborated by electron microscopy of Lpos cells showing reduced numbers of vesicles as well as by demonstrating decreased intracellular GLP-1 content in primary cultures from ileum of CONV-R compared with GF GLU-Venus mice. By analysing Lpos cells following colonization of GF mice we observed that the greatest transcriptional regulation was evident within 1 day of colonization. Thus, the microbiota has a rapid and pronounced effect on the L cell transcriptome, predominantly in the ileum

Soft Drink, Software and Softening of Teeth – a Case Report of Tooth Wear in the Mixed Dentition Due to a Combination of Dental Erosion and Attrition

This case report describes a 9-year-old boy with severe tooth wear as a result of drinking a single glass of soft drink per day. This soft drink was consumed over a period of one to two hours, while he was gaming intensively on his computer. As a result, a deep bite, enamel cupping, sensitivity of primary teeth and loss of fillings occurred. Therefore, dentists should be aware that in patients who are gaming intensively, the erosive potential of soft drinks can be potentiated by mechanical forces leading to excessive tooth wear

Pedestrian, Crowd, and Evacuation Dynamics

This contribution describes efforts to model the behavior of individual pedestrians and their interactions in crowds, which generate certain kinds of self-organized patterns of motion. Moreover, this article focusses on the dynamics of crowds in panic or evacuation situations, methods to optimize building designs for egress, and factors potentially causing the breakdown of orderly motion.Comment: This is a review paper. For related work see http://www.soms.ethz.c

Gene expression signatures in childhood acute leukemias are largely unique and distinct from those of normal tissues and other malignancies

<p>Abstract</p> <p>Background</p> <p>Childhood leukemia is characterized by the presence of balanced chromosomal translocations or by other structural or numerical chromosomal changes. It is well know that leukemias with specific molecular abnormalities display profoundly different global gene expression profiles. However, it is largely unknown whether such subtype-specific leukemic signatures are unique or if they are active also in non-hematopoietic normal tissues or in other human cancer types.</p> <p>Methods</p> <p>Using gene set enrichment analysis, we systematically explored whether the transcriptional programs in childhood acute lymphoblastic leukemia (ALL) and myeloid leukemia (AML) were significantly similar to those in different flow-sorted subpopulations of normal hematopoietic cells (n = 8), normal non-hematopoietic tissues (n = 22) or human cancer tissues (n = 13).</p> <p>Results</p> <p>This study revealed that e.g., the t(12;21) [<it>ETV6-RUNX1</it>] subtype of ALL and the t(15;17) [<it>PML-RARA</it>] subtype of AML had transcriptional programs similar to those in normal Pro-B cells and promyelocytes, respectively. Moreover, the 11q23/<it>MLL </it>subtype of ALL showed similarities with non-hematopoietic tissues. Strikingly however, most of the transcriptional programs in the other leukemic subtypes lacked significant similarity to ~100 gene sets derived from normal and malignant tissues.</p> <p>Conclusions</p> <p>This study demonstrates, for the first time, that the expression profiles of childhood leukemia are largely unique, with limited similarities to transcriptional programs active in normal hematopoietic cells, non-hematopoietic normal tissues or the most common forms of human cancer. In addition to providing important pathogenetic insights, these findings should facilitate the identification of candidate genes or transcriptional programs that can be used as unique targets in leukemia.</p

Cardiovascular Applications of Hyperpolarized MRI

Many applications of MRI are limited by an inherently low sensitivity. Previous attempts to overcome this insensitivity have focused on the use of MRI systems with stronger magnetic fields. However, the gains that can be achieved in this way are relatively small and increasing the magnetic field invariably leads to greater technical challenges. More recently, the development of a range of techniques, which can be gathered under the umbrella term of “hyperpolarization,” has offered potential solutions to the low sensitivity. Hyperpolarization techniques have been demonstrated to temporarily increase the signal available in an MRI experiment by as much as 100,000-fold. This article outlines the main hyperpolarization techniques that have been proposed and explains how they can increase MRI signals. With particular emphasis on the emerging technique of dynamic nuclear polarization, the existing preclinical cardiovascular applications are reviewed and the potential for clinical translation is discussed