Shared Genetics and Couple-Associated Environment Are Major Contributors to the Risk of Both Clinical and Self-Declared Depression.

Background: Both genetic and environmental factors contribute to risk of depression, but estimates of their relative contributions are limited. Commonalities between clinically-assessed major depressive disorder (MDD) and self-declared depression (SDD) are also unclear.

Methods: Using data from a large Scottish family-based cohort (GS:SFHS, N=19,994), we estimated the genetic and environmental variance components for MDD and SDD.

c-Rel is dispensable for the differentiation and functional maturation of M cells in the follicle-associated epithelium.

M cells reside within the follicle-associated epithelium (FAE) overlying the gut-associated lymphoid tissues. These unique phagocytic epithelial cells enable the mucosal immune system to sample antigens within the lumen of the intestine. The differentiation of M cells from uncommitted precursors in the FAE is dependent on the production of receptor activator of nuclear factor-κB ligand (RANKL) by subepithelial stromal cells.

A Combined Pathway and Regional Heritability Analysis Indicates NETRIN1 Pathway Is Associated With Major Depressive Disorder.

Background: Genome-wide association studies (GWASs) of major depressive disorder (MDD) have identified few significant associations. Testing the aggregation of genetic variants, in particular biological pathways, may be more powerful. Regional heritability analysis can be used to detect genomic regions that contribute to disease risk.

The influence of the commensal and pathogenic gut microbiota on prion disease pathogenesis.

Prion diseases are a unique group of transmissible, chronic, neurodegenerative disorders. Following peripheral exposure (e.g.

Genetically engineering milk.

It has been thirty years since the first genetically engineered animal with altered milk composition was reported. During the intervening years, the world population has increased from 5bn to 7bn people. An increasing demand for protein in the human diet has followed this population expansion, putting huge stress on the food supply chain.

An endogenous nanomineral chaperones luminal antigen and peptidoglycan to intestinal immune cells.

In humans and other mammals it is known that calcium and phosphate ions are secreted from the distal small intestine into the lumen. However, why this secretion occurs is unclear. Here, we show that the process leads to the formation of amorphous magnesium-substituted calcium phosphate nanoparticles that trap soluble macromolecules, such as bacterial peptidoglycan and orally fed protein antigens, in the lumen and transport them to immune cells of the intestinal tissue.

Complete genome sequences of novel anelloviruses from laboratory rats.

Anelloviruses are nonenveloped single-stranded DNA viruses infecting a wide range of mammals. We report three complete genomes of novel anelloviruses detected in laboratory rats. Phylogenetic analysis demonstrates that these viruses are related to but distinct from recently described rodent Torque teno viruses (RoTTVs) found in wild rodent species.

Reciprocal regulation of lymphoid tissue development in the large intestine by IL-25 and IL-23.

Isolated lymphoid follicles (ILFs) develop after birth in the small and large intestines (SI and LI) and represent a dynamic response of the gut immune system to the microbiota. Despite their similarities, ILF development in the SI and LI differs on a number of levels. We show that unlike ILF in the SI, the microbiota inhibits ILF development in the colon as conventionalization of germ-free mice reduced colonic ILFs.

Detecting epistasis in human complex traits.

Genome-wide association studies (GWASs) have become the focus of the statistical analysis of complex traits in humans, successfully shedding light on several aspects of genetic architecture and biological aetiology. Single-nucleotide polymorphisms (SNPs) are usually modelled as having additive, cumulative and independent effects on the phenotype. Although evidently a useful approach, it is often argued that this is not a realistic biological model and that epistasis (that is, the statistical interaction between SNPs) should be included.

Visualisation of chicken macrophages using transgenic reporter genes: insights into the development of the avian macrophage lineage.

We have generated the first transgenic chickens in which reporter genes are expressed in a specific immune cell lineage, based upon control elements of the colony stimulating factor 1 receptor (CSF1R) locus. The Fms intronic regulatory element (FIRE) within CSF1R is shown to be highly conserved in amniotes and absolutely required for myeloid-restricted expression of fluorescent reporter genes. As in mammals, CSF1R-reporter genes were specifically expressed at high levels in cells of the macrophage lineage and at a much lower level in granulocytes.

Prion protein-specific antibodies that detect multiple TSE agents with high sensitivity.

This paper describes the generation, characterisation and potential applications of a panel of novel anti-prion protein monoclonal antibodies (mAbs). The mAbs were generated by immunising PRNP null mice, using a variety of regimes, with a truncated form of recombinant ovine prion protein spanning residues 94-233. Epitopes of specific antibodies were mapped using solid-phase Pepscan analysis and clustered to four distinct regions within the PrP molecule.

Evidence of subclinical prion disease in aged mice following exposure to bovine spongiform encephalopathy.

The occurrence of variant Creutzfeldt-Jakob (vCJD) disease in humans was almost certainly the result of consumption of food contaminated with bovine spongiform encephalopathy (BSE) prions. Despite probable widespread exposure of the UK population to BSE-contaminated food in the 1980s, vCJD has been identified predominantly in young individuals, and there have been fewer cases of clinical disease than anticipated. The reasons for this are uncertain.

Identification of co-expressed gene signatures in mouse B1, marginal zone and B2 B-cell populations.

In mice, three major B-cell subsets have been identified with distinct functionalities: B1 B cells, marginal zone B cells and follicular B2 B cells. Here, we used the growing body of publicly available transcriptomics data to create an expression atlas of 84 gene expression microarray data sets of distinct mouse B-cell subsets. These data were subjected to network-based cluster analysis using BioLayout Express(3D).

Distinct molecular signature of human skin Langerhans cells denotes critical differences in cutaneous dendritic cell immune regulation.

Langerhans cells (LCs) are professional antigen-presenting cells (APCs) residing in the epidermis. Despite their high potential to activate T lymphocytes, current understanding of human LC biology is limited. Genome-wide comparison of the transcriptional profiles of human skin migratory CD1a+ LCs and CD11c+ dermal dendritic cells (DDCs) demonstrated significant differences between these "dendritic cell (DC)" types, including preferential expression of 625 genes (P<0.

Microfold (M) cells: important immunosurveillance posts in the intestinal epithelium.

The transcytosis of antigens across the gut epithelium by microfold cells (M cells) is important for the induction of efficient immune responses to some mucosal antigens in Peyer's patches. Recently, substantial progress has been made in our understanding of the factors that influence the development and function of M cells. This review highlights these important advances, with particular emphasis on: the host genes which control the functional maturation of M cells; how this knowledge has led to the rapid advance in our understanding of M-cell biology in the steady state and during aging; molecules expressed on M cells which appear to be used as "immunosurveillance" receptors to sample pathogenic microorganisms in the gut; how certain pathogens appear to exploit M cells to infect the host; and finally how this knowledge has been used to specifically target antigens to M cells to attempt to improve the efficacy of mucosal vaccines.

Ablation of the cellular prion protein, PrPC, specifically on follicular dendritic cells has no effect on their maturation or function.

Follicular dendritic cells (FDC) are situated in the primary follicles of lymphoid tissues where they maintain the structural integrity of the B-lymphocyte follicle, and help to drive immunoglobulin class-switch recombination, somatic hypermutation and affinity maturation during the germinal centre response. FDC can also provide a reservoir for pathogens that infect germinal centres including HIV and prions. FDC express high levels of the normal cellular form of the prion protein (PrP(C) ), which makes them susceptible to prion infection.

Identification of novel genes selectively expressed in the follicle-associated epithelium from the meta-analysis of transcriptomics data from multiple mouse cell and tissue populations.

The follicle-associated epithelium (FAE) overlying the Peyer's patches and the microfold cells (M cells) within it are important sites of antigen transcytosis across the intestinal epithelium. Using a meta-analysis approach, we identified a transcriptional signature that distinguished the FAE from a large collection of mouse cells and tissues. A co-expressed cluster of 21 FAE-specific genes was identified, and the analysis of the transcription factor binding site motifs in their promoter regions indicated that these genes shared an underlying transcriptional programme.

B cell-specific S1PR1 deficiency blocks prion dissemination between secondary lymphoid organs.

Many prion diseases are peripherally acquired (e.g., orally or via lesions to skin or mucous membranes).

M cell-depletion blocks oral prion disease pathogenesis.

Many prion diseases are orally acquired. Our data show that after oral exposure, early prion replication upon follicular dendritic cells (FDC) in Peyer's patches is obligatory for the efficient spread of disease to the brain (termed neuroinvasion). For prions to replicate on FDC within Peyer's patches after ingestion of a contaminated meal, they must first cross the gut epithelium.

The effects of host age on the transport of complement-bound complexes to the spleen and the pathogenesis of intravenous scrapie infection.

Infections with variant Creutzfeldt-Jakob disease (vCJD) have almost exclusively occurred in young patients, but the reasons for this age distribution are uncertain. Our data suggest that the pathogenesis of many peripherally acquired transmissible spongiform encephalopathy (TSE) agents is less efficient in aged individuals. Four vCJD cases linked to transfusion of vCJD-contaminated blood or blood products have been described.

Expression of mesenchyme-specific gene signatures by follicular dendritic cells: insights from the meta-analysis of microarray data from multiple mouse cell populations.

Follicular dendritic cells (FDC) are an important subset of stromal cells within the germinal centres of lymphoid tissues. They are specialized to trap and retain antigen-containing immune complexes on their surfaces to promote B-cell maturation and immunoglobulin isotype class-switching. However, little is known of the cell types from which FDC originate.

Strain-specific copy number variation in the intelectin locus on the 129 mouse chromosome 1.

Background: C57BL/6J mice possess a single intelectin (Itln) gene on chromosome 1. The function of intelectins is not well understood, but roles have been postulated in insulin sensitivity, bacterial recognition, intestinal lactoferrin uptake and response to parasites and allergens. In contrast to C57BL/6J mice, there is evidence for expansion of the Itln locus in other strains and at least one additional mouse Itln gene product has been described.

The effects of host age on follicular dendritic cell status dramatically impair scrapie agent neuroinvasion in aged mice.

Following peripheral exposure, many transmissible spongiform encephalopathy (TSE) agents accumulate first in lymphoid tissues before spreading to the CNS (termed neuroinvasion) where they cause neurodegeneration. Early TSE agent accumulation upon follicular dendritic cells (FDCs) in lymphoid follicles appears critical for efficient neuroinvasion. Most clinical cases of variant Creutzfeldt-Jakob disease have occurred in young adults, although the reasons behind this apparent age-related susceptibility are uncertain.