Host-Microbial Interactions that Modulate Luminal IgA

IgA is the most abundant immunoglobulin produced in the body, most of which can be found at mucosal sites such as the intestine where it plays an important role at a critical intersection between the host immune system and the microbiota. In the work detailed here, I sought to investigate IgA delivery and stability using in vitro and in vivo methods. First, I developed a primary intestinal epithelial monolayer system, and utilized this system to evaluate factors that modulate IgA transcytosis. In vivo, I interrogated baseline levels of fecal IgA in WT mice and surprisingly observed a binary phenotype in fecal IgA levels between cages. I found that the dichotomous IgA levels were heritable, transmissible, and microbially driven. In addition, the IgA-Low phenotype was dominant and functionally resulted in increased intestinal injury by DSS. Utilizing the primary epithelial monolayer system and IgA transcytosis assay, I found that anaerobically cultured microbes from IgA-Low mice had proteolytic activity capable of degrading secretory component (SC) in vitro. These findings support the idea that degradation of SC in vivo would make IgA more susceptible to degradation itself. These studies highlight the ability of the microbiota to produce phenotypic effects through IgA modulation

Out-of-frame T cell receptor beta transcripts are eliminated by multiple pathways In Vivo

Non-productive antigen receptor genes with frame shifts generated during the assembly of these genes are found in many mature lymphocytes. Transcripts from these genes have premature termination codons (PTCs) and could encode truncated proteins if they are not either inactivated or destroyed by nonsense-mediated decay (NMD). In mammalian cells, NMD can be activated by pathways that rely on the presence of an intron downstream of the PTC; however, NMD can also be activated by pathways that do not rely on these downstream introns, and pathways independent of NMD can inactivate PTC-containing transcripts. Here, through the generation and analysis of mice with gene-targeted modifications of the endogenous T cell receptor beta (Tcrb) locus, we demonstrate that in T cells in vivo, optimal clearance of PTC-containing Tcrb transcripts depends on the presence of an intron downstream of the PTC

The \u27Healthy Parks-Healthy People\u27 Movement in Canada: Progress, Challenges, and an Emerging Knowledge and Action Agenda

In this article, we outline progress and challenges in establishing effective health promotion tied to visitor experiences provided by protected and conserved areas in Canada. Despite an expanding global evidence base, case studies focused on aspects of health and well-being within Canada’s protected and conserved areas remain limited. Data pertaining to motivations, barriers and experiences of visitors are often not collected by governing agencies and, if collected, are not made generally available or reported on. There is an obvious, large gap in research and action focused on the needs and rights of groups facing systemic barriers related to a variety of issues including, but not limited to, access, nature experiences, and needs with respect to health and well-being outcomes. Activation of programmes at the site level continue to grow, and Park Prescription programmes, as well as changes to the Accessible Canada Act, represent significant, positive examples of recent cross-sector policy integration. Evaluations of outcomes associated with HPHP programmes have not yet occurred but will be important to adapting interventions and informing cross-sector capacity building. We conclude by providing an overview of gaps in evidence and practice that, if addressed, can lead to more effective human health promotion vis-à-vis nature contact in protected and conserved areas in Canada

Caloric restriction and intermittent fasting alter hepatic lipid droplet proteome and diacylglycerol species and prevent diabetes in NZO mice

AbstractCaloric restriction and intermittent fasting are known to improve glucose homeostasis and insulin resistance in several species including humans. The aim of this study was to unravel potential mechanisms by which these interventions improve insulin sensitivity and protect from type 2 diabetes. Diabetes-susceptible New Zealand Obese mice were either 10% calorie restricted (CR) or fasted every other day (IF), and compared to ad libitum (AL) fed control mice. AL mice showed a diabetes prevalence of 43%, whereas mice under CR and IF were completely protected against hyperglycemia. Proteomic analysis of hepatic lipid droplets revealed significantly higher levels of PSMD9 (co-activator Bridge-1), MIF (macrophage migration inhibitor factor), TCEB2 (transcription elongation factor B (SIII), polypeptide 2), ACY1 (aminoacylase 1) and FABP5 (fatty acid binding protein 5), and a marked reduction of GSTA3 (glutathione S-transferase alpha 3) in samples of CR and IF mice. In addition, accumulation of diacylglycerols (DAGs) was significantly reduced in livers of IF mice (P=0.045) while CR mice showed a similar tendency (P=0.062). In particular, 9 DAG species were significantly reduced in response to IF, of which DAG-40:4 and DAG-40:7 also showed significant effects after CR. This was associated with a decreased PKCε activation and might explain the improved insulin sensitivity. In conclusion, our data indicate that protection against diabetes upon caloric restriction and intermittent fasting associates with a modulation of lipid droplet protein composition and reduction of intracellular DAG species

Structure-based programming of lymph-node targeting in molecular vaccines

In cancer patients, visual identification of sentinel lymph nodes (LNs) is achieved by the injection of dyes that bind avidly to endogenous albumin, targeting these compounds to LNs, where they are efficiently filtered by resident phagocytes1, 2. Here we translate this ‘albumin hitchhiking’ approach to molecular vaccines, through the synthesis of amphiphiles (amph-vaccines) comprising an antigen or adjuvant cargo linked to a lipophilic albumin-binding tail by a solubility-promoting polar polymer chain. Administration of structurally optimized CpG-DNA/peptide amph-vaccines in mice resulted in marked increases in LN accumulation and decreased systemic dissemination relative to their parent compounds, leading to 30-fold increases in T-cell priming and enhanced anti-tumour efficacy while greatly reducing systemic toxicity. Amph-vaccines provide a simple, broadly applicable strategy to simultaneously increase the potency and safety of subunit vaccines.David H. Koch Institute for Integrative Cancer Research at MIT (Koch Institute Support (core) Grant P30-CA14051)National Cancer Institute (U.S.)National Institutes of Health (U.S.) (grant AI091693)National Institutes of Health (U.S.) (grant AI104715)National Institutes of Health (U.S.) (AI095109)United States. Dept. of Defense (contract W911NF-13-D-0001)United States. Dept. of Defense (contract W911NF-07-D-0004)Ragon Institute of MGH, MIT, and Harvar

Peripheral CD103+ dendritic cells form a unified subset developmentally related to CD8α+ conventional dendritic cells

Although CD103-expressing dendritic cells (DCs) are widely present in nonlymphoid tissues, the transcription factors controlling their development and their relationship to other DC subsets remain unclear. Mice lacking the transcription factor Batf3 have a defect in the development of CD8α(+) conventional DCs (cDCs) within lymphoid tissues. We demonstrate that Batf3(−/−) mice also lack CD103(+)CD11b(−) DCs in the lung, intestine, mesenteric lymph nodes (MLNs), dermis, and skin-draining lymph nodes. Notably, Batf3(−/−) mice displayed reduced priming of CD8 T cells after pulmonary Sendai virus infection, with increased pulmonary inflammation. In the MLNs and intestine, Batf3 deficiency resulted in the specific lack of CD103(+)CD11b(−) DCs, with the population of CD103(+)CD11b(+) DCs remaining intact. Batf3(−/−) mice showed no evidence of spontaneous gastrointestinal inflammation and had a normal contact hypersensitivity (CHS) response, despite previous suggestions that CD103(+) DCs were required for immune homeostasis in the gut and CHS. The relationship between CD8α(+) cDCs and nonlymphoid CD103(+) DCs implied by their shared dependence on Batf3 was further supported by similar patterns of gene expression and their shared developmental dependence on the transcription factor Irf8. These data provide evidence for a developmental relationship between lymphoid organ–resident CD8α(+) cDCs and nonlymphoid CD103(+) DCs

Australia\u27s health 2000 : the seventh biennial report of the Australian Institute of Health and Welfare

Australia\u27s Health 2000 is the seventh biennial health report of the Australian Institute of Health and Welfare. It is the nation\u27s authoritative source of information on patterns of health and illness, determinants of health, the supply and use of health services, and health services costs and performance.This 2000 edition serves as a summary of Australia\u27s health record at the end of the twentieth century. In addition, a special chapter is presented on changes in Australia\u27s disease profile over the last 100 years.Australia\u27s Health 2000 is an essential reference and information source for all Australians with an interest in health

Metagenomics-Based Proficiency Test of Smoked Salmon Spiked with a Mock Community

peer reviewedAn inter-laboratory proficiency test was organized to assess the ability of participants to perform shotgun metagenomic sequencing of cold smoked salmon, experimentally spiked with a mock community composed of six bacteria, one parasite, one yeast, one DNA, and two RNA viruses. Each participant applied its in-house wet-lab workflow(s) to obtain the metagenomic dataset(s), which were then collected and analyzed using MG-RAST. A total of 27 datasets were analyzed. Sample pre-processing, DNA extraction protocol, library preparation kit, and sequencing platform, influenced the abundance of specific microorganisms of the mock community. Our results highlight that despite differences in wet-lab protocols, the reads corresponding to the mock community members spiked in the cold smoked salmon, were both detected and quantified in terms of relative abundance, in the metagenomic datasets, proving the suitability of shotgun metagenomic sequencing as a genomic tool to detect microorganisms belonging to different domains in the same food matrix. The implementation of standardized wet-lab protocols would highly facilitate the comparability of shotgun metagenomic sequencing dataset across laboratories and sectors. Moreover, there is a need for clearly defining a sequencing reads threshold, to consider pathogens as detected or undetected in a food sample