A Delineation of Mesenchymal Stromal Cell Therapeutic Action in New Models of Acute and Chronic Graft versus Host Disease

The potent immune regulatory capacity of mesenchymal stromal cells (MSC) has been extensively characterised in terms of T cells, natural killer cells and dendritic cells suppression; however the ability of MSC to modulate B cell biology is not fully understood. This immune suppressive ability has led to the development of MSC therapy for the treatment of inflammatory and auto-immune disease, and has already demonstrated beneficial effects during GvHD and Crohn’s disease. However, the mechanisms employed by MSC therapy to modulate disease progression have not been identified. The key goals for this thesis were (1) to determine how MSC effect B cell function and to identify the mechanisms by which this effect is mediated, and (2) the development of novel mouse models of chronic and acute GvHD to elucidate the mechanism of action by which MSC attenuate disease progression. This study demonstrated than MSC support the activation, proliferation and survival of human CD19+ peripheral B cells in vitro. MSC support of B cell survival was mediated through the cell contact dependent up-regulation of VEGF production by the MSC. Soluble VEGF bound by B cells induced AKT phosphorylation, inhibited caspase 3 cleavage and reduced apoptosis. The second part of this thesis focused on developing murine models of chronic and acute GvHD and to investigate the efficacy of xenogeneic MSC therapy in these models. In addition, a robust humanised model of aGvHD was developed to investigate mechanism of MSC protection. MSC therapy significantly increased survival of aGvHD mice and this protection correlated with significantly reduced TNF-α production and significantly increased numbers of regulatory T cells in aGvHD target organs. These findings further the understanding of the immune regulation capacity of MSC in vitro and provide a robust and clinically relevant model of aGvHD from which the mechanisms behind MSC modulation can be investigated

Disparities in the analysis of morphological disparity

Analyses of morphological disparity have been used to characterize and investigate the evolution of variation in the anatomy, function and ecology of organisms since the 1980s. While a diversity of methods have been employed, it is unclear whether they provide equivalent insights. Here, we review the most commonly used approaches for characterizing and analysing morphological disparity, all of which have associated limitations that, if ignored, can lead to misinterpretation. We propose best practice guidelines for disparity analyses, while noting that there can be no ‘one-size-fits-all’ approach. The available tools should always be used in the context of a specific biological question that will determine data and method selection at every stage of the analysis

Testing gravitational-wave searches with numerical relativity waveforms: Results from the first Numerical INJection Analysis (NINJA) project

The Numerical INJection Analysis (NINJA) project is a collaborative effort between members of the numerical relativity and gravitational-wave data analysis communities. The purpose of NINJA is to study the sensitivity of existing gravitational-wave search algorithms using numerically generated waveforms and to foster closer collaboration between the numerical relativity and data analysis communities. We describe the results of the first NINJA analysis which focused on gravitational waveforms from binary black hole coalescence. Ten numerical relativity groups contributed numerical data which were used to generate a set of gravitational-wave signals. These signals were injected into a simulated data set, designed to mimic the response of the Initial LIGO and Virgo gravitational-wave detectors. Nine groups analysed this data using search and parameter-estimation pipelines. Matched filter algorithms, un-modelled-burst searches and Bayesian parameter-estimation and model-selection algorithms were applied to the data. We report the efficiency of these search methods in detecting the numerical waveforms and measuring their parameters. We describe preliminary comparisons between the different search methods and suggest improvements for future NINJA analyses.Comment: 56 pages, 25 figures; various clarifications; accepted to CQ

Intestinal B cells license metabolic T-cell activation in NASH microbiota/antigen-independently and contribute to fibrosis by IgA-FcR signalling

BACKGROUND & AIMS: The progression of non-alcoholic steatohepatitis (NASH) to fibrosis and hepatocellular carcinoma (HCC) is aggravated by auto-aggressive T cells. The gut-liver axis contributes to NASH, but the mechanisms involved and the consequences for NASH-induced fibrosis and liver cancer remain unknown. We investigated the role of gastrointestinal B cells in the development of NASH, fibrosis and NASH-induced HCC. METHODS: C57BL/6J wild-type (WT), B cell-deficient and different immunoglobulin-deficient or transgenic mice were fed distinct NASH-inducing diets or standard chow for 6 or 12 months, whereafter NASH, fibrosis, and NASH-induced HCC were assessed and analysed. Specific pathogen-free/germ-free WT and μMT mice (containing B cells only in the gastrointestinal tract) were fed a choline-deficient high-fat diet, and treated with an anti-CD20 antibody, whereafter NASH and fibrosis were assessed. Tissue biopsy samples from patients with simple steatosis, NASH and cirrhosis were analysed to correlate the secretion of immunoglobulins to clinicopathological features. Flow cytometry, immunohistochemistry and single-cell RNA-sequencing analysis were performed in liver and gastrointestinal tissue to characterise immune cells in mice and humans. RESULTS: Activated intestinal B cells were increased in mouse and human NASH samples and licensed metabolic T-cell activation to induce NASH independently of antigen specificity and gut microbiota. Genetic or therapeutic depletion of systemic or gastrointestinal B cells prevented or reverted NASH and liver fibrosis. IgA secretion was necessary for fibrosis induction by activating CD11b+CCR2+F4/80+CD11c-FCGR1+ hepatic myeloid cells through an IgA-FcR signalling axis. Similarly, patients with NASH had increased numbers of activated intestinal B cells; additionally, we observed a positive correlation between IgA levels and activated FcRg+ hepatic myeloid cells, as well the extent of liver fibrosis. CONCLUSIONS: Intestinal B cells and the IgA-FcR signalling axis represent potential therapeutic targets for the treatment of NASH. IMPACT AND IMPLICATIONS: There is currently no effective treatment for non-alcoholic steatohepatitis (NASH), which is associated with a substantial healthcare burden and is a growing risk factor for hepatocellular carcinoma (HCC). We have previously shown that NASH is an auto-aggressive condition aggravated, amongst others, by T cells. Therefore, we hypothesized that B cells might have a role in disease induction and progression. Our present work highlights that B cells have a dual role in NASH pathogenesis, being implicated in the activation of auto-aggressive T cells and the development of fibrosis via activation of monocyte-derived macrophages by secreted immunoglobulins (e.g., IgA). Furthermore, we show that the absence of B cells prevented HCC development. B cell-intrinsic signalling pathways, secreted immunoglobulins, and interactions of B cells with other immune cells are potential targets for combinatorial NASH therapies against inflammation and fibrosis

Early Fasting Is Long Lasting: Differences in Early Nutritional Conditions Reappear under Stressful Conditions in Adult Female Zebra Finches

Conditions experienced during early life can have profound effects on individual development and condition in adulthood. Differences in nutritional provisioning in birds during the first month of life can lead to differences in growth, reproductive success and survival. Yet, under natural conditions shorter periods of nutritional stress will be more prevalent. Individuals may respond differently, depending on the period of development during which nutritional stress was experienced. Such differences may surface specifically when poor environmental conditions challenge individuals again as adults. Here, we investigated long term consequences of differences in nutritional conditions experienced during different periods of early development by female zebra finches (Taeniopygia guttata) on measures of management and acquisition of body reserves. As nestlings or fledglings, subjects were raised under different nutritional conditions, a low or high quality diet. After subjects reached sexual maturity, we measured their sensitivity to periods of food restriction, their exploration and foraging behaviour as well as adult resting metabolic rate (RMR). During a short period of food restriction, subjects from the poor nutritional conditions had a higher body mass loss than those raised under qualitatively superior nutritional conditions. Moreover, subjects that were raised under poor nutritional conditions were faster to engage in exploratory and foraging behaviour. But RMR did not differ among treatments. These results reveal that early nutritional conditions affect adult exploratory behaviour, a representative personality trait, foraging and adult's physiological condition. As early nutritional conditions are reflected in adult phenotypic plasticity specifically when stressful situations reappear, the results suggest that costs for poor developmental conditions are paid when environmental conditions deteriorate

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure