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Masterson, C.

Publications and source records attributed to Masterson, C..

2 recordsLinked to original sources

Evolutionary dynamics of the tgr gene family in Dictyostelium allows escape from Crozier's Paradox

Croziers Paradox states that genetic kin recognition will select for its own demise, and theoretical analyses over the past decades have supported this conclusion. Here we examine the molecular evolution of two kin recognition genes in the social amoeba Dictyostelium discoideum, tgrB1 and tgrC1, which enable cells to recognize and reject unrelated cells during cooperative multicellular development. Our results reveal extraordinary polymorphism in these genes, placing them amongst the most rapidly evolving genes in the genome. Co-occurring amoebae, isolated from just a few grams of soil, show highly diverged recognition alleles, indicating plentiful sequence variation that can impact social decision-making on a micro-scale. Analyses of closely related gene duplicates show dynamic evolution of the gene family as a whole, suggesting a mechanism for replenishing genetic variation lost through Croziers Paradox. Our results provide evidence that kin recognition loci can retain sufficient genetic variation in real-world settings and suggest that large gene families may be crucial to retaining genetic variation necessary to evade Croziers paradox.

evolutionary biology↗

The PPARβ/δ-induced mesenchymal stromal cell secretome has cytoprotective effects via ANGPTL4 in a pre-clinical model of acute lung inflammation

RationaleHuman bone marrow-derived mesenchymal stromal cells (hBM-MSCs) are known to exert immunomodulatory and pro-reparative effects in vivo. This makes hBM-MSCs an enticing therapeutic candidate for inflammatory diseases, such as acute respiratory distress syndrome (ARDS). The ARDS microenvironment is complex and contains an abundance of free fatty acids (FFAs); which are known to differentially impact MSC functionality. PPAR{beta}/{delta} is a ubiquitously expressed nuclear receptor that is activated in response to FFA-binding. PPAR{beta}/{delta} has been shown to impact the therapeutic efficacy of mouse MSCs. ObjectiveThis study sought to investigate the impact of PPAR{beta}/{delta}-modulation on human MSC functionality in vitro and in vivo. MethodshBM-MSCs were exposed to a synthetic PPAR{beta}/{delta} agonist/antagonist in the presence or absence of ARDS patient serum and the immunomodulatory and pro-reparative capacity of the MSC secretome was investigated using in vitro assays and a pre-clinical model of LPS-induced acute lung inflammation (ALI). ResultsOur results highlighted enhanced pro-reparative capacity of PPAR{beta}/{delta}-agonised hBM-MSCs secretome in CALU-3 lung epithelial cells, mediated by MSC derived angiopoietin-like 4 (ANGPTL4). PPAR{beta}/{delta}-induced ANGPTL4-high MSC secretome facilitated enhanced endothelial barrier integrity in the lungs of ALI mice. Therapeutic effects of PPAR{beta}/{delta}-agonised hBM-MSCs secretome were further enhanced by licensing MSCs with human ARDS patient serum. ARDS-licensed PPAR{beta}/{delta}-induced ANGPTL4-high MSC secretome had reduced clinical score and weight loss. The role ANGPL4 in these protective effects was confirmed using an anti-ANGPTL4 antibody. ConclusionThese findings conclude that the MSC secretome therapeutic effects can be enhanced both in vitro and in vivo through licensing strategies that upregulate the angiogenic factor ANGPTL4. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=145 SRC="FIGDIR/small/667170v2_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@a03b3dorg.highwire.dtl.DTLVardef@1915253org.highwire.dtl.DTLVardef@1b3fd4aorg.highwire.dtl.DTLVardef@1ba27ff_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗