Crystal-Induced Inflammation: Studies of the Mechanism of Crystal-Membrane Interactions

Studies of the interactions of monosodium urate monohydrate (MSUM) crystals and calcium Pyrophosphate dihydrate triclinic (CPPD) crystals with biomembranes have been reviewed. Crystalmembrane binding and crystal-induced membranolysis have been studied using human erythrocytes as a model membrane system. The extent of MSUM-membrane binding was determined by incorporating a hydrophobic, fluorescent probe into the membranes, centrifugation to separate free membranes from membranes with bound crystals and quantitation of free membranes by measuring the total fluorescence intensity. The ability of MSUM and CPPD to hemolyse red cells was used as a measure of the membranolytic potential of the crystals. Fluorescence polarization studies showed that MSUM-membrane binding resulted in fluidization of the membrane. Cross-linking of the membrane proteins of the erythrocyte or the presence of divalent cations in the incubation medium inhibited MSUM induced hemolysis. These findings were explained by hypothesizing a pore model mechanism for MSUM induced membranolysis as follows. Binding of crystals to membranes induces the redistribution of transmembrane proteins into clusters or aggregates leading to pore formation. The pores permit the leakage of low molecular weight soluble compounds and ions across the membrane which is followed by osmotic rupture of the membran

Coral reef potential connectivity in the southwest Indian Ocean

The tropical southwest Indian Ocean is a coral biodiversity hotspot, with remote reefs physically connected by larval dispersal through eddies and a complex set of equatorial and boundary currents. Based on multidecadal, 2 km resolution hydrodynamic and larval dispersal models that incorporate temporal variability in dispersal, we find that powerful zonal currents, current bifurcations, and geographic isolation act as leaky dispersal barriers, partitioning the southwest Indian Ocean into clusters of reefs that tend to consistently retain larvae, and therefore gene flow, over many generations. Whilst exceptionally remote, the Chagos Archipelago can broadcast (and receive) considerable numbers of larvae to (and from) reefs across the wider southwest Indian Ocean, most significantly exchanging larvae with the Inner Islands of Seychelles, but also the Mozambique Channel region. Considering multi-generational dispersal indicates that most coral populations in the southwest Indian Ocean are physically connected within a few hundred steps of dispersal. These results suggest that regional biogeography and population structure can be largely attributed to geologically recent patterns of larval dispersal, although some notable discrepancies indicate that palaeogeography and environmental suitability also play an important role. The model output and connectivity matrices are available in full and will provide useful physical context to regional biogeography and connectivity studies, as well as supporting marine spatial planning efforts

Sources of marine debris for Seychelles and other remote islands in the western Indian Ocean

Vast quantities of debris are beaching at remote islands in the western Indian Ocean. We carry out marine dispersal simulations incorporating currents, waves, winds, beaching, and sinking, for both terrestrial and marine sources of debris, to predict where this debris comes from. Our results show that most terrestrial debris beaching at these remote western Indian Ocean islands drifts from Indonesia, India, and Sri Lanka. Debris associated with fisheries and shipping also poses a major risk. Debris accumulation at Seychelles is likely seasonal, peaking during February–April. This pattern is driven by monsoonal winds and may be amplified during positive Indian Ocean Dipole and El-Niño events. Our results underline the vulnerability of small island states to marine plastic pollution, and are a crucial step towards improved management of the issue. The trajectories used in this study are available for download, and our analyses can be rerun under different parameter choices.journal articl

Integration of population genetics with oceanographic models reveals strong connectivity among coral reefs across Seychelles

Many countries with tropical reef systems face hard choices preserving coral reefs in the face of climate change on limited budgets. One approach to maximising regional reef resilience is targeting management efforts and resources at reefs that export large numbers of larvae to other reefs. However, this requires reef connectivity to be quantified. To map coral connectivity in the Seychelles reef system we carried out a population genomic study of the Porites lutea species complex using 241 sequenced colonies from multiple islands. To identify oceanographic drivers of this connectivity and quantify variability, we further used a 2 km resolution regional ocean simulation coupled with a larval dispersal model to predict the flow of coral larvae between reef sites. Patterns of admixture and gene flow are broadly supported by model predictions, but the realised connectivity is greater than that predicted from model simulations. Both methods detected a biogeographic dispersal barrier between the Inner and Outer Islands of Seychelles. However, this barrier is permeable and substantial larval transport is possible across Seychelles, particularly for one of two putative species found in our genomic study. The broad agreement between predicted connectivity and observed genetic patterns supports the use of such larval dispersal simulations in reef system management in Seychelles and the wider region

A PDCD1 Role in the Genetic Predisposition to NAFLD-HCC?

Obesity and non-alcoholic fatty liver disease (NAFLD) are contributing to the global rise in deaths from hepatocellular carcinoma (HCC). The pathogenesis of NAFLD-HCC is not well understood. The severity of hepatic steatosis, steatohepatitis and fibrosis are key pathogenic mechanisms, but animal studies suggest altered immune responses are also involved. Genetic studies have so far highlighted a major role of gene variants promoting fat deposition in the liver (PNPLA3 rs738409; TM6SF2 rs58542926). Here, we have considered single-nucleotide polymorphisms (SNPs) in candidate immunoregulatory genes (MICA rs2596542; CD44 rs187115; PDCD1 rs7421861 and rs10204525), in 594 patients with NAFLD and 391 with NAFLD-HCC, from three European centres. Associations between age, body mass index, diabetes, cirrhosis and SNPs with HCC development were explored. PNPLA3 and TM6SF2 SNPs were associated with both progression to cirrhosis and NAFLD-HCC development, while PDCD1 SNPs were specifically associated with NAFLD-HCC risk, regardless of cirrhosis. PDCD1 rs7421861 was independently associated with NAFLD-HCC development, while PDCD1 rs10204525 acquired significance after adjusting for other risks, being most notable in the smaller numbers of women with NAFLD-HCC. The study highlights the potential impact of inter individual variation in immune tolerance induction in patients with NAFLD, both in the presence and absence of cirrhosis

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Genome-wide association study of non-alcoholic fatty liver and steatohepatitis in a histologically-characterised cohort

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A PDCD1 Role in the Genetic Predisposition to NAFLD-HCC?

Obesity and non-alcoholic fatty liver disease (NAFLD) are contributing to the global rise in deaths from hepatocellular carcinoma (HCC). The pathogenesis of NAFLD-HCC is not well understood. The severity of hepatic steatosis, steatohepatitis and fibrosis are key pathogenic mechanisms, but animal studies suggest altered immune responses are also involved. Genetic studies have so far highlighted a major role of gene variants promoting fat deposition in the liver (PNPLA3 rs738409; TM6SF2 rs58542926). Here, we have considered single-nucleotide polymorphisms (SNPs) in candidate immunoregulatory genes (MICA rs2596542; CD44 rs187115; PDCD1 rs7421861 and rs10204525), in 594 patients with NAFLD and 391 with NAFLD-HCC, from three European centres. Associations between age, body mass index, diabetes, cirrhosis and SNPs with HCC development were explored. PNPLA3 and TM6SF2 SNPs were associated with both progression to cirrhosis and NAFLD-HCC development, while PDCD1 SNPs were specifically associated with NAFLD-HCC risk, regardless of cirrhosis. PDCD1 rs7421861 was independently associated with NAFLD-HCC development, while PDCD1 rs10204525 acquired significance after adjusting for other risks, being most notable in the smaller numbers of women with NAFLD-HCC. The study highlights the potential impact of inter individual variation in immune tolerance induction in patients with NAFLD, both in the presence and absence of cirrhosis