NLRP3 inflamasome activation and mitochondrial ros production in platelets of SS and SC patients

International audienc

NLRP3 inflamasome activation and mitochondrial ros production in platelets of SS and SC patients

International audienc

NLRP3 inflamasome activation and mitochondrial ros production in platelets of SS and SC patients

International audienc

A new heterozygous mutation in GP1BA gene responsible for macrothrombocytopenia

International audienc

Tropical deforestation drivers and associated carbon emission factors derived from remote sensing data

Reducing emissions from deforestation and forest degradation, and enhancing carbon stocks (REDD+) is a crucial component of global climate change mitigation. Systematically measuring, reporting and verifying forest carbon emissions and removals is essential. Remote sensing combined with field measurements can provide continuous and spatially explicit aboveground biomass (AGB) estimates, which can be valuable for the analysis and quantification of carbon stocks and emission factors (EFs). Unfortunately, there is little information on the fate of the land following tropical deforestation and of the associated carbon stock. This study assessed carbon EFs in a spatially explicit manner across the tropics by capitalising on newly available remote sensing data on land use following deforestation, AGB density and tree cover with high spatial resolutions. In Latin America, pasture was the most common post-deforestation land use (72%), with large-scale cropland (11%) a distant second. In Africa deforestation was often followed by small-scale cropping (61%) with a smaller role for pasture (15%). In Asia, small-scale cropland was the dominant agricultural follow-up land use (35%), closely followed by tree crops (28%). EFs showed high spatial variation within eco-zones and countries. Eco-zone averaged forest carbon stocks often did not accurately represent carbon stocks of the specific forests that have undergone change. EFs for specific land use conversions were mostly dependent on the location of the land use conversion in combination with initial forest biomass. The estimates of the fraction of carbon lost were more robust, which might offer some shortcuts for REDD+ countries in generating local EFs from forest inventory data or good quality biomass maps. Our approach yields considerable progress towards better quantification of carbon fluxes from deforestation, and gives added insight into their link to human activities.JRC.D.1-Bio-econom

Tropical deforestation drivers and associated carbon emission factors derived from remote sensing data

Reducing emissions from deforestation and forest degradation, and enhancing carbon stocks (REDD+) is a crucial component of global climate change mitigation. Remote sensing can provide continuous and spatially explicit above-ground biomass (AGB) estimates, which can be valuable for the quantification of carbon stocks and emission factors (EFs). Unfortunately, there is little information on the fate of the land following tropical deforestation and of the associated carbon stock. This study quantified post-deforestation land use across the tropics for the period 1990 – 2000. This dataset was then combined with a pan-tropical AGB map at 30 m resolution to refine EFs from forest conversion by matching deforestation areas with their carbon stock before and after clearing and to assess spatial dynamics of EFs by follow-up land use. In Latin America, pasture was the most common follow-up land use (72%), with large-scale cropland (11%) a distant second. In Africa deforestation was often followed by small-scale cropping (61%) with a smaller role for pasture (15%). In Asia, small-scale cropland was the dominant agricultural follow-up land use (35%), closely followed by tree crops (28%). Deforestation often occurred in forests with lower than average carbon stocks. EFs showed high spatial variation within eco-zones and countries. While our EFs are only representative for the studied time period, our results show that EFs are mainly determined by the initial forest carbon stock. The estimates of the fraction of carbon lost were less dependent on initial forest biomass, which offers opportunities for REDD+ countries to use these fractions in combination with recent good quality national forest biomass maps or inventory data to quantify emissions from specific forest conversions. Our study highlights that the co-location of data on forest loss, biomass and fate of the land provides more insight into the spatial dynamics of land-use change and can help in attributing carbon emissions to human activities.<br/

Haematological spectrum and genotype-phenotype correlations in nine unrelated families with RUNX1 mutations from the French network on inherited platelet disorders.

International audienceLess than 50 patients with FPD/AML (OMIM 601309) have been reported as of today and there may an underestimation. The purpose of this study was to describe the natural history, the haematological features and the genotype-phenotype correlations of this entity in order to, first, screen it better and earlier, before leukaemia occurrence and secondly to optimize appropriate monitoring and treatment, in particular when familial stem cell transplantation is considered.We have investigated 41 carriers of RUNX1 alteration belonging to nine unrelated French families with FPD/AML and two syndromic patients, registered in the French network on rare platelet disorders from 2005 to 2015.Five missense, one non-sense, three frameshift mutations and two large deletions involving several genes including RUNX1 were evidenced. The history of familial leukaemia was suggestive of FPD/AML in seven pedigrees, whereas an autosomal dominant pattern of lifelong thrombocytopenia was the clinical presentation of two. Additional syndromic features characterized two large sporadic deletions. Bleeding tendency was mild and thrombocytopenia moderate (>50 x10(9)/L), with normal platelet volume. A functional platelet defect consistent with a δ-granule release defect was found in ten patients regardless of the type of RUNX1 alteration. The incidence of haematological malignancies was higher when the mutated RUNX1 allele was likely to cause a dominant negative effect (19/34) in comparison with loss of function alleles (3/9). A normal platelet count does not rule out the diagnosis of FPD/AML, since the platelet count was found normal for three mutated subjects, a feature that has a direct impact in the search for a related donor in case of allogeneic haematopoietic stem cell transplantation.Platelet dysfunction suggestive of defective δ-granule release could be of values for the diagnosis of FPD/AML particularly when the clinical presentation is an autosomal dominant thrombocytopenia with normal platelet size in the absence of familial malignancies. The genotype-phenotype correlations might be helpful in genetic counselling and appropriate optimal therapeutic management

Germline variants in ETV6 underlie reduced platelet formation, platelet dysfunction and increased levels of circulating CD34+ progenitors

Variants in ETV6, which encodes a transcription repressor of the E26 transformation-specific family, have recently been reported to be responsible for inherited thrombocytopenia and hematologic malignancy. We sequenced the DNA from cases with unexplained dominant thrombocytopenia and identified six likely pathogenic variants in ETV6, of which five are novel. We observed low repressive activity of all tested ETV6 variants and variants located in the E26 transformation-specific binding domain (encoding p.A377T, p.Y401N) led to reduced binding to co-repressors. We also observed large expansion of CFU-MKs derived from variant carriers and reduced proplatelet formation with abnormal cytoskeletal organization. The defect in proplatelet formation was also observed in control CD34+ cell-derived megakaryocytes transduced with lentiviral particles encoding mutant ETV6. Reduced expression levels of key regulators of the actin cytoskeleton Cdc42 and RhoA were measured. Moreover, changes in the actin structures are typically accompanied by a rounder platelet shape with a highly heterogeneous size, decreased platelet arachidonic response, spreading and retarded clot retraction in ETV6 deficient platelets. Elevated numbers of circulating CD34+ cells were found in p.P214L and p.Y401N carriers, and two patients from different families suffered from refractory anemia with excess blasts while one patient from a third family was successfully treated for acute myeloid leukemia. Overall, our study provides novel insights into the role of ETV6 as a driver of cytoskeletal regulatory gene expression during platelet production and the impact of variants resulting in platelets with altered size, shape and function and potentially also in changes in circulating progenitor levels.status: publishe

Germline variants in ETV6 underlie reduced platelet formation, platelet dysfunction and increased levels of circulating CD34+ progenitors.

International audienceVariants in ETV6, which encodes a transcription repressor of the E26 transformation-specific family, have recently been reported to be responsible for inherited thrombocytopenia and hematologic malignancy. We sequenced the DNA from cases with unexplained dominant thrombocytopenia and identified six likely pathogenic variants in ETV6, of which five are novel. We observed low repressive activity of all tested ETV6 variants, and variants located in the E26 transformation-specific binding domain (encoding p.A377T, p.Y401N) led to reduced binding to corepressors. We also observed a large expansion of megakaryocyte colony-forming units derived from variant carriers and reduced proplatelet formation with abnormal cytoskeletal organization. The defect in proplatelet formation was also observed in control CD34(+) cell-derived megakaryocytes transduced with lentiviral particles encoding mutant ETV6. Reduced expression levels of key regulators of the actin cytoskeleton CDC42 and RHOA were measured. Moreover, changes in the actin structures are typically accompanied by a rounder platelet shape with a highly heterogeneous size, decreased platelet arachidonic response, and spreading and retarded clot retraction in ETV6 deficient platelets. Elevated numbers of circulating CD34(+) cells were found in p.P214L and p.Y401N carriers, and two patients from different families suffered from refractory anemia with excess blasts, while one patient from a third family was successfully treated for acute myeloid leukemia. Overall, our study provides novel insights into the role of ETV6 as a driver of cytoskeletal regulatory gene expression during platelet production, and the impact of variants resulting in platelets with altered size, shape and function and potentially also in changes in circulating progenitor levels