The epigenetic regulator RINF (CXXC5) maintains SMAD7 expression in human immature erythroid cells and sustains red blood cells expansion

The gene CXXC5, encoding a Retinoid-Inducible Nuclear Factor (RINF), is located within a region at 5q31.2 commonly deleted in myelodysplastic syndrome (MDS) and adult acute myeloid leukemia (AML). RINF may act as an epigenetic regulator and has been proposed as a tumor suppressor in hematopoietic malignancies. However, functional studies in normal hematopoiesis are lacking, and its mechanism of action is unknow. Here, we evaluated the consequences of RINF silencing on cytokineinduced erythroid differentiation of human primary CD34+ progenitors. We found that RINF is expressed in immature erythroid cells and that RINF-knockdown accelerated erythropoietin-driven maturation, leading to a significant reduction (~45%) in the number of red blood cells (RBCs), without affecting cell viability. The phenotype induced by RINF-silencing was TGFβ-dependent and mediated by SMAD7, a TGFβ- signaling inhibitor. RINF upregulates SMAD7 expression by direct binding to its promoter and we found a close correlation between RINF and SMAD7 mRNA levels both in CD34+ cells isolated from bone marrow of healthy donors and MDS patients with del(5q). Importantly, RINF knockdown attenuated SMAD7 expression in primary cells and ectopic SMAD7 expression was sufficient to prevent the RINF knockdowndependent erythroid phenotype. Finally, RINF silencing affects 5’-hydroxymethylation of human erythroblasts, in agreement with its recently described role as a Tet2- anchoring platform in mouse. Altogether, our data bring insight into how the epigenetic factor RINF, as a transcriptional regulator of SMAD7, may fine-tune cell sensitivity to TGFβ superfamily cytokines and thus play an important role in both normal and pathological erythropoiesis

Soluble markers of B cell activation suggest a role of B cells in the pathogenesis of systemic sclerosis-associated pulmonary arterial hypertension

IntroductionSoluble markers of B cell activation are interesting diagnostic and prognostic tools in autoimmune diseases. Data in systemic sclerosis (SSc) are scarce and few studies focused on their association with disease characteristics.Methods1. Serum levels of 14 B cell biomarkers (β2-microglobulin, rheumatoid factor (RF), immunoglobulins (Ig) G, IgA, IgM, BAFF, APRIL, soluble (s)TACI, sBCMA sCD21, sCD23, sCD25, sCD27, CXCL13) were measured in SSc patients and healthy controls (HC). 2. Associations between these biomarkers and SSc characteristics were assessed. 3. The pathophysiological relevance of identified associations was explored by studying protein production in B cell culture supernatant.ResultsIn a discovery panel of 80 SSc patients encompassing the broad spectrum of disease manifestations, we observed a higher frequency of RF positivity, and increased levels of β2-microglobulin, IgG and CXCL13 compared with HC. We found significant associations between several biomarkers and SSc characteristics related to disease phenotype, activity and severity. Especially, serum IgG levels were associated with pulmonary hypertension (PH); β2-microglobulin with Nt-pro-BNP and DLCO; and BAFF with peak tricuspid regurgitation velocity (TRV). In a validation cohort of limited cutaneous SSc patients without extensive ILD, we observed lower serum IgG levels, and higher β2-microglobulin, sBCMA, sCD23 and sCD27 levels in patients with pulmonary arterial hypertension (PAH). BAFF levels strongly correlated with Nt-pro-BNP levels, FVC/DLCO ratio and peak TRV in SSc-PAH patients. Cultured SSc B cells showed increased production of various angiogenic factors (angiogenin, angiopoietin-1, VEGFR-1, PDGF-AA, MMP-8, TIMP-1, L-selectin) and decreased production of angiopoietin-2 compared to HC.ConclusionSoluble markers of B cell activation could be relevant tools to assess organ involvements, activity and severity in SSc. Their associations with PAH could plead for a role of B cell activation in the pathogenesis of pulmonary microangiopathy. B cells may contribute to SSc vasculopathy through production of angiogenic mediators

Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy

AbstractDevelopmental epileptic encephalopathies are devastating disorders characterized by intractable epileptic seizures and developmental delay. Here, we report an allelic series of germline recessive mutations in UGDH in 36 cases from 25 families presenting with epileptic encephalopathy with developmental delay and hypotonia. UGDH encodes an oxidoreductase that converts UDP-glucose to UDP-glucuronic acid, a key component of specific proteoglycans and glycolipids. Consistent with being loss-of-function alleles, we show using patients’ primary fibroblasts and biochemical assays, that these mutations either impair UGDH stability, oligomerization, or enzymatic activity. In vitro, patient-derived cerebral organoids are smaller with a reduced number of proliferating neuronal progenitors while mutant ugdh zebrafish do not phenocopy the human disease. Our study defines UGDH as a key player for the production of extracellular matrix components that are essential for human brain development. Based on the incidence of variants observed, UGDH mutations are likely to be a frequent cause of recessive epileptic encephalopathy.</jats:p

No detection of methane on Mars from early ExoMars Trace Gas Orbiter observations

The detection of methane on Mars has been interpreted as indicating that geochemical or biotic activities could persist on Mars today. A number of different measurements of methane show evidence of transient, locally elevated methane concentrations and seasonal variations in background methane concentrations. These measurements, however, are difficult to reconcile with our current understanding of the chemistry and physics of the Martian atmosphere, which-given methane's lifetime of several centuries-predicts an even, well mixed distribution of methane. Here we report highly sensitive measurements of the atmosphere of Mars in an attempt to detect methane, using the ACS and NOMAD instruments onboard the ESA-Roscosmos ExoMars Trace Gas Orbiter from April to August 2018. We did not detect any methane over a range of latitudes in both hemispheres, obtaining an upper limit for methane of about 0.05 parts per billion by volume, which is 10 to 100 times lower than previously reported positive detections. We suggest that reconciliation between the present findings and the background methane concentrations found in the Gale crater would require an unknown process that can rapidly remove or sequester methane from the lower atmosphere before it spreads globally

Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy

Developmental epileptic encephalopathies are devastating disorders characterized by intractable epileptic seizures and developmental delay. Here, we report an allelic series of germline recessive mutations in UGDH in 36 cases from 25 families presenting with epileptic encephalopathy with developmental delay and hypotonia. UGDH encodes an oxidoreductase that converts UDP-glucose to UDP-glucuronic acid, a key component of specific proteoglycans and glycolipids. Consistent with being loss-of-function alleles, we show using patients’ primary fibroblasts and biochemical assays, that these mutations either impair UGDH stability, oligomerization, or enzymatic activity. In vitro, patient-derived cerebral organoids are smaller with a reduced number of proliferating neuronal progenitors while mutant ugdh zebrafish do not phenocopy the human disease. Our study defines UGDH as a key player for the production of extracellular matrix components that are essential for human brain development. Based on the incidence of variants observed, UGDH mutations are likely to be a frequent cause of recessive epileptic encephalopathy

Martian dust storm impact on atmospheric H₂O and D/H observed by ExoMars Trace Gas Orbiter

Global dust storms on Mars are rare but can affect the Martian atmosphere for several months. They can cause changes in atmospheric dynamics and inflation of the atmosphere, primarily owing to solar heating of the dust. In turn, changes in atmospheric dynamics can affect the distribution of atmospheric water vapour, with potential implications for the atmospheric photochemistry and climate on Mars. Recent observations of the water vapour abundance in the Martian atmosphere during dust storm conditions revealed a high-altitude increase in atmospheric water vapour that was more pronounced at high northern latitudes, as well as a decrease in the water column at low latitudes. Here we present concurrent, high-resolution measurements of dust, water and semiheavy water (HDO) at the onset of a global dust storm, obtained by the NOMAD and ACS instruments onboard the ExoMars Trace Gas Orbiter. We report the vertical distribution of the HDO/H O ratio (D/H) from the planetary boundary layer up to an altitude of 80 kilometres. Our findings suggest that before the onset of the dust storm, HDO abundances were reduced to levels below detectability at altitudes above 40 kilometres. This decrease in HDO coincided with the presence of water-ice clouds. During the storm, an increase in the abundance of H2O and HDO was observed at altitudes between 40 and 80 kilometres. We propose that these increased abundances may be the result of warmer temperatures during the dust storm causing stronger atmospheric circulation and preventing ice cloud formation, which may confine water vapour to lower altitudes through gravitational fall and subsequent sublimation of ice crystals. The observed changes in H2O and HDO abundance occurred within a few days during the development of the dust storm, suggesting a fast impact of dust storms on the Martian atmosphere

Small cryptic fishes on coral reefs: ecological effects of extreme life history traits

On Indo-Pacific coral reefs, small cryptic fishes are extremely diverse, and represent approximately 50 % of individuals in reef fish assemblages. Yet, many of these species have been little studied, particularly in the Indo-Pacific, and the influence of their often extreme life history traits on population dynamics and the broader implications for the composition and resilience of coral reef fish assemblages as a whole, remain unclear. While past research has shown that many of these small species have short and challenging generation times of 47–74 days, we are yet to determine how small cryptic fishes overcome these extreme life history characteristics to successfully persist on coral reefs. The overall goal of this thesis is, therefore, to provide a better understanding of the demographics of short-lived taxa on the Great Barrier Reef (GBR), Australia. More specifically, the present study considers the consequences of extreme life history characteristics, and especially short lifespans, with respect to their ability to recolonise after disturbance, and maintain populations throughout the year. The findings are then discussed in relation to the potential importance of these short-lived species for coral reef trophodynamics.\ud \ud An understanding of the responses of fish assemblages to disturbance events is central to the on-going management of coral reefs habitats. Recovery of fish communities can occur by movement of fishes or recruitment processes. However, small cryptobenthic fishes have extremely limited post-settlement mobility, with home ranges often less than 2 m² and their responses to habitat disturbance has been seldom investigated. In order to understand the patterns of recovery of short-lived taxa, and in particular, to assess their ability to recover after a disturbance, the recolonisation of populations of small cryptic fishes was examined following experimental removal. After removing resident cryptobenthic reef fish assemblages from otherwise undisturbed coral rubble areas, a rapid recovery was observed. Within 8 weeks fish assemblages were similar to their pre-removal structure in terms of fish abundance, species diversity and species richness. However, species differed in the speed and nature of their return. The return of larger species (e.g. Parapercis cylindrica) was largely mediated by recolonisation through movement of adults, while smaller, less mobile, species (e.g. Eviota spp. and Enneapterygius spp.) relied primarily on recruitment from the plankton. Although patterns of settlement and recruitment are ultimately responsible for the replenishment of local populations, this study suggests that mobility may play a strong role in restoring fish assemblages in the short-term.\ud \ud The majority of coral reef goby species are short-lived, with a large proportion of small taxa, such as Eviota, living less than 100 days. Despite these exceptionally short lifespans presenting the demographic challenges of very little time to mature and reproduce, these sub-annual taxa persist and are highly abundant on reefs. To understand the role and consequences of extreme life history in shaping coral reef fish populations, the structure of small reef fish populations was quantitatively documented over a 26 month study period (> 14 short-lived fish generations). Fish density varied over time, but species richness did not change significantly. These patterns were driven by the differential trends in density shown among species within the fish community. Most species with lifespans > 1 year, such as pomacentrids, exhibited a peak in recruitment during the Austral summer. In contrast, despite exceptionally short lifespans, species of Eviota showed consistent densities of both adults and newly settled recruits over the 26 months. These different temporal patterns among taxa drove changes in the overall fish community composition among seasons but there were few apparent differences in the composition of the Eviota populations over time. These results provide evidence of on-going recruitment of these small cryptic fishes, which appears to compensate for an exceptionally short life span on the reef. This study suggests that gobiid populations are able to overcome demographic limitations, and by maintaining reproduction, larval survival and recruitment throughout the year, they may avoid population bottlenecks. These findings also underline the potential trophodynamic importance of these small species; because of extremely high turn-over, and year-round recruitment, Eviota species and other short-lived fishes may be particularly valuable contributors to the flow of energy on coral reefs, underpinning the year-round trophic structure.\ud \ud In examining previously unstudied aspects of the demography of small cryptic fishes on the GBR, this thesis presents evidence of a rapid recruitment of small cryptic fishes to reefs after a disturbance event. Furthermore, this thesis highlights temporal stability (over 26 months) in the size structure of short-lived taxa, specifically for the gobiid genus Eviota. These findings have significant implications for the proposal that small cryptic fishes play an important, yet often forgotten, role in coral reef energetics. Sub-annual taxa provide a constant food resource and supply of reproductive energy to coral reefs trophodynamics throughout the year via predatory pathways. Although not as conspicuous as other coral reef fishes, the unique life-history of short-lived fishes and their proposed important contribution to coral reef trophodynamics suggests these taxa warrant further studies. Two important future research directions are: teasing apart the relative effects of larval supply and post-settlement mortality on abundance of recruits, and assessing the generality of these results for other short-lived taxa. Coral reef ecosystems operate over a broad range of temporal and spatial scales. The exceptional life history features and resulting population dynamics of short-lived species form an integral part of the diversity and dynamics of reef systems and thus are an important research focus

Temporal variation in coral reef ecosystem processes: herbivory of macroalgae by fishes

Despite the widely accepted importance of fish herbivory on coral reefs, few studies have considered the temporal variability in the nature of algal–herbivore interactions. We therefore quantified monthly feeding intensity on Sargassum sp. bioassays for 12 mo with remote underwater video cameras deployed to identify the herbivores responsible for macroalgal removal on an inshore island of the Great Barrier Reef, Australia. Significantly higher removal rates were observed during the summer months whereas winter months were characterized by 4 times lower removal rates. However, rather than being simply changes in the feeding activity of a single species, this temporal pattern in herbivory also incorporated changes in the species responsible for the removal of Sargassum. Video analyses revealed that, of the 43 herbivore species recorded from the bay, only 3 played a significant role in Sargassum removal: Kyphosus vaigiensis, Naso unicornis and Scarus rivulatus. K. vaigiensis, a rudderfish, was primarily responsible for the removal of Sargassum during the summer months (83% of the total recorded bites; 85553 bites). There was almost no feeding activity on Sargassum by K. vaigiensis during the winter months (82 bites). However, there was a reciprocal increase in feeding intensity on Sargassum by parrotfishes in the winter months, particularly S. rivulatus (71 bites during summer versus 2884 bites in winter). This temporal variability in herbivore functional roles suggests that functional redundancy on reefs may be less than previously assumed in that the feeding activities of fishes may be both spatially and temporally constrained