Biosynthesis of gold nanoparticles by the living freshwater diatom Eolimna minima, a species developed in river biofilms.

Testing biotransformation capacities of living aquatic microalgae diatoms to naturally synthetize gold nanoparticles (AuNP) from gold salts and assessing aftereffects on their viability by microscope observations is a great challenge. In this work, a laboratory experiment was conducted, which aimed to observe (i) directly by transmission electronic and light microscopy and (ii) through indirect measurements (UV-visible spectroscopy) the periphytic freshwater diatom Eolimna minima exposed to gold salts. This work revealed the capacity of E. minima to intracellularly biosynthetize AuNP and to tolerate it. AuNP synthesis appears as a mechanism of detoxification to protect diatom from gold salt contamination. We also pointed out the risks associated with the spread of diatoms full of AuNP, through the trophic web of freshwater ecosystems. The preponderant part of the diatoms in natural biofilms associated with their position at the basis of the trophic webs in rivers could then make them responsible for the contamination of their consumers (grazer animals) and consequently for the potential release of AuNP through the entire food web.Approches à différentes échelles pour caractériser les interactions cellulaires, le transfert trophique et les impacts toxiques de nanoparticules métalliques chez les organismes aquatique

Sonic Hedgehog Is a Remotely Produced Cue that Controls Axon Guidance Trans-axonally at a Midline Choice Point

At the optic chiasm choice point, ipsilateral retinal ganglion cells (RGCs) are repelled away from the midline by guidance cues, including Ephrin-B2 and Sonic Hedgehog (Shh). Although guidance cues are normally produced by cells residing at the choice point, the mRNA for Shh is not found at the optic chiasm. Here we show that Shh protein is instead produced by contralateral RGCs at the retina, transported anterogradely along the axon, and accumulates at the optic chiasm to repel ipsilateral RGCs. In vitro, contralateral RGC axons, which secrete Shh, repel ipsilateral RGCs in a Boc- and Smo-dependent manner. Finally, knockdown of Shh in the contralateral retina causes a decrease in the proportion of ipsilateral RGCs in a non-cell-autonomous manner. These findings reveal a role for axon-axon interactions in ipsilateral RGC guidance, and they establish that remotely produced cues can act at axon guidance midline choice points

Generation of a heterozygous SCN5A knockout human induced pluripotent stem cell line by CRISPR/Cas9 edition

International audienceMutations leading to haploinsufficiency in SCN5A, the gene encoding the cardiac sodium channel Na v 1.5 α-subunit, are involved in life-threatening cardiac disorders. Using CRISPR/Cas9-mediated genome edition, we generated here a human induced-pluripotent stem cell (hiPSC) line carrying a heterozygous mutation in exon 2 of SCN5A, which leads to apparition of a premature stop codon. SCN5A-clone 5 line maintained normal karyotype, morphology and pluripotency and differentiated into three germ layers. Cardiomyocytes derived from these hiPSCs would be a useful model for investigating channelopathies related to SCN5A heterozygous deficiency

Genome wide association analysis in dilated cardiomyopathy reveals two new key players in systolic heart failure on chromosomes 3p25.1 and 22q11.23

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Application of a multidisciplinary and integrative weight-of-evidence approach to a 1-year monitoring survey of the Seine River

International audienceQuality assessment of environments under high anthropogenic pressures such as the Seine Basin, subjected to complex and chronic inputs, can only be based on combined chemical and biological analyses. The present study integrates and summarizes a multidisciplinary dataset acquired throughout a 1-year monitoring survey conducted at three workshop sites along the Seine River (PIREN-Seine program), upstream and downstream of the Paris conurbation, during four seasonal campaigns using a weight-of-evidence approach. Sediment and water column chemical analyses, bioaccumulation levels and biomarker responses in caged gammarids, and laboratory (eco)toxicity bioassays were integrated into four lines of evidence (LOEs). Results from each LOE clearly reflected an anthropogenic gradient, with contamination levels and biological effects increasing from upstream to downstream of Paris, in good agreement with the variations in the structure and composition of bacterial communities from the water column. Based on annual average data, the global hazard was summarized as “moderate” at the upstream station and as “major” at the two downstream ones. Seasonal variability was also highlighted; the winter campaign was least impacted. The model was notably improved using previously established reference and threshold values from national-scale studies. It undoubtedly represents a powerful practical tool to facilitate the decision-making processes of environment managers within the framework of an environmental risk assessment strategy

A genome-wide association study identifies two loci associated with heart failure due to dilated cardiomyopathy

Aims: Dilated cardiomyopathy (DCM) is a major cause of heart failure with a high familial recurrence risk. So far, the genetics of DCM remains largely unresolved. We conducted the first genome-wide association study (GWAS) to identify loci contributing to sporadic DCM. Methods and results: One thousand one hundred and seventy-nine DCM patients and 1108 controls contributed to the discovery phase. Pools of DNA stratified on disease status, population, age, and gender were constituted and used for testing association of DCM with 517 382 single nucleotide polymorphisms (SNPs). Three DCM-associated SNPs were confirmed by individual genotyping (P < 5.0 10−7), and two of them, rs10927875 and rs2234962, were replicated in independent samples (1165 DCM patients and 1302 controls), with P-values of 0.002 and 0.009, respectively. rs10927875 maps to a region on chromosome 1p36.13 which encompasses several genes among which HSPB7 has been formerly suggested to be implicated in DCM. The second identified locus involves rs2234962, a non-synonymous SNP (c.T757C, p. C151R) located within the sequence of BAG3 on chromosome 10q26. To assess whether coding mutations of BAG3 might cause monogenic forms of the disease, we sequenced BAG3 exons in 168 independent index cases diagnosed with familial DCM and identified four truncating and two missense mutations. Each mutation was heterozygous, present in all genotyped relatives affected by the disease and absent in a control group of 347 healthy individuals, strongly suggesting that these mutations are causing the disease. Conclusion: This GWAS identified two loci involved in sporadic DCM, one of them probably implicates BAG3. Our results show that rare mutations in BAG3 contribute to monogenic forms of the disease, while common variant(s) in the same gene are implicated in sporadic DCM

Genome-wide association analysis in dilated cardiomyopathy reveals two new players in systolic heart failure on chromosomes 3p25.1 and 22q11.23

Aims: Our objective was to better understand the genetic bases of dilated cardiomyopathy (DCM), a leading cause of systolic heart failure. Methods and results: We conducted the largest genome-wide association study performed so far in DCM, with 2719 cases and 4440 controls in the discovery population. We identified and replicated two new DCM-associated loci on chromosome 3p25.1 [lead single-nucleotide polymorphism (SNP) rs62232870, P = 8.7 x 10(-11) and 7.7 x 10(-4) in the discovery and replication steps, respectively] and chromosome 22q11.23 (lead SNP rs7284877, P = 3.3 x 10(-8) and 1.4 x 10(-3) in the discovery and replication steps, respectively), while confirming two previously identified DCM loci on chromosomes 10 and 1, BAG3 and HSPB7. A genetic risk score constructed from the number of risk alleles at these four DCM loci revealed a 3-fold increased risk of DCM for individuals with 8 risk alleles compared to individuals with 5 risk alleles (median of the referral population). In silico annotation and functional 4C-sequencing analyses on iPSC-derived cardiomyocytes identify SLC6A6 as the most likely DCM gene at the 3p25.1 locus. This gene encodes a taurine transporter whose involvement in myocardial dysfunction and DCM is supported by numerous observations in humans and animals. At the 22q11.23 locus, in silico and data mining annotations, and to a lesser extent functional analysis, strongly suggest SMARCB1 as the candidate culprit gene. Conclusion: This study provides a better understanding of the genetic architecture of DCM and sheds light on novel biological pathways underlying heart failure. [GRAPHICS

Risk Scores in ST-Segment Elevation Myocardial Infarction Patients with Refractory Cardiogenic Shock and Veno-Arterial Extracorporeal Membrane Oxygenation

International audienceAlthough many risk models have been tested in patients implanted by veno-arterial extracorporeal membrane oxygenation (VA-ECMO), few scores assessed patients’ prognosis in the setting of ST-segment elevation myocardial infarction (STEMI) with refractory cardiogenic shock. We aimed at assessing the performance of risk scores, notably the prEdictioN of Cardiogenic shock OUtcome foR AMI patients salvaGed by VA-ECMO (ENCOURAGE) score, for predicting mortality in this particular population. This retrospective observational study included patients admitted to Tours University Hospital for STEMI with cardiogenic shock and requiring hemodynamic support by VA-ECMO. Among the fifty-one patients, the 30-day and 6-month survival rates were 63% and 56% respectively. Thirty days after VA-ECMO therapy, probabilities of mortality were 12, 17, 33, 66, 80% according to the ENCOURAGE score classes 0–12, 13–18, 19–22, 23–27, and ≥28, respectively. The ENCOURAGE score (AUC of the Receiving Operating Characteristic curve = 0.83) was significantly better compared to other risk scores. The hazard ratio for survival at 30 days for each point of the ENCOURAGE score was 1.10 (CI 95% (1.06, 1.15); p < 0.001). Decision curve analysis indicated that the ENCOURAGE score had the best clinical usefulness of the tested risk scores and the Hosmer–Lemeshow test suggested an accurate calibration. Our data suggest that the ENCOURAGE score is valid and the most relevant score to predict 30-day mortality after VA-ECMO therapy in STEMI patients with refractory cardiogenic shock. It may help decision-making teams to better select STEMI patients with shock for VA-ECMO therapy