A small protein coded within the mitochondrial canonical gene nd4 regulates mitochondrial bioenergetics

BACKGROUND: Mitochondria have a central role in cellular functions, aging, and in certain diseases. They possess their own genome, a vestige of their bacterial ancestor. Over the course of evolution, most of the genes of the ancestor have been lost or transferred to the nucleus. In humans, the mtDNA is a very small circular molecule with a functional repertoire limited to only 37 genes. Its extremely compact nature with genes arranged one after the other and separated by short non-coding regions suggests that there is little room for evolutionary novelties. This is radically different from bacterial genomes, which are also circular but much larger, and in which we can find genes inside other genes. These sequences, different from the reference coding sequences, are called alternatives open reading frames or altORFs, and they are involved in key biological functions. However, whether altORFs exist in mitochondrial protein-coding genes or elsewhere in the human mitogenome has not been fully addressed. RESULTS: We found a downstream alternative ATG initiation codon in the + 3 reading frame of the human mitochondrial nd4 gene. This newly characterized altORF encodes a 99-amino-acid-long polypeptide, MTALTND4, which is conserved in primates. Our custom antibody, but not the pre-immune serum, was able to immunoprecipitate MTALTND4 from HeLa cell lysates, confirming the existence of an endogenous MTALTND4 peptide. The protein is localized in mitochondria and cytoplasm and is also found in the plasma, and it impacts cell and mitochondrial physiology. CONCLUSIONS: Many human mitochondrial translated ORFs might have so far gone unnoticed. By ignoring mtaltORFs, we have underestimated the coding potential of the mitogenome. Alternative mitochondrial peptides such as MTALTND4 may offer a new framework for the investigation of mitochondrial functions and diseases

Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk

Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome associated with COVID-19: An Emulated Target Trial Analysis.

RATIONALE: Whether COVID patients may benefit from extracorporeal membrane oxygenation (ECMO) compared with conventional invasive mechanical ventilation (IMV) remains unknown. OBJECTIVES: To estimate the effect of ECMO on 90-Day mortality vs IMV only Methods: Among 4,244 critically ill adult patients with COVID-19 included in a multicenter cohort study, we emulated a target trial comparing the treatment strategies of initiating ECMO vs. no ECMO within 7 days of IMV in patients with severe acute respiratory distress syndrome (PaO2/FiO2 <80 or PaCO2 ≥60 mmHg). We controlled for confounding using a multivariable Cox model based on predefined variables. MAIN RESULTS: 1,235 patients met the full eligibility criteria for the emulated trial, among whom 164 patients initiated ECMO. The ECMO strategy had a higher survival probability at Day-7 from the onset of eligibility criteria (87% vs 83%, risk difference: 4%, 95% CI 0;9%) which decreased during follow-up (survival at Day-90: 63% vs 65%, risk difference: -2%, 95% CI -10;5%). However, ECMO was associated with higher survival when performed in high-volume ECMO centers or in regions where a specific ECMO network organization was set up to handle high demand, and when initiated within the first 4 days of MV and in profoundly hypoxemic patients. CONCLUSIONS: In an emulated trial based on a nationwide COVID-19 cohort, we found differential survival over time of an ECMO compared with a no-ECMO strategy. However, ECMO was consistently associated with better outcomes when performed in high-volume centers and in regions with ECMO capacities specifically organized to handle high demand. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P = 9.2 x 10(-20)), ER-negative BC (P = 1.1 x 10(-13)), BRCA1-associated BC (P = 7.7 x 10(-16)) and triple negative BC (P-diff = 2 x 10(-5)). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P = 2 x 10(-3)) and ABHD8 (PPeer reviewe

A ‘social Europe’ for workers? Framing analysis of the posted work debate in the Council (2016-2017)

In a context of rising inequalities in the European Union, accompanied by a certain mistrust in the capacity of the European institutions to improve and secure the social conditions of the citizens, the question of ‘social Europe’ is more than ever source of debate and interrogations. Focusing on the revision of the Posting of Workers Directive, proposed by the Commission in 2016, this thesis analyses the way the European Ministers framed this revision and ‘social Europe’ more broadly during the negotiations.This work contributes to the existing research on elite framing and expands this field to ‘negotiations analysis’, a topic which has rarely been addressed. The analysis, based on Helbling’s frame categorisation, shows that workers’ social protection is a divisive issue which opposes two main groups: the proponents (high wage member states) and the opponents (low wage member states). The first group frames ‘social Europe’ as a way to restore trust in the European economic model, jeopardised by the downward pressure on wages and social conditions caused by low wage member states. On the other hand, opponents to the revision frame social policies as disruptive forces damaging the single market’s competitiveness and economic freedoms. They portray themselves as the victims of an unwelcome protectionism orchestrated by high wage member states.These findings question the future of ‘social Europe’, as they bring to light the unwillingness of both sides to rethink the European economic system. In the absence of a strong and positive ‘counter-narrative’, it seems that social policies will continue to beseen as hindering economic freedoms or as a mean to legitimise a system that has proven to be unequal. In that sense, the European social project did not yet reach the ‘status’ of the economic project and is still understood as a side issue that cannot challenge the status quo. If framed differently, social welfare in the Union could become a priority and take precedence over the fundamental freedoms that have been defined twenty-five years ago, in a very different socio-economic and political context

Les émulsions corrodées : l’intrusion du temps dans la série photographique Moires de Éric Rondepierre

La Photographie est par excellence le médium de la mise en évidence du dérisoire. Elle permet de cadrer spatialement le négligeable en vue de lui procurer une singularité. Seulement, la délimitation du cadrage n’est pas nécessairement spatiale, elle peut aussi être temporelle, notamment lorsqu’il s’agit de circonscrire le médium cinématographique, qu’il se réclame du régime argentique ou numérique. Solliciter ainsi photographiquement une entité déjà préexistante telle que le Septième art impl..

A ‘social Europe’ for workers? Framing analysis of the posted work debate in the Council (2016-2017)

In a context of rising inequalities in the European Union, accompanied by a certain mistrust in the capacity of the European institutions to improve and secure the social conditions of the citizens, the question of ‘social Europe’ is more than ever source of debate and interrogations. Focusing on the revision of the Posting of Workers Directive, proposed by the Commission in 2016, this thesis analyses the way the European Ministers framed this revision and ‘social Europe’ more broadly during the negotiations.This work contributes to the existing research on elite framing and expands this field to ‘negotiations analysis’, a topic which has rarely been addressed. The analysis, based on Helbling’s frame categorisation, shows that workers’ social protection is a divisive issue which opposes two main groups: the proponents (high wage member states) and the opponents (low wage member states). The first group frames ‘social Europe’ as a way to restore trust in the European economic model, jeopardised by the downward pressure on wages and social conditions caused by low wage member states. On the other hand, opponents to the revision frame social policies as disruptive forces damaging the single market’s competitiveness and economic freedoms. They portray themselves as the victims of an unwelcome protectionism orchestrated by high wage member states.These findings question the future of ‘social Europe’, as they bring to light the unwillingness of both sides to rethink the European economic system. In the absence of a strong and positive ‘counter-narrative’, it seems that social policies will continue to beseen as hindering economic freedoms or as a mean to legitimise a system that has proven to be unequal. In that sense, the European social project did not yet reach the ‘status’ of the economic project and is still understood as a side issue that cannot challenge the status quo. If framed differently, social welfare in the Union could become a priority and take precedence over the fundamental freedoms that have been defined twenty-five years ago, in a very different socio-economic and political context

Rôle de la protéine de choc thermique HSP27 dans les processus d'ubiquitination et de sumoylation

DIJON-BU Médecine Pharmacie (212312103) / SudocSudocFranceF

The light is red: Uncertainty behaviours displayed by pedestrians during illegal road crossing

International audienc