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

Follow-up of loci from the International Genomics of Alzheimer's Disease Project identifies TRIP4 as a novel susceptibility gene

To follow-up loci discovered by the International Genomics of Alzheimer's Disease Project, we attempted independent replication of 19 single nucleotide polymorphisms (SNPs) in a large Spanish sample (Fundació ACE data set; 1808 patients and 2564 controls). Our results corroborate association with four SNPs located in the genes INPP5D, MEF2C, ZCWPW1 and FERMT2, respectively. Of these, ZCWPW1 was the only SNP to withstand correction for multiple testing (P=0.000655). Furthermore, we identify TRIP4 (rs74615166) as a novel genome-wide significant locus for Alzheimer's disease risk (odds ratio=1.31; confidence interval 95% (1.19-1.44); P=9.74 × 10 - 9)

Determinants of cognitive performance and decline in 20 diverse ethno-regional groups: A COSMIC collaboration cohort study.

BACKGROUND: With no effective treatments for cognitive decline or dementia, improving the evidence base for modifiable risk factors is a research priority. This study investigated associations between risk factors and late-life cognitive decline on a global scale, including comparisons between ethno-regional groups. METHODS AND FINDINGS: We harmonized longitudinal data from 20 population-based cohorts from 15 countries over 5 continents, including 48,522 individuals (58.4% women) aged 54-105 (mean = 72.7) years and without dementia at baseline. Studies had 2-15 years of follow-up. The risk factors investigated were age, sex, education, alcohol consumption, anxiety, apolipoprotein E ε4 allele (APOE*4) status, atrial fibrillation, blood pressure and pulse pressure, body mass index, cardiovascular disease, depression, diabetes, self-rated health, high cholesterol, hypertension, peripheral vascular disease, physical activity, smoking, and history of stroke. Associations with risk factors were determined for a global cognitive composite outcome (memory, language, processing speed, and executive functioning tests) and Mini-Mental State Examination score. Individual participant data meta-analyses of multivariable linear mixed model results pooled across cohorts revealed that for at least 1 cognitive outcome, age (B = -0.1, SE = 0.01), APOE*4 carriage (B = -0.31, SE = 0.11), depression (B = -0.11, SE = 0.06), diabetes (B = -0.23, SE = 0.10), current smoking (B = -0.20, SE = 0.08), and history of stroke (B = -0.22, SE = 0.09) were independently associated with poorer cognitive performance (p < 0.05 for all), and higher levels of education (B = 0.12, SE = 0.02) and vigorous physical activity (B = 0.17, SE = 0.06) were associated with better performance (p < 0.01 for both). Age (B = -0.07, SE = 0.01), APOE*4 carriage (B = -0.41, SE = 0.18), and diabetes (B = -0.18, SE = 0.10) were independently associated with faster cognitive decline (p < 0.05 for all). Different effects between Asian people and white people included stronger associations for Asian people between ever smoking and poorer cognition (group by risk factor interaction: B = -0.24, SE = 0.12), and between diabetes and cognitive decline (B = -0.66, SE = 0.27; p < 0.05 for both). Limitations of our study include a loss or distortion of risk factor data with harmonization, and not investigating factors at midlife. CONCLUSIONS: These results suggest that education, smoking, physical activity, diabetes, and stroke are all modifiable factors associated with cognitive decline. If these factors are determined to be causal, controlling them could minimize worldwide levels of cognitive decline. However, any global prevention strategy may need to consider ethno-regional differences

A C6orf10/LOC101929163 locus is associated with age of onset in C9orf72 carriers.

The G4C2-repeat expansion in C9orf72 is the most common known cause of amyotrophic lateral sclerosis and frontotemporal dementia. The high phenotypic heterogeneity of C9orf72 patients includes a wide range in age of onset, modifiers of which are largely unknown. Age of onset could be influenced by environmental and genetic factors both of which may trigger DNA methylation changes at CpG sites. We tested the hypothesis that age of onset in C9orf72 patients is associated with some common single nucleotide polymorphisms causing a gain or loss of CpG sites and thus resulting in DNA methylation alterations. Combined analyses of epigenetic and genetic data have the advantage of detecting functional variants with reduced likelihood of false negative results due to excessive correction for multiple testing in genome-wide association studies. First, we estimated the association between age of onset in C9orf72 patients (n = 46) and the DNA methylation levels at all 7603 CpG sites available on the 450 k BeadChip that are mapped to common single nucleotide polymorphisms. This was followed by a genetic association study of the discovery (n = 144) and replication (n = 187) C9orf72 cohorts. We found that age of onset was reproducibly associated with polymorphisms within a 124.7 kb linkage disequilibrium block tagged by top-significant variation, rs9357140, and containing two overlapping genes (LOC101929163 and C6orf10). A meta-analysis of all 331 C9orf72 carriers revealed that every A-allele of rs9357140 reduced hazard by 30% (P = 0.0002); and the median age of onset in AA-carriers was 6 years later than GG-carriers. In addition, we investigated a cohort of C9orf72 negative patients (n = 2634) affected by frontotemporal dementia and/or amyotrophic lateral sclerosis; and also found that the AA-genotype of rs9357140 was associated with a later age of onset (adjusted P = 0.007 for recessive model). Phenotype analyses detected significant association only in the largest subgroup of patients with frontotemporal dementia (n = 2142, adjusted P = 0.01 for recessive model). Gene expression studies of frontal cortex tissues from 25 autopsy cases affected by amyotrophic lateral sclerosis revealed that the G-allele of rs9357140 is associated with increased brain expression of LOC101929163 (a non-coding RNA) and HLA-DRB1 (involved in initiating immune responses), while the A-allele is associated with their reduced expression. Our findings suggest that carriers of the rs9357140 GG-genotype (linked to an earlier age of onset) might be more prone to be in a pro-inflammatory state (e.g. by microglia) than AA-carriers. Further, investigating the functional links within the C6orf10/LOC101929163/HLA-DRB1 pathway will be critical to better define age-dependent pathogenesis of frontotemporal dementia and amyotrophic lateral sclerosis

A C6orf10/LOC101929163 locus is associated with age of onset in C9orf72 carriers

The G4C2-repeat expansion in C9orf72 is the most common known cause of amyotrophic lateral sclerosis and frontotemporal dementia. The high phenotypic heterogeneity of C9orf72 patients includes a wide range in age of onset, modifiers of which are largely unknown. Age of onset could be influenced by environmental and genetic factors both of which may trigger DNA methylation changes at CpG sites. We tested the hypothesis that age of onset in C9orf72 patients is associated with some common single nucleotide polymorphisms causing a gain or loss of CpG sites and thus resulting in DNA methylation alterations. Combined analyses of epigenetic and genetic data have the advantage of detecting functional variants with reduced likelihood of false negative results due to excessive correction for multiple testing in genome-wide association studies. First, we estimated the association between age of onset in C9orf72 patients (n = 46) and the DNA methylation levels at all 7603 CpG sites available on the 450 k BeadChip that are mapped to common single nucleotide polymorphisms. This was followed by a genetic association study of the discovery (n = 144) and replication (n = 187) C9orf72 cohorts. We found that age of onset was reproducibly associated with polymorphisms within a 124.7 kb linkage disequilibrium

Le sentiment Harki d'appartenance collective (perspectives sociologiques et psychanalytiques de l'ethnicité et de ses enjeux)

Suite à un travail de terrain réalisé auprès de Harkis en France et en Allemagne, nous sommes passés d'une analyse de l'ethnicité en terme de traits sociaux culturellement différenciateurs à l'examen de la référence généalogique dans la constrution du sentiment d'appartenance collective. Notre étude de la reconstruction de l'histoire personnelle et collective met en évidence les enjeux des pratiques collectives et du refoulement dans la construction identitaire et culturelle. La référence généalogique est apparue pour être un matériel culturel. Elle agit comme mécanisme de défense contre l'expression directe des pulsions fratricides, pulsions à la fois fondatrices et destructrices de lien social. Ces constats nous amènent à poser l'ethinicté pour être la résultante de processus d'identification collectifs et psychiques issus de pulsions de vie et de pulsions de mort fraticides plus ou moins efficacement refoulées par les sociétés et les sujets.Following a grass-roots study of Harkis in France and Germany, we present readjustments to pre-existing theoretical models concerning ethinicity, exile and the ambivalent feelings stemming from colonization. The fact that offspring of Algerian parents joined the French army during the Algerian war all themselves Harkis enables several generations to identify with the name and all that it represents. reference to the past generation is a requisite for membership of the harki community and the latter acts as a regulator of instinctual forces. Both the individual and society on a whole subconsciously oscillate between botherly love and murderous sibling impulses. Ethnicity constituted through collective identity works as a defence mechanism, muffhing outright instinctual forces and enabling the development of a social belonging as the individual identity.PARIS3-BU (751052102) / SudocPARIS-Fondation MSH (751062301) / SudocSudocFranceF

Does using pressure-controlled ventilation to rest respiratory muscles improve sleep in ICU patients?

Purpose: Sleep is commonly altered in critically ill patients. Ventilatory mode may impact on quality of sleep. The aim of our study was to evaluate the effect on sleep of pressure-controlled ventilation (PCV) to spontaneous ventilation with 6 cm H2O inspiratory pressure (low-PSV). Methods: Thirty-five patients intubated and mechanically ventilated for acute-on-chronic respiratory failure were included in this prospective randomized cross-over study. Nine were discarded, 13 received PCV first (10 p.m.-2 a.m.) and then low-PSV (2-6 a.m.) and 13 patients received low-PSV first and then PCV. Results: Sleep architecture was altered (50.4% of the night was spent in wakefulness). PCV was associated with significantly improved sleep quality and quantity compared to low-PSV: sleep efficiency (total sleep time/total recording time) was 63% (range: 9-100) vs. 37% (0-96; p = 0.0002), stage 2 NREM sleep was 33% vs. 13% (p = 0.0005), stages 3 and 4 NREM sleep were 9% vs. 3.5% (p = 0.003) and REM sleep was 6.5% vs. 0% (p = 0.003). Conclusions: Sleep quantity and quality were significantly improved with PCV compared to low-PSV. Nocturnal respiratory muscles rest through PCV is recommended to improve sleep in ICU patients with acute-on-chronic respiratory failur

Assist-control ventilation vs. low levels of pressure support ventilation on sleep quality in intubated ICU patients

Objective: To compare the impact of assist-control ventilation (ACV) and pressure support ventilation with 6cmH(2)O inspiratory pressure (low PSV) on sleep quality. Design: Prospective randomized cross-over study. Patients: Twenty intubated and mechanically ventilated patients for acute on chronic respiratory failure. Measurements: Patients were monitored by standard polysomnography at the end of their weaning period. Patients were assigned to receive either ACV from 10p.m. to 2a.m. and low PSV from 2a.m. to 6a.m. ACV/low PSV group) or low PSV from 10p.m. to 2a.m. and ACV from 2a.m. to 6a.m. (low PSV/ACV group). Result: There were significant increases in stages 1 and 2 non-rapid eye movement (NREM) sleep and reduction in wakefulness during the first part of the night and significant increases in stages 3 and 4 NREM sleep during the second part of the night were observed with ACV compared to low PSV. A significant negative correlation was observed between the perceived sleep quality and the amount of wakefulness while the amount of stage 2 NREM sleep was positively correlated with perceived sleep quality. Conclutions: ACV was significantly associated with a better sleep quality than those recorded during pressure support. The perception of sleep quality appeared to be better with ACV than with low PSV. On the basis of these results we recommend that intubated and mechanically ventilated patients for acute on chronic respiratory failure should be reventilated at night during their weaning period

Integrated analyses of translatome and proteome identify the rules of translation selectivity in RPS14-deficient cells

In ribosomopathies, the Diamond-Blackfan anemia (DBA) or 5q- syndrome, ribosomal protein (RP) genes are affected by mutation or deletion, resulting in bone marrow erythroid hypoplasia. Unbalanced production of ribosomal subunits leading to a limited ribosome cellular content, regulates translation at the expense of the master erythroid transcription factor GATA1. In RPS14-deficient cells mimicking 5q- syndrome erythroid defects, we show that the transcript length, codon bias of the coding sequence (CDS) and 3'UTR structure are the key determinants of translation. In these cells, short transcripts with a structured 3'UTR and high CAI showed a decreased translation efficiency. Quantitative analysis of the whole proteome confirmed that the post-transcriptional changes depended on the transcript characteristics that governed the translation efficiency in conditions of low ribosome availability. In addition, proteins involved in normal erythroid differentiation share most determinants of translation selectivity. Our findings thus indicate that impaired erythroid maturation due to 5q- syndrome may proceed from a translational selectivity at the expense of the erythroid differentiation program and suggest that an interplay between the CDS and UTRs may regulate mRNA translation