RIPK1 promotes death receptor-independent caspase-8-mediated apoptosis under unresolved ER stress conditions

Accumulation of unfolded proteins in the endoplasmic reticulum (ER) causes ER stress and results in the activation of the unfolded protein response (UPR), which aims at restoring ER homeostasis. However, when the stress is too severe the UPR switches from being a pro-survival response to a pro-death one, and the molecular mechanisms underlying ER stress-mediated death have remained incompletely understood. In this study, we identified receptor interacting protein kinase 1 (RIPK1)-a kinase at the crossroad between life and death downstream of various receptors-as a new regulator of ER stress-induced death. We found that Ripk1-deficient MEFs are protected from apoptosis induced by ER stressors, which is reflected by reduced caspase activation and PARP processing. Interestingly, the pro-apoptotic role of Ripk1 is independent of its kinase activity, is not regulated by its cIAP1/2-mediated ubiquitylation, and does not rely on the direct regulation of JNK or CHOP, two reportedly main players in ER stress-induced death. Instead, we found that ER stress-induced apoptosis in these cells relies on death receptor-independent activation of caspase-8, and identified Ripk1 upstream of caspase-8. However, in contrast to RIPK1-dependent apoptosis downstream of TNFR1, we did not find Ripk1 associated with caspase-8 in a death-inducing complex upon unresolved ER stress. Our data rather suggest that RIPK1 indirectly regulates caspase-8 activation, in part via interaction with the ER stress sensor inositol-requiring protein 1 (IRE1)

Mitral valve prolapse syndrome and MASS phenotype: stability of aortic dilatation but progression of mitral valve prolapse

AbstractBackgroundMitral valve prolapse syndrome (MVPS) and MASS phenotype (MASS) are Marfan-like syndromes that exhibit aortic dilatation and mitral valve prolapse. Unlike in Marfan syndrome (MFS), the presence of ectopia lentis and aortic aneurysm preclude diagnosis of MVPS and MASS. However, it is unclear whether aortic dilatation and mitral valve prolapse remain stable in MVPS or MASS or whether they progress like in MFS.MethodsThis retrospective longitudinal observational study examines clinical characteristics and long-term prognosis of 44 adults with MVPS or MASS (18 men, 26 women aged 38±17years) as compared with 81 adults with Marfan syndrome (MFS) with similar age and sex distribution. The age at final contact was 42±15years with mean follow-up of 66±49months.ResultsAt baseline, ectopia lentis and aortic sinus aneurysm were absent in MVPS and MASS, and systemic scores defined by the revised Ghent nosology were lower than in MFS (all P<.001). Unlike in MFS, no individual with MVPS and MASS developed aortic complications (P<.001). In contrast, the incidence of endocarditis (P=.292), heart failure (P=.644), and mitral valve surgery (P=.140) was similar in all syndromes. Cox regression analysis identified increased LV end-diastolic (P=.013), moderate MVR (P=.019) and flail MV leaflet (P=.017) as independent predictors of mitral valve surgery.ConclusionsThe study provides evidence that MVPS and MASS are Marfan-like syndromes with stability of aortic dilatation but with progression of mitral valve prolapse. Echocardiographic characteristics of mitral valve disease rather than the type of syndrome, predict clinical progression of mitral valve prolapse

a controlled multicenter study with assessment of echocardiographic reference values, and the frequency of dilatation and aneurysm in Marfan syndrome

Background Echocardiographic upper normal limits of both main pulmonary artery (MPA) diameters (MPA-d) and ratio of MPA to aortic root diameter (MPA-r) are not defined in healthy adults. Accordingly, frequency of MPA dilatation based on echocardiography remains to be assessed in adults with Marfan syndrome (MFS). Methods We enrolled 123 normal adults (72 men, 52 women aged 42 ± 14 years) and 98 patients with MFS (42 men, 56 women aged 39 ± 14 years) in a retrospective cross-sectional observational controlled study in four tertiary care centers. We defined outcome measures including upper normal limits of MPA-d and MPA-r as 95 quantile of normal persons, MPA dilatation as diameters > upper normal limits, MPA aneurysm as diameters >4 cm, and indication for surgery as MPA diameters >6 cm. Results MPA diameters revealed normal distribution without correlation to age, sex, body weight, body height, body mass index and body surface area. The upper normal limit was 2.6 cm (95% confidence interval (CI) =2.44-2.76 cm) for MPA-d, and 1.05 (95% CI = .86–1.24) for MPA-r. MPA dilatation presented in 6 normal persons (4.9%) and in 68 MFS patients (69.4%; P < .001), MPA aneurysm presented only in MFS (15 patients; 15.3%; P < .001), and no patient required surgery. Mean MPA-r were increased in MFS (P 1.05 were equally frequent in 7 normal persons (5%) and in 8 MFS patients (10.5%; P = .161). MPA-r related to aortic root diameters (P = .042), reduced left ventricular ejection fraction (P = .006), and increased pulmonary artery systolic pressures (P = .040). No clinical manifestations of MFS and no FBN1 mutation characteristics related to MPA diameters. Conclusions We established 2.6 cm for MPA-d and 1.05 for MPA-r as upper normal limits. MFS exhibits a high prevalence of MPA dilatation and aneurysm. However, patients may require MPA surgery only in scarce circumstances, most likely because formation of marked MPA aneurysm may require LV dysfunction and increased PASP

The main pulmonary artery in adults : a controlled multicenter study with assessment of echocardiographic reference values, and the frequency of dilatation and aneurysm in Marfan syndrome

BACKGROUND: Echocardiographic upper normal limits of both main pulmonary artery (MPA) diameters (MPA-d) and ratio of MPA to aortic root diameter (MPA-r) are not defined in healthy adults. Accordingly, frequency of MPA dilatation based on echocardiography remains to be assessed in adults with Marfan syndrome (MFS). METHODS: We enrolled 123 normal adults (72 men, 52 women aged 42 ± 14 years) and 98 patients with MFS (42 men, 56 women aged 39 ± 14 years) in a retrospective cross-sectional observational controlled study in four tertiary care centers. We defined outcome measures including upper normal limits of MPA-d and MPA-r as 95 quantile of normal persons, MPA dilatation as diameters > upper normal limits, MPA aneurysm as diameters >4 cm, and indication for surgery as MPA diameters >6 cm. RESULTS: MPA diameters revealed normal distribution without correlation to age, sex, body weight, body height, body mass index and body surface area. The upper normal limit was 2.6 cm (95% confidence interval (CI) =2.44-2.76 cm) for MPA-d, and 1.05 (95% CI = .86–1.24) for MPA-r. MPA dilatation presented in 6 normal persons (4.9%) and in 68 MFS patients (69.4%; P < .001), MPA aneurysm presented only in MFS (15 patients; 15.3%; P < .001), and no patient required surgery. Mean MPA-r were increased in MFS (P < .001), but ratios >1.05 were equally frequent in 7 normal persons (5%) and in 8 MFS patients (10.5%; P = .161). MPA-r related to aortic root diameters (P = .042), reduced left ventricular ejection fraction (P = .006), and increased pulmonary artery systolic pressures (P = .040). No clinical manifestations of MFS and no FBN1 mutation characteristics related to MPA diameters. CONCLUSIONS: We established 2.6 cm for MPA-d and 1.05 for MPA-r as upper normal limits. MFS exhibits a high prevalence of MPA dilatation and aneurysm. However, patients may require MPA surgery only in scarce circumstances, most likely because formation of marked MPA aneurysm may require LV dysfunction and increased PASP

GDF15, a distinct TGFb family member, is differentially regulated in spondyloarthritides compared to other rheumatic diseases

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Conception de systèmes de culture innovants pour la filière des légumes industrie de plein champ en Bretagne

Ce numéro est constitué d’articles issus du colloque CIAg « Construire et diffuser des systèmes légumiers multi-performants », organisé le 14 septembre 2017 à Angers.National audienceAs part of a project carried out with various partners of the industrial vegetable sector in Brittany, the codesignof innovative cropping systems is implemented with 4 farmers. The target is to reduce as muchas possible the environmental and health impact of their practices and to anticipate the phasing-out ofagrochemical products. After an analysis of initial cropping systems, collective workshops led to thedesign of innovative systems integrating a diversity of agro-ecological practices. These systems wereexperimented by farmers in 2016, and analyzed using a multicriteria evaluation model. Although resultsshow a decrease in economic and social performances of the systems, the 4 farmers were able toreduce their TFIs and were highly satisfied with the first modifications. A second design-experimentationstep has therefore been scheduled for 2017 in order to adjust the systems and to realize themodifications that could not be made in 2016. These first results are promising given the importantconstraints associated to the industrial vegetable sector. Ultimately, the various partners are planning todisseminate on a larger scale the virtuous agro-ecological practices identified.Dans le cadre d’un projet mené en partenariat avec différents acteurs de la filière des légumes industriede Bretagne, une démarche de co-conception de systèmes de culture innovants est mise en place chez4 agriculteurs. L’objectif est de réduire autant que possible l’impact environnemental et sanitaire deleurs pratiques et d’anticiper la disparition des produits phytosanitaires. Après une analyse dessystèmes de culture initiaux, des ateliers collectifs ont permis de concevoir des systèmes innovantsintégrant une diversité de pratiques agro-écologiques. Ces systèmes ont été expérimentés dès 2016par les agriculteurs puis analysés à l’aide d’un modèle d’évaluation multicritères. Bien que les résultatsmettent en évidence une diminution des performances économiques et sociales des systèmes, les 4agriculteurs ont pu diminuer leurs IFT et se sont montrés très satisfaits des premiers changementsréalisés. Une deuxième phase de conception-expérimentation a donc été programmée pour 2017, afinde pouvoir ajuster les systèmes conçus et réaliser les changements de pratiques qui n’ont pas pu êtrefaits en 2016. Ces premiers résultats sont prometteurs compte tenu des importantes contraintesrelatives à la filière des légumes industrie. A terme, les différents partenaires envisagent donc dediffuser les pratiques agro-écologiques vertueuses identifiées à plus large échelle

The Effect of Age and Sex on Clinical Outcome after Intravenous Recombinant Tissue Plasminogen Activator Treatment in Patients with Acute Ischemic Stroke

Background: There are conflicting results regarding the effect of intravenous (IV) recombinant tissue plasminogen activator (rtPA) stroke treatment between men and women. Studies evaluating the impact of sex differences on functional outcome in relation to different age groups are nonexistent. Aim: The objective of the study is to examine the influence of sex differences in relation to age on the prognosis after IV rtPA treatment in acute stroke patients. Methods: In this cohort study, 887 patients with acute ischemic stroke were treated with rtPA. Functional outcome after 3 months was determined with the modified Rankin Scale (mRS). Good outcome was defined as an mRS score of 2 or lower. Age was stratified in decades (41-50, 51-60, 61-70, 71-80, and >80 years). Multivariable analyses were performed with adjustment for age, sex, stroke severity (National Institutes of Health Stroke Scale [NIHSS]), and stroke subtype (Trial of Org 10172 in Acute Stroke Treatment). Results: Fifty-five percent of the patients were men. The mean age was 67.4 (men) and 72.0 (women) years. Fifty-six percent of the men and 45% of the women had a favorable outcome (P=.001). After adjustment for NIHSS score and stroke subtype, the women had a better outcome in the age group 51-60 years compared with men (odds ratio [OR] .38, 95% confidence interval [CI] .15-.96). In the age group >80 years, men had a better outcome than women (OR 2.69, 95% CI 1.21-5.96). There were no significant differences in the other age groups. Conclusion: Men and women have different prognoses after IV rtPA treatment for acute ischemic stroke, which also depends on age. Women in middle age appear to have a better outcome than men, whereas at a more advanced age men appear to have a better outcome than women

Transcriptional and post-transcriptional regulation of a NAC1 transcription factor in Medicago truncatula roots

Legume roots develop two types of lateral organs, lateral roots and nodules. Nodules develop as a result of a symbiotic interaction with rhizobia and provide a niche for the bacteria to fix atmospheric nitrogen for the plant. The Arabidopsis NAC1 transcription factor is involved in lateral root formation, and is regulated post-transcriptionally by miRNA164 and by SINAT5-dependent ubiquitination. We analyzed in Medicago truncatula the role of the closest NAC1 homolog in lateral root formation and in nodulation. MtNAC1 shows a different expression pattern in response to auxin than its Arabidopsis homolog and no changes in lateral root number or nodulation were observed in plants affected in MtNAC1 expression. In addition, no interaction was found with SINA E3 ligases, suggesting that post-translational regulation of MtNAC1 does not occur in M. truncatula. Similar to what was found in Arabidopsis, a conserved miR164 target site was retrieved in MtNAC1, which reduced protein accumulation of a GFP-miR164 sensor. Furthermore, miR164 and MtNAC1 show an overlapping expression pattern in symbiotic nodules, and overexpression of this miRNA led to a reduction in nodule number. This work suggests that regulatory pathways controlling a conserved transcription factor are complex and divergent between M. truncatula and Arabidopsis