Cyclophilin A supports translation of intrinsically disordered proteins and affects haematopoietic stem cell ageing.

Loss of protein function is a driving force of ageing. We have identified peptidyl-prolyl isomerase A (PPIA or cyclophilin A) as a dominant chaperone in haematopoietic stem and progenitor cells. Depletion of PPIA accelerates stem cell ageing. We found that proteins with intrinsically disordered regions (IDRs) are frequent PPIA substrates. IDRs facilitate interactions with other proteins or nucleic acids and can trigger liquid-liquid phase separation. Over 20% of PPIA substrates are involved in the formation of supramolecular membrane-less organelles. PPIA affects regulators of stress granules (PABPC1), P-bodies (DDX6) and nucleoli (NPM1) to promote phase separation and increase cellular stress resistance. Haematopoietic stem cell ageing is associated with a post-transcriptional decrease in PPIA expression and reduced translation of IDR-rich proteins. Here we link the chaperone PPIA to the synthesis of intrinsically disordered proteins, which indicates that impaired protein interaction networks and macromolecular condensation may be potential determinants of haematopoietic stem cell ageing.

Genome-wide map of nuclear protein degradation shows NCoR1 turnover as a key to mitochondrial gene regulation.

Transcription factor activity and turnover are functionally linked, but the global patterns by which DNA-bound regulators are eliminated remain poorly understood. We established an assay to define the chromosomal location of DNA-associated proteins that are slated for degradation by the ubiquitin-proteasome system. The genome-wide map described here ties proteolysis in mammalian cells to active enhancers and to promoters of specific gene families. Nuclear-encoded mitochondrial genes in particular correlate with protein elimination, which positively affects their transcription. We show that the nuclear receptor corepressor NCoR1 is a key target of proteolysis and physically interacts with the transcription factor CREB. Proteasome inhibition stabilizes NCoR1 in a site-specific manner and restrains mitochondrial activity by repressing CREB-sensitive genes. In conclusion, this functional map of nuclear proteolysis links chromatin architecture with local protein stability and identifies proteolytic derepression as highly dynamic in regulating the transcription of genes involved in energy metabolism.

Power training in patients with knee osteoarthritis: a pilot study on feasibility and efficacy.

PURPOSE: To explore the feasibility and efficacy of using a power training exercise programme for the quadriceps femoris (QF) in elderly women with knee osteoarthritis (OA). METHOD: A one-group quasi-experimental design with pre- and post-intervention measurements was conducted on 17 older adult women with knee OA pain. A bilateral QF exercise programme (24 sessions over 8 weeks) consisting of 3 series of 10 repetitions of flexion-extension as fast as possible at 40% of their one-repetition maximum (1RM) was performed in an outpatient physiotherapy clinic. The primary outcome measures were the knee function and associated problems using the Knee injury Osteoarthritis Outcome Score (KOOS) questionnaire and the weekly mean pain score from pain diaries using a visual analogue scale (VAS). QF strength (QFS), power (QFP) and work (QFW) were measured with an isokinetic dynamometer as secondary outcomes. RESULTS: Significant improvements (p<0.05) were noted on the five categories of the KOOS. Significant decrease (p<0.01) was noted in pain intensity on VAS. QFP and QFW increased significantly on both sides (p<0.05). Exercise compliance was 99.5% for 16 participants. CONCLUSIONS: A short power-training exercise programme is a feasible training modality for patients with knee OA, and significant functional improvements can be achieved. Further studies must be conducted to better understand the effects of the programme parameters and the generalizability of the findings.

Objectif : Analyser la faisabilité d'utiliser un programme d'entrainement en puissance des quadriceps cruraux (QC) et son efficacité chez des personnés âgées atteintes d'arthrose. Méthodologie : Devis quasi expérimental avec mesures pré et post intervention sur un groupe de 17 femmes de plus de 65 ans avec douleur au genou causée par l'arthrose. Programme individuel d'exercices bilatéraux pour les QC (24 séances en 8 semaines) comprenant 3 séries de 10 répétitions de flexion-extension à 40 % de la force maximum à une répétition (1RM) exécutées a vitesse maximale et réalisé sous supervision en clinique externe de physiothérapie. Les principales mesures de résultat étaient la fonction du genou et les problèmes connexes, à l'aide du questionnaire KOOS (Knee injury Osteoarthritis Outcome Score) et la douleur moyenne hebdomadaire calculée à partir des valeurs de douleur sur une échelle visuelle analogue (EVA) consignées dans un journal de la douleur. La force des QC (FQC), la puissance (PQC) et le travail musculaire (TQC) ont été mesurés à l'aide d'un dynamomètre isocinétique et consignés comme résultats secondaires. Résultats : Des améliorations appréciables (p<0,05) ont été observées dans cinq catégories du KOOS. Une diminution considérable (p<0,01) a été notée dans l'intensité de la douleur à l'EVA. La puissance des QC et le travail musculaire des QC se sont considérablement accrus des deux côtés (p<0,05). Le programme d'exercices a été observé par 99,5 % des 16 participantes. Conclusions : Un programme court d'exercice en puissance est une modalité d'entrainement envisageable pour les patients avec arthrose du genou et permet des améliorations fonctionnelles appréciables. D'autres études devront être réalisées afin de mieux comprendre les effets des paramètres du programme et la généralisation des conclusions.

Prospective serial evaluation of 2-hydroxyglutarate, during treatment of newly diagnosed acute myeloid leukemia, to assess disease activity and therapeutic response.

Mutations of genes encoding isocitrate dehydrogenase (IDH1 and IDH2) have been recently described in acute myeloid leukemia (AML). Serum and myeloblast samples from patients with IDH-mutant AML contain high levels of the metabolite 2-hydroxyglutarate (2-HG), a product of the altered IDH protein. In this prospective study, we sought to determine whether 2-HG can potentially serve as a noninvasive biomarker of disease burden through serial measurements in patients receiving conventional therapy for newly diagnosed AML. Our data demonstrate that serum, urine, marrow aspirate, and myeloblast 2-HG levels are significantly higher in IDH-mutant patients, with a correlation between baseline serum and urine 2-HG levels. Serum and urine 2-HG, along with IDH1/2-mutant allele burden in marrow, decreased with response to treatment. 2-HG decrease was more rapid with induction chemotherapy compared with DNA-methyltransferase inhibitor therapy. Our data suggest that serum or urine 2-HG may serve as noninvasive biomarkers of disease activity for IDH-mutant AML.