72 research outputs found
The DDX6-4E-T interaction mediates translational repression and P-body assembly.
4E-Transporter binds eIF4E via its consensus sequence YXXXXLΊ, shared with eIF4G, and is a nucleocytoplasmic shuttling protein found enriched in P-(rocessing) bodies. 4E-T inhibits general protein synthesis by reducing available eIF4E levels. Recently, we showed that 4E-T bound to mRNA however represses its translation in an eIF4E-independent manner, and contributes to silencing of mRNAs targeted by miRNAs. Here, we address further the mechanism of translational repression by 4E-T by first identifying and delineating the interacting sites of its major partners by mass spectrometry and western blotting, including DDX6, UNR, unrip, PAT1B, LSM14A and CNOT4. Furthermore, we document novel binding between 4E-T partners including UNR-CNOT4 and unrip-LSM14A, altogether suggesting 4E-T nucleates a complex network of RNA-binding protein interactions. In functional assays, we demonstrate that joint deletion of two short conserved motifs that bind UNR and DDX6 relieves repression of 4E-T-bound mRNA, in part reliant on the 4E-T-DDX6-CNOT1 axis. We also show that the DDX6-4E-T interaction mediates miRNA-dependent translational repression and de novo P-body assembly, implying that translational repression and formation of new P-bodies are coupled processes. Altogether these findings considerably extend our understanding of the role of 4E-T in gene regulation, important in development and neurogenesis.BBSRC [BB/J00779X/1 to N.S.]; CNRS PICS (to D.W.); Agence Nationale pour la Recherche [ANR-14-CE09-0013-01ANR to D.W.]; Gates Cambridge Foundation (to A.K.); Fondation Wiener â Anspach of the UniversitĂ© Libre de Bruxelles and the Cambridge Newton Trust (C.V.). Funding for open access charge: BBSRC
GC content shapes mRNA storage and decay in human cells.
mRNA translation and decay appear often intimately linked although the rules of this interplay are poorly understood. In this study, we combined our recent P-body transcriptome with transcriptomes obtained following silencing of broadly acting mRNA decay and repression factors, and with available CLIP and related data. This revealed the central role of GC content in mRNA fate, in terms of P-body localization, mRNA translation and mRNA stability: P-bodies contain mostly AU-rich mRNAs, which have a particular codon usage associated with a low protein yield; AU-rich and GC-rich transcripts tend to follow distinct decay pathways; and the targets of sequence-specific RBPs and miRNAs are also biased in terms of GC content. Altogether, these results suggest an integrated view of post-transcriptional control in human cells where most translation regulation is dedicated to inefficiently translated AU-rich mRNAs, whereas control at the level of 5' decay applies to optimally translated GC-rich mRNAs
Outcome Measures for Disease-Modifying Trials in Parkinson's Disease:Consensus Paper by the EJS ACT-PD Multi-Arm Multi-Stage Trial Initiative
BACKGROUND: Multi-arm, multi-stage (MAMS) platform trials can accelerate the identification of disease-modifying treatments for Parkinson's disease (PD) but there is no current consensus on the optimal outcome measures (OM) for this approach.OBJECTIVE: To provide an up-to-date inventory of OM for disease-modifying PD trials, and a framework for future selection of OM for such trials.METHODS: As part of the Edmond J Safra Accelerating Clinical Trials in Parkinson Disease (EJS ACT-PD) initiative, an expert group with Patient and Public Involvement and Engagement (PPIE) representatives' input reviewed and evaluated available evidence on OM for potential use in trials to delay progression of PD. Each OM was ranked based on aspects such as validity, sensitivity to change, participant burden and practicality for a multi-site trial. Review of evidence and expert opinion led to the present inventory.RESULTS: An extensive inventory of OM was created, divided into: general, motor and non-motor scales, diaries and fluctuation questionnaires, cognitive, disability and health-related quality of life, capability, quantitative motor, wearable and digital, combined, resource use, imaging and wet biomarkers, and milestone-based. A framework for evaluation of OM is presented to update the inventory in the future. PPIE input highlighted the need for OM which reflect their experience of disease progression and are applicable to diverse populations and disease stages.CONCLUSION: We present a range of OM, classified according to a transparent framework, to aid selection of OM for disease-modifying PD trials, whilst allowing for inclusion or re-classification of relevant OM as new evidence emerges.</p
Outcome Measures for Disease-Modifying Trials in Parkinson's Disease: Consensus Paper by the EJS ACT-PD Multi-Arm Multi-Stage Trial Initiative
BACKGROUND: Multi-arm, multi-stage (MAMS) platform trials can accelerate the identification of disease-modifying treatments for Parkinson's disease (PD) but there is no current consensus on the optimal outcome measures (OM) for this approach. OBJECTIVE: To provide an up-to-date inventory of OM for disease-modifying PD trials, and a framework for future selection of OM for such trials. METHODS: As part of the Edmond J Safra Accelerating Clinical Trials in Parkinson Disease (EJS ACT-PD) initiative, an expert group with Patient and Public Involvement and Engagement (PPIE) representatives' input reviewed and evaluated available evidence on OM for potential use in trials to delay progression of PD. Each OM was ranked based on aspects such as validity, sensitivity to change, participant burden and practicality for a multi-site trial. Review of evidence and expert opinion led to the present inventory. RESULTS: An extensive inventory of OM was created, divided into: general, motor and non-motor scales, diaries and fluctuation questionnaires, cognitive, disability and health-related quality of life, capability, quantitative motor, wearable and digital, combined, resource use, imaging and wet biomarkers, and milestone-based. A framework for evaluation of OM is presented to update the inventory in the future. PPIE input highlighted the need for OM which reflect their experience of disease progression and are applicable to diverse populations and disease stages. CONCLUSION: We present a range of OM, classified according to a transparent framework, to aid selection of OM for disease-modifying PD trials, whilst allowing for inclusion or re-classification of relevant OM as new evidence emerges
Towards a multi-arm multi-stage platform trial of disease modifying approaches in Parkinsonâs disease
An increase in the efficiency of clinical trial conduct has been successfully demonstrated in the oncology field, by the use of multi-arm, multi-stage trials allowing the evaluation of multiple therapeutic candidates simultaneously, and seamless recruitment to phase 3 for those candidates passing an interim signal of efficacy. Replicating this complex innovative trial design in diseases such as Parkinsonâs disease is appealing, but in addition to the challenges associated with any trial assessing a single potentially disease modifying intervention in Parkinsonâs disease, a multiarm platform trial must also specifically consider the heterogeneous nature of the disease, alongside the desire to potentially test multiple treatments with different mechanisms of action. In a multi-arm trial, there is a need to appropriately stratify treatment arms to ensure each are comparable with a shared placebo/standard of care arm; however, in Parkinsonâs disease there may be a preference to enrich an arm with a subgroup of patients that may be most likely to respond to a specific treatment approach. The solution to this conundrum lies in having clearly defined criteria for inclusion in each treatment arm as well as an analysis plan that takes account of predefined subgroups of interest, alongside evaluating the impact of each treatment on the broader population of Parkinsonâs disease patients. Beyond this, there must be robust processes of treatment selection, and consensus derived measures to confirm target engagement and interim assessments of efficacy, as well as consideration of the infrastructure needed to support recruitment, and the long-term funding and sustainability of the platform. This has to incorporate the diverse priorities of clinicians, triallists, regulatory authorities and above all the views of people with Parkinsonâs disease.</p
Towards a multi-arm multi-stage platform trial of disease modifying approaches in Parkinsonâs disease
An increase in the efficiency of clinical trial conduct has been successfully demonstrated in the oncology field, by the use of multi-arm, multi-stage trials allowing the evaluation of multiple therapeutic candidates simultaneously, and seamless recruitment to phase 3 for those candidates passing an interim signal of efficacy. Replicating this complex innovative trial design in diseases such as Parkinsonâs disease is appealing, but in addition to the challenges associated with any trial assessing a single potentially disease modifying intervention in Parkinsonâs disease, a multiarm platform trial must also specifically consider the heterogeneous nature of the disease, alongside the desire to potentially test multiple treatments with different mechanisms of action. In a multi-arm trial, there is a need to appropriately stratify treatment arms to ensure each are comparable with a shared placebo/standard of care arm; however, in Parkinsonâs disease there may be a preference to enrich an arm with a subgroup of patients that may be most likely to respond to a specific treatment approach. The solution to this conundrum lies in having clearly defined criteria for inclusion in each treatment arm as well as an analysis plan that takes account of predefined subgroups of interest, alongside evaluating the impact of each treatment on the broader population of Parkinsonâs disease patients. Beyond this, there must be robust processes of treatment selection, and consensus derived measures to confirm target engagement and interim assessments of efficacy, as well as consideration of the infrastructure needed to support recruitment, and the long-term funding and sustainability of the platform. This has to incorporate the diverse priorities of clinicians, triallists, regulatory authorities and above all the views of people with Parkinsonâs disease.</p
FiliÚre « Territoires, espaces, sociétés »
Participants : Isabelle Backouche, Juan Carlos Garavaglia, Nancy L. Green, Alexandra Laclau, Christian Lamouroux, MichĂšle de La Pradelle, Susanna Magri, Marie-Claude Maurel, Alain Musset, Daniel Nordman, Marie-Vic Ozouf-Marignier, Jacques Poloni-Simard, Paul-AndrĂ© Rosental, Annie Sevin, Annick Tanter-Toubon, Christian Topalov, Caroline Varlet, Nicolas Verdier, Françoise Vergneault-Belmont, François Weil, Pierre-Paul Zalio Lâenseignement de la filiĂšre sâinscrit dans le cadre du sĂ©minaire bimen..
FiliÚre « Territoires, espaces, sociétés »
Participants : Isabelle Backouche, Juan Carlos Garavaglia, Nancy L. Green, Alexandra Laclau, Christian Lamouroux, MichĂšle de La Pradelle, Susanna Magri, Marie-Claude Maurel, Alain Musset, Daniel Nordman, Marie-Vic Ozouf-Marignier, Jacques Poloni-Simard, Paul-AndrĂ© Rosental, Annie Sevin, Annick Tanter-Toubon, Christian Topalov, Caroline Varlet, Nicolas Verdier, Françoise Vergneault-Belmont, François Weil, Pierre-Paul Zalio Lâenseignement de la filiĂšre sâinscrit dans le cadre du sĂ©minaire bimen..
Comment repérer et définir le topos ?
De quoi sâagit-il ? Du topos dans ses manifestations narratives, non du lieu vide de la tradition rhĂ©torique. Dâun repĂ©rage textuel, propre au corpus formĂ© par les fictions narratives des origines Ă 1789, en langue française. Pourquoi, dira-t-on, Ă©carter les topiques aristotĂ©liciennes, les topos propres au thĂ©Ăątre ou Ă la poĂ©sie, Ă la littĂ©rature des XIXe et XXe siĂšcles ou aux littĂ©ratures Ă©trangĂšres ? Parce que cette mise Ă lâĂ©cart, provisoire dâailleurs, permet seule, par la â trĂšs relative â modestie du corpus restant, dâapprocher une dĂ©finition qui puisse servir dâoutil de prĂ©cision dans un travail collectif de recherche sur la formation du roman.La dĂ©finition et les procĂ©dures de repĂ©rage ici proposĂ©es ne se veulent donc quâexpĂ©rimentales. Ce nâest quâen superposant les textes narratifs, en les lisant comme par transparence, que lâon peut voir se dessiner les topos propres au genre romanesque, puisse dĂ©finir lâidĂ©e [idea] de topos spĂ©cifique. DâoĂč cette proposition de dĂ©finition, en cours dâexpĂ©rimentation, du topos comme configuration narrative rĂ©currente
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