ORCID Profile
0000-0002-6839-3651
Current Organisations
Uppsala University Hospital
,
Uppsala University
,
Temple University
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Publisher: Cold Spring Harbor Laboratory
Date: 02-04-2022
DOI: 10.1101/2022.04.01.486713
Abstract: FOXO1, a member of the family of winged-helix motif Forkhead box (FOX) transcription factors, is the most abundantly expressed FOXO member in mature B-cells. Sequencing of diffuse large B-cell lymphoma (DLBCL) tumors and cell lines identified specific mutations in the forkhead domain linked to loss of function. Differential scanning calorimetry and thermal shift assays were used to characterize how eight of these mutations affect the stability of the FOX domain. Mutations L183P and L183R were found to be particularly destabilizing. Electrophoresis mobility shift assays show these same mutations also disrupt FOXO1 binding to their canonical DNA sequences, suggesting the loss of function is due to destabilization of the folded structure. Computational modeling of the effects of mutations on FOXO1 folding was performed using alchemical FEP, and a Markov model of the entire folding reaction was constructed from massively parallel molecular simulations, which predicts folding pathways involving the late folding of helix α3. Although FEP is able to qualitatively predict the destabilization from L183 mutations, we find that a simple hydrophobic transfer model, combined with estimates of unfolded-state solvent accessible surface areas from molecular simulation, is able to more accurately predict changes in folding free energies due to mutations. These results suggest that atomic detail provided from simulation is important for accurate prediction of mutational effects on folding stability. Corresponding disease-associated mutations in other FOX family members support further experimental and computational studies of the folding mechanism of FOX domains.
Publisher: American Chemical Society (ACS)
Date: 26-02-2021
Publisher: American Chemical Society (ACS)
Date: 27-07-2022
Publisher: Georg Thieme Verlag KG
Date: 17-04-2020
Abstract: Objective: Human and Organizational Factors (HOF) studies in health technology involve human beings and thus require Institutional Review Board (IRB) approval. Yet HOF studies have specific constraints and methods that may not fit standard regulations and IRB practices. Gaining IRB approval may pose difficulties for HOF researchers. This paper aims to provide a first overview of HOF study challenges to get IRB review by exploring differences and best practices across different countries. Methods: HOF researchers were contacted by email to provide a testimony about their experience with IRB review and approval. Testimonies were thematically analyzed and synthesized to identify and discuss shared themes. Results: Researchers from seven European countries, Argentina, Canada, Australia, and the United States answered the call. Four themes emerged that indicate shared challenges in legislation, IRB inefficiencies and inconsistencies, general regulation and costs, and lack of HOF study knowledge by IRB members. We propose a model for IRB review of HOF studies based on best practices. Conclusion: International criteria are needed that define low and high-risk HOF studies, to allow identification of studies that can undergo an expedited (or exempted) process from those that need full IRB review. Enhancing IRB processes in such a way would be beneficial to the conduct of HOF studies. Greater knowledge and promotion of HOF methods and evidence-based HOF study designs may support the evolving discipline. Based on these insights, training and guidance to IRB members may be developed to support them in ensuring that appropriate ethical issues for HOF studies are considered.
Location: United States of America
Location: United States of America
No related grants have been discovered for Maria Hägglund.