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Record W2988184724 · doi:10.1172/jci124000

KBTBD13 is an actin-binding protein that modulates muscle kinetics

2019· article· en· W2988184724 on OpenAlexaff
Josine M. de Winter, J. Molenaar, Michaela Yuen, Robbert van der Pijl, Shengyi Shen, Stefan Conijn, Martijn van de Locht, M. van Willigenburg, Sylvia J. P. Bogaards, Esmee S.B. van Kleef, Saskia Lassche, Malin Persson, Dilson E. Rassier, Tamar E. Sztal, Avnika A. Ruparelia, Viola Oorschot, Georg Ramm, Thomas E. Hall, Zherui Xiong, Christopher N. Johnson, Frank Li, Balázs Kiss, Noelia Lozano‐Vidal, Reinier A. Boon, Manuela Marabita, Leonardo Nogara, Bert Blaauw, Richard J. Rodenburg, Benno Küsters, Jonne Doorduin, Alan H. Beggs, Henk Granzier, Kenneth S. Campbell, Weikang Ma, Thomas C. Irving, Edoardo Malfatti, Norma B. Romero, Robert J. Bryson‐Richardson, Baziel G.M. van Engelen, Nicol C. Voermans, Coen A. C. Ottenheijm

Bibliographic record

VenueJournal of Clinical Investigation · 2019
Typearticle
Languageen
FieldMedicine
TopicCardiomyopathy and Myosin Studies
Canadian institutionsMcGill University
FundersNational Institute of Child Health and Human DevelopmentMedical Research CouncilNational Institute of Arthritis and Musculoskeletal and Skin DiseasesNational Institute of General Medical SciencesNational Health and Medical Research CouncilHorizon 2020 Framework ProgrammeOffice of ScienceNational Institutes of HealthNational Heart, Lung, and Blood InstituteVetenskapsrådetMuscular Dystrophy AssociationArgonne National LaboratoryEunice Kennedy Shriver National Institute of Child Health and Human DevelopmentU.S. Department of Energy
KeywordsSarcomereActinContractilityMuscle relaxationNebulinBiophysicsNemaline myopathyKineticsMyosinCell biologyMyofibrilMuscle contractionBiologyChemistryMyocyteEndocrinologyTitin

Abstract

fetched live from OpenAlex

The mechanisms that modulate the kinetics of muscle relaxation are critically important for muscle function. A prime example of the impact of impaired relaxation kinetics is nemaline myopathy caused by mutations in KBTBD13 (NEM6). In addition to weakness, NEM6 patients have slow muscle relaxation, compromising contractility and daily life activities. The role of KBTBD13 in muscle is unknown, and the pathomechanism underlying NEM6 is undetermined. A combination of transcranial magnetic stimulation-induced muscle relaxation, muscle fiber- and sarcomere-contractility assays, low-angle x-ray diffraction, and superresolution microscopy revealed that the impaired muscle-relaxation kinetics in NEM6 patients are caused by structural changes in the thin filament, a sarcomeric microstructure. Using homology modeling and binding and contractility assays with recombinant KBTBD13, Kbtbd13-knockout and Kbtbd13R408C-knockin mouse models, and a GFP-labeled Kbtbd13-transgenic zebrafish model, we discovered that KBTBD13 binds to actin - a major constituent of the thin filament - and that mutations in KBTBD13 cause structural changes impairing muscle-relaxation kinetics. We propose that this actin-based impaired relaxation is central to NEM6 pathology.

Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.

How this classification was reachedexpand

Full frame distilled prediction

Teacher imitation

Not calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.

metaresearch head score (Codex)0.001
metaresearch head score (Gemma)0.001
Version: codex-gemma-dda1882f352aValidation status: machine_predicted_unvalidated
Candidate categoriesnone
Consensus categoriesnone
DomainCandidate signal: none · Consensus signal: none
Study designCandidate signal: Observational · Consensus signal: Observational
GenreCandidate signal: Empirical · Consensus signal: Empirical
Teacher disagreement score0.263
Threshold uncertainty score0.361

Codex and Gemma teacher scores by category

CategoryCodexGemma
Metaresearch0.0010.001
Meta-epidemiology (narrow)0.0000.000
Meta-epidemiology (broad)0.0010.000
Bibliometrics0.0000.000
Science and technology studies0.0000.000
Scholarly communication0.0000.000
Open science0.0000.000
Research integrity0.0000.000
Insufficient payload (model declined to judge)0.0000.000

Machine scores (provisional)

The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.

Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.

Opus teacher head0.143
GPT teacher head0.388
Teacher spread0.245 · how far apart the two teachers sit on this one work
Validation statusscore_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from it

Classification

machine, unvalidated

Machine predicted; a candidate call from one teacher head, not a consensus.

The models applied no category: nothing in the taxonomy fit this work.
Study designObservational
Domainnot available
GenreEmpirical

How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".

Quick stats

Citations43
Published2019
Admission routes1
Has abstractyes

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