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Record W3041635606 · doi:10.1126/science.aay5663

HEM1 deficiency disrupts mTORC2 and F-actin control in inherited immunodysregulatory disease

2020· article· en· W3041635606 on OpenAlexaff
Sarah A. Cook, William A. Comrie, M. Cecilia Poli, Morgan Similuk, Andrew J. Oler, Aiman Faruqi, Douglas B. Kuhns, Sheng Yang, Alexander Vargas‐Hernández, Alexandre F. Carisey, Benjamin Fournier, David E. Anderson, Susan Price, Margery Smelkinson, Wadih Abou Chahla, Lisa R. Forbes, Emily M. Mace, Tram N. Cao, Zeynep Coban‐Akdemir, Shalini N. Jhangiani, Donna M. Muzny, Richard A. Gibbs, James R. Lupski, Jordan S. Orange, Geoff D.E. Cuvelier, Moza Al Hassani, Nawal Al Kaabi, Zain Al Yafei, Soma Jyonouchi, Nikita Raje, Jason W. Caldwell, Yanping Huang, Janis K. Burkhardt, Sylvain Latour, Baoyu Chen, Gehad ElGhazali, V. Koneti Rao, Iván K. Chinn, Michael J. Lenardo

Bibliographic record

VenueScience · 2020
Typearticle
Languageen
FieldImmunology and Microbiology
TopicImmunodeficiency and Autoimmune Disorders
Canadian institutionsCancerCare Manitoba
FundersNational Institutes of HealthNational Cancer InstituteNational Human Genome Research InstituteNational Institute of Allergy and Infectious DiseasesDivision of Intramural Research, National Institute of Allergy and Infectious DiseasesNational Institute of General Medical SciencesAmerican Diabetes Association
KeywordsImmune systemActinActin cytoskeletonMissense mutationBiologyPhenotypeGeneCell biologyCytoskeletonImmunologyGeneticsCell

Abstract

fetched live from OpenAlex

, which encodes the hematopoietic-specific HEM1 protein. These mutations cause the loss of the HEM1 protein and the WAVE regulatory complex (WRC) or disrupt binding to the WRC regulator, Arf1, thereby impairing actin polymerization, synapse formation, and immune cell migration. Diminished cortical actin networks caused by WRC loss led to uncontrolled cytokine release and immune hyperresponsiveness. HEM1 loss also blocked mechanistic target of rapamycin complex 2 (mTORC2)-dependent AKT phosphorylation, T cell proliferation, and selected effector functions, leading to immunodeficiency. Thus, the evolutionarily conserved HEM1 protein simultaneously regulates filamentous actin (F-actin) and mTORC2 signaling to achieve equipoise in immune responses.

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)0.000
metaresearch head score (Gemma)0.000
Version: codex-gemma-dda1882f352aValidation status: machine_predicted_unvalidated
Candidate categoriesnone
Consensus categoriesnone
DomainCandidate signal: none · Consensus signal: none
Study designCandidate signal: Bench or experimental · Consensus signal: none
GenreCandidate signal: Empirical · Consensus signal: Empirical
Teacher disagreement score0.962
Threshold uncertainty score0.703

Codex and Gemma teacher scores by category

CategoryCodexGemma
Metaresearch0.0000.000
Meta-epidemiology (narrow)0.0000.000
Meta-epidemiology (broad)0.0000.000
Bibliometrics0.0000.001
Science and technology studies0.0000.002
Scholarly communication0.0000.000
Open science0.0010.000
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 head0.009
GPT teacher head0.219
Teacher spread0.210 · 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 designBench or experimental
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

Citations100
Published2020
Admission routes1
Has abstractyes

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