Aggregation and antibody‐based inhibition of TDP‐43
Bibliographic record
Abstract
Abstract Background TAR DNA‐binding protein 43 (TDP‐43) is a highly conserved nuclear protein, predominantly associated with RNA metabolism. Aberrant TDP‐43 inclusions are present in over 95% of post‐mortem brain tissue samples from Amyotrophic Lateral Sclerosis (ALS) patients. The highly disordered TDP‐43 C‐Terminal Domain (CTD) is associated with the greatest amount of disease‐related mutations and phosphorylation sites. The exact mechanism of TDP‐43 aggregation and formation into a pathological state has yet to be elucidated but is an important therapeutic target to consider. Method Full‐length phosphorylated TDP‐43 (pS410) protein was treated with 6 hours of daily agitation over 9 days in vitro. Agitation and aging took place with and without the presence of TDP‐43 RRM2‐CTD specific antibodies. Dot‐blot analysis was performed to confirm the binding of antibodies to TDP‐43. Aggregation was monitored and characterized using biophysical analysis; methods included Thioflavin T (ThT), turbidity, and transmission electron microscopy (TEM). Result Phospho‐TDP‐43 that had undergone agitation and extensive aging formed insoluble aggregates and ThT positive fibrils. The incubation with antibodies specific to the RRM2‐CTD inhibited aggregation and fibril formation in a concentration‐dependent manner. Conclusion Similar immunotherapies exist for other neurodegenerative disease‐related proteins; inhibition of TDP‐43 aggregation and fibril formation using antibodies demonstrates the potential for the epitope‐specific treatment of TDP‐43 proteinopathies. 1) Esposto, J., & Martic‐Milne, S. (2021). Biochimica et Biophysica Acta (BBA) ‐ Molecular Basis of Disease, 1867, https://doi.org/10.1016/j.bbadis.2021.166234 .
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
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.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
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".