Bibliographic record
Abstract
Calcium (Ca²⁺) is required in the cytoplasm as a potent second messenger for a variety of vital physiological events in the cell. Its supply to the cytoplasm can either be from extracellular sources, or from intracellular sarcoplasmic reticulum stores, predominantly through the ryanodine receptors (RyRs). The latter are large, ~2 MDa homotetrameric channels that sense initial Ca²⁺ blips due to voltage-‐gated calcium channel influx and respond by opening to result in physiologically significant concentration spikes. This action is known as calcium induced calcium release and is the major process by which an excitation signal is translated to a physical, muscular contraction. Cytoplasmic Ca²⁺ concentrations have to be very well regulated and must return to resting levels for subsequent contractions to occur. The importance of this with regard to the RyR can be seen in two different ways: Firstly, its large cytoplasmic bulk, a huge docking site for modulators, emphasizes the necessity for regulation, and secondly, mutations in the RyR can cause severe genetic diseases as a result of Ca²⁺ mishandling. Presented here, are preliminary structural and binding studies for several different RyR regulators, both physiological and pharmacological. Skeletal muscle RyR (RyR1) 1-‐617 that contains the drug dantrolene’s supposed binding site was crystallized and its structure determined. Isothermal Titration Calorimetry (ITC) and co-‐crystallization attempts have not confirmed the binding of dantrolene. The structure does however shed light on the physical involvement of phosphatases as modulators of the channel. Caffeine binding was detected successfully by ITC and attributed to RyR1 217-‐ 536. A co-‐crystal structure yielded a binding site in the construct that could not be knocked out by site-‐directed mutagenesis according to ITC. Three types of modulators were shown to bind RyR1 4071-‐4128 by ITC. 1) Ca²⁺, which affects the channel both positively and negatively, 2) magnesium ions, which inhibit the channel, and 3) an intrinsic ligand in RyR1: residues 4295-‐4325; a peptide that shows affinity for Calmodulin, yet another modulator of RyR. The results provide insight into allosteric reactions as a result of RyR ligand or modulator binding.
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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) | 0.003 | 0.001 |
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".