Bibliographic record
Abstract
from the A site to the P site.The previous tRNA will simultaneously be transferred to the exit (E) site and leave the ribosome.Once an in-frame stop codon in the mRNA is recognized by the eukaryotic release factor eRF1, the peptide chain is released from the tRNA and the protein is finished.Translation initiation is tightly regulated by several different pathways, such as the integrated stress response (ISR).The ISR comprises a complex network of sensor, mediator, and effector proteins, that together detect and respond to cellular stress.In mammalian cells, four different sensor proteins can be activated by a plethora of different stressors, via mechanisms that are often incompletely understood.Upon detection of their respective stressor, the ISR sensor proteins phosphorylate a conserved residue, S51, in the alpha subunit of translation initiation factor 2 (eIF2α).Phosphorylated eIF2 (p-eIF2) binds and sequesters the eIF2-specific guanidine exchange factor (GEF) eIF2B, thereby interfering with GDP/GTP exchange on native eIF2.As this is a crucial step in the recycling of eIF2•GDP into a TC, p-eIF2 effectively represses translation.Counterintuitively, under conditions of stress, a selection of mRNAs is more efficiently translated.The ensuing ISR-induced proteins have functions that help cells deal with stress situations, which will be addressed in more detail later in this introduction.Collectively, ISR-mediated inhibition of general translation conserves energy, and together with the enhanced synthesis of a subset of stress-related proteins, it alters the cells proteome to optimize the chances to restore cellular homeostasis. ISR sensor proteinsMammalian cells have four different ISR sensor proteins, Protein Kinase R (PKR), PKR-like ER-resident kinase (PERK), Heme Responsive Inhibitor (HRI), and General Control Non-derepressible 2 (GCN2) (Fig 1).These proteins differ in their activation domain, and thus in the types of stressors they respond to.Upon detection of their respective stressors, they activate by homodimerization and autophosphorylation, and subsequently phosphorylate eIF2 via a largely conserved eIF2α kinase domain.PKR activity is negatively affected by inhibitory sequences in its N-terminal domain, which encompasses two double-stranded RNA binding domains (dsRBDs) (1).Cytoplasmic dsRNAs, which are a danger signal that can indicate for example mitochondrial leakage or viral infections (2), bind these dsRBDs and lift the inhibitory effect, thus activating PKR.For efficient dimerization and subsequent activation, both dsRBDs of two separate PKR molecules interact with the same dsRNA (3).Consequently, PKR is inhibited by excessive amounts of dsRNA which cause separate PKR molecules to interact with different dsRNAs(4).Besides its ability to respond to dsRNA, PKR can also be activated independently of dsRNA, via interaction with PACT.An interaction of PKR with PACT, like an interaction Interference in Viral Protein Synthesis.J.
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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 | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.005 | 0.002 |
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".