Lessons from the Mouse Model
Bibliographic record
Abstract
Abstract Shwachman-Diamond syndrome (SDS) is a member of the growing list of inherited diseases that result from mutations in genes that encode components of the protein synthesis machinery. Collectively referred to as ribosomopathies, these diseases have selective organ involvement and serious hematological issues with increased susceptibility to malignancy. SDS is caused by mutations in the highly conserved SBDS gene. Recent studies have implicated SBDS in facilitating ribosomal subunit joining for translation initiation. We study mouse models with disease-associated alleles to determine the consequences of loss of Sbds and gain insight into ribosomopathy phenotypes. Mice that are homozygous for a disease-associated allele (SbdsR126T/R126T) die at birth. Growth issues and developmental delay are evident in mid-to-late-stage embryos, and analysis of ribosome profiles indicate disturbed protein synthesis in all tissues examined. SDS-related pathologies in the fetal liver, bone, and brain are also observed. For example, flow cytometry analyses and culturing of fetal liver cells show growth impairment of myeloid lineage progenitors. Ossification is delayed in the developing phalanges. Poor proliferation is evident in early neurons and death due to apoptosis occurs in differentiating neurons, as early as E14.5. As with the brain, the fetal spleen also shows disproportionate growth restriction. These responses reflect varying underlying molecular pathways that hinge on p53 activation. Breeding to Trp53 (p53) deficient mice attenuates the SDS phenotypes but does not rescue the overall growth impairment or the perinatal death. Loss of Sbds leads to a range of organ responses, with engagement of stress pathways at different times and stages. As the severity of the organ pathology does not correlate directly with alteration of 80S or polysome component peak levels in ribosome profiles, we conclude that the organ phenotype reflects limitations in gene expression and timing of expression, or results from disturbed regulation that is specific to cell type and respective protein synthesis demand. Disclosures: No relevant conflicts of interest to declare.
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 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 | 0.003 | 0.003 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.001 | 0.003 |
| Scholarly communication | 0.002 | 0.003 |
| Open science | 0.002 | 0.002 |
| Research integrity | 0.004 | 0.011 |
| Insufficient payload (model declined to judge) | 0.008 | 0.004 |
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".