Utilization of primary cultures of macrophages for biologic validation of candidate genes linked to left ventricular hypertrophy
Bibliographic record
Abstract
Cardiac left ventricular mass (LVM) correlates tightly with cardiovascular morbidity and mortality in human populations, and constitutes an important independent predictor of cardiovascular risk. Using 24 mouse AxB/BxA recombinant inbred strains (RIS) (derived from crosses between A/J and C57BL/6J parents), our laboratory previously detected one major QTL linked to LVM on Chromosome (chr) 13. To extend these data, our laboratory used Illumina microarrays to obtain the profile of gene expression in 4 hearts of male mice from all RIS. By using first a publicly available genomic map, our laboratory identified initially a total of 456 cis-acting eQTLs (cis-eQTLs), 15 of which showing expression levels correlating with LVM. Although little functional annotation was available for these genes, the SymAtlas database indicated that most of them were expressed at higher levels in cells from the myeloid lineage (i.e. macrophages and/or mast cells) than in cardiac myocytes. By further using bone-marrow derived macrophages (BMDMΦ) from Balb/c mice, we: 1) verified that these genes were indeed expressed in such cells; 2) observed that their expression level was modulated by conditions known to affect the phenotypic properties of macrophages; 3) demonstrated that their expression could be knocked down by transfection with Dicer silencing RNAs. In a second phase of the project, the laboratory obtained a denser genetic map that allowed for the identification of a total of 1195 cis-eQTLs. Among corresponding genes, 33 showed significant correlation (p < 0.05) with LVM, and 10/33 genes clustered within a 10 MB interval centered around the QTL linked to LVM on chr 13. Further RT-PCR analyses revealed that the expression levels of these genes varied in BMDMΦ cells according to the A/B genotype. Since the clustering of 10 cis-eQTLs all correlating with LVM suggested the presence of a common regulator, we further analyzed genome databases and noticed that the same interval contained the locus of the mir-23b-27b-24-1 microRNA gene cluster. Interestingly, mir-27b has been reported to be functionally related to changes in LVM. Altogether, these experiments establish the feasibility of using primary macrophage cultures for further biologic validation of the roles and/or properties of candidate genes linked to LVM. Using these cells, it will be possible to test whether alterations in the intracellular concentration of miR-27b may regulate the abundance of the transcripts of other candidate genes from our locus of interest. In light of evidence reporting that macrophages may play a role in left ventricular remodeling, this may lead to future experiments testing how these genes may contribute via expression within macrophages to changes in LVM.
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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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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".