Inhibition of PCSK6 May Play a Protective Role in the Development of Rheumatoid Arthritis
Bibliographic record
Abstract
OBJECTIVE: To assess the effect of proprotein convertase subtilisin/kexin type 6 (PCSK6) in the synovial fibroblasts of rheumatoid arthritis (RA). PCSK6 is a proteinase implicated in the proteolytic activity of various precursor proteins and involved in the regulation of protein maturation. METHODS: PCSK6 expression was detected in the synovial tissue of 10 patients with RA, 10 controls with osteoarthritis, and 10 controls with ankylosing spondylitis using Western blotting and quantitative real-time PCR. Genotyping of 67 tag single-nucleotide polymorphisms (SNP) was performed using an Illumina VeraCode (Illumina) microarray in a case-control study including 267 patients with RA and 160 healthy controls. Genotyping of 4 other tag SNP was performed using a TaqMan probe genotyping assay in 1056 healthy controls and 1151 patients with RA. Cultured RA synovial fibroblasts (RASF) were transfected with PCSK6 small interfering RNA to study changes in the proliferation, invasion, migration capacity, secretion of inflammatory cytokines, cell cycle, and expression profiles of the RASF. RESULTS: Expression of PCSK6 mRNA and protein was significantly higher in the synovial tissues of individuals with RA than in control tissues. One SNP, rs8029797, was significantly associated with RA (p = 0.011). Knockdown of PCSK6 by RNA interference significantly decreased proliferation, invasion, and migration of RASF. These changes in RASF appeared to be related to reduced tumor necrosis factor-α secretion, G0/G1 arrest, and altered expression of various proteins including those involved in angiogenesis (matrix metalloproteinase 9, nitric oxide synthase trafficking), hypoxia (hypoxia-inducible factor-α, thioredoxin domain containing 5), proliferation (chromosome 10 open reading frame 116), and inflammation [CCL7, chemokine (C-X-C motif) ligand 9, interleukin 26]. CONCLUSION: PCSK6 is upregulated in the synovial tissues of patients with RA and has a genetic effect on the risk of RA. Inhibition of PCSK6 may play a protective role in the development of RA.
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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) | 0.002 | 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".