Oscillatory stimuli differentiate adapting circuit topologies

This is the author accepted manuscript. The final version is available from Springer Nature via the DOI in this record.Biology emerges from interactions between molecules, which are challenging to elucidate with current techniques. An orthogonal approach is to probe for 'response signatures' that identify specific circuit motifs. For example, bistability, hysteresis, or irreversibility are used to detect positive feedback loops. For adapting systems, such signatures are not known. Only two circuit motifs generate adaptation: negative feedback loops (NFLs) and incoherent feed-forward loops (IFFLs). On the basis of computational testing and mathematical proofs, we propose differential signatures: in response to oscillatory stimulation, NFLs but not IFFLs show refractory-period stabilization (robustness to changes in stimulus duration) or period skipping. Applying this approach to yeast, we identified the circuit dominating cell cycle timing. In Caenorhabditis elegans AWA neurons, which are crucial for chemotaxis, we uncovered a Ca2+ NFL leading to adaptation that would be difficult to find by other means. These response signatures allow direct access to the outlines of the wiring diagrams of adapting systems.The work was supported by US National Institutes of Health grant 5RO1-GM078153-07 (F.R.C.), NRSA Training Grant CA009673-36A1 (S.J.R.), a Merck Postdoctoral Fellowship at The Rockefeller University (S.J.R.), and the Simons Foundation (S.J.R.). J.L. was supported by a fellowship from the Boehringer Ingelheim Fonds. E.D.S. was partially supported by the US Office of Naval Research (ONR N00014-13-1-0074) and the US Air Force Office of Scientific Research (AFOSR FA9550-14-1-0060)

Anti-carbamylated protein antibodies in unaffected first-degree relatives of rheumatoid arthritis patients: lack of correlation with anti-cyclic citrullinated protein antibodies and rheumatoid factor

OBJECTIVES: To investigate the prevalence of anti-carbamylated protein antibodies (anti-CarP) in the healthy first-degree relatives (HFDRs) of patients with rheumatoid arthritis (RA). METHODS: We enrolled 141 HFDRs of 63 patients with RA diagnosed accordingly to the 2010 ACR/EULAR criteria. Fifty-six normal healthy subjects (NHS), sex- and age-matched, served as controls. Anti-CarP IgG, anti-cyclic citrullinated peptide antibody (anti-CCP) IgG and rheumatoid factors (RF) isotypes (IgG, IgA, IgM) were assessed by solid-phase ELISA. RESULTS: Anti-CarP were detectable in 13 HFDRs (9.2%), anti-CCP in 9 (6.3%), IgG-RF in 10 (7%), IgA-RF in 17 (12%), and IgM-RF in 13 (9.2%) HFDRs. Twenty-nine (46%) RA patients were positive for anti-CarP, 31 (49.2%) for anti-CCP, and 34 (53.9%) for RF. One NHS (1.7%) resulted positive for anti-CarP, none for anti-CCP and RF. Anti-CarP showed significantly higher serum levels in RA and HFDRs than in NHS (p<0.0001 and p=0.0012, respectively). A significant correlation between anti-CCP and RF were found among RA patients (p=0.0002), whereas no correlations were reported between autoantibodies tested in the HFDRs. CONCLUSIONS: Anti-CarP can be found in the sera of HFDRs of RA patients and their prevalence is significantly higher than in NHS. No correlation of anti-CarP with anti-CCP and RF antibodies in RA HFDRs was found

Microparticles and autophagy: a new frontier in the understanding of atherosclerosis in rheumatoid arthritis

Microparticles (MPs) are small membrane vesicles released by many cell types under physiological and pathological conditions. In the last years, these particles were considered as inert cell debris, but recently many studies have demonstrated they could have a role in intercellular communication. Increased levels of MPs have been reported in various pathological conditions including infections, malignancies, and autoimmune diseases, such as rheumatoid arthritis (RA). RA is an autoimmune systemic inflammatory disease characterized by chronic synovial inflammation, resulting in cartilage and bone damage with accelerated atherosclerosis increasing mortality. According to the literature data, also MPs could have a role in endothelial dysfunction, contributing to atherosclerosis in RA patients. Moreover many researchers have shown that a dysregulated autophagy seems to be involved in endothelial dysfunction. Autophagy is a reparative process by which cytoplasmic components are sequestered in double-membrane vesicles and degraded on fusion with lysosomal compartments. It has been shown in many works that basal autophagy is essential to proper vascular function. Taking into account these considerations, we hypothesized that in RA patients MPs could contribute to atherosclerosis process by dysregulation of endothelial autophagy process

Anti-carbamylated protein antibodies in systemic lupus erythematosus patients with articular involvement

Objective Several studies have evaluated the prevalence of rheumatoid factor (RF) and anti-citrullinated proteins antibodies (ACPA) in systemic lupus erythematosus (SLE) patients but no data are available on the anti-carbamylated proteins (anti-CarP), a new biomarker for rheumatoid arthritis (RA). We evaluated the anti-CarP prevalence in SLE patients with joint involvement and the associations with different phenotypes. Methods Seventy-eight SLE patients with joint involvement were enrolled (F/M 73/5; mean ± SD age 47.6 ± 11.2 years; mean ± SD disease duration 214.3 ± 115.6 months). As control groups, we evaluated SLE patients without joint manifestations ( N = 15), RA ( N = 78) and healthy individuals (HS, N = 98). Anti-CarP were assessed by home-made ELISA in all patients and controls, RF and ACPA in SLE patients with joint involvement (commercial ELISA kit). Results The prevalence of anti-CarP in SLE patients with joint involvement was similar to RA ( p = NS) and significantly higher compared with SLE without joint involvement and HS ( p < 0.0001, p < 0.0001, respectively). Four patients were positive for all three antibodies: seventy-five percent of these showed Jaccoud arthropathy. Fourty-five percent of ACPA-ve/RF-ve patients were anti-CarP + ve. Conclusions The evaluation of anti-CarP in SLE joint involvement demonstrated a prevalence of almost 50%, similar to RA and significantly higher than SLE without joint involvement and HS