Martensson, J. | Search bioRxiv

bioRxiv2018

Allosteric receptor modulation of FFA2R turns natural agonists into potent activators of the superoxide generating neutrophil NADPH-oxidase

Acetate, agonist for the free fatty acid receptor 2 (FFA2R/GPR43), triggers an increase in the cytosolic concentration of free Ca2+ in neutrophils without any assembly of the superoxide generating NADPH-oxidase. We show that the phenylacetamide compound 58 (Cmp58; (S)-2-(4-chlorophenyl)-3,3-dimethyl-N-(5-phenylthiazol-2-yl)butanamide, lacking a direct activating effect on neutrophils, acts as a positive allosteric FFA2R modulator that turns acetate into a potent activating agonist that triggers an assembly of the NADPH-oxidase. The NADPH-oxidase activity could be further increased in neutrophils treated with the pro-inflammatory cytokine TNF. Many neutrophil chemoattractant receptors are stored in secretory organelles but no FFA2R mobilization was induced in neutrophils treated with TNF. The receptor selectivity was demonstrated through the inhibition of the neutrophil response induced by the combined action of acetate and Cmp58 by the FFA2R antagonist CATPB. Allosteric modulators that positively co-operate with natural FFA2R agonists and prime neutrophils in their response to such agonists, may serve as good tools for further unraveling the physiological functions of the FFA2R and its involvement in various diseases. In this study, allosteric modulation of FFA2R is introduced as a novel receptor selective mechanism to prime neutrophils to produce increased amounts of reactive oxygen species.

cell biology↗

bioRxiv2016

Resting-state fMRI correlations: from link-wiseunreliability to whole brain stability

The functional architecture of spontaneous BOLD fluctuations has been characterized in detail by numerous studies, demonstrating its potential relevance as a biomarker. However, the systematic investigation of its consistency is still in its infancy. Here, we analyze both the within- and between-subject variability as well as the test-retest reliability of resting-state functional connectivity (FC) estimates in a unique data set comprising multiple fMRI scans (42) from 5 subjects, and 50 single scans from 50 subjects. To this aim we adopted a statistical framework enabling us to disentangle the contribution of different sources of variability and their dependence on scan duration, and showed that the low reliability of single links can be largely improved using multiple scans per subject. Moreover, we show that practically all observed inter-region variability (at the link-level) is not significant and due to the statistical uncertainty of the estimator itself rather than to genuine variability among areas. Finally, we use the proposed statistical framework to demonstrate that, despite the poor consistency of single links, the information carried by the whole-brain spontaneous correlation structure is indeed robust, and can in fact be used as a functional fingerprint.

neuroscience↗