Effects of vitamin D supplementation on FGF23: a randomized-controlled trial.

PURPOSE: Fibroblast growth factor-23 (FGF23) is critical for phosphate homeostasis. Considering the high prevalence of vitamin D deficiency and the association of FGF23 with adverse outcomes, we investigated effects of vitamin D3 supplementation on FGF23 concentrations. METHODS: This is a post-hoc analysis of the Styrian Vitamin D Hypertension trial, a single-center, double-blind, randomized, placebo-controlled trial, conducted from 2011 to 2014 at the Medical University of Graz, Austria. Two hundred subjects with 25(OH)D concentrations < 30 ng/mL and arterial hypertension were randomized to receive either 2800 IU of vitamin D3 daily or placebo over 8 weeks. Primary outcome was the between-group difference in FGF23 levels at study end while adjusting for baseline values. RESULTS: Overall, 181 participants (mean ± standard deviation age, 60.1 ± 11.3; 48% women) with available c-term FGF23 concentrations were considered for the present analysis. Mean treatment duration was 54 ± 10 days in the vitamin D3 group and 54 ± 9 days in the placebo group. At baseline, FGF23 was significantly correlated with serum phosphate (r = 0.135; p = 0.002). Vitamin D3 supplementation had no significant effect on FGF23 in the entire cohort (mean treatment effect 0.374 pmol/L; 95% confidence interval - 0.024 to 0.772 pmol/L; p = 0.065), but increased FGF23 concentrations in subgroups with baseline 25(OH)D concentrations below 20 ng/mL (n = 70; mean treatment effect 0.973 pmol/L; 95% confidence interval - 0.032 to 1.979 pmol/L; p = 0.019) and 16 ng/mL (n = 40; mean treatment effect 0.593 pmol/L; 95% confidence interval 0.076 to 1.109; p = 0.022). CONCLUSIONS: Vitamin D3 supplementation had no significant effect on FGF23 in the entire study cohort. We did, however, observe an increase of FGF23 concentrations in subgroups with low baseline 25(OH)D.

Unexpectedly broad target recognition of the CRISPR-mediated virus defence system in the archaeon Sulfolobus solfataricus.

The hyperthermophilic archaeon Sulfolobus solfataricus carries an extensive array of clustered regularly interspaced short palindromic repeats (CRISPR) systems able to mediate DNA degradation of invading genetic elements when complementarity to the small CRISPR-derived (cr)RNAs is given. Studying virus defence in vivo with recombinant viral variants, we demonstrate here that an unexpectedly high number of mutations are tolerated between the CRISPR-derived guide RNAs (crRNAs) and their target sequences (protospacer). Up to 15 mismatches in the crRNA still led to ∼50% of DNA degradation, when these mutations were outside the 'seed' region. More than 15 mutations were necessary to fully abolished interference. Different from other CRISPR systems investigated in vivo, mutations outside the protospacer region indicated no need for a protospacer adjacent motif sequence to confer DNA interference. However, complementarity of only 3 nucleotides between the repeat-derived 5' handle of the crRNA and nucleotides adjacent to the protospacer enabled self-recognition, i.e. protection of the host locus. Our findings show commonalities and differences among the various CRISPR-mediated defence systems and suggest that they should not merely be perceived as a 'first-barrier-defence system' but may be considered to have a broader mechanism that allows host cells to cope with viruses keeping them at reduced levels.