Various disorders including pseudoxanthoma elasticum (PXE) and generalized arterial calcification of infancy (GACI), which are caused by inactivating mutations in ABCC6 and ENPP1, respectively, present with extensive tissue calcification due to reduced plasma pyrophosphate (PPi). However, it has always been assumed that the bioavailability of orally administered PPi is negligible. Here, we demonstrate increased PPi concentration in the circulation of humans after oral PPi administration. Furthermore, in mouse models of PXE and GACI, oral PPi provided via drinking water attenuated their ectopic calcification phenotype. Noticeably, provision of drinking water with 0.3 mM PPi to mice heterozygous for inactivating mutations in Enpp1 during pregnancy robustly inhibited ectopic calcification in their Enpp1
−/− offspring. Our work shows that orally administered PPi is readily absorbed in humans and mice and inhibits connective tissue calcification in mouse models of PXE and GACI. PPi, which is recognized as safe by the FDA, therefore not only has great potential as an effective and extremely low‐cost treatment for these currently intractable genetic disorders, but also in other conditions involving connective tissue calcification.
Since 1997 a considerable effort has been spent to study the mixing time of switch Markov chains on the realizations of graphic degree sequences of simple graphs. Several results were proved on rapidly mixing Markov chains on unconstrained, bipartite, and directed sequences, using different mechanisms. The aim of this paper is to unify these approaches. We will illustrate the strength of the unified method by showing that on any P -stable family of unconstrained/bipartite/directed degree sequences the switch Markov chain is rapidly mixing. This is a common generalization of every known result that shows the rapid mixing nature of the switch Markov chain on a region of degree sequences. Two applications of this general result will be presented. One is an almost uniform sampler for power-law degree sequences with exponent γ > 1 + √ 3. The other one shows that the switch Markov chain on the degree sequence of an Erds-Rnyi random graph G(n, p) is asymptotically almost surely rapidly mixing if p is bounded away from 0 and 1 by at least 5 log n n−1 .
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