Ectopic Calcification and Hypophosphatemic Rickets: Natural History of ENPP1 and ABCC6 Deficiencies

Generalized arterial calcification of infancy (GACI) is a rare disorder caused by ENPP1 or ABCC6 variants. GACI is characterized by low pyrophosphate, arterial calcification, and high mortality during the first year of life, but the natural course and possible differences between the causative genes remain unknown. In all, 247 individual records for patients with GACI (from birth to 58.3 years of age) across 19 countries were reviewed. Overall mortality was 54.7% (13.4% in utero or stillborn), with a 50.4% probability of death before the age of 6 months (critical period). Contrary to previous publications, we found that bisphosphonate treatment had no survival benefit based on a start-time matched analysis and inconclusive results when initiated within 2 weeks of birth. Despite a similar prevalence of GACI phenotypes between ENPP1 and ABCC6 deficiencies, including arterial calcification (77.2% and 89.5%, respectively), organ calcification (65.8% and 84.2%, respectively), and cardiovascular complications (58.4% and 78.9%, respectively), mortality was higher for ENPP1 versus ABCC6 variants (40.5% versus 10.5%, respectively; p = 0.0157). Higher prevalence of rickets was reported in 70.8% of surviving affected individuals with ENPP1 compared with that of ABCC6 (11.8%; p = 0.0001). Eleven affected individuals presenting with rickets and without a GACI diagnosis, termed autosomal recessive hypophosphatemic rickets type 2 (ARHR2), all had confirmed ENPP1 variants. Approximately 70% of these patients demonstrated evidence of ectopic calcification or complications similar to those seen in individuals with GACI, which shows that ARHR2 is not a distinct condition from GACI but represents part of the spectrum of ENPP1 deficiency. Overall, this study identified an early mortality risk in GACI patients despite attempts to treat with bisphosphonates, high prevalence of rickets almost exclusive to ENPP1 deficiency, and a spectrum of heterogenous calcification and multiple organ complications with both ENPP1 and ABCC6 variants, which suggests an overlapping pathology. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR). This article has been contributed to by US Government employees and their work is in the public domain in the USA.     

Transduction pathways of GH in ovine mammary acini involving regulated and functional growth hormone receptors

We have investigated the localization and regulation of growth hormone (GH) receptor-related proteins in the ovine mammary gland. Using a new rabbit polyclonal antibody (7122A) directed against the recombinant extracellular domain of GH receptor (GHR-ECD) for western blot assays, we found two bands with apparent molecular weights of 70,000 and 50–60,000?Da in ovine mammary gland solubilized proteins. The 70,000-protein was consistent with a membrane GH receptor form deprived of post-translational modifications such as phosphorylation, glycosylation or ubiquitin binding. The 50–60,000?Da was consistent with soluble GH binding protein, generated by the cleavage of membrane GH receptor. The intensity of related GHR proteins increased slightly throughout mammary gland development and was correlated with the amount of GHR immunoreactivity observed in the mammary gland sections. Moreover, a temporal and spatial regulation of GHR immunoreactivity was found in alveolar epithelial cells. Clearly, marked GHR immunoreactivity was associated with the apical membranes of alveolar epithelial cells at lactation. The up-regulation of related GHR proteins during the differentiation of mammary tissue supports the hypothesis that GH may act specifically via its own receptors. In ovine mammary cells, GH was able to promote a time-dependent activation of MAP kinases such as prolactin (Prl) and placental lactogen (PL). GH was also able to promote slight and transient Stat5 DNA-binding activity. Differences in the time dependence of Stat5 DNA-binding activation by the three different ligands, GH, Prl and PL, were found. All these results emphasize the direct action of GH on ovine mammary cells and highlight the specificity of action of this ligand.     

Aging-like Spontaneous Epigenetic Silencing Facilitates Wnt Activation,Stemness, and BrafV600E-Induced Tumorigenesis

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Global silicate weathering flux overestimated because of sediment–water cation exchange

Rivers carry the dissolved and solid products of silicate mineral weathering, a process that removes CO2 from the atmosphere and provides a key negative climate feedback over geological timescales. Here we show that, in some river systems, a reactive exchange pool on river suspended particulate matter, bonded weakly to mineral surfaces, increases the mobile cation flux by 50%. The chemistry of both river waters and the exchange pool demonstrates exchange equilibrium, confirmed by Sr isotopes. Global silicate weathering fluxes are calculated based on riverine dissolved sodium (Na⁺) from silicate minerals. The large exchange pool supplies Na⁺ of nonsilicate origin to the dissolved load, especially in catchments with widespread marine sediments, or where rocks have equilibrated with saline basement fluids. We quantify this by comparing the riverine sediment exchange pool and river water chemistry. In some basins, cation exchange could account for the majority of sodium in the river water, significantly reducing estimates of silicate weathering. At a global scale, we demonstrate that silicate weathering fluxes are overestimated by 12 to 28%. This overestimation is greatest in regions of high erosion and high sediment loads where the negative climate feedback has a maximum sensitivity to chemical weathering reactions. In the context of other recent findings that reduce the net CO2 consumption through chemical weathering, the magnitude of the continental silicate weathering fluxes and its implications for solid Earth CO2 degassing fluxes need to be further investigated.

For decades, silicate weathering has been postulated to provide the negative climate feedback on Earth that prevents a runaway greenhouse climate like on Venus (1). Silicate mineral dissolution with carbonic acid converts atmospheric CO2 into carbonate, and releases essential nutrients to the terrestrial and marine biosphere (2). There have been many attempts to quantify the silicate weathering flux (3), mostly assuming that riverine dissolved sodium (Na+) is derived only from silicate minerals and rock salt. Here we show that there is a major addition of nonsilicate Na+ to the critical zone from ancient seawater, weakly bonded to sedimentary rocks and supplied to waters via the cation exchange process. The implication is not only that the silicate weathering flux is overestimated at a global scale, but that this nonsilicate Na+ is most important in regions previously thought to have the highest silicate weathering fluxes (so called weathering-limited regions) and greatest climate sensitivity.Cation exchange is a rapid chemical reaction between cations in the dissolved phase and mineral surfaces, particularly clays (4). Major and trace cations such as calcium (Ca2+), magnesium (Mg2+), sodium (Na+), potassium (K+), and strontium (Sr2+) form the cation exchange pool, which balances negative charges on river-borne clay particle surfaces. This exchange takes place on interlayer sites, between the tetrahedral and octahedral layers, or on exposed surfaces (4). The importance of the cation exchange pool is well recognized in soils and aquifers (4, 5), has significant implications for enhanced weathering (6), and has been proposed as an important mechanism for buffering the composition of river waters (7–9). However, data on the riverine exchange pool are only available for two large river systems [Amazon and Ganges-Brahmaputra (10, 11)], despite its significance in providing a source of elements that are immediately bioavailable (12), and their potential for biasing the quantification of silicate weathering (9).It is increasingly recognized that rapidly reactive phases have a strong influence on the chemistry of river waters (13, 14). Cation exchange is a rapid reaction occurring continuously in soils, as riverine freshwaters evolve downstream interacting with particulate matter, and when they mix with seawater (15, 16). Important examples of cation exchange are the “swapping” of divalent cations Ca2+ and Mg2+ with Na+, in particular when there is a major change in water composition such as when fluvial clays reach the ocean,Caclay2++2Nawater+⇋2Naclay++Cawater2+.[1]As a result, marine sediments have an exchange pool that is dominated by Na+ (17). Subsequently, these marine sediments are uplifted and emplaced on the continents where Na+ in the exchange pool is released by cation exchange with Ca-rich fresh waters (9). This has major implications for estimates of silicate weathering fluxes and associated CO2 consumption, because they are calculated using the Na+ content of rivers (3). Cerling et al. (9) proposed that the Na+-rich exchange pool exerts an important control on natural waters, based on charge balance arguments from river water chemistry, but this hypothesis has never been rigorously tested (18) by determining the flux and composition of the exchange pool of rivers around the world.In this contribution, we present a large dataset of fluvial sediment cation exchange capacity (CEC) and composition in several of the world’s largest river basins. By comparing with the concomitant dissolved load chemistry, we demonstrate that 1) the exchange pool in river sediments is in equilibrium with the river water; 2) the fraction of mobile elements in the exchange pool relative to the dissolved pool can be significant, particularly in rapidly eroding, weathering-limited catchments; and 3) given reasonable inferences on the composition of old marine sedimentary rocks, modern-day silicate weathering has been overestimated and carbonate weathering has been underestimated. The results reduce the estimated magnitude of the silicate weathering flux, but increase the supply of base cations (e.g., Ca2+, which can be a limiting nutrient) to the biosphere, suggesting a greater role of organic carbon burial compared with silicate weathering for the long-term atmospheric CO2 sink.     

Randomized,double-blind,controlled trial of pneumococcal vaccination in renal transplant recipients

Renal transplant recipients are at increased risk for developing invasive pneumococcal disease but may have a poor response to pneumococcal polysaccharide vaccine (PPV23). For them, pneumococcal conjugate vaccine (PCV7) may be more immunogenic. Patients were given a single dose of PPV23 or PCV7 in our randomized, controlled, double-blind trial. Immunogenicity was assessed 8 weeks after vaccination by serotype-specific enzyme-linked immunosorbent assay (ELISA) and opsonophagocytic assay (OPA). Baseline demographics, renal function, time since transplantation, and immunosuppression were comparable. In the PCV7 group, the vaccine response rate was improved for serotypes 23F (P=.046) and 6B (P=.067), and mean fold increases in antibody titer were higher for serotypes 23F (P=.046) and 9V (P=.09). The response rate and mean fold increase in OPA titers were not significantly different between groups. There was a trend toward enhanced immunogenicity for PCV7 by ELISA. However, functional antibody responses were not different.