Elevated dietary magnesium during pregnancy and postnatal life prevents ectopic mineralization in Enpp1asj mice, a model for generalized arterial calcification of infancy.

Generalized arterial calcification of infancy (GACI) is an autosomal recessive disorder caused by mutations in the ENPP1 gene. It is characterized by mineralization of the arterial blood vessels, often diagnosed prenatally, and associated with death in early childhood. There is no effective treatment for this devastating disorder. We previously characterized the Enpp1asjmutant mouse as a model of GACI, and we have now explored the effect of elevated dietary magnesium (five-fold) in pregnant mothers and continuing for the first 14 weeks of postnatal life. The mothers were kept on either control diet or experimental diet supplemented with magnesium. Upon weaning at 4 weeks of age the pups were placed either on control diet or high magnesium diet. The degree of mineralization was assessed at 14 weeks of age by histopathology and a chemical calcium assay in muzzle skin, kidney and aorta. Mice placed on high magnesium diet showed little, if any, evidence of mineralization when their corresponding mothers were also placed on diet enriched with magnesium during pregnancy and nursing. The reduced ectopic mineralization in these mice was accompanied by increased calcium and magnesium content in the urine, suggesting that magnesium competes calcium-phosphate binding thereby preventing the mineral deposition. These results have implications for dietary management of pregnancies in which the fetus is suspected of having GACI. Moreover, augmenting a diet with high magnesium may be beneficial for other ectopic mineralization diseases, including nephrocalcinosis

The Minimal UV-induced Effective QCD Axion Theory

The characteristic axion couplings could be generated via effective couplings between the Standard Model (SM) fermions to a pseudo-Goldstone from a high-scale $U(1)$ Peccei-Quinn (PQ) symmetry breaking. Assuming that the UV-induced effective operators generate necessary couplings before the PQ symmetry breaking, and any low-scale couplings to the SM are restricted to the Yukawa sector, three minimal natural scenarios can be formulated, which provides a connection between the QCD-axions and mediators at the GUT/string scales. We find that the PQ symmetry breaking scale could be about $10^{15}$ GeV, higher than the classical QCD dark matter axion window but possible if the anthropic window is considered. We also propose an experiment to probe such scenarios. If the dark matter axion is discovered, they might suggest that we live in an atypical Hubble volume.Comment: 4 page

Novel Treatments for PXE: Targeting the Systemic and Local Drivers of Ectopic Calcification

Pseudoxanthoma elasticum (PXE) is a heritable multisystem ectopic calcification disorder. The gene responsible for PXE, ABCC6, encodes ABCC6, a hepatic efflux transporter regulating extracellular inorganic pyrophosphate (PPi), a potent endogenous calcification inhibitor. Recent studies demonstrated that in addition to the deficiency of plasma PPi, the activated DDR/PARP signaling in calcified tissues provides an additional possible mechanism of ectopic calcification in PXE. This study examined the effects of etidronate (ETD), a stable PPi analog, and its combination with minocycline (Mino), a potent inhibitor of DDR/PARP, on ectopic calcification in an Abcc6-/- mouse model of PXE. Abcc6-/- mice, at 4 weeks of age, before the development of ectopic calcification, were treated with ETD, Mino, or both for 18 weeks. Micro-computed tomography, histopathologic examination, and quantification of the calcium content in Abcc6-/- mice treated with both ETD and Mino revealed further reduced calcification than either treatment alone. The effects were associated with reduced serum alkaline phosphatase activity without changes in plasma PPi concentrations. These results suggest that ETD and Mino combination therapy might provide an effective therapeutic approach for PXE, a currently intractable disease

Etidronate prevents, but does not reverse, ectopic mineralization in a mouse model of pseudoxanthoma elasticum (

Pseudoxanthoma elasticum (PXE) and generalized arterial calcification of infancy (GACI) are heritable disorders manifesting with ectopic tissue mineralization. Most cases of PXE and some cases of GACI are caused by mutations in the ABCC6 gene, resulting in reduced plasma pyrophosphate (PPi) levels. There is no effective treatment for these disorders. It has been suggested that administration of bisphosphonates, stable and non-hydrolyzable PPi analogs, could counteract ectopic mineralization in these disorders. In this study we tested the potential efficacy of etidronate, a first generation bisphosphonate, on ectopic mineralization in the muzzle skin of Abcc6-/- mice, a model of PXE. The Abcc6-/- mice received subcutaneous injections of etidronate, 0.283 and 3.40 mg/kg per injection (0.01× and 0.12×), twice a week, in both prevention and reversal studies. Ectopic mineralization in the dermal sheath of vibrissae in muzzle skin was determined by histopathologic analysis and by direct chemical assay for calcium content. Subcutaneous injection of etidronate prevented ectopic mineralization but did not reverse existing mineralization. The effect of etidronate was accompanied by alterations in the trabecular bone microarchitecture, determined by micro-computed tomography. The results suggest that etidronate may offer a potential treatment modality for PXE and GACI caused by ABCC6 mutations. Etidronate therapy should be initiated in PXE patients as soon as the diagnosis is made, with careful monitoring of potential side effects

Towards human-compatible autonomous car: A study of non-verbal Turing test in automated driving with affective transition modelling

Autonomous cars are indispensable when humans go further down the hands-free route. Although existing literature highlights that the acceptance of the autonomous car will increase if it drives in a human-like manner, sparse research offers the naturalistic experience from a passenger's seat perspective to examine the human likeness of current autonomous cars. The present study tested whether the AI driver could create a human-like ride experience for passengers based on 69 participants' feedback in a real-road scenario. We designed a ride experience-based version of the non-verbal Turing test for automated driving. Participants rode in autonomous cars (driven by either human or AI drivers) as a passenger and judged whether the driver was human or AI. The AI driver failed to pass our test because passengers detected the AI driver above chance. In contrast, when the human driver drove the car, the passengers' judgement was around chance. We further investigated how human passengers ascribe humanness in our test. Based on Lewin's field theory, we advanced a computational model combining signal detection theory with pre-trained language models to predict passengers' humanness rating behaviour. We employed affective transition between pre-study baseline emotions and corresponding post-stage emotions as the signal strength of our model. Results showed that the passengers' ascription of humanness would increase with the greater affective transition. Our study suggested an important role of affective transition in passengers' ascription of humanness, which might become a future direction for autonomous driving.Comment: 16 pages, 9 figures, 3 table