Functionally confirmed compound heterozygous ADAM17 missense loss-of-function variants cause neonatal inflammatory skin and bowel disease 1

A disintegrin and metalloprotease 17 (ADAM17) is the major sheddase that processes more than 80 substrates, including tumour necrosis factor-α (TNFα). The homozygous genetic deficiency of ADAM17 causing a complete loss of ADAM17 expression was reported to be linked to neonatal inflammatory skin and bowel disease 1 (NISBD1). Here we report for the first time, a family with NISBD1 caused by functionally confirmed compound heterozygous missense variants of ADAM17, namely c.1699T>C (p.Cys567Arg) and c.1799G>A (p.Cys600Tyr). Both variants were detected in two siblings with clinical features of NISBD1, such as erythroderma with exudate in whole body, recurrent skin infection and sepsis and prolonged diarrhoea. In a cell-based assay using Adam10/17 double-knockout mouse embryonic fibroblasts (Adam10/17−/− mEFs) exogenously expressing each of these mutants, phorbol 12-myristate 13-acetate-stimulated shedding was strongly reduced compared with wild-type ADAM17. Thus, in vitro functional assays demonstrated that both missense variants cause the loss-of-function of ADAM17, resulting in the development of NISBD1. Our study further expands the spectrum of genetic pathology underlying ADAM17 in NISBD1 and establishes functional assay systems for its missense variants

Simultaneous generation of ultrahigh pressure and temperature to 50 GPa and 3300 K in multi-anvil apparatus

We attempted to generate ultrahigh pressure and temperature simultaneously using a multi-anvil apparatus by combining the technologies of ultrahigh-pressure generation using sintered diamond (SD) anvils, which can reach 120 GPa, and ultrahigh-temperature generation using a boron-doped diamond (BDD) heater, which can reach 4000 K. Along with this strategy, we successfully generated a temperature of 3300 K and a pressure of above 50 GPa simultaneously. Although the high hardness of BDD significantly prevents high-pressure generation at low temperatures, its high-temperature softening allows for effective pressure generation at temperatures above 1200 K. High temperature also enhances high-pressure generation because of the thermal pressure. We expect to generate even higher pressure in the future by combining SD anvils and a BDD heater with advanced multi-anvil technology

Depressed 660-km discontinuity caused by akimotoite-bridgmanite transition

The 660-km seismic discontinuity is the boundary between the Earth’s lower mantle and transition zone and is commonly interpreted as the dissociation of ringwoodite to bridgmanite plus ferropericlase (post-spinel transition)1-3. A distinct feature of the 660-km discontinuity is its depression to 750 km beneath subduction zones4-10. However, in situ X-ray diffraction studies using multianvil techniques have demonstrated negative but gentle Clapeyron slopes of the post-spinel transition that do not allow a significant depression11-13. On the other hand, conventional high-pressure experiments face difficulties in accurate phase identification due to inevitable pressure changes during heating and the persistent presence of metastable phases1,3. Here, we determined the post-spinel and akimotoite-bridgmanite transition boundaries by multi-anvil experiments using in situ X-ray diffraction strictly based on the definition of phase equilibrium. The post-spinel boundary has almost no temperature dependence, whereas the akimotoite–bridgmanite transition has a very steep negative boundary at temperatures lower than ambient mantle geotherms. The large depressions of the 660-km discontinuity in cold subduction zones are thus interpreted as the akimotoite–bridgmanite transition. The steep negative boundary of the akimotoite-bridgmanite transition will cause slab stagnation due to significant upward buoyancy14,15

Liquid Structure of Tantalum under Internal Negative Pressure

International audienceIn situ femtosecond x-ray diffraction measurements and ab initio molecular dynamics simulations were performed to study the liquid structure of tantalum shock released from several hundred gigapascals (GPa) on the nanosecond timescale. The results show that the internal negative pressure applied to the liquid tantalum reached −5.6 ð0.8Þ GPa, suggesting the existence of a liquid-gas mixing state due to cavitation. This is the first direct evidence to prove the classical nucleation theory which predicts that liquids with high surface tension can support GPa regime tensile stress

Liquid structure of tantalum under internal negative pressure

In situ femtosecond x-ray diffraction measurements and ab initio molecular dynamics simulations were performed to study the liquid structure of tantalum shock-released from several hundred gigapascals (GPa) to the ambient condition on the nanosecond timescale. The results show that the internal negative pressure applied to the liquid tantalum reached -5.6 (0.8) GPa, suggesting the existence of a liquid-gas mixing state due to cavitation. This is the first direct evidence to prove the classical nucleation theory which predicts that liquids with high surface tension can support GPa regime tensile stress