Provenance and tectonic significance of late Mesoproterozoic detrital zircons from the Tonian system, northern margin of the North China Craton

<p>The involvement of the North China Craton (NCC) in the assembly or breakup of Rodinia has long been debated. Studies of palaeomagnetism, mafic sills (dikes), igneous events, and sedimentary records have led to contrasting opinions on this topic. No igneous events related to the late Mesoproterozoic assembly of Rodinia have been reported in the NCC. However, the authors found numerous late Mesoproterozoic zircons in the Tonian system on the northern margin of the NCC. The Tonian Zhulazhagamaodao formation is composed of meta-sandstone, siltstone, slate, carbonate, and dolomine of the littoral to neritic facies and occurs mainly in the western part of the Bayan Obo–Zhaertai–Langshan rift. U–Pb dating of detrital zircons from the Tonian system reveals age peaks at 1079 ± 23 Ma, 1092 ± 22 Ma, 1175 ± 50 Ma, 1175 ± 18 Ma, 1260 ± 45 Ma, 1266 ± 16 Ma, and 1270 ± 26 Ma, which correspond to the timing of Rodinia assembly. Considering that coeval igneous rocks and orogenic belts developed mostly in the Laurentia–Baltica cratons, we propose that these cratons supplied clastic material to the northern margin of the NCC and that they had a close spatial relationship between each other during the Tonian.</p

Relationship of binding-site occupancy, transthyretin stabilisation and disease modification in patients with tafamidis-treated transthyretin amyloid cardiomyopathy

Tafamidis inhibits progression of transthyretin (TTR) amyloid cardiomyopathy (ATTR-CM) by binding TTR tetramer and inhibiting dissociation to monomers capable of denaturation and deposition in cardiac tissue. While the phase 3 ATTR-ACT trial demonstrated the efficacy of tafamidis, the degree to which the approved dose captures the full potential of the mechanism has yet to be assessed. We developed a model of dynamic TTR concentrations in plasma to relate TTR occupancy by tafamidis to TTR stabilisation. We then developed population pharmacokinetic–pharmacodynamic models to characterise the relationship between stabilisation and measures of disease progression. Modelling individual patient data of tafamidis exposure and increased plasma TTR confirmed that single-site binding provides complete tetramer stabilisation in vivo. The approved dose was estimated to reduce unbound TTR tetramer by 92%, and was associated with 53%, 56% and 49% decreases in the rate of change in NT-proBNP, KCCQ-OS, and six-minute walk test disease progression measures, respectively. Simulating complete TTR stabilisation predicted slightly greater reductions of 58%, 61% and 54%, respectively. These findings support the value of TTR stabilisation as a clinically beneficial treatment option in ATTR-CM and the ability of tafamidis to realise nearly the full therapeutic benefit of this mechanism. NCT01994889</p

Interpretation and sensitivity analysis of the InSAR line of sight displacements in landslide measurements

Landslides are major geological hazards and frequently occur in mountainous areas with steep slopes, often causing significant loss. Interferometric Synthetic Aperture Radar (InSAR) has been widely used in landslide measurement over the last three decades. However, InSAR only can measure one-dimensional displacements (i.e. those in the radar’s line of sight (LOS) direction), resulting in the uncertainty between LOS displacement and the real slope displacement. In this paper, based on ascending and descending data from Sentinel-1 satellite, a wide-area potential landslide early identification was carried out using SBAS-InSAR in the whole of Mao County, a mountainous area in western Sichuan (China), with a total of 41 potential landslides successfully detected. Based on the quantitative analysis, the results show that the InSAR LOS measurement values are slope aspect and gradient-dependent. Finally, we innovatively derived a LOS displacement sensitivity map of InSAR in landslide measurement, revealing the relationship between LOS displacement, real displacements on slopes with arbitrary aspects and gradients, and SAR geometric distortion. This is a generalized finding useful for any slopes. It provides theoretical support to acquire and understand the real slope displacement from InSAR landslide measurement, which is vital to assist in correctly interpreting LOS displacement and carrying out subsequent quantitative geological engineering analysis

Optimization of a Dicarboxylic Series for in Vivo Inhibition of Citrate Transport by the Solute Carrier 13 (SLC13) Family

Inhibition of the sodium-coupled citrate transporter (NaCT or SLC13A5) has been proposed as a new therapeutic approach for prevention and treatment of metabolic diseases. In a previous report, we discovered dicarboxylate <b>1a</b> (PF-06649298) which inhibits the transport of citrate in in vitro and in vivo settings via a specific interaction with NaCT. Herein, we report the optimization of this series leading to <b>4a</b> (PF-06761281), a more potent inhibitor with suitable in vivo pharmacokinetic profile for assessment of in vivo pharmacodynamics. Compound <b>4a</b> was used to demonstrate dose-dependent inhibition of radioactive [¹⁴C]­citrate uptake in liver and kidney in vivo, resulting in modest reductions in plasma glucose concentrations