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Mibavademab (previously known as REGN4461), a fully human monoclonal antibody, is being investigated for the treatment of conditions associated with leptin deficiency. Here, we report pharmacokinetics (PKs), pharmacodynamics, and immunogenicity from a phase I study in healthy participants (NCT03530514). In part A, lean or overweight healthy participants were randomized to single‐ascending‐dose cohorts of 0.3, 1.0, 3.0, 10, and 30 mg/kg intravenous (i.v.), or 300 and 600 mg subcutaneous doses of mibavademab or placebo. In part B, overweight or obese participants were randomized to receive multiple doses of mibavademab (15 mg/kg i.v. loading dose and 10 mg/kg i.v. at weeks 3, 6, and 9) or placebo, stratified by body mass index and baseline leptin levels: low leptin (<5 ng/mL) or relatively low leptin (5–8 ng/mL in men and 5–24 ng/mL in women). Fifty‐six and 55 participants completed the single‐ascending‐dose and multiple‐dose parts, respectively. In the single‐ascending‐dose cohorts, mibavademab PKs were nonlinear with target‐mediated elimination, greater than dose‐proportional increases in exposure, and there were no dose‐dependent differences in total soluble leptin receptor (sLEPR) levels in serum over time. Following multiple‐dose administration of mibavademab in participants with leptin <8 ng/mL, lower mean mibavademab concentrations, higher mean total sLEPR concentrations, and larger mean decreases in body weight than in the relatively low leptin cohorts were observed. Baseline leptin was correlated with mibavademab PKs and pharmacodynamics. No treatment‐emergent anti‐mibavademab antibodies were observed in any mibavademab‐treated participant. Results from this study collectively inform further development of mibavademab to treat conditions associated with leptin deficiency. [ABSTRACT FROM AUTHOR]

We investigate the present‐day strike‐slip faulting and intracontinental deformation of North China using horizontal GPS velocities and a block modeling strategy. The data demonstrate that the fault slip rates and block rotations in North China can be better constrained using GPS velocities where the influence of groundwater extraction has been reduced by applying median spatial filtering of the velocity field. The modeled senses of motion and slip rates on active faults are generally in good agreement with the geological estimates. The left‐lateral slip rate along the boundary fault of Weihe Graben is apparently lower than the differential motion between the South China Block and Ordos Block. The missing left‐lateral slip is accommodated by the counterclockwise rotation of the Ordos Block. The sinistral slip rate along the eastern segment of the Altyn Tagh‐Haiyuan‐Qinling fault system decreases eastward from ∼1.0 to ∼0 mm/yr, much slower than that expected in the fast eastward extrusion hypothesis. We interpret the systematic counterclockwise rotation of blocks and left/right‐lateral faulting in North China to be driven both by the left‐lateral shear between the South China Block to the south and Yinshan‐Yanshan Block to the north and a push from the Tibetan Plateau on the southwestern margin of the Ordos Block. Plain Language Summary: North China is in a complex tectonic regime with all types of faults (strike‐slip, normal, and thrust faults) around its margins and internal blocks rotating counterclockwise. Why and how such a complex deformation occurs in North China is a crucial scientific question but unsolved. Based on the newly improved GPS data, we quantitatively determined the present‐day fault slip rates and block rotations in and around North China. Our research indicates a low left‐lateral slip rate (0–1.0 mm/yr) along faults between North China and South China, in contrast to much faster values (8 to >10 mm/yr) given in previous studies and expected by the continental escape hypothesis. Therefore, we propose that the complex tectonic deformation in North China is mainly driven by both left‐lateral shear between South China and Yinshan‐Yanshan Block and an eastward push from the Tibetan Plateau at the southwestern margin of the Ordos Block in western North China. Key Points: Geodetic data are used to obtain fault slip rates on North China using a carefully regularized block model and noise‐reduced GPS velocitiesLeft‐lateral slip rate at the eastern termination of the South China Block extrusion boundary decreases eastward from ∼1.0 to ∼0 mm/yrRight‐later shear in the Shanxi Graben results from a combination of block rotations and relative motions [ABSTRACT FROM AUTHOR]

Itepekimab is a monoclonal antibody that targets interleukin (IL‐33) and has been shown to reduce airway inflammation and associated tissue damage in preclinical studies. We assessed the safety, tolerability, pharmacokinetics (PKs), and pharmacodynamic profiles of single‐ascending and multiple‐ascending doses of itepekimab in two randomized, double‐blind, placebo‐controlled phase I studies. Healthy adults (N = 40) were randomized to the single‐dose study and patients with moderate asthma (N = 23) to the multiple‐dose study. Itepekimab was administered intravenously (0.3, 1, 3, or 10 mg/kg infusion) or subcutaneously (150 mg) in the single‐dose study and subcutaneously (75 or 150 mg weekly for 4 weeks) in the multiple‐dose study. Itepekimab exhibited linear PKs across studies and dose‐proportional increases in mean maximum concentration in serum and area under the concentration–time curve following single intravenous or multiple subcutaneous doses. Itepekimab demonstrated mean subcutaneous bioavailability of 59–73% and a long terminal half‐life (30.0–31.6 days). IL‐33 concentrations in most healthy participants and patients with asthma were undetectable at baseline. Following administration of itepekimab in both studies, total IL‐33 concentrations increased and blood eosinophils decreased, both with durable effect. Itepekimab was well‐tolerated in both studies with no detection of treatment‐emergent anti‐drug antibody responses. [ABSTRACT FROM AUTHOR]

Tectonic deformation of blocks neighboring fault zones has been thought to aid in accommodating regional displacements. In general, these block‐bounding faults possess continuous geometry and similar kinematics. However, the northwestern boundary of the Tianshan Mountains (NWBTS) involves two groups of faults that strike NW and NE. GPS velocities show that contemporary deformation takes place in a zone of 300 km wide in the NWBTS and is roughly dominated by left‐lateral shear. Left‐lateral shear motion of ∼5–6 mm/yr along the NWBTS is accommodated by right‐lateral slip and counterclockwise rotation of fault wallrocks on the NW‐striking faults and left‐lateral faulting on the NE‐striking faults. Present‐day deformation associated with the ongoing India‐Eurasia collision in the NWBTS is best described as the opposite sense of strike‐slip faulting and crustal rotation. The difference in lithospheric strengthening between the Kazakh Platform and Tianshan deflects strain toward the northeast and drives the dynamic process in this region. Plain Language Summary: The NWBTS has undergone notable tectonic deformation, which involves two groups of NW‐striking and NE‐striking faults instead of displacement only along a major bounding fault. How the two groups of faults interact to bound this deformation boundary belt and accommodate the regional strain associated with the ongoing India‐Eurasia collision remains unclear. Investigating the fault kinematics and strain distribution is essential for understanding the interactions between active tectonic blocks and determining crustal deformation patterns and dynamic mechanisms in this region. In this study, we utilize the latest GPS data from Wang and Shen (2020), https://doi.org/10.1029/2019jb018774 to define the kinematics and deformation rates of the major faults in the NWBTS. Left‐lateral shear of ∼5–6 mm/yr along the NE‐trending NWBTS is accommodated by right‐lateral faulting of the NW‐striking faults and left‐lateral faulting of the NE‐striking faults, which can be interpreted as a pattern resembling the opposite sense of strike‐slip faulting and crustal rotation of the surrounding rock. Our results provide clear evidence of how active deformation is distributed in this area and the tectonic role of the different faults in regional deformation. Key Points: Northwestern boundary of the Tianshan Mountains involves two groups of faults that strike NW and NEFault kinematics and deformation rates of the major faults are determined based on the GPS dataCrustal deformation in the NWBTS can be interpreted as a pattern resembling the opposite sense of strike‐slip faulting and crustal rotation [ABSTRACT FROM AUTHOR]

Based on the teleseismic records of the dense broadband seismic array, the crustal anisotropy parameters of the west Ordos block and its adjacent regions were determined with P wave receiver functions. The results indicate that the dominant direction of the fast wave is NEE‐SWW, N‐S in Yingshan block and north Ordos block, N‐S in the south Ordos block, and E‐W in the Qinling–Dabie orogen belt. The fast wave direction of crustal anisotropy in the north Ordos block is distinctly different from that in the south Ordos block, both well related to the major geological events, such as the Paleoproterozoic continent‐to‐continent collision between the Ordos Block and the Yinshan Block, the collision between the Western Block and Eastern Block of the North China Craton and the material migration from the Tibetan plateau in Cenozoic. Our results indicate that the crustal anisotropy in the Ordos block preserves the traces of ancient tectonic movements. Combining the results of previous geophysical studies, we presented a crust‐mantle interaction model to explain the geophysical observations. The most prominent features of the model are the horizontal eastward expansion of the mantle material in the southern Ordos and the vertical upwelling of the mantle material in the northern Ordos. The different modes of movement of the mantle material led to the deep contrasting structures of north and south Ordos, including the crustal anisotropy. The mantle upwelling also implies that the north Ordos block might be currently experiencing craton destruction. Plain Language Summary: The Ordos block was stable without strong tectonic activity and showed rigid movement characteristics, which has been interpreted as a typical craton. However, some of the new results from geophysics showed that the crust of the Ordos block is not a single and stable structure with an evident low‐velocity layer within the crust, strikingly high Poisson's ratio in the north Ordos block, and a low‐velocity anomaly in the mantle in the north Ordos, which indicated that the interior of the Ordos is no longer a stable block, and also laid a good foundation further to explore the deep dynamic process of this area. Here, we constrain the crustal anisotropy by the teleseismic records of the dense broadband seismic array in the west Ordos block and its adjacent regions. The results indicated the contrasting structures beneath north and south Ordos blocks, which implied different movements of the mantle material. Key Points: The crust anisotropy has been constrained by the records of the dense broadband seismic array in the west Ordos blockThe fast wave direction of crustal anisotropy in the north Ordos block is distinctly different from the south Ordos block and the Alxa blockThe contrasting structures beneath the north and south Ordos block are controlled by the different movements of the mantle material [ABSTRACT FROM AUTHOR]