Evidence for Small-Scale Mantle Convection in the Upper Mantle beneath the Baikal Rift Zone

Inversion of teleseismic P wave travel time residuals collected along a 1280-km-long profile traversing the Baikal rift zone (BRZ) reveals the existence of an upwarped lithosphere/asthenosphere interface, which causes a travel time delay of about 1 s at the rift axis ( central high ). An area with early arrivals relative to the stable Siberian platform of up to 0.5 s is observed on each side of the rift, about 200 km from the rift axis ( flank lows ). While the location of the central high is approximately fixed in the vicinity of the rift axis, those of the flank lows vary as much as 200 km with the azimuth of the arriving rays. We use three techniques to invert the travel time residuals for velocity anomalies beneath the profile. Two of the techniques assume an isotropic velocity structure, and one of them considers a transversely isotropic velocity model with a vertical axis of symmetry. We use independent geophysical observations such as gravity, active source seismic exploration, and crustal thickness measurements to compare the applicability of the models. Other types of geophysical measurements suggest that the model involving transverse isotropy is a plausible one, which suggests that the central high and flank lows are caused by the combined effects of an upwarped asthenosphere with a 2.5% lateral velocity reduction, and a velocity increase due to transverse isotropy with a vertical axis of symmetry. We consider the anisotropy to be the result of the vertical component of a lithosphere/asthenosphere small-scale mantle convection system that is associated with the rifting

Asymmetric Upwarp of the Asthenosphere beneath the Baikal Rift Zone, Siberia

In the summer of 1991 we installed 27 seismic stations about lake Baikal, Siberia, aimed at obtaining accurately timed digital seismic data to investigate the deep structure and geodynamics of the Baikal rift zone and adjacent regions. Sixty-six teleseismic events with high signal-to-noise ratio were recorded. Travel time and Q analysis of teleseisms characterize an upwarp of the lithosphere-asthenosphere boundary under Baikal. Theoretical arrival times were calculated by using the International Association of Seismology and Physics of the Earth\u27s interior 1991 Earth model, and travel time residuals were found by subtracting computed arrival times from observed ones. A three-dimensional downward projection inversion method is used to invert the P wave velocity structure with constraints from deep seismic sounding data. Our results suggest that (1) the lithosphere-asthenosphere transition upwarps beneath the rift zone, (2) the upwarp has an asymmetric shape, (3) the velocity contrast is -4.9% in the asthenosphere, (4) the density contrast is -0.6%, and (5) the P wave attenuation contrast t* is 0.1 s

S K S Splitting beneath Continental Rift Zones

We present measurements of S K S splitting at 28 digital seismic stations and 35 analog stations in the Baikal rift zone, Siberia, and adjacent areas, and at 17 stations in the East African Rift in Kenya and compare them with previous measurements from the Rio Grande Rift of North America. Fast directions in the inner region of the Baikal rift zone are distributed in two orthogonal directions, NE and NW, approximately parallel and perpendicular to the NE strike of the rift. In the adjacent Siberian platform and northern Mongolian fold belt, only the rift-orthogonal fast direction is observed. In southcentral Mongolia, the dominant fast direction changes to rift-parallel again, although a small number of measurements are still rift-orthogonal. For the axial zones of the East African and Rio Grande Rifts, fast directions are oriented on average NNE, that is, rotated clockwise from the N-S trending rift. All three rifts are underlain by low-velocity upper mantle as determined from teleseismic tomography. Rift-related mantle flow provides a plausible interpretation for the rift-orthogonal fast directions. The rift-parallel fast directions near the rift axes can be interpreted by oriented magmatic cracks in the mantle or small-scale mantle convection with rift-parallel flow. The agreement between stress estimates and corresponding crack orientations lends some weight to the suggestion that the rift-parallel fast directions are caused by oriented magmatic cracks

Reply [to “Comment on “SKS Splitting beneath Continental Rifts Zones” by Gao et al.”]

Vauchez et al. [this issue] (hereinafter refered to as VBN) interpret the petrologic, tomographic, and anisotropy data from continental rifts to support a model of continental rifting [Nicolas, 1993; Nicolas et al., 1994] in which the lithosphere splits along the rift axis and asthenosphere flows in from the sides to fill the resulting gap. We suggest here that the data can also be described by a model in which the lower lithosphere is modified or eroded by active mantle upwelling over a region of significantly greater dimensions than the rift graben and that partial melt developing in the upwelling region can account for the widespread volcanism, as well as the seismic properties. Nicolas [1993] argued that rift-aligned anisotropy could be explained by rift-parallel mantle flow. We thank VBN for bringing this relevant paper to our attention. Volcanism about the East African Rift and the Rio Grande is not confined to the rifts but extends hundreds of kilometers from the rift axes (Mount Kilimanjaro, Mount Elgon, Mount Kenya in East Africa, The Jemez Lineament on the Rio Grande) in regions uplifted relative to their surroundings. The low-velocity tomographic anomalies also extend beneath the uplifted regions and are thought to be related to the uplift possibly supporting it by thermostatic buoyancy. The size of the P and S velocity contrasts and attenuation of high frequencies have led to the suggestion that large regions of the anomalous bodies have temperatures at or above the solidus [Achauer et al, 1994; Slack et al., 1994, 1996]. The wide extent of the anomalous regions is not explicable as resulting from an abyssal lithospheric dike beneath the rift intruded by asthenosphere. The extension of the East African, Baikal, and Rio Grande rift grabens has been estimated to be about 10 km [Baker et al., 1972; Baldridge et al., 1984; Morgan and Golombek, 1984; Logatchev and Florensov, 1978]. Passive influx of asthenosphere into a 10 km lithospheric dike is insufficient to explain the tomographic anomalies [Davis, 1991]. In addition, the amount of finite strain from lithospheric diking is insufficient to explain the anisotropy anomalies. Active replacement or modification of lower lithosphere either prior to, or contemporaneous with, rifting could generate tomographic anomalies of this magnitude

A Prospective Randomized Crossover Trial of Systemic Chemotherapy in Patients with Low-Grade Mucinous Appendiceal Adenocarcinoma

View full abstracthttps://openworks.mdanderson.org/leading-edge/1048/thumbnail.jp

Quality of medication use in primary care - mapping the problem, working to a solution: a systematic review of the literature

Background: The UK, USA and the World Health Organization have identified improved patient safety in healthcare as a priority. Medication error has been identified as one of the most frequent forms of medical error and is associated with significant medical harm. Errors are the result of the systems that produce them. In industrial settings, a range of systematic techniques have been designed to reduce error and waste. The first stage of these processes is to map out the whole system and its reliability at each stage. However, to date, studies of medication error and solutions have concentrated on individual parts of the whole system. In this paper we wished to conduct a systematic review of the literature, in order to map out the medication system with its associated errors and failures in quality, to assess the strength of the evidence and to use approaches from quality management to identify ways in which the system could be made safer. Methods: We mapped out the medicines management system in primary care in the UK. We conducted a systematic literature review in order to refine our map of the system and to establish the quality of the research and reliability of the system. Results: The map demonstrated that the proportion of errors in the management system for medicines in primary care is very high. Several stages of the process had error rates of 50% or more: repeat prescribing reviews, interface prescribing and communication and patient adherence. When including the efficacy of the medicine in the system, the available evidence suggested that only between 4% and 21% of patients achieved the optimum benefit from their medication. Whilst there were some limitations in the evidence base, including the error rate measurement and the sampling strategies employed, there was sufficient information to indicate the ways in which the system could be improved, using management approaches. The first step to improving the overall quality would be routine monitoring of adherence, clinical effectiveness and hospital admissions. Conclusion: By adopting the whole system approach from a management perspective we have found where failures in quality occur in medication use in primary care in the UK, and where weaknesses occur in the associated evidence base. Quality management approaches have allowed us to develop a coherent change and research agenda in order to tackle these, so far, fairly intractable problems

Functional Role of Dimerization of Human Peptidylarginine Deiminase 4 (PAD4)

Peptidylarginine deiminase 4 (PAD4) is a homodimeric enzyme that catalyzes Ca2+-dependent protein citrullination, which results in the conversion of arginine to citrulline. This paper demonstrates the functional role of dimerization in the regulation of PAD4 activity. To address this question, we created a series of dimer interface mutants of PAD4. The residues Arg8, Tyr237, Asp273, Glu281, Tyr435, Arg544 and Asp547, which are located at the dimer interface, were mutated to disturb the dimer organization of PAD4. Sedimentation velocity experiments were performed to investigate the changes in the quaternary structures and the dissociation constants (Kd) between wild-type and mutant PAD4 monomers and dimers. The kinetic data indicated that disrupting the dimer interface of the enzyme decreases its enzymatic activity and calcium-binding cooperativity. The Kd values of some PAD4 mutants were much higher than that of the wild-type (WT) protein (0.45 µM) and were concomitant with lower kcat values than that of WT (13.4 s−1). The Kd values of the monomeric PAD4 mutants ranged from 16.8 to 45.6 µM, and the kcat values of the monomeric mutants ranged from 3.3 to 7.3 s−1. The kcat values of these interface mutants decreased as the Kd values increased, which suggests that the dissociation of dimers to monomers considerably influences the activity of the enzyme. Although dissociation of the enzyme reduces the activity of the enzyme, monomeric PAD4 is still active but does not display cooperative calcium binding. The ionic interaction between Arg8 and Asp547 and the Tyr435-mediated hydrophobic interaction are determinants of PAD4 dimer formation

Characterization and applications of a Crimean-Congo hemorrhagic fever virus nucleoprotein-specific Affimer: Inhibitory effects in viral replication and development of colorimetric diagnostic tests.

peer reviewedCrimean-Congo hemorrhagic fever orthonairovirus (CCHFV) is one of the most widespread medically important arboviruses, causing human infections that result in mortality rates of up to 60%. We describe the selection of a high-affinity small protein (Affimer-NP) that binds specifically to the nucleoprotein (NP) of CCHFV. We demonstrate the interference of Affimer-NP in the RNA-binding function of CCHFV NP using fluorescence anisotropy, and its inhibitory effects on CCHFV gene expression in mammalian cells using a mini-genome system. Solution of the crystallographic structure of the complex formed by these two molecules at 2.84 Å resolution revealed the structural basis for this interference, with the Affimer-NP binding site positioned at the critical NP oligomerization interface. Finally, we validate the in vitro application of Affimer-NP for the development of enzyme-linked immunosorbent and lateral flow assays, presenting the first published point-of-care format test able to detect recombinant CCHFV NP in spiked human and animal sera

A positron emission tomography imaging study to confirm target engagement in the lungs of patients with idiopathic pulmonary fibrosis following a single dose of a novel inhaled αvβ6 integrin inhibitor

© 2020 The Author(s). Background: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease with poor prognosis and a significant unmet medical need. This study evaluated the safety, pharmacokinetics (PK) and target engagement in the lungs, of GSK3008348, a novel inhaled alpha-v beta-6 (αvβ6) integrin inhibitor, in participants with IPF. Methods: This was a phase 1b, randomised, double-blind (sponsor unblind) study, conducted in the UK (two clinical sites, one imaging unit) between June 2017 and July 2018 (NCT03069989). Participants with a definite or probable diagnosis of IPF received a single nebulised dose of 1000 mcg GSK3008348 or placebo (ratio 5:2) in two dosing periods. In period 1, safety and PK assessments were performed up to 24 h post-dose; in period 2, after a 7-day to 28-day washout, participants underwent a total of three positron emission tomography (PET) scans: Baseline, Day 1 (~ 30 min post-dosing) and Day 2 (~ 24 h post-dosing), using a radiolabelled αvβ6-specific ligand, [18F]FB-A20FMDV2. The primary endpoint was whole lung volume of distribution (VT), not corrected for air volume, at ~ 30 min post-dose compared with pre-dose. The study success criterion, determined using Bayesian analysis, was a posterior probability (true % reduction in VT > 0%) of ≥80%. Results: Eight participants with IPF were enrolled and seven completed the study. Adjusted posterior median reduction in uncorrected VT at ~ 30 min after GSK3008348 inhalation was 20% (95% CrI:-9 to 42%). The posterior probability that the true % reduction in VT > 0% was 93%. GSK3008348 was well tolerated with no reports of serious adverse events or clinically significant abnormalities that were attributable to study treatment. PK was successfully characterised showing rapid absorption followed by a multiphasic elimination. Conclusions: This study demonstrated engagement of the αvβ6 integrin target in the lung following nebulised dosing with GSK3008348 to participants with IPF. To the best of our knowledge this is the first time a target-specific PET radioligand has been used to assess target engagement in the lung, not least for an inhaled drug. Trial registration: Clinicaltrials.gov: NCT03069989; date of registration: 3 March 2017

Translational pharmacology of an inhaled small molecule αvβ6 integrin inhibitor for idiopathic pulmonary fibrosis

The αvβ6 integrin plays a key role in the activation of transforming growth factor-β (TGFβ), a pro-fibrotic mediator that is pivotal to the development of idiopathic pulmonary fibrosis (IPF). We identified a selective small molecule αvβ6 RGD-mimetic, GSK3008348, and profiled it in a range of disease relevant pre-clinical systems. To understand the relationship between target engagement and inhibition of fibrosis, we measured pharmacodynamic and diseaserelated end points. Here we report, GSK3008348 binds to αvβ6 with high affinity in human IPF lung and reduces downstream pro-fibrotic TGFβ signaling to normal levels. In human lung epithelial cells, GSK3008348 induces rapid internalization and lysosomal degradation of the αvβ6 integrin. In the murine bleomycin-induced lung fibrosis model, GSK3008348 engages αvβ6, induces prolonged inhibition of TGFβ signaling and reduces lung collagen deposition and serum C3M, a marker of IPF disease progression. These studies highlight the potential of inhaled GSK3008348 as an anti-fibrotic therapy