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Synergistic inhibition of SARS-CoV-2 cell entry by otamixaban and covalent protease inhibitors: pre-clinical assessment of pharmacological and molecular properties
No full textSARS-CoV-2, the cause of the COVID-19 pandemic, exploits host cell proteins for viral entry into human lung cells. One of them, the protease TMPRSS2, is required to activate the viral spike protein (S). Even though two inhibitors, camostat and nafamostat, are known to inhibit TMPRSS2 and block cell entry of SARS-CoV-2, finding further potent therapeutic options is still an important task. In this study, we report that a late-stage drug candidate, otamixaban, inhibits SARS-CoV-2 cell entry. We show that otamixaban suppresses TMPRSS2 activity and SARS-CoV-2 infection of a human lung cell line, although with lower potency than camostat or nafamostat. In contrast, otamixaban inhibits SARS-CoV-2 infection of precision cut lung slices with the same potency as camostat. Furthermore, we report that otamixaban's potency can be significantly enhanced by (sub-) nanomolar nafamostat or camostat supplementation. Dominant molecular TMPRSS2-otamixaban interactions are assessed by extensive 109 μs of atomistic molecular dynamics simulations. Our findings suggest that combinations of otamixaban with supplemental camostat or nafamostat are a promising option for the treatment of COVID-19
Alpha 1 Antitrypsin is an Inhibitor of the SARS-CoV-2–Priming Protease TMPRSS2
No full textBackground:
Host proteases have been suggested to be crucial for dissemination of MERS, SARS-CoV, and SARS-CoV-2 coronaviruses, but the relative contribution of membrane versus intracellular proteases remains controversial. Transmembrane serine protease 2 (TMPRSS2) is regarded as one of the main proteases implicated in the coronavirus S protein priming, an important step for binding of the S protein to the angiotensin-converting enzyme 2 (ACE2) receptor before cell entry.
Methods:
We developed a cell-based assay to identify TMPRSS2 inhibitors. Inhibitory activity was established in SARS-CoV-2 viral load systems.
Results:
We identified the human extracellular serine protease inhibitor (serpin) alpha 1 anti-trypsin (A1AT) as a novel TMPRSS2 inhibitor. Structural modeling revealed that A1AT docked to an extracellular domain of TMPRSS2 in a conformation that is suitable for catalysis, resembling similar serine protease inhibitor complexes. Inhibitory activity of A1AT was established in a SARS-CoV-2 viral load system. Notably, plasma A1AT levels were associated with COVID-19 disease severity.
Conclusions:
Our data support the key role of extracellular serine proteases in SARS CoV-2 infections and indicate that treatment with serpins, particularly the FDA-approved drug A1AT, may be effective in limiting SARS-CoV-2 dissemination by affecting the surface of the host cells.
Keywords: COVID, coronavirus, TMPRSS2, protease, alpha 1 antitrypsin, camostat mesylat
Rough McKean-Vlasov dynamics for robust ensemble Kalman filtering
Get PDFMotivated by the challenge of incorporating data into misspecified and multiscale dynamical models, we
study a McKean-Vlasov equation that contains the data stream as a common driving rough path. This setting
allows us to prove well-posedness as well as continuity with respect to the driver in an appropriate rough-path
topology. The latter property is key in our subsequent development of a robust data assimilation methodology:
We establish propagation of chaos for the associated interacting particle system, which in turn is suggestive of
a numerical scheme that can be viewed as an extension of the ensemble Kalman filter to a rough-path framework.
Finally, we discuss a data-driven method based on subsampling to construct suitable rough path lifts and
demonstrate the robustness of our scheme in a number of numerical experiments related to parameter estimation
problems in multiscale contexts
Forecast verification: relating deterministic and probabilistic metrics
No full textThe philosophy of forecast verification is rather different between deterministic and probabilistic verification metrics: generally speaking, deterministic metrics measure differences, whereas probabilistic metrics assess reliability and sharpness of predictive distributions. This paper considers the root-mean-square error (RMSE), which can be seen as a deterministic metric, and the probabilistic metric Continuous Ranked Probability Score (CRPS), and demonstrates that under certain conditions, the CRPS can be mathematically expressed in terms of the RMSE when these metrics are aggregated. One of the required conditions is the normality of distributions. The other condition is that, while the forecast ensemble need not be calibrated, any bias or over- / under-dispersion cannot depend on the forecast distribution itself. Under these conditions, the CRPS is a fraction of the RMSE, and this fraction depends only on the heteroscedasticity of the ensemble spread and the measures of calibration. The derived CRPS-RMSE relationship for the case of perfect ensemble reliability is tested on simulations of idealised two-dimensional barotropic turbulence. Results suggest that the relationship holds approximately despite that the normality condition is not met
The spectrum of slip behaviours of a granular fault gouge analogue governed by rate and state friction
No full textCurrently, it is unknown how seismic and aseismic slip influences the recurrence and magnitude of earthquakes. Modern seismic hazard assessment is therefore based on statistics combined with numerical simulations of fault slip and stress transfer. To improve the underlying statistical models we conduct low velocity shear experiments with glass micro-beads as fault gouge analogue at confining stresses of 5-20 kPa. As a result, we show that characteristic slip events emerge, ranging from fast and large slip to small scale oscillating creep and stable sliding. In particular we observe small scale slip events that occur immediately before large scale slip events for a specific set of experiments. Similar to natural faults we find a separation of scales by several orders of magnitude for slow events and fast events. Enhanced creep and transient dilatational events pinpoint that the granular analogue is close to failure. From slide-hold-slide tests, we find that the rate-and-state properties are in the same range as estimates for natural faults and fault rocks. The fault shows velocity weakening characteristics with a reduction of frictional strength between 0.8 to 1.3 % per e-fold increase in sliding velocity. Furthermore, the slip modes that are observed in the normal shear experiments are in good agreement with analytical solutions. Our findings highlight the influence of micromechanical processes on macroscopic fault behaviour. The comprehensive dataset associated with this study can act as a benchmark for numerical simulations and improve the understanding of observations of natural faults
Γ-convergence of Onsager–Machlup functionals: II. Infinite product measures on Banach spaces
No full textWe derive Onsager–Machlup functionals for countable product measures on weighted ℓp subspaces of the sequence space . Each measure in the product is a shifted and scaled copy of a reference probability measure on that admits a sufficiently regular Lebesgue density. We study the equicoercivity and Γ-convergence of sequences of Onsager–Machlup functionals associated to convergent sequences of measures within this class. We use these results to establish analogous results for probability measures on separable Banach or Hilbert spaces, including Gaussian, Cauchy, and Besov measures with summability parameter 1 ⩽ p ⩽ 2. Together with part I of this paper, this provides a basis for analysis of the convergence of maximum a posteriori estimators in Bayesian inverse problems and most likely paths in transition path theory
A rigorous derivation and energetics of a wave equation with fractional damping
Get PDFWe consider a linear system that consists of a linear wave equation on a horizontal hypersurface and a parabolic equation in the half space below. The model describes longitudinal elastic waves in organic monolayers at the water-air interface, which is an experimental setup that is relevant for understanding wave propagation in biological membranes. We study the scaling regime where the relevant horizontal length scale is much larger than the vertical length scale and provide a rigorous limit leading to a fractionally-damped wave equation for the membrane. We provide the associated existence results via linear semigroup theory and show convergence of the solutions in the scaling limit. Moreover, based on the energy-dissipation
structure for the full model, we derive a natural energy and a natural dissipation function for the fractionally-damped wave equation with a time derivative of order
3/2.
Keywords: bulk-interface coupling, surface waves, energy-dissipation balance, fractional
derivatives, convergence of semigroups, parabolic Dirichlet-to-Neumann map.
MOS: 35Q35 35Q74 74J1
QG-DL: Dynamics of a diabatic layer in the quasi-geostrophic framework
Get PDFQuasi-geostrophic (QG) theory describes the dynamics of synoptic scale flows in the trophosphere that are balanced with respect to both
acoustic and internal gravity waves. Within this framework, effects of (turbulent) friction near the ground are usually represented by Ekman
Layer theory. The troposphere covers roughly the lowest ten kilometers of the atmosphere while Ekman layer heights are typically just a few
hundred meters. However, this two-layer asymptotic theory does not explicitly account for substantial changes of the potential temperature
stratification due to diabatic heating associated with cloud formation or with radiative and turbulent heat fluxes, which, in the middle
latitudes, can be particularly important in about the lowest three kilometers. To address this deficiency, this paper extends the classical
QG–Ekman layer model by introducing an intermediate, dynamically and thermodynamically active layer, called the “diabatic layer” (DL)
from here on. The flow in this layer is also in acoustic, hydrostatic, and geostrophic balance but, in contrast to QG flow, variations of
potential temperature are not restricted to small deviations from a stable and time independent background stratification. Instead, within
the diabatic layer, diabatic processes are allowed to affect the leading-order stratification. As a consequence, the diabatic layer modifies
the pressure field at the top of the Ekman layer, and with it the intensity of Ekman pumping seen by the quasi-geostrophic bulk flow. The
result is the proposed extended quasi-geostrophic three-layer QG-DL-Ekman model for mid-latitude (dry and moist) dynamics
Influence of zones of pre-existing crustal weakness on strain localization and partitioning during rifting: Insights from analogue modeling using high resolution 3D digital image correlation
Get PDFThe factors controlling the selective reactivation of pre-existing crustal structures and strain localization process in natural rifts have been studied for decades but remain poorly understood. We present the results of surface strain analysis of a series of analogue rifting experiments designed to test the influence of the size, orientation, depth, and geometry of pre-existing crustal weak zones on strain localization and partitioning. We apply distributed basal extension to crustal-scale models that consist of a silicone weak zone embedded in a quartz sand layer. We vary the size and orientation (θ-angle) of the weak zone with respect to the extension direction, reduce the thickness of the sand layer to simulate a shallow weak zone, and vary the geometry of the weak zone to reflect a range of anticlinal, either linear or curvilinear natural weak zone geometries. Our results show that at higher θ-angle (≤ 60o) both small- and large-scale weak zones localize strain into graben-bounding (oblique-) normal faults. At lower θ-angle (≤ 45o), small-scale weak zones do not localize strain effectively, unless they are shallow. We observe diffuse, second-order strike-slip internal graben structures, which are conjugate and antithetic under orthogonal and oblique extension, respectively. In general, the changing nature of the rift faults (from discrete fault planes to diffuse fault zones, from normal to oblique and strike-slip) highlights the sensitivity of rift architecture to the orientation, size, depth, and geometry of pre-existing weak zones. Our generic models are comparable to observations from many natural rift systems like the northern North Sea and East Africa, and thus have implications for understanding the role of structural inheritance in rift basins globally
Targets and holes
No full textAbstract: We address the extreme value problem of a one-dimensional dynamical system approaching a fixed target while constrained to avoid a fixed set, which can be thought of as a small hole. The presence of the latter influences the extremal index which depends explicitly on the escape rate