The response to the coronavirus disease 2019 (COVID-19) pandemic has been hampered by lack of an effective severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antiviral therapy. Here we report the use of remdesivir in a patient with COVID-19 and the prototypic genetic antibody deficiency X-linked agammaglobulinaemia (XLA). Despite evidence of complement activation and a robust T cell response, the patient developed persistent SARS-CoV-2 pneumonitis, without progressing to multi-organ involvement. This unusual clinical course is consistent with a contribution of antibodies to both viral clearance and progression to severe disease. In the absence of these confounders, we take an experimental medicine approach to examine the in vivo utility of remdesivir. Over two independent courses of treatment, we observe a temporally correlated clinical and virological response, leading to clinical resolution and viral clearance, with no evidence of acquired drug resistance. We therefore provide evidence for the antiviral efficacy of remdesivir in vivo, and its potential benefit in selected patients.

We have developed a theory for self-diffusion in single-file Langmuirian zeolites of finite extent, which has been validated by open system kinetic Monte Carlo simulations. Our theory is based on a two-stage, Fickian diffusion mechanism, wherein a vacancy must traverse the entire file length to produce particle displacements of one lattice spacing. For times shorter than the vacancy diffusion time, t c , particle transport proceeds via the nonFickian, single-file diffusion mode, with mean-square displacements increasing with the square-root of time. For times longer than t c , however, we find that self-diffusion in single-file systems is completely described by Fick's laws. We find that the fraction of time in the single-file diffusion mode scales inversely with file length for long files, suggesting that Fickian self-diffusion dominates transport in longer single-file zeolites. Through correlations among the particle movements, the single-file self-diffusivity is sensitive to sorption limitations for short files, and scales inversely with file length for long files. Experimental verification of the theory by pulsed field gradient NMR and tracer zero-length column experiments is discussed.

Equilibrium size and shape distributions of self-assembled micelles are investigated using lattice Monte Carlo simulation techniques. The micellar size distributions are shown to include a Gaussian peak of spherical micelles, in combination with an exponential tail of cylindrical micelles.

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How many steps are required to model permeation through ion channels? This question is investigated by comparing one-and two-step models of permeation with experiment and MD simulation for the first time. In recent MD simulations, the observed permeation mechanism was identified as resembling a Hodgkin and Keynes knock-on mechanism with one voltage-dependent rate-determining step [Jensen et al., PNAS 107, 5833 (2010)]. These previously published simulation data are fitted to a one-step knock-on model that successfully explains the highly non-Ohmic current-voltage curve observed in the simulation. However, these predictions (and the simulations upon which they are based) are not representative of real channel behavior, which is typically Ohmic at low voltages. A two-step association/dissociation (A/D) model is then compared with experiment for the first time. This two-parameter model is shown to be remarkably consistent with previously published permeation experiments through the MaxiK potassium channel over a wide range of concentrations and positive voltages. The A/D model also provides a first-order explanation of permeation through the Shaker potassium channel, but it does not explain the asymmetry observed experimentally. To address this, a new asymmetric variant of the A/D model is developed using the present theoretical framework. It includes a third parameter that represents the value of the "permeation coordinate" (fractional electric potential energy) corresponding to the triply occupied state n of the channel. This asymmetric A/D model is fitted to published permeation data through the Shaker potassium channel at physiological concentrations, and it successfully predicts qualitative changes in the negative current-voltage data (including a transition to super-Ohmic behavior) based solely on a fit to positive-voltage data (that appear linear). The A/D model appears to be qualitatively consistent with a large group of published MD simulations, but no quantitative comparison has yet been made. The A/D model makes a network of predictions for how the elementary steps and the channel occupancy vary with both concentration and voltage. In addition, the proposed theoretical framework suggests a new way of plotting the energetics of the simulated system using a one-dimensional permeation coordinate that uses electric potential energy as a metric for the net fractional progress through the permeation mechanism. This approach has the potential to provide a quantitative connection between atomistic simulations and permeation experiments for the first time.