Engineering topics

Zhou, Shuntai

Publications and source records attributed to Zhou, Shuntai.

6 records

DOE OSTI2019

Picomolar to Micromolar: Elucidating the Role of Distal Mutations in HIV-1 Protease in Conferring Drug Resistance

Drug resistance continues to be a growing global problem. The efficacy of small molecule inhibitors is threatened by pools of genetic diversity in all systems, including antibacterials, antifungals, cancer therapeutics, and antivirals. Resistant variants often include combinations of active site mutations and distal “secondary” mutations, which are thought to compensate for losses in enzymatic activity. HIV-1 protease is the ideal model system to investigate these combinations and underlying molecular mechanisms of resistance. Darunavir (DRV) binds wild-type (WT) HIV-1 protease with a potency of <5 pM, but here we have identified a protease variant that loses potency to DRV 150 000-fold, with 11 mutations in and outside the active site. To elucidate the roles of these mutations in DRV resistance, we used a multidisciplinary approach, combining enzymatic assays, crystallography, and molecular dynamics simulations. Analysis of protease variants with 1, 2, 4, 8, 9, 10, and 11 mutations showed that the primary active site mutations caused ~50-fold loss in potency (2 mutations), while distal mutations outside the active site further decreased DRV potency from 13 nM (8 mutations) to 0.76 μM (11 mutations). Crystal structures and simulations revealed that distal mutations induce subtle changes that are dynamically propagated through the protease. Our results reveal that changes remote from the active site directly and dramatically impact the potency of the inhibitor. Moreover, we find interdependent effects of mutations in conferring high levels of resistance. These mechanisms of resistance are likely applicable to many other quickly evolving drug targets, and the insights may have implications for the design of more robust inhibitors.

60 APPLIED LIFE SCIENCES↗

NASA NTRS1999

Constructing Synoptic Maps of Stratospheric Column Ozone from HALOE, SAGE and Balloonsonde Data Using Potential Vorticity Isentropic Coordinate Transformations

In this study we utilize potential vorticity - isentropic (PVI) coordinate transformations as a means of combining ozone data from different sources to construct daily, synthetic three-dimensional ozone fields. This methodology has been used successfully to reconstruct ozone maps in particular regions from aircraft data over the period of the aircraft campaign. We expand this method to create high-resolution daily global maps of profile ozone data, particularly in the lower stratosphere, where high-resolution ozone data are sparse. Ozone climatologies in PVI-space are constructed from satellite-based SAGE II and UARS/HALOE data, both of which-use solar occultation techniques to make high vertical resolution ozone profile measurements, but with low spatial resolution. A climatology from ground-based balloonsonde data is also created. The climatologies are used to establish the relationship between ozone and dynamical variability, which is defined by the potential vorticity (in the form of equivalent latitude) and potential temperature fields. Once a PVI climatology has been created from data taken by one or more instruments, high-resolution daily profile ozone field estimates are constructed based solely on the PVI fields, which are available on a daily basis from NCEP analysis. These profile ozone maps could be used for a variety of applications, including use in conjunction with total ozone maps to create a daily tropospheric ozone product, as input to forecast models, or as a tool for validating independent ozone measurements when correlative data are not available. This technique is limited to regions where the ozone is a long-term tracer and the flow is adiabatic. We evaluate the internal consistency of the technique by transforming the ozone back to physical space and comparing to the original profiles. Biases in the long-term average of the differences are used to identify regions where the technique is consistently introducing errors. Initial results show the technique is useful in the lower stratosphere at most latitudes throughout the year,and in the winter hemisphere in the middle stratosphere. The results are problematic in the summer hemisphere middle stratosphere due to increased ozone photochemistry and weak PV gradients. Alternate techniques in these regions will be discussed. An additional limitation is the quality and resolution of the meteorological data.

Hollandsworth, Stacey M.↗

NASA NTRS1997

A Three-Wave Model of the Stratosphere with Coupled Dynamics, Radiation and Photochemistry

A zonal mean chemistry transport model (2-D CTM) coupled with a semi-spectral dynamical model is used to simulate the distributions of trace gases in the present day atmosphere. The zonal-mean and eddy equations for the velocity and the geopotential height are solved in the semi-spectral dynamical model. The residual mean circulation is derived from these dynamical variables and used to advect the chemical species in the 2- D CTM. Based on a linearized wave transport equation, the eddy diffusion coefficients for chemical tracers are expressed in terms of the amplitude, frequency and growth rate of dynamical waves; local chemical loss rates; and a time constant parameterizing small scale mixing. The contributions to eddy flux are from the time varying wave amplitude (transient eddy), chemical reactions (chemical eddy) and small scale mixing. In spite of the high truncation in the dynamical module (only three longest waves are resolved), the model has simulated many observed characteristics of stratospheric dynamics and distribution of chemical species including ozone. Compared with the values commonly used in 2-D CTMs, the eddy diffusion coefficients for chemical species calculated in this model are smaller, especially in the subtropics. It is also found that the chemical eddy diffusion has only a small effects in determining the distribution of most slow species, including ozone in the stratosphere.

Shia, Run-Lie↗

NASA NTRS1997

An Estimation of the Climatic Effects of Stratospheric Ozone Losses during the 1980s

In order to study the potential climatic effects of the ozone hole more directly and to assess the validity of previous lower resolution model results, the latest high spatial resolution version of the Atmospheric and Environmental Research, Inc., seasonal radiative dynamical climate model is used to simulate the climatic effects of ozone changes relative to the other greenhouse gases. The steady-state climatic effect of a sustained decrease in lower stratospheric ozone, similar in magnitude to the observed 1979-90 decrease, is estimated by comparing three steady-state climate simulations: 1) 1979 greenhouse gas concentrations and 1979 ozone, II) 1990 greenhouse gas concentrations with 1979 ozone, and III) 1990 greenhouse gas concentrations with 1990 ozone. The simulated increase in surface air temperature resulting from nonozone greenhouse gases is 0.272 K. When changes in lower stratospheric ozone are included, the greenhouse warming is 0.165 K, which is approximately 39% lower than when ozone is fixed at the 1979 concentrations. Ozone perturbations at high latitudes result in a cooling of the surface-troposphere system that is greater (by a factor of 2.8) than that estimated from the change in radiative forcing resulting from ozone depiction and the model's 2 x CO, climate sensitivity. The results suggest that changes in meridional heat transport from low to high latitudes combined with the decrease in the infrared opacity of the lower stratosphere are very important in determining the steady-state response to high latitude ozone losses. The 39% compensation in greenhouse warming resulting from lower stratospheric ozone losses is also larger than the 28% compensation simulated previously by the lower resolution model. The higher resolution model is able to resolve the high latitude features of the assumed ozone perturbation, which are important in determining the overall climate sensitivity to these perturbations.

MacKay, Robert M.↗

NASA NTRS1993

The role of large-scale eddies in the climate equilibrium. Part 2: Variable static stability

Lorenz's two-level model on a sphere is used to investigate how the results of Part 1 are modified when the interaction of the vertical eddy heat flux and static stability is included. In general, the climate state does not depend very much on whether or not this interaction is included, because the poleward eddy heat transport dominates the eddy forcing of mean temperature and wind fields. However, the climatic sensitivity is significantly affected. Compared to two-level model results with fixed static stability, the poleward eddy heat flux is less sensitive to the meridional temperature gradient and the gradient is more sensitive to the forcing. For example, the logarithmic derivative of the eddy flux with respect to the gradient has a slope that is reduced from approximately 15 on a beta-plane with fixed static stability and approximately 6 on a sphere with fixed static stability, to approximately 3 to 4 in the present model. This last result is more in line with analyses from observations. The present model also has a stronger baroclinic adjustment than that in Part 1, more like that in two-level beta-plane models with fixed static stability, that is, the midlatitude isentropic slope is very insensitive to the forcing, the diabatic heating, and the friction, unless the forcing is very weak.

Zhou, Shuntai↗

NASA NTRS1993

The role of large-scale eddies in the climate equilibrium. I - Fixed static stability

An efficient two-level model on a sphere that is based on the balance equations with fixed static stability is developed and used to study how eddies arising from baroclinic instability interact with the temperature structure. The model gives a much better simulation of the eddy momentum flux and of the total eddy forcing of the zonal-mean temperature and zonal wind fields than do quasi-geostrophic beta-plane models. Nonetheless, the results are qualitatively similar. The midlatitude eddy regimes range between two extreme cases. In one, the eddies have no effect on the temperature and zonal wind fields, and in the other (similar to the observed atmosphere), the eddy forcing of the temperature and zonal wind fields is dominated by the eddy heat flux. Quantitatively, some of the model's results differ significantly from those based on the quasi-geostrophic beta-plane. For example, the temperature structure is much more sensitive to the external forcing, and the eddy heat flux is less sensitive to the temperature structure.

Zhou, Shuntai↗