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At least 1,693 records · Page 94

A multi-scale pipeline linking drug transcriptomics with pharmacokinetics predicts in vivo interactions of tuberculosis drugs

Tuberculosis (TB) is the deadliest infectious disease worldwide. The design of new treatments for TB is hindered by the large number of candidate drugs, drug combinations, dosing choices, and complex pharmaco-kinetics/dynamics (PK/PD). Here we study the interplay of these factors in designing combination therapies by linking a machine-learning model, INDIGO-MTB, which predicts in vitro drug interactions using drug transcriptomics, with a multi-scale model of drug PK/PD and pathogen-immune interactions called GranSim. We calculate an in vivo drug interaction score (iDIS) from dynamics of drug diffusion, spatial distribution, and activity within lesions against various pathogen sub-populations. The iDIS of drug regimens evaluated against non-replicating bacteria significantly correlates with efficacy metrics from clinical trials. Our approach identifies mechanisms that can amplify synergistic or mitigate antagonistic drug interactions in vivo by modulating the relative distribution of drugs. Our mechanistic framework enables efficient evaluation of in vivo drug interactions and optimization of combination therapies.

59 BASIC BIOLOGICAL SCIENCES↗

First inductively coupled plasma-distance-of-flight mass spectrometer: instrument performance with a microchannel plate/phosphor imaging detector

Here we describe the first combination of a Distance-of-Flight Mass Spectrometry (DOFMS) instrument and an inductively coupled plasma (ICP) ion source. DOFMS is a velocity-based MS technique in which ions of a range of mass-to-charge (m/z) values are detected simultaneously along the length of a spatially selective detector. As a relative of time-of-flight (TOF) MS, DOFMS leverages benefits fromboth TOFMS and spatially dispersive MS. The simultaneous detection of groups of m/z values improves dynamic range by spreading ion signal across many detector elements and reduces correlated noise by signal ratioing. To ascertain the performance characteristics of the ICP-DOFMS instrument, we have employed a microchannel-plate/phosphor detection assembly with a scientific CCD to capture images of the phosphor plate. With this simple (and commercially available) detection scheme, elemental detection limits from 2–30 ng L*1 and a linear dynamic range of 5 orders of magnitude (10–106 ng L1) have been demonstrated. Additionally, a competitive isotope-ratio precision of 0.1% RSD has been achieved with only a 6 s signal integration period. In addition to first figures of merit, this paper outlines technical considerations for the design of the ICP-DOFMS.

Gundlach-Graham, Alexander W.↗

Synchrotron nanoimaging of single In-rich InGaN nanowires

This work reports on the elemental distribution and local structure of single In{sub x}Ga{sub 1-x}N nanowires (NWs) grown by molecular beam epitaxy on Si (111) substrates using X-ray fluorescence nanoprobe. Ga and In maps reveal an inhomogeneous elemental distribution along the NWs, with a higher Ga concentration at the bottom of the NW. Scanning electron microscopy images show that the inhomogeneous axial distribution is not correlated with a X-ray beam induced damage, and therefore, should be an intrinsic characteristic of the NWs arising from the growth process. Spatially resolved X-ray absorption near edge structure spectroscopy data acquired around the In K-edge show that the tetrahedral structure is preserved around the absorbing In-atoms all along the NW, and suggests that the compositional modulation could be affecting its long-range order.

77 NANOSCIENCE AND NANOTECHNOLOGY↗

Freezing lines of colloidal Yukawa spheres. II. Local structure and characteristic lengths

Using the Rogers-Young (RY) integral equation scheme for the static pair correlation functions combined with the liquid-phase Hansen-Verlet freezing rule, we study the generic behavior of the radial distribution function and static structure factor of monodisperse charge-stabilized suspensions with Yukawa-type repulsive particle interactions at freezing. In a related article, labeled Paper I [J. Gapinski, G. Nägele, and A. Patkowski, J. Chem. Phys. 136, 024507 (2012)], this hybrid method was used to determine two-parameter freezing lines for experimentally controllable parameters, characteristic of suspensions of charged silica spheres in dimethylformamide. A universal scaling of the RY radial distribution function maximum is shown to apply to the liquid-bcc and liquid-fcc segments of the universal freezing line. A thorough analysis is made of the behavior of characteristic distances and wavenumbers, next-neighbor particle coordination numbers, osmotic compressibility factor, and the Ravaché-Mountain-Streett minimum-maximum radial distribution function ratio.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

Lagrangian statistics in weakly forced two-dimensional turbulence

Measurements of Lagrangian single-point and multiple-point statistics in a quasi-two-dimensional stratified layer system are reported. The system consists of a layer of salt water over an immiscible layer of Fluorinert and is forced electromagnetically so that mean-squared vorticity is injected at a well-defined spatial scale r i . Simultaneous cascades develop in which enstrophy flows predominately to small scales whereas energy cascades, on average, to larger scales. Lagrangian correlations and one- and two-point displacements are measured for random initial conditions and for initial positions within topological centers and saddles. Some of the behavior of these quantities can be understood in terms of the trapping characteristics of long-lived centers, the slow motion near strong saddles, and the rapid fluctuations outside of either centers or saddles. We also present statistics of Lagrangian velocity fluctuations using energy spectra in frequency space and structure functions in real space. We compare with complementary Eulerian velocity statistics. We find that simultaneous inverse energy and enstrophy ranges present in spectra are not directly echoed in real-space moments of velocity difference. Nevertheless, the spectral ranges line up well with features of moment ratios, indicating that although the moments are not exhibiting unambiguous scaling, the behavior of the probability distribution functions is changing over short ranges of length scales. Furthermore, implications for understanding weakly forced 2D turbulence with simultaneous inverse and direct cascades are discussed.

72 PHYSICS OF ELEMENTARY PARTICLES AND FIELDS↗

Structural analysis of graphene and h-BN: A molecular dynamics approach

Classical molecular dynamics simulation is employed to analyze pair correlations in graphene and h-BN at various temperatures to explore the integrity of their respective structures. As the temperature increases, the height fluctuations in the out-of-plane direction of both graphene and h-BN are found to increase. The positional spread of atoms also increases with temperature. Thus the amplitude of the peak positions in the radial distribution function (RDF) decreases with temperature. It is found that FWHM of peaks in the RDF of h-BN is smaller as compared to those of graphene which implies that the structure of h-BN is more robust as compared to that of graphene with respect to their respective empirical potential.

77 NANOSCIENCE AND NANOTECHNOLOGY↗

Gravitational memory and soft theorems: The local perspective

In general relativity, gravitational memory describes the lasting change in the separation and relative velocity of freely falling detectors after the passage of gravitational waves (GWs). In this paper, we elucidate the relation between Bondi-Metzner-Sachs transformations at future null infinity and the description of gravitational memory in local synchronous coordinates, commonly used in GW detectors like LISA. We show that gravitational memory corresponds to large residual diffeomorphisms in this gauge, such as volume-preserving spatial rescalings. We reproduce the associated soft theorems for scattering amplitudes. Finally, we derive novel soft theorems for equal-time (in-in) correlation functions, which are recognized as the flat space analogues of inflationary consistency relations with a soft tensor mode. Furthermore, these relations provide a pathway toward uncovering deeper connections between gravitational memory and cosmological correlators.

General relativity↗

Generalization of Anderson's theorem for disordered superconductors

Here, we show that at the level of BCS mean-field theory, the superconducting T c is always increased in the presence of disorder, regardless of order parameter symmetry, disorder strength, and spatial dimension. This result reflects the physics of rare events—formally analogous to the problem of Lifshitz tails in disordered semiconductors—and arises from considerations of spatially inhomogeneous solutions of the gap equation. So long as the clean-limit superconducting coherence length, ξ 0 , is large compared to disorder correlation length, a, when fluctuations about mean-field theory are considered, the effects of such rare events are small (typically exponentially in [ξ 0 /a] d ); however, when this ratio is ~1, these considerations are important. The linearized gap equation is solved numerically for various disorder ensembles to illustrate this general principle.

75 CONDENSED MATTER PHYSICS, SUPERCONDUCTIVITY AND↗

Microfocus diffraction from different regions of a protein crystal: structural variations and unit-cell polymorphism

Real macromolecular crystals can be non-ideal in a myriad of ways. This often creates challenges for structure determination, while also offering opportunities for greater insight into the crystalline state and the dynamic behavior of macromolecules. To evaluate whether different parts of a single crystal of a dynamic protein, EutL, might be informative about crystal and protein polymorphism, a microfocus X-ray synchrotron beam was used to collect a series of 18 separate data sets from non-overlapping regions of the same crystal specimen. A principal component analysis (PCA) approach was employed to compare the structure factors and unit cells across the data sets, and it was found that the 18 data sets separated into two distinct groups, with large R values (in the 40% range) and significant unit-cell variations between the members of the two groups. This categorization mapped the different data-set types to distinct regions of the crystal specimen. Atomic models of EutL were then refined against two different data sets obtained by separately merging data from the two distinct groups. A comparison of the two resulting models revealed minor but discernable differences in certain segments of the protein structure, and regions of higher deviation were found to correlate with regions where larger dynamic motions were predicted to occur by normal-mode molecular-dynamics simulations. The findings emphasize that large spatially dependent variations may be present across individual macromolecular crystals. This information can be uncovered by simultaneous analysis of multiple partial data sets and can be exploited to reveal new insights about protein dynamics, while also improving the accuracy of the structure-factor data ultimately obtained in X-ray diffraction experiments.

Thompson, Michael C. (ORCID:0000000260992027)↗

Respiratory effort correction strategies to improve the reproducibility of lung expansion measurements

Purpose: Four-dimensional computed tomography (4DCT) can be used to make measurements of pulmonary function longitudinally. The sensitivity of such measurements to identify change depends on measurement uncertainty. Previously, intrasubject reproducibility of Jacobian-based measures of lung tissue expansion was studied in two repeat prior-RT 4DCT human acquisitions. Difference in respiratory effort such as breathing amplitude and frequency may affect longitudinal function assessment. In this study, the authors present normalization schemes that correct ventilation images for variations in respiratory effort and assess the reproducibility improvement after effort correction.Methods: Repeat 4DCT image data acquired within a short time interval from 24 patients prior to radiation therapy (RT) were used for this analysis. Using a tissue volume preserving deformable image registration algorithm, Jacobian ventilation maps in two scanning sessions were computed and compared on the same coordinate for reproducibility analysis. In addition to computing the ventilation maps from end expiration to end inspiration, the authors investigated the effort normalization strategies using other intermediated inspiration phases upon the principles of equivalent tidal volume (ETV) and equivalent lung volume (ELV). Scatter plots and mean square error of the repeat ventilation maps and the Jacobian ratio map were generated for four conditions: no effort correction, global normalization, ETV, and ELV. In addition, gamma pass rate was calculated from a modified gamma index evaluation between two ventilation maps, using acceptance criterions of 2 mm distance-to-agreement and 5% ventilation difference.Results: The pattern of regional pulmonary ventilation changes as lung volume changes. All effort correction strategies improved reproducibility when changes in respiratory effort were greater than 150 cc (p < 0.005 with regard to the gamma pass rate). Improvement of reproducibility was correlated with respiratory effort difference (R = 0.744 for ELV in the cohort with tidal volume difference greater than 100 cc). In general for all subjects, global normalization, ETV and ELV significantly improved reproducibility compared to no effort correction (p = 0.009, 0.002, 0.005 respectively). When tidal volume difference was small (less than 100 cc), none of the three effort correction strategies improved reproducibility significantly (p = 0.52, 0.46, 0.46 respectively). For the cohort (N = 13) with tidal volume difference greater than 100 cc, the average gamma pass rate improves from 57.3% before correction to 66.3% after global normalization, and 76.3% after ELV. ELV was found to be significantly better than global normalization (p = 0.04 for all subjects, and p = 0.003 for the cohort with tidal volume difference greater than 100 cc).Conclusions: All effort correction strategies improve the reproducibility of the authors' pulmonary ventilation measures, and the improvement of reproducibility is highly correlated with the changes in respiratory effort. ELV gives better results as effort difference increase, followed by ETV, then global. However, based on the spatial and temporal heterogeneity in the lung expansion rate, a single scaling factor (e.g., global normalization) appears to be less accurate to correct the ventilation map when changes in respiratory effort are large.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

Uncertainty Quantification in Vibro-Acoustics Diagnosis of Alkali-Silica Reaction Degradation in Medium-Sized Concrete Samples

The objectives of this ongoing research project focus on health monitoring and data analytics of concrete slabs containing reactive aggregates and thus subjected to degradation due to alkali-silica reaction (ASR). A controlled concrete slab with four pockets of reactive aggregates (pure silica, wells, placitas, and spratt) was cast at Vanderbilt University and cured in representative conditions to accelerate degradation due to ASR. A set of four concrete samples were also cast and cured at the University of Alabama for ASR testing. Of these four samples, two slabs contained reactive aggregates while the other two had the non-reactive aggregate counterparts mixed throughout the samples. Vibro-acoustic testing was used on these slabs to locate ASR damage within the reactive samples. Vibro-acoustic modulation (VAM) is a vibration-based NDE method that utilizes signatures of nonlinear dynamic interactions on contact surfaces of crack or delamination damage to detect and localize the damage. VAM analysis was conducted on both the Vanderbilt and Alabama samples using multiple variables for damage detection and localization. The results from the data analysis of the vibro-acoustic testing on concrete slabs cured at Vanderbilt University and the University of Alabama are discussed in detail in this report. Results for damage localization are dependent on multiple variables used in the vibro-acoustic modulation experiments. A major focus of this report is to quantify the uncertainty in the diagnosis due to multiple factors and uncertainty sources. The uncertainty quantification methodology presented in this report was applied to VAM-based diagnosis and prognosis. However, the methodology is general, and is capable of being applied to multiple technique that collect spatially distributed data. Future work needs to investigate the incorporation of uncertainty quantification in developing a robust Prognostics and Health Management framework. Digital image correlation is a three-dimensional, full-field, optical NDE technique to measure contour, deformation, vibration, and strain. The application of the digital image correlation technique to study ASR-related degradation on a large concrete specimen at the University of Tennessee is discussed and observations are presented in this report.

46 INSTRUMENTATION RELATED TO NUCLEAR SCIENCE AND ↗

Imaging Nanoscale Energy Transport and Conversion with Ultrafast Electron Microscopy (Final Technical Report)

Light-matter interactions are ubiquitous in nature and reside at the heart of innumerable technologies. The cascade of processes that occur when a material absorbs a photon of light are exceedingly complex and are interwoven in both space and time, rendering precise determination of the atomic-scale and ultrafast mechanisms immensely challenging. The advent of methods for generating short pulses of light several decades ago led to major advances in understanding the initial moments of light absorption and the resultant effects, though directly interrogating the response of the atoms within the material continued to prove challenging. More recently, methods for generating ultrashort pulses of X-rays and fast electrons have opened the way to probing photoinduced structural dynamics of a wide range of matter in multiple phases. An especially promising laboratory-scale method is ultrafast electron microscopy (UEM), wherein the modalities of conventional transmission electron microscopes (imaging, diffraction, spectroscopy) are extended into the femtosecond temporal regime. Here, the ultrafast imaging and diffraction modalities of UEM were used to study the transient structural aspects of photoexcitation of semiconducting materials (e.g., spatially-resolved electron-phonon coupling, excitation and emission of acoustic phonons, and discrete nanoscale scattering processes). The project had three main objectives: (1) determination of the excitation mechanisms of dense, hypersonic charge-carrier waves and the spatially mediated means by which they couple to the lattice via coherent phonon emission, especially with UEM imaging, wherein effects of nanoscale structural and morphological features on the coupling and relaxation dynamics are expected to dictate nucleation sites and preferred wave vectors, (2) elucidation of photoinduced acoustic-phonon seeding, emergence, propagation, and decay over nanoscale crystal regions and especially with respect to local strain fields and atomic-scale disruptions in lattice order, and (3) interwoven with the first two were efforts aimed at realizing combined angstrom-femtosecond spatiotemporal imaging with UEM. The outcomes and impacts of this project were the generation of new knowledge with respect to fundamental light-matter interactions and, especially, the spatially-mediated excitation and evolution of the structural response of materials following coherent photoexcitation. Importantly, the spatial and temporal resolutions of the UEM imaging modalities used are well-suited for such studies and enable spatially-resolved mechanisms to be determined as a function of atomic order, structural features, and morphology. In addition, ultrafast crystallographic measurements were used to correlate real- and reciprocal-space dynamics in order to determine atomic-scale preferential wave vectors and ultrafast scattering mechanisms, especially as dictated by specimen boundary conditions. The obtained results, as detailed in peer-reviewed publications and presentations, illustrate the importance of ultrafast, angstrom-scale real-space imaging for developing a comprehensive understanding of energy transport and conversion in materials.

47 OTHER INSTRUMENTATION↗

Local Atomic Configuration in Pristine and A-Site Doped Silver Niobate Perovskite Antiferroelectrics

Antiferroelectrics have attracted increasing research interests in recent years due to both their great potential in energy storage applications and intriguing structural characteristics. However, the links between the electrical properties and structural characteristics of distorted perovskite antiferroelectrics are yet to be fully deciphered. Here, we adopt local-structure methods to elucidate the nanoscale atomic structure of AgNbO3-based antiferroelectrics and their structural evolution upon La doping. The local structural features including interatomic distance distributions and atomic displacements have been analyzed using neutron small-box pair distribution function (PDF) refinement in conjunction with large-box Reverse Monte Carlo modelling. Our results highlight the correlation of cation displacements in AgNbO 3 and its disruption by the incorporation of La, apparently in corroboration with the observed anomalous dielectric properties. Spatial ordering of cation vacancies is observed in La-doped AgNbO 3 samples, which coordinates with oxygen octahedral tilting to relieve lattice strain. These results provide renewed insights into the atomic structure and antiferroelectric phase instabilities of AgNbO 3 and relevant perovskite materials, further lending versatile opportunities for enhancing their functionalities.

36 MATERIALS SCIENCE↗

Turbulent Transport in a Three-dimensional Solar Wind

Turbulence in the solar wind can play essential roles in the heating of coronal and solar wind plasma and the acceleration of the solar wind and energetic particles. Turbulence sources are not well understood and thought to be partly enhanced by interaction with the large-scale inhomogeneity of the solar wind and the interplanetary magnetic field and/or transported from the solar corona. To investigate the interaction with background inhomogeneity and the turbulence sources, we have developed a new 3D MHD model that includes the transport and dissipation of turbulence using the theoretical model of Zank et al. We solve for the temporal and spatial evolution of three moments or variables, the energy in the forward and backward fluctuating modes and the residual energy and their three corresponding correlation lengths. The transport model is coupled to our 3D model of the inhomogeneous solar wind. We present results of the coupled solar wind-turbulence model assuming a simple tilted dipole magnetic configuration that mimics solar minimum conditions, together with several comparative intermediate cases. By considering eight possible solar wind and turbulence source configurations, we show that the large-scale solar wind and IMF inhomogeneity and the strength of the turbulence sources significantly affect the distribution of turbulence in the heliosphere within 6 au. We compare the predicted turbulence distribution results from a complete solar minimum model with in situ measurements made by the Helios and Ulysses spacecraft, finding that the synthetic profiles of the turbulence intensities show reasonable agreement with observations.

79 ASTRONOMY AND ASTROPHYSICS↗

Outflow Kinematics Manifested by the Hα Line: Gas Outflows in Type 2 AGNs. IV

Energetic ionized gas outflows driven by active galactic nuclei (AGNs) have been studied as a key phenomenon related to AGN feedback. To probe the kinematics of the gas in the narrow-line region, [O iii] λ 5007 has been utilized in a number of studies showing nonvirial kinematic properties due to AGN outflows. In this paper, we statistically investigate whether the H α emission line is influenced by AGN-driven outflows by measuring the kinematic properties based on the H α line profile and comparing them with those of [O iii]. Using the spatially integrated spectra of ∼37,000 Type 2 AGNs at z < 0.3 selected from the Sloan Digital Sky Survey DR7, we find a nonlinear correlation between H α velocity dispersion and stellar velocity dispersion that reveals the presence of the nongravitational component, especially for AGNs with a wing component in H α . The large H α velocity dispersion and velocity shift of luminous AGNs are clear evidence of AGN outflow impacts on hydrogen gas, while relatively smaller kinematic properties compared to those of [O iii] imply that the observed outflow effect on the H α line is weaker than the case of [O iii].

79 ASTRONOMY AND ASTROPHYSICS↗

Spatial and temporal variability of turbulence dissipation rate in complex terrain

To improve parameterizations of the turbulence dissipation rate (ϵ) in numerical weather prediction models, the temporal and spatial variability of ϵ must be assessed. In this study, we explore influences on the variability of ϵ at various scales in the Columbia River Gorge during the WFIP2 field experiment between 2015 and 2017. We calculate ϵ from five sonic anemometers all deployed in a ~4 km 2 area as well as from two scanning Doppler lidars and four profiling Doppler lidars, whose locations span a ~300 km wide region. We retrieve ϵ from the sonic anemometers using the second-order structure function method, from the scanning lidars with the azimuth structure function approach, and from the profiling lidars with a novel technique using the variance of the line-of-sight velocity. The turbulence dissipation rate shows large spatial variability, even at the microscale, especially during nighttime stable conditions. Orographic features have a strong impact on the variability of ϵ, with the correlation between ϵ at different stations being highly influenced by terrain. ϵ shows larger values in sites located downwind of complex orographic structures or in wind farm wakes. A clear diurnal cycle in ϵ is found, with daytime convective conditions determining values over an order of magnitude higher than nighttime stable conditions. ϵ also shows a distinct seasonal cycle, with differences greater than an order of magnitude between average ϵ values in summer and winter.

54 ENVIRONMENTAL SCIENCES↗

Robust historical evapotranspiration trends across climate regimes

Evapotranspiration (ET) links the hydrological, energy and carbon cycles on the land surface. Quantifying ET and its spatio-temporal changes is also key to understanding climate extremes such as droughts, heatwaves and flooding. Regional ET estimates require reliable observation-based gridded ET datasets, and while many have been developed using physically based, empirically based and hybrid techniques, their efficacy, and particularly the efficacy of their uncertainty estimates, is difficult to verify. In this work, we extend the methodology used in Hobeichi et al. (2018) to derive two new versions of the Derived Optimal Linear Combination Evapotranspiration (DOLCE) product, with observationally constrained spatio-temporally varying uncertainty estimates, higher spatial resolution, more constituent products and extended temporal coverage (1980–2018). After demonstrating the efficacy of these uncertainty estimates with out-of-sample testing, we derive novel ET climatology clusters for the land surface, based on the magnitude and variability of ET at each location on land. The new clusters include three wet and three dry regimes and provide an approximation of Köppen–Geiger climate classes. The verified uncertainty estimates and extended time period then allow us to examine the robustness of historical trends spatially and in each of these six ET climatology clusters. We find that despite robust decreasing ET trends in some regions these do not correlate with behavioural ET clusters. Each cluster, and the majority of the Earth's surface, shows clear robust increases in ET over the recent historical period. The new datasets DOLCE V2.1 and DOLCE V3 can be used for benchmarking global ET estimates and for examining ET trends respectively.

54 ENVIRONMENTAL SCIENCES↗

Point Cloud Based Mapping of Understory Shrub Fuel Distribution, Estimation of Fuel Consumption and Relationship to Pyrolysis Gas Emissions on Experimental Prescribed Burns

Forest fires spread via production and combustion of pyrolysis gases in the understory. The goal of the present paper is to understand the spatial location, distribution, and fraction (relative to the overstory) of understory plants, in this case, sparkleberry shrub, namely its degree of understory consumption upon burn, and to search for correlations between the degree of shrub consumption to the composition of emitted pyrolysis gases. Data were collected in situ at seven small experimental prescribed burns at Ft. Jackson, an army base in South Carolina, USA. Using airborne laser scanning (ALS) to map overstory tree crowns and terrestrial laser scanning (TLS) to characterize understory shrub fuel density, both pre- and postburn estimates of sparkleberry coverage were obtained. Sparkleberry clump polygons were manually digitized from a UAV-derived orthoimage of the understory and intersected with the TLS point cloud-derived rasters of pre- and postburn shrub fuel bulk density; these were compared in relation to overstory crown cover as well as to ground truth. Shrub fuel consumption was estimated from the digitized images; sparkleberry clump distributions were generally found to not correlate well to the overstory tree crowns, suggesting it is shade-tolerant. Moreover, no relationship was found between the magnitude of the fuel consumption and the chemical composition of pyrolysis gases, even though mixing ratios of 25 individual gases were measured.

54 ENVIRONMENTAL SCIENCES↗