Automated quantification of steatosis: agreement with stereological point counting

Background: Steatosis is routinely assessed histologically in clinical practice and research. Automated image analysis can reduce the effort of quantifying steatosis. Since reproducibility is essential for practical use, we have evaluated different analysis methods in terms of their agreement with stereological point counting (SPC) performed by a hepatologist. Methods: The evaluation was based on a large and representative data set of 970 histological images from human patients with different liver diseases. Three of the evaluated methods were built on previously published approaches. One method incorporated a new approach to improve the robustness to image variability. Results: The new method showed the strongest agreement with the expert. At 20× resolution, it reproduced steatosis area fractions with a mean absolute error of 0.011 for absent or mild steatosis and 0.036 for moderate or severe steatosis. At 10× resolution, it was more accurate than and twice as fast as all other methods at 20× resolution. When compared with SPC performed by two additional human observers, its error was substantially lower than one and only slightly above the other observer. Conclusions: The results suggest that the new method can be a suitable automated replacement for SPC. Before further improvements can be verified, it is necessary to thoroughly assess the variability of SPC between human observers

Plasma Electronics

Contains research objectives and reports on seven research projects.U. S. ArmyLincoln Laboratory, Purchase Order DDL B-00368U. S. Air Force under Air Force Contract AF19(604)-7400U. S. NavyNational Science Foundation (Grant G-24073)U.S. Navy (Office of Naval Research) under Contract Nonr-1841(78

Convective transport and scavenging of peroxides by thunderstorms observed over the central U.S. during DC3

One of the objectives of the Deep Convective Clouds and Chemistry (DC3) field experiment was to determine the scavenging of soluble trace gases by thunderstorms. We present an analysis of scavenging of hydrogen peroxide (H_2O_2) and methyl hydrogen peroxide (CH_3OOH) from six DC3 cases that occurred in Oklahoma and northeast Colorado. Estimates of H_2O_2 scavenging efficiencies are comparable to previous studies ranging from 79 to 97% with relative uncertainties of 5–25%. CH_3OOH scavenging efficiencies ranged from 12 to 84% with relative uncertainties of 18–558%. The wide range of CH_3OOH scavenging efficiencies is surprising, as previous studies suggested that CH_3OOH scavenging efficiencies would be <10%. Cloud chemistry model simulations of one DC3 storm produced CH_3OOH scavenging efficiencies of 26–61% depending on the ice retention factor of CH_3OOH during cloud drop freezing, suggesting ice physics impacts CH_3OOH scavenging. The highest CH_3OOH scavenging efficiencies occurred in two severe thunderstorms, but there is no obvious correlation between the CH_3OOH scavenging efficiency and the storm thermodynamic environment. We found a moderate correlation between the estimated entrainment rates and CH_3OOH scavenging efficiencies. Changes in gas-phase chemistry due to lightning production of nitric oxide and aqueous-phase chemistry have little effect on CH_3OOH scavenging efficiencies. To determine why CH_3OOH can be substantially removed from storms, future studies should examine effects of entrainment rate, retention of CH_3OOH in frozen cloud particles during drop freezing, and lightning-NO_x production

Two TPX2-Dependent Switches Control the Activity of Aurora A

Aurora A is an important oncogenic kinase for mitotic spindle assembly and a potentially attractive target for human cancers. Its activation could be regulated by ATP cycle and its activator TPX2. To understand the activation mechanism of Aurora A, a series of 20 ns molecular dynamics (MD) simulations were performed on both the wild-type kinase and its mutants. Analyzing the three dynamic trajectories (Aurora A-ATP, Aurora A-ADP, and Aurora A-ADP-TPX2) at the residue level, for the first time we find two TPX2-dependent switches, i.e., switch-1 (Lys-143) and switch-2 (Arg-180), which are tightly associated with Aurora A activation. In the absence of TPX2, Lys-143 exhibits a “closed” state, and becomes hydrogen-bonded to ADP. Once TPX2 binding occurs, switch-1 is forced to “open” the binding site, thus pulling ADP away from Aurora A. Without facilitation of TPX2, switch-2 exits in an “open” conformation which accompanies the outward-flipping movement of P·Thr288 (in an inactive conformation), leading to the crucial phosphothreonine exposed and accessible for deactivation. However, with the binding of TPX2, switch-2 is forced to undergo a “closed” movement, thus capturing P·Thr288 into a buried position and locking its active conformation. Analysis of two Aurora A (K143A and R180A) mutants for the two switches further verifies their functionality and reliability in controlling Aurora activity. Our systems therefore suggest two switches determining Aurora A activation, which are important for the development of aurora kinase inhibitors

Vertical Transport, Entrainment, and Scavenging Processes Affecting Trace Gases in a Modeled and Observed SEAC⁴RS Case Study

The convectively driven transport of soluble trace gases from the lower to the upper troposphere can occur on timescales of less than an hour, and recent studies suggest that microphysical scavenging is the dominant removal process of tropospheric ozone precursors. We examine the processes responsible for vertical transport, entrainment, and scavenging of soluble ozone precursors (formaldehyde and peroxides) for midlatitude convective storms sampled on 2 September 2013 during the Studies of Emissions, Atmospheric Composition, Clouds and Climate Coupling by Regional Surveys (SEAC⁴RS) study. Cloud‐resolving simulations using the Weather Research and Forecasting with Chemistry model combined with aircraft measurements were performed to understand the effect of entrainment, scavenging efficiency (SE), and ice physics processes on these trace gases. Analysis of the observations revealed that the SEs of formaldehyde (43–53%) and hydrogen peroxide (~80–90%) were consistent between SEAC⁴RS storms and the severe convection observed during the Deep Convective Clouds and Chemistry Experiment (DC3) campaign. However, methyl hydrogen peroxide SE was generally smaller in the SEAC⁴RS storms (4%–27%) compared to DC3 convection. Predicted ice retention factors exhibit different values for some species compared to DC3, and we attribute these differences to variations in net precipitation production. The analyses show that much larger production of precipitation between condensation and freezing levels for DC3 severe convection compared to smaller SEAC⁴RS storms is largely responsible for the lower amount of soluble gases transported to colder temperatures, reducing the amount of soluble gases which eventually interact with cloud ice particles

Molecular determinants of binding to the Plasmodium subtilisin-like protease 1.

PfSUB1, a subtilisin-like protease of the human malaria parasite Plasmodium falciparum, is known to play important roles during the life cycle of the parasite and has emerged as a promising antimalarial drug target. In order to provide a detailed understanding of the origin of binding determinants of PfSUB1 substrates, we performed molecular dynamics simulations in combination with MM-GBSA free energy calculations using a homology model of PfSUB1 in complex with different substrate peptides. Key interactions, as well as residues that potentially make a major contribution to the binding free energy, are identified at the prime and nonprime side of the scissile bond and comprise peptide residues P4 to P2'. This finding stresses the requirement for peptide substrates to interact with both prime and nonprime side residues of the PfSUB1 binding site. Analyzing the energetic contributions of individual amino acids within the peptide-PfSUB1 complexes indicated that van der Waals interactions and the nonpolar part of solvation energy dictate the binding strength of the peptides and that the most favorable interactions are formed by peptide residues P4 and P1. Hot spot residues identified in PfSUB1 are dispersed over the entire binding site, but clustered areas of hot spots also exist and suggest that either the S4-S2 or the S1-S2' binding site should be exploited in efforts to design small molecule inhibitors. The results are discussed with respect to which binding determinants are specific to PfSUB1 and, therefore, might allow binding selectivity to be obtained

A fast and robust hepatocyte quantification algorithm including vein processing

<p>Abstract</p> <p>Background</p> <p>Quantification of different types of cells is often needed for analysis of histological images. In our project, we compute the relative number of proliferating hepatocytes for the evaluation of the regeneration process after partial hepatectomy in normal rat livers.</p> <p>Results</p> <p>Our presented automatic approach for hepatocyte (HC) quantification is suitable for the analysis of an entire digitized histological section given in form of a series of images. It is the main part of an automatic hepatocyte quantification tool that allows for the computation of the ratio between the number of proliferating HC-nuclei and the total number of all HC-nuclei for a series of images in one processing run. The processing pipeline allows us to obtain desired and valuable results for a wide range of images with different properties without additional parameter adjustment. Comparing the obtained segmentation results with a manually retrieved segmentation mask which is considered to be the ground truth, we achieve results with sensitivity above 90% and false positive fraction below 15%.</p> <p>Conclusions</p> <p>The proposed automatic procedure gives results with high sensitivity and low false positive fraction and can be applied to process entire stained sections.</p