The Heat Shock Protein 90 Inhibitor, AT13387, Protects the Alveolo-Capillary Barrier and Prevents HCI-Induced Chronic Lung Injury and Pulmonary Fibrosis

Hydrochloric acid (HCl) exposure causes asthma-like conditions, reactive airways dysfunction syndrome, and pulmonary fibrosis. Heat Shock Protein 90 (HSP90) is a molecular chaperone that regulates multiple cellular processes. HSP90 inhibitors are undergoing clinical trials for cancer and are also being studied in various pre-clinical settings for their anti-inflammatory and anti-fibrotic effects. Here we investigated the ability of the heat shock protein 90 (HSP90) inhibitor AT13387 to prevent chronic lung injury induced by exposure to HCl in vivo and its protective role in the endothelial barrier in vitro. We instilled C57Bl/6J mice with 0.1N HCl (2 µL/g body weight, intratracheally) and after 24 h began treatment with vehicle or AT13387 (10 or 15 mg/kg, SC), administered 3×/week; we analyzed histological, functional, and molecular markers 30 days after HCl. In addition, we monitored transendothelial electrical resistance (TER) and protein expression in a monolayer of human lung microvascular endothelial cells (HLMVEC) exposed to HCl (0.02 N) and treated with vehicle or AT13387 (2 µM). HCl provoked persistent alveolar inflammation; activation of profibrotic pathways (MAPK/ERK, HSP90); increased deposition of collagen, fibronectin and elastin; histological evidence of fibrosis; and a decline in lung function reflected in a downward shift in pressure–volume curves, increased respiratory system resistance (Rrs), elastance (Ers), tissue damping (G), and hyperresponsiveness to methacholine. Treatment with 15 mg/kg AT13387 reduced alveolar inflammation, fibrosis, and NLRP3 staining; blocked activation of ERK and HSP90; and attenuated the deposition of collagen and the development of chronic lung injury and airway hyperreactivity. In vitro, AT13387 prevented HCl-induced loss of barrier function and AKT, ERK, and ROCK1 activation, and restored HSP70 and cofilin expression. The HSP90 inhibitor, AT13387, represents a promising drug candidate for chronic lung injury that can be administered subcutaneously in the field, and at low, non-toxic doses

Visualizing Multivariate Hierarchic Data Using Enhanced Radial Space-Filling Layout

Currently, visualization tools for large ontologies (e.g., pathway and gene ontologies) result in a very flat wide tree that is difficult to fit on a single display. This paper develops the concept of using an enhanced radial space-filling (ERSF) layout to show biological ontologies efficiently. The ERSF technique represents ontology terms as circular regions in 3D. Orbital connections in a third dimension correspond to non-tree edges in the ontology that exist when an ontology term belongs to multiple categories. Biologists can use the ERSF layout to identify highly activated pathway or gene ontology categories by mapping experimental statistics such as coefficient of variation and overrepresentation values onto the visualization. This paper illustrates the use of the ERSF layout to explore pathway and gene ontologies using a gene expression dataset from E. coli

Efficiently Calculating Evolutionary Tree Measures Using SAT

We develop techniques to calculate important measures in evolutionary biology by encoding to CNF formulas and using powerful SAT solvers. Comparing evolutionary trees is a necessary step in tree reconstruction algorithms, locating recombination and lateral gene transfer, and in analyzing and visualizing sets of trees. We focus on two popular comparison measures for trees: the hybridization number and the rooted subtree-prune-and-regraft (rSPR) distance. Both have recently been shown to be NP-hard, and effcient algorithms are needed to compute and approximate these measures. We encode these as a Boolean formula such that two trees have hybridization number k (or rSPR distance k) if and only if the corresponding formula is satisfiable. We use state-of-the-art SAT solvers to determine if the formula encoding the measure has a satisfying assignment. Our encoding also provides a rich source of real-world SAT instances, and we include a comparison of several recent solvers (minisat, adaptg2wsat, novelty+p, Walksat, March KS and SATzilla).Postprint (author’s final draft

Associations of autozygosity with a broad range of human phenotypes

In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (F-ROH) for >1.4 million individuals, we show that F-ROH is significantly associated (p <0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: F-ROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44-66%] in the odds of having children. Finally, the effects of F-ROH are confirmed within full-sibling pairs, where the variation in F-ROH is independent of all environmental confounding.Peer reviewe

Velocity-space sensitivity of the time-of-flight neutron spectrometer at JET

The velocity-space sensitivities of fast-ion diagnostics are often described by so-called weight functions. Recently, we formulated weight functions showing the velocity-space sensitivity of the often dominant beam-target part of neutron energy spectra. These weight functions for neutron emission spectrometry (NES) are independent of the particular NES diagnostic. Here we apply these NES weight functions to the time-of-flight spectrometer TOFOR at JET. By taking the instrumental response function of TOFOR into account, we calculate time-of-flight NES weight functions that enable us to directly determine the velocity-space sensitivity of a given part of a measured time-of-flight spectrum from TOFOR