Different effects of deep inspirations on central and peripheral airways in healthy and allergen-challenged mice

<p>Abstract</p> <p>Background</p> <p>Deep inspirations (DI) have bronchodilatory and bronchoprotective effects in healthy human subjects, but these effects appear to be absent in asthmatic lungs. We have characterized the effects of DI on lung mechanics during mechanical ventilation in healthy mice and in a murine model of acute and chronic airway inflammation.</p> <p>Methods</p> <p>Balb/c mice were sensitized to ovalbumin (OVA) and exposed to nebulized OVA for 1 week or 12 weeks. Control mice were challenged with PBS. Mice were randomly selected to receive DI, which were given twice during the minute before assessment of lung mechanics.</p> <p>Results</p> <p>DI protected against bronchoconstriction of central airways in healthy mice and in mice with acute airway inflammation, but not when OVA-induced chronic inflammation was present. DI reduced lung resistance induced by methacholine from 3.8 ± 0.3 to 2.8 ± 0.1 cmH₂O·s·mL^-1in healthy mice and 5.1 ± 0.3 to 3.5 ± 0.3 cmH₂O·s·mL^-1in acute airway inflammation (both <it>P </it>< 0.001). In healthy mice, DI reduced the maximum decrease in lung compliance from 15.9 ± 1.5% to 5.6 ± 0.6% (<it>P </it>< 0.0001). This protective effect was even more pronounced in mice with chronic inflammation where DI attenuated maximum decrease in compliance from 44.1 ± 6.6% to 14.3 ± 1.3% (<it>P </it>< 0.001). DI largely prevented increased peripheral tissue damping (G) and tissue elastance (H) in both healthy (G and H both <it>P </it>< 0.0001) and chronic allergen-treated animals (G and H both <it>P </it>< 0.0001).</p> <p>Conclusion</p> <p>We have tested a mouse model of potential value for defining mechanisms and sites of action of DI in healthy and asthmatic human subjects. Our current results point to potent protective effects of DI on peripheral parts of chronically inflamed murine lungs and that the presence of DI may blunt airway hyperreactivity.</p

The importance of understanding individual differences in Down syndrome

In this article, we first present a summary of the general assumptions about Down syndrome (DS) still to be found in the literature. We go on to show how new research has modified these assumptions, pointing to a wide range of individual differences at every level of description. We argue that, in the context of significant increases in DS life expectancy, a focus on individual differences in trisomy 21 at all levels—genetic, cellular, neural, cognitive, behavioral, and environmental—constitutes one of the best approaches for understanding genotype/phenotype relations in DS and for exploring risk and protective factors for Alzheimer’s disease in this high-risk population

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery