Drug Repurposing: The Anthelmintics Niclosamide and Nitazoxanide Are Potent TMEM16A Antagonists That Fully Bronchodilate Airways

There is an unmet need in severe asthma where approximately 40% of patients exhibit poor β-agonist responsiveness, suffer daily symptoms and show frequent exacerbations. Antagonists of the Ca2+-activated Cl− channel, TMEM16A, offers a new mechanism to bronchodilate airways and block the multiple contractiles operating in severe disease. To identify TMEM16A antagonists we screened a library of ∼580,000 compounds. The anthelmintics niclosamide, nitazoxanide, and related compounds were identified as potent TMEM16A antagonists that blocked airway smooth muscle depolarization and contraction. To evaluate whether TMEM16A antagonists resist use- and inflammatory-desensitization pathways limiting β-agonist action, we tested their efficacy under harsh conditions using maximally contracted airways or airways pretreated with a cytokine cocktail. Stunningly, TMEM16A antagonists fully bronchodilated airways, while the β-agonist isoproterenol showed only partial effects. Thus, antagonists of TMEM16A and repositioning of niclosamide and nitazoxanide represent an important additional treatment for patients with severe asthma and COPD that is poorly controlled with existing therapies. It is of note that drug repurposing has also attracted wide interest in niclosamide and nitazoxanide as a new treatment for cancer and infectious disease. For the first time we identify TMEM16A as a molecular target for these drugs and thus provide fresh insights into their mechanism for the treatment of these disorders in addition to respiratory disease

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

Aspen and Spruce Densities Affect Tree Size, Future Stand Volume, and Aboveground Carbon Following Precommercial Thinning

Data collected over a 30-year period from an experiment replicated across 21 locations in western Canada are used to explore the effects of precommercial thinning of trembling aspen to a range of densities in combination with three initial white spruce densities on tree growth and stand dynamics. Increasing differentiation amongst the 15 treatments was observed with age after thinning for both spruce and aspen responses. Spruce height and diameter declined with increasing aspen density. At age 10 spruce diameter with no aspen was 1.5× that of spruce in unthinned while it was 2.6× that of spruce in unthinned at age 28. Following thinning aspen DBH and crown width declined with increasing density of retained aspen while slenderness and height to crown base of aspen increased. Thinning to 1500 aspen·ha−1 resulted in aspen DBH that was 22% larger relative to the unthinned at age 28. Spruce volume and stemwood biomass at age 90, estimated using the Mixedwood Growth Model (MGM21), declined with increasing initial aspen density, with the complete removal of aspen resulting in nearly double the spruce volume of unthinned plots. However, total stand volume, total stand biomass, and stemwood carbon at age 90 are predicted to be largest in mixed stands with aspen densities of 1500 stems·ha−1 or higher

Deterministic Models of Growth and Mortality for Jack Pine in Boreal Forests of Western Canada

We developed individual tree deterministic growth and mortality models for jack pine (Pinus banksiana Lamb.) using data from permanent sample plots in Alberta, Saskatchewan and Manitoba, Canada. Height and diameter increment equations were fitted using nonlinear mixed effects models. Logistic mixed models were used to estimate jack pine survival probability based on tree and stand characteristics. The resulting models showed that (1) jack pine growth is significantly influenced by competition; (2) competitive effects differ between species groups; and (3) survival probability is affected by tree size and growth, stand composition, and stand density. The estimated coefficients of selected growth and mortality functions were implemented into the Mixedwood Growth Model (MGM) and the simulated predictions were evaluated against independently measured data. The validation showed that the MGM can effectively model jack pine trees and stands, providing support for its use in management planning

Managed Mixtures of Aspen and White Spruce 21 to 25 Years after Establishment

Intimate mixtures of trembling aspen (Populus tremuloides Michx.) and white spruce (Picea glauca (Moench) Voss) are a key feature of western Canadian boreal forests. These mixtures have the potential to produce high yields of merchantable fibre and provide numerous ecological services. Achievement of this potential has been difficult, and often expensive, to realize as a regeneration goal in managed forests. We report 21 to 25 year results of managed mixtures on two study sites where the white spruce was planted, and the density of aspen natural regeneration manipulated within five years of the stand initiation disturbance. On both sites, white spruce mortality did not increase with increasing aspen density. While height and diameter growth of white spruce declined with increasing aspen density, the effect was not entirely consistent across the two sites. Abrasion from aspen branches was the most common source of damage to spruce crowns. Mixed stands had greater merchantable volume production than pure spruce stands based on model projections. Application of aspen harvest at year 60, while protecting the spruce component for a second harvest entry at year 90, was projected to optimize combined yield for the mixedwood stands

The Validation of the Mixedwood Growth Model (MGM) for Use in Forest Management Decision Making

We evaluated the Mixedwood Growth Model (MGM) at a whole model scale for pure and mixed species stands of aspen and white spruce in the western boreal forest. MGM is an individual tree-based, distance-independent growth model, designed to evaluate growth and yield implications relating to the management of white spruce, black spruce, aspen, lodgepole pine, and mixedwood stands in Alberta, British Columbia, Saskatchewan, and Manitoba. Our validation compared stand-level model predictions against re-measured data (volume, basal area, diameter at breast height (DBH), average and top height and density) from permanent sample plots using combined analysis of residual plots, bias statistics, efficiency and an innovative application of the equivalence test. For state variables, the model effectively simulated juvenile and mature stages of stand development for both pure and mixed species stands of aspen and white spruce in Alberta. MGM overestimates increment in older stands likely due to age-related pathology and weather-related stand damage. We identified underestimates of deciduous density and volume in Saskatchewan. MGM performs well for increment in postharvest stands less than 30 years of age. These results illustrate the comprehensive application of validation metrics to evaluate a complex model, and provide support for the use of MGM in management planning

BioCreative V BioC track overview:collaborative biocurator assistant task for BioGRID

BioC is a simple XML format for text, annotations and relations, and was developed to achieve interoperability for biomedical text processing. Following the success of BioC in BioCreative IV, the BioCreative V BioC track addressed a collaborative task to build an assistant system for BioGRID curation. In this paper, we describe the framework of the collaborative BioC task and discuss our findings based on the user survey. This track consisted of eight subtasks including gene/protein/organism named entity recognition, protein–protein/genetic interaction passage identification and annotation visualization. Using BioC as their data-sharing and communication medium, nine teams, world-wide, participated and contributed either new methods or improvements of existing tools to address different subtasks of the BioC track. Results from different teams were shared in BioC and made available to other teams as they addressed different subtasks of the track. In the end, all submitted runs were merged using a machine learning classifier to produce an optimized output. The biocurator assistant system was evaluated by four BioGRID curators in terms of practical usability. The curators’ feedback was overall positive and highlighted the user-friendly design and the convenient gene/protein curation tool based on text mining. Database URL: http://www.biocreative.org/tasks/biocreative-v/track-1-bioc