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

Inshore and offshore marine migration pathways of Atlantic salmon post-smolts from multiple rivers in Scotland, England, Northern Ireland and Ireland

The migratory behavior of Atlantic salmon (Salmo salar) post-smolts in coastal waters is poorly understood. In this collaborative study, 1914 smolts, from 25 rivers, in four countries were tagged with acoustic transmitters during a single seasonal migration. In total, 1105 post-smolts entered the marine study areas and 438 (39.6%) were detected on a network of 414 marine acoustic receivers and an autonomous underwater vehicle. Migration pathways (defined as the shortest distance between two detections) of up to 575 km and over 100 days at sea were described for all 25 populations. Post-smolts from different rivers, as well as individuals from the same river, used different pathways in coastal waters. Although difficult to generalize to all rivers, at least during the year of this study, no tagged post-smolts from rivers draining into the Irish Sea were detected entering the areas of sea between the Hebrides and mainland Scotland, which is associated with a high density of finfish aquaculture. An important outcome of this study is that a high proportion of post-smolts crossed through multiple legislative jurisdictions and boundaries during their migration. This study provides the basis for spatially explicit assessment of the impact risk of coastal pressures on salmon during their first migration to sea

Inshore and offshore marine migration pathways of Atlantic salmon post-smolts from multiple rivers in Scotland, England, Northern Ireland, and Ireland

The migratory behavior of Atlantic salmon (Salmo salar) post-smolts in coastal waters is poorly understood. In this collaborative study, 1914 smolts, from 25 rivers, in four countries were tagged with acoustic transmitters during a single seasonal migration. In total, 1105 post-smolts entered the marine study areas and 438 (39.6%) were detected on a network of 414 marine acoustic receivers and an autonomous underwater vehicle. Migration pathways (defined as the shortest distance between two detections) of up to 575 km and over 100 days at sea were described for all 25 populations. Post-smolts from different rivers, as well as individuals from the same river, used different pathways in coastal waters. Although difficult to generalize to all rivers, at least during the year of this study, no tagged post-smolts from rivers draining into the Irish Sea were detected entering the areas of sea between the Hebrides and mainland Scotland, which is associated with a high density of finfish aquaculture. An important outcome of this study is that a high proportion of post-smolts crossed through multiple legislative jurisdictions and boundaries during their migration. This study provides the basis for spatially explicit assessment of the impact risk of coastal pressures on salmon during their first migration to sea

Aquatic animal telemetry : a panoramic window into the underwater world

The distribution and interactions of aquatic organisms across space and time structure our marine, freshwater, and estuarine ecosystems. Over the past decade, technological advances in telemetry have transformed our ability to observe aquatic animal behavior and movement. These advances are now providing unprecedented ecological insights by connecting animal movements with measures of their physiology and environment. These developments are revolutionizing the scope and scale of questions that can be asked about the causes and consequences of movement and are redefining how we view and manage individuals, populations, and entire ecosystems. The next advance in aquatic telemetry will be the development of a global collaborative effort to facilitate infrastructure and data sharing and management over scales not previously possible.10 page(s

Pan-Holarctic assessment of post-release mortality of angled Atlantic salmon Salmo salar

Recreational Atlantic salmon Salmo salar fisheries are culturally and economically important, but confronted with global population declines, catch-and-release has frequently replaced harvest in these fisheries. Many studies have evaluated the effects of catch-and-release angling on Atlantic salmon; however, studies typically focused on a single system and had small sample sizes. Using data from Atlantic salmon catch-and-release studies conducted in 12 rivers throughout the pan-Holarctic range of wild Atlantic salmon, we modeled delayed mortality data using logistic regression. The model was based on 512 salmon (75 ± 15 cm TL) captured and released with electronic tags (i.e. radio or acoustic transmitters), which permitted the determination of fish fate after release (delayed mortality). The percentage of salmon categorized as survivors after release was high (93%). Salmon with longer body length tended to be played for longer durations (R2 = 0.60) but there was no significant effect of fish length or playing time on mortality. Water temperature at capture emerged as a significant predictor of delayed mortality of salmon. Individuals captured by flies had significantly higher survival (96%) compared to lure (86%) and natural bait (85%) caught salmon. Data from throughout the range of Atlantic salmon confirm that fish captured by anglers adhering to best practices have high probability of surviving catch-and-release angling

Discovery, Optimization, and in Vivo Evaluation of Benzimidazole Derivatives AM-8508 and AM-9635 as Potent and Selective PI3Kδ Inhibitors

Lead optimization efforts resulted in the discovery of two potent, selective, and orally bioavailable PI3Kδ inhibitors, <b>1</b> (AM-8508) and <b>2</b> (AM-9635), with good pharmacokinetic properties. The compounds inhibit B cell receptor (BCR)-mediated AKT phosphorylation (pAKT) in PI3Kδ-dependent in vitro cell based assays. These compounds which share a benzimidazole bicycle are effective when administered in vivo at unbound concentrations consistent with their in vitro cell potency as a consequence of improved unbound drug concentration with lower unbound clearance. Furthermore, the compounds demonstrated efficacy in a Keyhole Limpet Hemocyanin (KLH) study in rats, where the blockade of PI3Kδ activity by inbibitors <b>1</b> and <b>2</b> led to effective inhibition of antigen-specific IgG and IgM formation after immunization with KLH

Envisioning the Future of Aquatic Animal Tracking: Technology, Science, and Application

Electronic tags are significantly improving our understanding of aquatic animal behavior and are emerging as key sources of information for conservation and management practices. Future aquatic integrative biology and ecology studies will increasingly rely on data from electronic tagging. Continued advances in tracking hardware and software are needed to provide the knowledge required by managers and policymakers to address the challenges posed by the world's changing aquatic ecosystems. We foresee multiplatform tracking systems for simultaneously monitoring the position, activity, and physiology of animals and the environment through which they are moving. Improved data collection will be accompanied by greater data accessibility and analytical tools for processing data, enabled by new infrastructure and cyberinfrastructure. To operationalize advances and facilitate integration into policy, there must be parallel developments in the accessibility of education and training, as well as solutions to key governance and legal issues