Optimization of TAM16, a Benzofuran That Inhibits the Thioesterase Activity of Pks13; Evaluation toward a Preclinical Candidate for a Novel Antituberculosis Clinical Target

[Image: see text] With increasing drug resistance in tuberculosis (TB) patient populations, there is an urgent need for new drugs. Ideally, new agents should work through novel targets so that they are unencumbered by preexisting clinical resistance to current treatments. Benzofuran 1 was identified as a potential lead for TB inhibiting a novel target, the thioesterase domain of Pks13. Although, having promising activity against Mycobacterium tuberculosis, its main liability was inhibition of the hERG cardiac ion channel. This article describes the optimization of the series toward a preclinical candidate. Despite improvements in the hERG liability in vitro, when new compounds were assessed in ex vivo cardiotoxicity models, they still induced cardiac irregularities. Further series development was stopped because of concerns around an insufficient safety window. However, the demonstration of in vivo activity for multiple series members further validates Pks13 as an attractive novel target for antitubercular drugs and supports development of alternative chemotypes

Ultra-Low Velocity Zone Beneath the Atlantic Near St. Helena

Publication status: PublishedAbstractThere are various hotspots in the Atlantic Ocean, which are underlain by mantle plumes that likely cross the mantle and originate at the core‐mantle boundary. We use teleseismic core‐diffracted shear waves to look for an Ultra‐Low Velocity Zone (ULVZ) at the potential base of central Atlantic mantle plumes. Our data set shows delayed postcursory phases after the core‐diffracted shear waves. The observed patterns are consistent in frequency dependence, delay time, and scatter pattern with those caused by mega‐ULVZs previously modeled elsewhere. Synthetic modeling of a cylindrical structure on the core‐mantle boundary below St. Helena provides a good fit to the data. The preferred model is 600 km across and 20 km high, centered at approximately 15° South, 15° West, and with a 30% S‐wave velocity reduction. Significant uncertainties and trade‐offs do remain to these parameters, but a large ULVZ is needed to explain the data. The location is west of St. Helena and south of Ascension. Helium and neon isotopic systematics observed in samples from this region could point to a less‐outgassed mantle component mixed in with the dominant signature of recycled material. These observations could be explained by a contribution from the Large Low Shear Velocity Province (LLSVP). Tungsten isotopic measurements would be needed to understand whether a contribution from the mega‐ULVZ is also required at St. Helena or Ascension.</jats:p

A NOTE ON THE ECONOMICS OF STANDBY VERSUS STANDING PEACEKEEPING FORCES

With UN peacekeeping activities in recent years having become more numerous, complex and costly, alternative means of responding to emerging crises and conflicts are being proposed and considered, along with their financial costs and funding. This paper analyzes the economic costs and benefits of recent options from a global resource point of view. It is concluded that standby forces provided by Member States to the UN, such as the multinational Stand-by Forces High Readiness Brigade for UN Operations (SHIRBRIG) and the more recent European Union (EU) Rapid Reaction Force (RRF), appear presently to be economically the most efficient means of providing UN peacekeeping. Standby forces, acknowledged by the UN as a feasible alternative to a UN standing army or police force, are economically the most efficient basically because they utilize more fully the existing military resources of Member States, rather than require major additional new resources for peacekeeping.Peacekeeping, Standing army, Standby arrangement, United Nations,

Lung matrix and vascular remodeling in mechanically ventilated elastin haplo-insufficient (<em>Eln^+/-</em>) newborn mice.

Elastin plays a pivotal role in lung development. We therefore queried if elastin haplo-insufficient newborn mice (Eln(+/-)) would exhibit abnormal lung structure and function related to modified extracellular matrix (ECM) composition. As mechanical ventilation (MV) has been linked to dysregulated elastic fiber formation in the newborn lung, we also asked if elastin haplo-insufficiency would accentuate lung growth arrest seen after prolonged MV of neonatal mice. We studied 5d-old wild-type (Eln(+/+)) and Eln(+/-) littermates at baseline, and after MV with air for 8-24h. Lungs of unventilated Eln(+/-) mice contained ~50% less elastin and ~100% more collagen-1 and lysyl oxidase compared to Eln(+/+) pups. Eln(+/-) lungs contained fewer capillaries than Eln(+/+) lungs, without discernible differences in alveolar structure. In response to MV, lung tropoelastin and elastase activity increased in Eln(+/+) neonates, whereas tropoelastin decreased and elastase activity was unchanged in Eln(+/-) mice. Fibrillin-1 protein increased in lungs of both groups during MV, more in Eln(+/-) than in Eln(+/+) pups. In both groups, MV caused capillary loss, with larger and fewer alveoli compared with unventilated controls. Respiratory system elastance, which was less in unventilated Eln(+/-) compared to Eln(+/+) mice, was similar in both groups after MV. These results suggest that elastin haplo-insufficiency adversely impacts pulmonary angiogenesis, and that MV dysregulates elastic fiber integrity, with further loss of lung capillaries, lung growth arrest, and impaired respiratory function in both Eln(+/+) and Eln(+/-) mice. Paucity of lung capillaries in Eln(+/-) newborns might help explain subsequent development of pulmonary hypertension previously reported in adult Eln(+/-) mice

Slab mantle dehydrates beneath Kamchatka – yet recycles water into the deep mantle

The subduction of hydrated slab mantle is the most important and yet weakly constrained factor in the quantification of the Earth's deep geologic water cycle. The most critical unknowns are the initial hydration state and the dehydration behavior of the subducted oceanic mantle. Here we present a combined thermomechanical, thermodynamic, and geochemical model of the Kamchatka subduction zone that indicates significant dehydration of subducted slab mantle beneath Kamchatka. Evidence for the subduction of hydrated oceanic mantle comes from across‐arc trends of boron concentrations and isotopic compositions in arc volcanic rocks. Our thermodynamic‐geochemical models successfully predict the complex geochemical patterns and the spatial distribution of arc volcanoes in Kamchatka assuming the subduction of hydrated oceanic mantle. Our results show that water content and dehydration behavior of the slab mantle beneath Kamchatka can be directly linked to compositional features in arc volcanic rocks. Depending on hydration depth of the slab mantle, our models yield water recycling rates between 1.1 × 103 and 7.4 × 103 Tg/Ma/km corresponding to values between 0.75 × 106 and 5.2 × 106 Tg/Ma for the entire Kamchatkan subduction zone. These values are up to one order of magnitude lower than previous estimates for Kamchatka, but clearly show that subducted hydrated slab mantle significantly contributes to the water budget in the Kamchatkan subduction zone