7 research outputs found
Repeated, long-distance migrations by a philopatric predator targeting highly contrasting ecosystems
Long-distance movements of animals are an important driver of population spatial dynamics and determine the extent of overlap with area-focused human activities, such as fishing. Despite global concerns of declining shark populations, a major limitation in assessments of population trends or spatial management options is the lack of information on their long-term migratory behaviour. For a large marine predator, the tiger shark Galeocerdo cuvier, we show from individuals satellite-tracked for multiple years (up to 1101 days) that adult males undertake annually repeated, round-trip migrations of over 7,500 km in the northwest Atlantic. Notably, these migrations occurred between the highly disparate ecosystems of Caribbean coral reef regions in winter and high latitude oceanic areas in summer, with strong, repeated philopatry to specific overwintering insular habitat. Partial migration also occurred, with smaller, immature individuals displaying reduced migration propensity. Foraging may be a putative motivation for these oceanic migrations, with summer behaviour showing higher path tortuosity at the oceanic range extremes. The predictable migratory patterns and use of highly divergent ecosystems shown by male tiger sharks appear broadly similar to migrations seen in birds, reptiles and mammals, and highlight opportunities for dynamic spatial management and conservation measures of highly mobile sharks
Understanding the Conformational Impact of Chemical Modifications on Monoclonal Antibodies with Diverse Sequence Variation Using Hydrogen/Deuterium Exchange Mass Spectrometry and Structural Modeling
DNA-Encoded Library Screening Identifies Benzo[<i>b</i>][1,4]oxazepin-4-ones as Highly Potent and Monoselective Receptor Interacting Protein 1 Kinase Inhibitors
The
recent discovery of the role of receptor interacting protein
1 (RIP1) kinase in tumor necrosis factor (TNF)-mediated inflammation
has led to its emergence as a highly promising target for the treatment
of multiple inflammatory diseases. We screened RIP1 against GSK’s
DNA-encoded small-molecule libraries and identified a novel highly
potent benzoxazepinone inhibitor series. We demonstrate that this
template possesses complete monokinase selectivity for RIP1 plus unique
species selectivity for primate versus nonprimate RIP1. We elucidate
the conformation of RIP1 bound to this benzoxazepinone inhibitor driving
its high kinase selectivity and design specific mutations in murine
RIP1 to restore potency to levels similar to primate RIP1. This series
differentiates itself from known RIP1 inhibitors in combining high
potency and kinase selectivity with good pharmacokinetic profiles
in rodents. The favorable developability profile of this benzoxazepinone
template, as exemplified by compound <b>14</b> (GSK’481),
makes it an excellent starting point for further optimization into
a RIP1 clinical candidate
DNA-Encoded Library Screening Identifies Benzo[<i>b</i>][1,4]oxazepin-4-ones as Highly Potent and Monoselective Receptor Interacting Protein 1 Kinase Inhibitors
The
recent discovery of the role of receptor interacting protein
1 (RIP1) kinase in tumor necrosis factor (TNF)-mediated inflammation
has led to its emergence as a highly promising target for the treatment
of multiple inflammatory diseases. We screened RIP1 against GSK’s
DNA-encoded small-molecule libraries and identified a novel highly
potent benzoxazepinone inhibitor series. We demonstrate that this
template possesses complete monokinase selectivity for RIP1 plus unique
species selectivity for primate versus nonprimate RIP1. We elucidate
the conformation of RIP1 bound to this benzoxazepinone inhibitor driving
its high kinase selectivity and design specific mutations in murine
RIP1 to restore potency to levels similar to primate RIP1. This series
differentiates itself from known RIP1 inhibitors in combining high
potency and kinase selectivity with good pharmacokinetic profiles
in rodents. The favorable developability profile of this benzoxazepinone
template, as exemplified by compound <b>14</b> (GSK’481),
makes it an excellent starting point for further optimization into
a RIP1 clinical candidate