Structure and dynamics of the active Gs-coupled human secretin receptor

The class B secretin GPCR (SecR) has broad physiological effects, with target potential for treatment of metabolic and cardiovascular disease. Molecular understanding of SecR binding and activation is important for its therapeutic exploitation. We combined cryo-electron microscopy, molecular dynamics, and biochemical cross-linking to determine a 2.3 Å structure, and interrogate dynamics, of secretin bound to the SecR:Gs complex. SecR exhibited a unique organization of its extracellular domain (ECD) relative to its 7-transmembrane (TM) core, forming more extended interactions than other family members. Numerous polar interactions formed between secretin and the receptor extracellular loops (ECLs) and TM helices. Cysteine-cross-linking, cryo-electron microscopy multivariate analysis and molecular dynamics simulations revealed that interactions between peptide and receptor were dynamic, and suggested a model for initial peptide engagement where early interactions between the far N-terminus of the peptide and SecR ECL2 likely occur following initial binding of the peptide C-terminus to the ECD

Movement Patterns for a Critically Endangered Species, the Leatherback Turtle (Dermochelys coriacea), Linked to Foraging Success and Population Status

Foraging success for pelagic vertebrates may be revealed by horizontal and vertical movement patterns. We show markedly different patterns for leatherback turtles in the North Atlantic versus Eastern Pacific, which feed on gelatinous zooplankton that are only occasionally found in high densities. In the Atlantic, travel speed was characterized by two modes, indicative of high foraging success at low speeds (<15 km d−1) and transit at high speeds (20–45 km d−1). Only a single mode was evident in the Pacific, which occurred at speeds of 21 km d−1 indicative of transit. The mean dive depth was more variable in relation to latitude but closer to the mean annual depth of the thermocline and nutricline for North Atlantic than Eastern Pacific turtles. The most parsimonious explanation for these findings is that Eastern Pacific turtles rarely achieve high foraging success. This is the first support for foraging behaviour differences between populations of this critically endangered species and suggests that longer periods searching for prey may be hindering population recovery in the Pacific while aiding population maintenance in the Atlantic

Transitioning towards continuous experimentation in a large software product and service development organisation – a case study

Context: Companies need capabilities to evaluate the customer value of software intensive products and services. One way of systematically acquiring data on customer value is running continuous experiments as part of the overall development process. Objective: This paper investigates the first steps of transitioning towards continuous experimentation in a large company, including the challenges faced. Method: We conduct a single-case study using participant observation, interviews, and qualitative analysis of the collected data. Results: Results show that continuous experimentation was well received by the practitioners and practising experimentation helped them to enhance understanding of their product value and user needs. Although the complexities of a large multi-stakeholder business to-business (B2B) environment presented several challenges such as inaccessible users, it was possible to address impediments and integrate an experiment in an ongoing development project. Conclusion: Developing the capability for continuous experimentation in large organisations is a learning process which can be supported by a systematic introduction approach with the guidance of experts. We gained experience by introducing the approach on a small scale in a large organisation, and one of the major steps for future work is to understand how this can be scaled up to the whole development organisation