Total synthesis 2-epi-alpha-cedren-3-one via a cobalt-catalysed Pauson-Khand reaction

Herein we target the total synthesis of 2-epi-alpha-cedren-3-one, a natural compound isolated from the essential oil of Juniperus thurifera. Overall, our synthetic sequence presents an optimised and robust series of chemical transformations, with prominent features including a low temperature and highly (Z)-selective Wittig olefination reaction, which is vital for the establishment of the relative stereochemistry within the final natural product, and a microwave-assisted, catalytic, intramolecular Pauson-Khand cyclisation reaction, which is used to construct the intriguing tricyclic core of the target molecule. Our optimum cyclisation protocol utilises only 20 mol% of transition metal, and delivers the complex tricyclic structure in just 10 minutes. Further manipulations of the annulation product culminate in the first total synthesis of the described natural target

Genomics reveal population structure, evolutionary history, and signatures of selection in the northern bottlenose whale, Hyperoodon ampullatus

Funding: This work was supported by Fisheries and Oceans Canada (DFO) Maritimes and National Geographic emerging explorer grant to L.J.F, with support by and Natural Sciences and Engineering Research Council of Canada (NSERC) and Killam Nova Scotia Doctoral Scholarships. Work was also supported by US Office of Naval Research and US Strategic Environmental Research and Development Program (SERDP), DFO, University of Windsor, Crown-Indigenous Relations and Northern Affairs Canada, Nunavut Fisheries Association, Government of Nunavut, and NSERC. Funding and resources for sequencing the northern bottlenose whale genome was supported by the CanSeq150 program of Canada’s Genomics Enterprise.Information on wildlife population structure, demographic history, and adaptations are fundamental to understanding species evolution and informing conservation strategies. To study this ecological context for a cetacean of conservation concern, we conducted the first genomic assessment of the northern bottlenose whale, Hyperoodon ampullatus, using whole-genome resequencing data (n = 37) from five regions across the North Atlantic Ocean. We found a range-wide pattern of isolation-by-distance with a genetic subdivision distinguishing three subgroups: the Scotian Shelf, western North Atlantic, and Jan Mayen regions. Signals of elevated levels of inbreeding in the Endangered Scotian Shelf population indicate this population may be more vulnerable than the other two subgroups. In addition to signatures of inbreeding, evidence of local adaptation in the Scotian Shelf was detected across the genome. We found a long-term decline in effective population size for the species, which poses risks to their genetic diversity and may be exacerbated by the isolating effects of population subdivision. Protecting important habitat and migratory corridors should be prioritized to rebuild population sizes that were diminished by commercial whaling, strengthen gene flow, and ensure animals can move across regions in response to environmental changes.Publisher PDFPeer reviewe

Advances in the cobalt-catalysed Pauson-Khand reaction : development of a sulfide-promoted, microwave-assisted protocol

The development of a sulfide-promoted, microwave-assisted Pauson-Khand reaction has enabled the formation of fused cyclopentenones using sub-stoichiometric quantities of a cobalt mediator over rapid reaction times and with no requirement for an external source of toxic carbon monoxide gas. This protocol displays applicability to both intra- and intermolecular Pauson-Khand reaction examples

Utilising Assured Multi-Agent Reinforcement Learning within safety-critical scenarios

Multi-agent reinforcement learning allows a team of agents to learn how to work together to solve complex decision-making problems in a shared environment. However, this learning process utilises stochastic mechanisms, meaning that its use in safety-critical domains can be problematic. To overcome this issue, we propose an Assured Multi-Agent Reinforcement Learning (AMARL) approach that uses a model checking technique called quantitative verification to provide formal guarantees of agent compliance with safety, performance, and other non-functional requirements during and after the reinforcement learning process. We demonstrate the applicability of our AMARL approach in three different patrolling navigation domains in which multi-agent systems must learn to visit key areas by using different types of reinforcement learning algorithms (temporal difference learning, game theory, and direct policy search). Furthermore, we compare the effectiveness of these algorithms when used in combination with and without our approach. Our extensive experiments with both homogeneous and heterogeneous multi-agent systems of different sizes show that the use of AMARL leads to safety requirements being consistently satisfied and to better overall results than standard reinforcement learning

Environmental change: prospects for conservation and agriculture in a southwest Australia biodiversity hotspot

Accelerating environmental change is perhaps the greatest challenge for natural resource management; successful strategies need to be effective for decades to come. Our objective is to identify opportunities that new environmental conditions may provide for conservation, restoration, and resource use in a globally recognized biodiversity hotspot in southwestern Australia. We describe a variety of changes to key taxonomic groups and system-scale characteristics as a consequence of environmental change (climate and land use), and outline strategies for conserving and restoring important ecological and agricultural characteristics. Opportunities for conservation and economic adaptation are substantial because of gradients in rainfall, temperature, and land use, extensive areas of remnant native vegetation, the ability to reduce and ameliorate areas affected by secondary salinization, and the existence of large national parks and an extensive network of nature reserves. Opportunities presented by the predicted environmental changes encompass agricultural as well as natural ecosystems. These may include expansion of aquaculture, transformation of agricultural systems to adapt to drier autumns and winters, and potential increases in spring and summer rain, carbon-offset plantings, and improving the network of conservation reserves. A central management dilemma is whether restoration/preservation efforts should have a commercial or biodiversity focus, and how they could be integrated. Although the grand challenge is conserving, protecting, restoring, and managing for a future environment, one that balances economic, social, and environmental values, the ultimate goal is to establish a regional culture that values the unique regional environment and balances the utilization of natural resources against protecting remaining natural ecosystems

A four-helix bundle stores copper for methane oxidation

Methane-oxidising bacteria (methanotrophs) require large quantities of copper for the membrane-bound (particulate) methane monooxygenase (pMMO). Certain methanotrophs are also able to switch to using the iron-containing soluble MMO (sMMO) to catalyse methane oxidation, with this switchover regulated by copper. MMOs are Nature’s primary biological mechanism for suppressing atmospheric levels of methane, a potent greenhouse gas. Furthermore, methanotrophs and MMOs have enormous potential in bioremediation and for biotransformations producing bulk and fine chemicals, and in bioenergy, particularly considering increased methane availability from renewable sources and hydraulic fracturing of shale rock. We have discovered and characterised a novel copper storage protein (Csp1) from the methanotroph Methylosinus trichosporium OB3b that is exported from the cytosol, and stores copper for pMMO. Csp1 is a tetramer of 4-helix bundles with each monomer binding up to 13 Cu(I) ions in a previously unseen manner via mainly Cys residues that point into the core of the bundle. Csp1 is the first example of a protein that stores a metal within an established protein-folding motif. This work provides a detailed insight into how methanotrophs accumulate copper for the oxidation of methane. Understanding this process is essential if the wide-ranging biotechnological applications of methanotrophs are to be realised. Cytosolic homologues of Csp1 are present in diverse bacteria thus challenging the dogma that such organisms do not use copper in this location

Aloft: Self-Adaptive Drone Controller Testbed

Aerial drones are increasingly being considered as a valuable tool for inspection in safety critical contexts. Nowhere is this more true than in mining operations which present a dynamic and dangerous environment for human operators. Drones can be deployed in a number of contexts including efficient surveying as well as search and rescue missions. Operating in these dynamic contexts is challenging however and requires the drones control software to detect and adapt to conditions at run-time. To help in the development of such systems we present Aloft, a simulation supported testbed for investigating self-adaptive controllers for drones in mines. Aloft, utilises the Robot Operating system (ROS) and a model environment using Gazebo to provide a physics-based testing. The simulation environment is constructed from a 3D point cloud collected in a physical mock-up of a mine and contains features expected to be found in real-world contexts. Aloft allows members of the research community to deploy their own self-adaptive controllers into the control loop of the drone to evaluate the effectiveness and robustness of controllers in a challenging environment. To demonstrate our system we provide a self-adaptive drone controller and operating scenario as an exemplar. The self-adaptive drone controller provided, utilises a two-layered architecture with a MAPE-K feedback loop. The scenario is an inspection task during which we inject a communications failure. The aim of the controller is to detect this loss of communication and autonomously perform a return home behaviour. Limited battery life presents a constraint on the mission, which therefore means that the drone should complete its mission as fast as possible. Humans, however, might also be present within the environment. This poses a safety risk and the drone must be able to avoid collisions during autonomous flight. In this paper we describe the controller framework and the simulation environment and provide information on how a user might construct and evaluate their own controllers in the presence of disruptions at run-time

The state of the Martian climate

60°N was +2.0°C, relative to the 1981–2010 average value (Fig. 5.1). This marks a new high for the record. The average annual surface air temperature (SAT) anomaly for 2016 for land stations north of starting in 1900, and is a significant increase over the previous highest value of +1.2°C, which was observed in 2007, 2011, and 2015. Average global annual temperatures also showed record values in 2015 and 2016. Currently, the Arctic is warming at more than twice the rate of lower latitudes

Genome-Wide Association Study of Peripheral Artery Disease

Background: Peripheral artery disease (PAD) affects >200 million people worldwide and is associated with high mortality and morbidity. We sought to identify genomic variants associated with PAD overall and in the contexts of diabetes and smoking status. Methods: We identified genetic variants associated with PAD and then meta-analyzed with published summary statistics from the Million Veterans Program and UK Biobank to replicate their findings. Next, we ran stratified genome-wide association analysis in ever smokers, never smokers, individuals with diabetes, and individuals with no history of diabetes and corresponding interaction analyses, to identify variants that modify the risk of PAD by diabetic or smoking status. Results: We identified 5 genome-wide significant (P-associationPeer reviewe

β-Amyloid 1-42 Oligomers Impair Function of Human Embryonic Stem Cell-Derived Forebrain Cholinergic Neurons

Cognitive impairment in Alzheimer's disease (AD) patients is associated with a decline in the levels of growth factors, impairment of axonal transport and marked degeneration of basal forebrain cholinergic neurons (BFCNs). Neurogenesis persists in the adult human brain, and the stimulation of regenerative processes in the CNS is an attractive prospect for neuroreplacement therapy in neurodegenerative diseases such as AD. Currently, it is still not clear how the pathophysiological environment in the AD brain affects stem cell biology. Previous studies investigating the effects of the β-amyloid (Aβ) peptide on neurogenesis have been inconclusive, since both neurogenic and neurotoxic effects on progenitor cell populations have been reported. In this study, we treated pluripotent human embryonic stem (hES) cells with nerve growth factor (NGF) as well as with fibrillar and oligomeric Aβ1-40 and Aβ1-42 (nM-µM concentrations) and thereafter studied the differentiation in vitro during 28-35 days. The process applied real time quantitative PCR, immunocytochemistry as well as functional studies of intracellular calcium signaling. Treatment with NGF promoted the differentiation into functionally mature BFCNs. In comparison to untreated cells, oligomeric Aβ1–40 increased the number of functional neurons, whereas oligomeric Aβ1–42 suppressed the number of functional neurons. Interestingly, oligomeric Aβ exposure did not influence the number of hES cell-derived neurons compared with untreated cells, while in contrast fibrillar Aβ1–40 and Aβ1–42 induced gliogenesis. These findings indicate that Aβ1–42 oligomers may impair the function of stem cell-derived neurons. We propose that it may be possible for future AD therapies to promote the maturation of functional stem cell-derived neurons by altering the brain microenvironment with trophic support and by targeting different aggregation forms of Aβ