Discovery and Synthesis of Caracolamide A, an Ion Channel Modulating Dichlorovinylidene Containing Phenethylamide from a Panamanian Marine Cyanobacterium cf. Symploca Species

A recent untargeted metabolomics investigation into the chemical profile of 10 organic extracts from cf. Symploca spp. revealed several interesting chemical leads for further natural product drug discovery. Subsequent targetdirected isolation efforts with one of these, a Panamanian marine cyanobacterium cf. Symploca sp., yielded a phenethylamide metabolite that terminates in a relatively rare gemdichlorovinylidene moiety, caracolamide A (1), along with a known isotactic polymethoxy-1-alkene (2). Detailed NMR and HRESIMS analyses were used to determine the structures of these molecules, and compound 1 was confirmed by a threestep synthesis. Pure compound 1 was shown to have in vitro calcium influx and calcium channel oscillation modulatory activity when tested as low as 10 pM using cultured murine cortical neurons, but was not cytotoxic to NCI-H460 human non-small-cell lung cancer cells in vitro (IC50 > 10 μM).A recent untargeted metabolomics investigation into the chemical profile of 10 organic extracts from cf. Symploca spp. revealed several interesting chemical leads for further natural product drug discovery. Subsequent targetdirected isolation efforts with one of these, a Panamanian marine cyanobacterium cf. Symploca sp., yielded a phenethylamide metabolite that terminates in a relatively rare gemdichlorovinylidene moiety, caracolamide A (1), along with a known isotactic polymethoxy-1-alkene (2). Detailed NMR and HRESIMS analyses were used to determine the structures of these molecules, and compound 1 was confirmed by a threestep synthesis. Pure compound 1 was shown to have in vitro calcium influx and calcium channel oscillation modulatory activity when tested as low as 10 pM using cultured murine cortical neurons, but was not cytotoxic to NCI-H460 human non-small-cell lung cancer cells in vitro (IC50 > 10 μM)

The role of networks to overcome large-scale challenges in tomography : the non-clinical tomography users research network

Our ability to visualize and quantify the internal structures of objects via computed tomography (CT) has fundamentally transformed science. As tomographic tools have become more broadly accessible, researchers across diverse disciplines have embraced the ability to investigate the 3D structure-function relationships of an enormous array of items. Whether studying organismal biology, animal models for human health, iterative manufacturing techniques, experimental medical devices, engineering structures, geological and planetary samples, prehistoric artifacts, or fossilized organisms, computed tomography has led to extensive methodological and basic sciences advances and is now a core element in science, technology, engineering, and mathematics (STEM) research and outreach toolkits. Tomorrow's scientific progress is built upon today's innovations. In our data-rich world, this requires access not only to publications but also to supporting data. Reliance on proprietary technologies, combined with the varied objectives of diverse research groups, has resulted in a fragmented tomography-imaging landscape, one that is functional at the individual lab level yet lacks the standardization needed to support efficient and equitable exchange and reuse of data. Developing standards and pipelines for the creation of new and future data, which can also be applied to existing datasets is a challenge that becomes increasingly difficult as the amount and diversity of legacy data grows. Global networks of CT users have proved an effective approach to addressing this kind of multifaceted challenge across a range of fields. Here we describe ongoing efforts to address barriers to recently proposed FAIR (Findability, Accessibility, Interoperability, Reuse) and open science principles by assembling interested parties from research and education communities, industry, publishers, and data repositories to approach these issues jointly in a focused, efficient, and practical way. By outlining the benefits of networks, generally, and drawing on examples from efforts by the Non-Clinical Tomography Users Research Network (NoCTURN), specifically, we illustrate how standardization of data and metadata for reuse can foster interdisciplinary collaborations and create new opportunities for future-looking, large-scale data initiatives

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Selective Inhibition of Bacterial and Human Topoisomerases by <i>N</i>‑Arylacyl <i>O</i>‑Sulfonated Aminoglycoside Derivatives

Numerous therapeutic applications have been proposed for molecules that bind heparin-binding proteins. Development of such compounds has primarily focused on optimizing the degree and orientation of anionic groups on a scaffold, but utility of these polyanions has been diminished by their typically large size and nonspecific interactions with many proteins. In this study, <i>N</i>-arylacyl <i>O-</i>sulfonated aminoglycosides were synthesized and evaluated for their ability to selectively inhibit structurally similar bacterial and human topoisomerases. It is demonstrated that the structure of the aminoglycoside and of the <i>N-</i>arylacyl moiety imparts selective inhibition of different topoisomerases and alters the mechanism. The results here outline a strategy that will be applicable to identifying small, structurally defined oligosaccharides that bind heparin-binding proteins with a high degree of selectivity

Medusamide A, a Panamanian Cyanobacterial Depsipeptide with Multiple β‑Amino Acids

From a collection of marine cyanobacteria made in the Coiba National Park along the Pacific coast of the Republic of Panama a novel cyclic depsipeptide, given the trivial name medusamide A, has been isolated and fully characterized. Medusamide A contains four contiguous β-amino acid (2<i>R</i>,3<i>R</i>)-3-amino-2-methylhexanoic acid (Amha) residues. This is the first report of multiple Amha residues and contiguous β-amino acid residues within a single cyclic peptide-type natural product. Stereochemical assignment of the Amha residues was completed following the synthesis of reference standards for this β-amino acid and the subsequent derivatization with Marfey’s reagent and LC–MS analysis

The Chemical Evolution of Magnesium Isotopic Abundances in the Solar Neighbourhood

The abundance of the neutron-rich magnesium isotopes observed in metal-poor stars is explained quantitatively with a chemical evolution model of the local Galaxy that considers - for the first time - the metallicity-dependent contribution from intermediate mass stars. Previous models that simulate the variation of Mg isotopic ratios with metallicity in the solar neighbourhood have attributed the production of 25Mg and 26Mg exclusively to hydrostatic burning in massive stars. These models match the data well for [Fe/H] > -1.0 but severely underestimate 25,26Mg/24Mg at lower metallicities. Earlier studies have noted that this discrepancy may indicate a significant role played by intermediate mass stars. Only recently have detailed calculations of intermediate mass stellar yields of 25Mg and 26Mg become available with which to test this hypothesis. In an extension of previous work, we present a model that successfully matches the Mg isotopic abundances in nearby Galactic disk stars through the incorporation of nucleosynthesis predictions of Mg isotopic production in asymptotic giant branch stars

Molecular Networking as a Dereplication Strategy

A major goal in natural product discovery programs is to rapidly dereplicate known entities from complex biological extracts. We demonstrate here that molecular networking, an approach that organizes MS/MS data based on chemical similarity, is a powerful complement to traditional dereplication strategies. Successful dereplication with molecular networks requires MS/MS spectra of the natural product mixture along with MS/MS spectra of known standards, synthetic compounds, or well-characterized organisms, preferably organized into robust databases. This approach can accommodate different ionization platforms, enabling cross correlations of MS/MS data from ambient ionization, direct infusion, and LC-based methods. Molecular networking not only dereplicates known molecules from complex mixtures, it also captures related analogues, a challenge for many other dereplication strategies. To illustrate its utility as a dereplication tool, we apply mass spectrometry-based molecular networking to a diverse array of marine and terrestrial microbial samples, illustrating the dereplication of 58 molecules including analogues

Sequestration and cyanobacterial diet preferences in the opisthobranch molluscs Dolabrifera nicaraguana and Stylocheilus rickettsi

A multidisciplinary approach was used to assess chemical ecological dietary interactions between marine organisms as a tool to isolate novel ecologically relevant compounds with biotechnological potential. First, laboratory-based feeding preference assays of the sea hare Dolabrifera nicaraguana (previously known as D. dolabrifera), an anaspidean mollusc, were conducted by simultaneously offering six food options collected from nearby tidal pools in the Coiba National Park in the Tropical Eastern Pacific of Panama. An evaluation of preferred dietary repertoire revealed D. nicaraguana significantly preferred cf. Lyngbya sp. over the cyanobacterium Symploca sp., green alga Chaetomorpha sp., and red alga Spyridia sp. A no-choice feeding assay using cf. Lyngbya sp. or green alga Cladophora sp. supported this finding. Secondly, we conducted bioactivity-guided fractionation using the preferred food source of D. nicaraguana, the ‘hair-like” cf. Lyngbya sp. from which we also isolated and elucidated two new depsipeptide compounds, veraguamide M (1) and veraguamide N (2). Veraguamides M (1) and N (2) showed in vitro activity toward the malaria-causing parasite Plasmodium falciparum with GI50 values of 4.2 and 4.3 mM, respectively, and therapeutic windows of 7.0–8.0 (based on moderate cytotoxicities to mammalian Vero cells with GI50 values of 29.3 and 34.1 mM, respectively). Veraguamide N (2) was also active against Leishmania donovani, the causative agent of visceral leishmaniasis, with a GI50 value of 6.9 mM. We then evaluated sequestration of these new compounds by D. nicaraguana used in the feeding assays and found trace amounts of the dietary sequestered compounds. Finally, we evaluated sequestration of these new compounds by the sea hare Stylocheilus rickettsi (previously known as S. striatus) that were grazing on the cf. Lyngbya sp. used in the feeding assays and found both to be sequestered. This study is the first example whereby compounds with significant activity against tropical parasites have been found in both the sea hare S. rickettsi and its cyanobacterial food source. These results suggest that chemical ecological studies involving sea hares and cyanobacteria continue to provide a diverse source of bioactive compounds with biotechnological potential