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Dr. Samuel Robinson
Institute for Molecular Bioscience, The University of Queensland, QLD 4072, Australia

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Original article
Published: 10 May 2021 in Cellular and Molecular Life Sciences
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Velvet ants (Hymenoptera: Mutillidae) are a family of solitary parasitoid wasps that are renowned for their painful stings. We explored the chemistry underlying the stings of mutillid wasps of the genus Dasymutilla Ashmead. Detailed analyses of the venom composition of five species revealed that they are composed primarily of peptides. We found that two kinds of mutillid venom peptide appear to be primarily responsible for the painful effects of envenomation. These same peptides also have defensive utility against invertebrates, since they were able to incapacitate and kill honeybees. Both act directly on cell membranes where they directly increase ion conductivity. The defensive venom peptides of Dasymutilla bear a striking similarity, in structure and mode of action, to those of the ant Myrmecia gulosa (Fabricius), suggesting either retention of ancestral toxins, or convergence driven by similar life histories and defensive selection pressures. Finally, we propose that other highly expressed Dasymutilla venom peptides may play a role in parasitisation, possible in delay or arrest of host development. This study represents the first detailed account of the composition and function of the venoms of the Mutillidae.

ACS Style

Timo Jensen; Andrew A. Walker; Son H. Nguyen; Ai-Hua Jin; Jennifer R. Deuis; Irina Vetter; Glenn F. King; Justin O. Schmidt; Samuel D. Robinson. Venom chemistry underlying the painful stings of velvet ants (Hymenoptera: Mutillidae). Cellular and Molecular Life Sciences 2021, 78, 5163 -5177.

AMA Style

Timo Jensen, Andrew A. Walker, Son H. Nguyen, Ai-Hua Jin, Jennifer R. Deuis, Irina Vetter, Glenn F. King, Justin O. Schmidt, Samuel D. Robinson. Venom chemistry underlying the painful stings of velvet ants (Hymenoptera: Mutillidae). Cellular and Molecular Life Sciences. 2021; 78 (12):5163-5177.

Chicago/Turabian Style

Timo Jensen; Andrew A. Walker; Son H. Nguyen; Ai-Hua Jin; Jennifer R. Deuis; Irina Vetter; Glenn F. King; Justin O. Schmidt; Samuel D. Robinson. 2021. "Venom chemistry underlying the painful stings of velvet ants (Hymenoptera: Mutillidae)." Cellular and Molecular Life Sciences 78, no. 12: 5163-5177.

Journal article
Published: 23 April 2021 in Proceedings of the National Academy of Sciences
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Venoms have evolved independently several times in Lepidoptera. Limacodidae is a family with worldwide distribution, many of which are venomous in the larval stage, but the composition and mode of action of their venom is unknown. Here, we use imaging technologies, transcriptomics, proteomics, and functional assays to provide a holistic picture of the venom system of a limacodid caterpillar, Doratifera vulnerans. Contrary to dogma that defensive venoms are simple in composition, D. vulnerans produces a complex venom containing 151 proteinaceous toxins spanning 59 families, most of which are peptides <10 kDa. Three of the most abundant families of venom peptides (vulnericins) are 1) analogs of the adipokinetic hormone/corazonin-related neuropeptide, some of which are picomolar agonists of the endogenous insect receptor; 2) linear cationic peptides derived from cecropin, an insect innate immune peptide that kills bacteria and parasites by disrupting cell membranes; and 3) disulfide-rich knottins similar to those that dominate spider venoms. Using venom fractionation and a suite of synthetic venom peptides, we demonstrate that the cecropin-like peptides are responsible for the dominant pain effect observed in mammalian in vitro and in vivo nociception assays and therefore are likely to cause pain after natural envenomations by D. vulnerans. Our data reveal convergent molecular evolution between limacodids, hymenopterans, and arachnids and demonstrate that lepidopteran venoms are an untapped source of novel bioactive peptides.

ACS Style

Andrew A. Walker; Samuel D. Robinson; Jean-Paul V. Paluzzi; David J. Merritt; Samantha A. Nixon; Christina I. Schroeder; Jiayi Jin; Mohaddeseh Hedayati Goudarzi; Andrew C. Kotze; Zoltan Dekan; Andy Sombke; Paul F. Alewood; Bryan G. Fry; Marc E. Epstein; Irina Vetter; Glenn F. King. Production, composition, and mode of action of the painful defensive venom produced by a limacodid caterpillar, Doratifera vulnerans. Proceedings of the National Academy of Sciences 2021, 118, 1 .

AMA Style

Andrew A. Walker, Samuel D. Robinson, Jean-Paul V. Paluzzi, David J. Merritt, Samantha A. Nixon, Christina I. Schroeder, Jiayi Jin, Mohaddeseh Hedayati Goudarzi, Andrew C. Kotze, Zoltan Dekan, Andy Sombke, Paul F. Alewood, Bryan G. Fry, Marc E. Epstein, Irina Vetter, Glenn F. King. Production, composition, and mode of action of the painful defensive venom produced by a limacodid caterpillar, Doratifera vulnerans. Proceedings of the National Academy of Sciences. 2021; 118 (18):1.

Chicago/Turabian Style

Andrew A. Walker; Samuel D. Robinson; Jean-Paul V. Paluzzi; David J. Merritt; Samantha A. Nixon; Christina I. Schroeder; Jiayi Jin; Mohaddeseh Hedayati Goudarzi; Andrew C. Kotze; Zoltan Dekan; Andy Sombke; Paul F. Alewood; Bryan G. Fry; Marc E. Epstein; Irina Vetter; Glenn F. King. 2021. "Production, composition, and mode of action of the painful defensive venom produced by a limacodid caterpillar, Doratifera vulnerans." Proceedings of the National Academy of Sciences 118, no. 18: 1.

Report
Published: 21 January 2021 in Science
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Convergent evolution provides insights into the selective drivers underlying evolutionary change. Snake venoms, with a direct genetic basis and clearly defined functional phenotype, provide a model system for exploring the repeated evolution of adaptations. While snakes use venom primarily for predation, and venom composition often reflects diet specificity, three lineages of cobras have independently evolved the ability to spit venom at adversaries. Using gene, protein, and functional analyses, we show that the three spitting lineages possess venoms characterized by an up-regulation of phospholipase A2 (PLA2) toxins, which potentiate the action of preexisting venom cytotoxins to activate mammalian sensory neurons and cause enhanced pain. These repeated independent changes provide a fascinating example of convergent evolution across multiple phenotypic levels driven by selection for defense.

ACS Style

T. D. Kazandjian; D. Petras; S. D. Robinson; J. van Thiel; H. W. Greene; K. Arbuckle; A. Barlow; D. A. Carter; R. M. Wouters; G. Whiteley; S. C. Wagstaff; A. S. Arias; L.-O. Albulescu; A. Plettenberg Laing; C. Hall; A. Heap; S. Penrhyn-Lowe; C. V. McCabe; S. Ainsworth; R. R. da Silva; P. C. Dorrestein; M. K. Richardson; J. M. Gutiérrez; J. J. Calvete; R. A. Harrison; I. Vetter; E. A. B. Undheim; W. Wüster; N. R. Casewell. Convergent evolution of pain-inducing defensive venom components in spitting cobras. Science 2021, 371, 386 -390.

AMA Style

T. D. Kazandjian, D. Petras, S. D. Robinson, J. van Thiel, H. W. Greene, K. Arbuckle, A. Barlow, D. A. Carter, R. M. Wouters, G. Whiteley, S. C. Wagstaff, A. S. Arias, L.-O. Albulescu, A. Plettenberg Laing, C. Hall, A. Heap, S. Penrhyn-Lowe, C. V. McCabe, S. Ainsworth, R. R. da Silva, P. C. Dorrestein, M. K. Richardson, J. M. Gutiérrez, J. J. Calvete, R. A. Harrison, I. Vetter, E. A. B. Undheim, W. Wüster, N. R. Casewell. Convergent evolution of pain-inducing defensive venom components in spitting cobras. Science. 2021; 371 (6527):386-390.

Chicago/Turabian Style

T. D. Kazandjian; D. Petras; S. D. Robinson; J. van Thiel; H. W. Greene; K. Arbuckle; A. Barlow; D. A. Carter; R. M. Wouters; G. Whiteley; S. C. Wagstaff; A. S. Arias; L.-O. Albulescu; A. Plettenberg Laing; C. Hall; A. Heap; S. Penrhyn-Lowe; C. V. McCabe; S. Ainsworth; R. R. da Silva; P. C. Dorrestein; M. K. Richardson; J. M. Gutiérrez; J. J. Calvete; R. A. Harrison; I. Vetter; E. A. B. Undheim; W. Wüster; N. R. Casewell. 2021. "Convergent evolution of pain-inducing defensive venom components in spitting cobras." Science 371, no. 6527: 386-390.

Journal article
Published: 30 June 2020 in Biomedicines
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Ant venoms have recently attracted increased attention due to their chemical complexity, novel molecular frameworks, and diverse biological activities. The heterodimeric peptide ∆-myrtoxin-Mp1a (Mp1a) from the venom of the Australian jack jumper ant, Myrmecia pilosula, exhibits antimicrobial, membrane-disrupting, and pain-inducing activities. In the present study, we examined the activity of Mp1a and a panel of synthetic analogues against the gastrointestinal parasitic nematode Haemonchus contortus, the fruit fly Drosophila melanogaster, and for their ability to stimulate pain-sensing neurons. Mp1a was found to be both insecticidal and anthelmintic, and it robustly activated mammalian sensory neurons at concentrations similar to those reported to elicit antimicrobial and cytotoxic activity. The native antiparallel Mp1a heterodimer was more potent than heterodimers with alternative disulfide connectivity, as well as monomeric analogues. We conclude that the membrane-disrupting effects of Mp1a confer broad-spectrum biological activities that facilitate both predation and defense for the ant. Our structure–activity data also provide a foundation for the rational engineering of analogues with selectivity for particular cell types.

ACS Style

Samantha A. Nixon; Zoltan Dekan; Samuel D. Robinson; Shaodong Guo; Irina Vetter; Andrew C. Kotze; Paul F. Alewood; Glenn F. King; Volker Herzig. It Takes Two: Dimerization Is Essential for the Broad-Spectrum Predatory and Defensive Activities of the Venom Peptide Mp1a from the Jack Jumper Ant Myrmecia pilosula. Biomedicines 2020, 8, 185 .

AMA Style

Samantha A. Nixon, Zoltan Dekan, Samuel D. Robinson, Shaodong Guo, Irina Vetter, Andrew C. Kotze, Paul F. Alewood, Glenn F. King, Volker Herzig. It Takes Two: Dimerization Is Essential for the Broad-Spectrum Predatory and Defensive Activities of the Venom Peptide Mp1a from the Jack Jumper Ant Myrmecia pilosula. Biomedicines. 2020; 8 (7):185.

Chicago/Turabian Style

Samantha A. Nixon; Zoltan Dekan; Samuel D. Robinson; Shaodong Guo; Irina Vetter; Andrew C. Kotze; Paul F. Alewood; Glenn F. King; Volker Herzig. 2020. "It Takes Two: Dimerization Is Essential for the Broad-Spectrum Predatory and Defensive Activities of the Venom Peptide Mp1a from the Jack Jumper Ant Myrmecia pilosula." Biomedicines 8, no. 7: 185.

Journal article
Published: 11 June 2020 in Biomedicines
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NaV1.3 is a subtype of the voltage-gated sodium channel family. It has been implicated in the pathogenesis of neuropathic pain, although the contribution of this channel to neuronal excitability is not well understood. Tf2, a β-scorpion toxin previously identified from the venom of Tityus fasciolatus, has been reported to selectively activate NaV1.3. Here, we describe the activity of synthetic Tf2 and assess its suitability as a pharmacological probe for NaV1.3. As described for the native toxin, synthetic Tf2 (1 µM) caused early channel opening, decreased the peak current, and shifted the voltage dependence of NaV1.3 activation in the hyperpolarizing direction by −11.3 mV, with no activity at NaV1.1, NaV1.2, and NaV1.4-NaV1.8. Additional activity was found at NaV1.9, tested using the hNav1.9_C4 chimera, where Tf2 (1 µM) shifted the voltage dependence of activation by −6.3 mV. In an attempt to convert Tf2 into an NaV1.3 inhibitor, we synthetized the analogue Tf2[S14R], a mutation previously described to remove the excitatory activity of related β-scorpion toxins. Indeed, Tf2[S14R](10 µM) had reduced excitatory activity at NaV1.3, although it still caused a small −5.8 mV shift in the voltage dependence of activation. Intraplantar injection of Tf2 (1 µM) in mice caused spontaneous flinching and swelling, which was not reduced by the NaV1.1/1.3 inhibitor ICA-121431 nor in NaV1.9-/- mice, suggesting off-target activity. In addition, despite a loss of excitatory activity, intraplantar injection of Tf2[S14R](10 µM) still caused swelling, providing strong evidence that Tf2 has additional off-target activity at one or more non-neuronal targets. Therefore, due to activity at NaV1.9 and other yet to be identified target(s), the use of Tf2 as a selective pharmacological probe may be limited.

ACS Style

Mathilde R. Israel; Thomas S. Dash; Stefanie N. Bothe; Samuel D. Robinson; Jennifer R. Deuis; David J. Craik; Angelika Lampert; Irina Vetter; Thomas Durek. Characterization of Synthetic Tf2 as a NaV1.3 Selective Pharmacological Probe. Biomedicines 2020, 8, 155 .

AMA Style

Mathilde R. Israel, Thomas S. Dash, Stefanie N. Bothe, Samuel D. Robinson, Jennifer R. Deuis, David J. Craik, Angelika Lampert, Irina Vetter, Thomas Durek. Characterization of Synthetic Tf2 as a NaV1.3 Selective Pharmacological Probe. Biomedicines. 2020; 8 (6):155.

Chicago/Turabian Style

Mathilde R. Israel; Thomas S. Dash; Stefanie N. Bothe; Samuel D. Robinson; Jennifer R. Deuis; David J. Craik; Angelika Lampert; Irina Vetter; Thomas Durek. 2020. "Characterization of Synthetic Tf2 as a NaV1.3 Selective Pharmacological Probe." Biomedicines 8, no. 6: 155.

Journal article
Published: 14 May 2020 in Toxins
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A critical hurdle in ant venom proteomic investigations is the lack of databases to comprehensively and specifically identify the sequence and function of venom proteins and peptides. To resolve this, we used venom gland transcriptomics to generate a sequence database that was used to assign the tandem mass spectrometry (MS) fragmentation spectra of venom peptides and proteins to specific transcripts. This was performed alongside a shotgun liquid chromatography–mass spectrometry (LC-MS/MS) analysis of the venom to confirm that these assigned transcripts were expressed as proteins. Through the combined transcriptomic and proteomic investigation of Paraponera clavata venom, we identified four times the number of proteins previously identified using 2D-PAGE alone. In addition to this, by mining the transcriptomic data, we identified several novel peptide sequences for future pharmacological investigations, some of which conform with inhibitor cysteine knot motifs. These types of peptides have the potential to be developed into pharmaceutical or bioinsecticide peptides.

ACS Style

Samira R. Aili; Axel Touchard; Regan Hayward; Samuel D. Robinson; Sandy S. Pineda; Hadrien Lalagüe; Irina Vetter; Eivind A. B. Undheim; R. Manjunatha Kini; Pierre Escoubas; Matthew P. Padula; Garry S. A. Myers; Graham M. Nicholson. An Integrated Proteomic and Transcriptomic Analysis Reveals the Venom Complexity of the Bullet Ant Paraponera clavata. Toxins 2020, 12, 324 .

AMA Style

Samira R. Aili, Axel Touchard, Regan Hayward, Samuel D. Robinson, Sandy S. Pineda, Hadrien Lalagüe, Irina Vetter, Eivind A. B. Undheim, R. Manjunatha Kini, Pierre Escoubas, Matthew P. Padula, Garry S. A. Myers, Graham M. Nicholson. An Integrated Proteomic and Transcriptomic Analysis Reveals the Venom Complexity of the Bullet Ant Paraponera clavata. Toxins. 2020; 12 (5):324.

Chicago/Turabian Style

Samira R. Aili; Axel Touchard; Regan Hayward; Samuel D. Robinson; Sandy S. Pineda; Hadrien Lalagüe; Irina Vetter; Eivind A. B. Undheim; R. Manjunatha Kini; Pierre Escoubas; Matthew P. Padula; Garry S. A. Myers; Graham M. Nicholson. 2020. "An Integrated Proteomic and Transcriptomic Analysis Reveals the Venom Complexity of the Bullet Ant Paraponera clavata." Toxins 12, no. 5: 324.

Journal article
Published: 18 November 2019 in Toxins
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Assassin bugs (Reduviidae) produce venoms that are insecticidal, and which induce pain in predators, but the composition and function of their individual venom components is poorly understood. We report findings on the venom system of the red-spotted assassin bug Platymeris rhadamanthus, a large species of African origin that is unique in propelling venom as a projectile weapon when threatened. We performed RNA sequencing experiments on venom glands (separate transcriptomes of the posterior main gland, PMG, and the anterior main gland, AMG), and proteomic experiments on venom that was either defensively propelled or collected from the proboscis in response to electrostimulation. We resolved a venom proteome comprising 166 polypeptides. Both defensively propelled venom and most venom samples collected in response to electrostimulation show a protein profile similar to the predicted secretory products of the PMG, with a smaller contribution from the AMG. Pooled venom samples induce calcium influx via membrane lysis when applied to mammalian neuronal cells, consistent with their ability to cause pain when propelled into the eyes or mucus membranes of potential predators. The same venom induces rapid paralysis and death when injected into fruit flies. These data suggest that the cytolytic, insecticidal venom used by reduviids to capture prey is also a highly effective defensive weapon when propelled at predators.

ACS Style

Andrew Walker; Samuel Robinson; Eivind Undheim; Jiayi Jin; Xiao Han; Bryan Fry; Irina Vetter; Glenn King. Missiles of Mass Disruption: Composition and Glandular Origin of Venom Used as a Projectile Defensive Weapon by the Assassin Bug Platymeris rhadamanthus. Toxins 2019, 11, 673 .

AMA Style

Andrew Walker, Samuel Robinson, Eivind Undheim, Jiayi Jin, Xiao Han, Bryan Fry, Irina Vetter, Glenn King. Missiles of Mass Disruption: Composition and Glandular Origin of Venom Used as a Projectile Defensive Weapon by the Assassin Bug Platymeris rhadamanthus. Toxins. 2019; 11 (11):673.

Chicago/Turabian Style

Andrew Walker; Samuel Robinson; Eivind Undheim; Jiayi Jin; Xiao Han; Bryan Fry; Irina Vetter; Glenn King. 2019. "Missiles of Mass Disruption: Composition and Glandular Origin of Venom Used as a Projectile Defensive Weapon by the Assassin Bug Platymeris rhadamanthus." Toxins 11, no. 11: 673.

Journal article
Published: 24 July 2019 in Marine Drugs
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Conus ateralbus is a cone snail endemic to the west side of the island of Sal, in the Cabo Verde Archipelago off West Africa. We describe the isolation and characterization of the first bioactive peptide from the venom of this species. This 30AA venom peptide is named conotoxin AtVIA (δ-conotoxin-like). An excitatory activity was manifested by the peptide on a majority of mouse lumbar dorsal root ganglion neurons. An analog of AtVIA with conservative changes on three amino acid residues at the C-terminal region was synthesized and this analog produced an identical effect on the mouse neurons. AtVIA has homology with δ-conotoxins from other worm-hunters, which include conserved sequence elements that are shared with δ-conotoxins from fish-hunting Conus. In contrast, there is no comparable sequence similarity with δ-conotoxins from the venoms of molluscivorous Conus species. A rationale for the potential presence of δ-conotoxins, that are potent in vertebrate systems in two different lineages of worm-hunting cone snails, is discussed.

ACS Style

Jorge L. B. Neves; Julita S. Imperial; David Morgenstern; Beatrix Ueberheide; Joanna Gajewiak; Agostinho Antunes; Samuel D. Robinson; Samuel Espino; Maren Watkins; Vitor Vasconcelos; Baldomero M. Olivera. Characterization of the First Conotoxin from Conus ateralbus, a Vermivorous Cone Snail from the Cabo Verde Archipelago. Marine Drugs 2019, 17, 432 .

AMA Style

Jorge L. B. Neves, Julita S. Imperial, David Morgenstern, Beatrix Ueberheide, Joanna Gajewiak, Agostinho Antunes, Samuel D. Robinson, Samuel Espino, Maren Watkins, Vitor Vasconcelos, Baldomero M. Olivera. Characterization of the First Conotoxin from Conus ateralbus, a Vermivorous Cone Snail from the Cabo Verde Archipelago. Marine Drugs. 2019; 17 (8):432.

Chicago/Turabian Style

Jorge L. B. Neves; Julita S. Imperial; David Morgenstern; Beatrix Ueberheide; Joanna Gajewiak; Agostinho Antunes; Samuel D. Robinson; Samuel Espino; Maren Watkins; Vitor Vasconcelos; Baldomero M. Olivera. 2019. "Characterization of the First Conotoxin from Conus ateralbus, a Vermivorous Cone Snail from the Cabo Verde Archipelago." Marine Drugs 17, no. 8: 432.

Research paper
Published: 18 June 2019 in The Journal of Physiology
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Key points Voltage‐gated sodium channels are critical for peripheral sensory neuron transduction and have been implicated in a number of painful and painless disorders. The β‐scorpion toxin, Cn2, is selective for NaV1.6 in dorsal root ganglion neurons. NaV1.6 plays an essential role in peripheral sensory neurons, specifically at the distal terminals of mechanosensing fibres innervating the skin and colon. NaV1.6 activation also leads to enhanced response to mechanical stimulus in vivo. This works highlights the use of toxins in elucidating pain pathways moreover the importance of non‐peripherally restricted NaV isoforms in pain generation. Abstract Peripheral sensory neurons express multiple voltage‐gated sodium channels (NaV) critical for the initiation and propagation of action potentials and transmission of sensory input. Three pore‐forming sodium channel isoforms are primarily expressed in the peripheral nervous system (PNS): NaV1.7, NaV1.8 and NaV1.9. These sodium channels have been implicated in painful and painless channelopathies and there has been intense interest in them as potential therapeutic targets in human pain. Emerging evidence suggests NaV1.6 channels are an important isoform in pain sensing. This study aimed to assess, using pharmacological approaches, the function of NaV1.6 channels in peripheral sensory neurons. The potent and NaV1.6 selective β‐scorpion toxin Cn2 was used to assess the effect of NaV1.6 channel activation in the PNS. The multidisciplinary approach included Ca2+ imaging, whole‐cell patch‐clamp recordings, skin–nerve and gut–nerve preparations and in vivo behavioural assessment of pain. Cn2 facilitates NaV1.6 early channel opening, and increased persistent and resurgent currents in large‐diameter dorsal root ganglion (DRG) neurons. This promotes enhanced excitatory drive and tonic action potential firing in these neurons. In addition, NaV1.6 channel activation in the skin and gut leads to increased response to mechanical stimuli. Finally, intra‐plantar injection of Cn2 causes mechanical but not thermal allodynia. This study confirms selectivity of Cn2 on NaV1.6 channels in sensory neurons. Activation of NaV1.6 channels, in terminals of the skin and viscera, leads to profound changes in neuronal responses to mechanical stimuli. In conclusion, sensory neurons expressing NaV1.6 are important for the transduction of mechanical information in sensory afferents innervating the skin and viscera.

ACS Style

Mathilde R. Israel; Brian S. Tanaka; Joel Castro; Panumart Thongyoo; Samuel D. Robinson; Peng Zhao; Jennifer Deuis; David J. Craik; Thomas Durek; Stuart M. Brierley; Stephen G Waxman; Sulayman D. Dib‐Hajj; Irina Vetter. Na V 1.6 regulates excitability of mechanosensitive sensory neurons. The Journal of Physiology 2019, 597, 3751 -3768.

AMA Style

Mathilde R. Israel, Brian S. Tanaka, Joel Castro, Panumart Thongyoo, Samuel D. Robinson, Peng Zhao, Jennifer Deuis, David J. Craik, Thomas Durek, Stuart M. Brierley, Stephen G Waxman, Sulayman D. Dib‐Hajj, Irina Vetter. Na V 1.6 regulates excitability of mechanosensitive sensory neurons. The Journal of Physiology. 2019; 597 (14):3751-3768.

Chicago/Turabian Style

Mathilde R. Israel; Brian S. Tanaka; Joel Castro; Panumart Thongyoo; Samuel D. Robinson; Peng Zhao; Jennifer Deuis; David J. Craik; Thomas Durek; Stuart M. Brierley; Stephen G Waxman; Sulayman D. Dib‐Hajj; Irina Vetter. 2019. "Na V 1.6 regulates excitability of mechanosensitive sensory neurons." The Journal of Physiology 597, no. 14: 3751-3768.

Journal article
Published: 01 May 2019 in Journal of Biological Chemistry
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Venomous marine cone snails produce peptide toxins (conotoxins) that bind ion channels and receptors with high specificity and therefore are important pharmacological tools. Conotoxins contain conserved cysteine residues that form disulfide bonds that stabilize their structures. To gain structural insight into the large, yet poorly characterized conotoxin H-superfamily, we used NMR and CD spectroscopy along with MS-based analyses to investigate H-Vc7.2 from Conus victoriae, a peptide with a VI/VII cysteine framework. This framework has CysI-CysIV/CysII-CysV/CysIII-CysVI connectivities, which have invariably been associated with the inhibitor cystine knot (ICK) fold. However, the solution structure of recombinantly expressed and purified H-Vc7.2 revealed that although it displays the expected cysteine connectivities, H-Vc7.2 adopts a different fold consisting of two stacked β-hairpins with opposing β-strands connected by two parallel disulfide bonds, a structure homologous to the N-terminal region of the human granulin protein. Using structural comparisons, we subsequently identified several toxins and nontoxin proteins with this "mini-granulin" fold. These findings raise fundamental questions concerning sequence-structure relationships within peptides and proteins and the key determinants that specify a given fold.

ACS Style

Lau D. Nielsen; Mads M. Foged; Anastasia Albert; Andreas B. Bertelsen; Cecilie L. Søltoft; Samuel D. Robinson; Steen V. Petersen; Anthony W. Purcell; Baldomero M. Olivera; Raymond S. Norton; Terje Vasskog; Helena Safavi-Hemami; Kaare Teilum; Lars Ellgaard. The three-dimensional structure of an H-superfamily conotoxin reveals a granulin fold arising from a common ICK cysteine framework. Journal of Biological Chemistry 2019, 294, 8745 -8759.

AMA Style

Lau D. Nielsen, Mads M. Foged, Anastasia Albert, Andreas B. Bertelsen, Cecilie L. Søltoft, Samuel D. Robinson, Steen V. Petersen, Anthony W. Purcell, Baldomero M. Olivera, Raymond S. Norton, Terje Vasskog, Helena Safavi-Hemami, Kaare Teilum, Lars Ellgaard. The three-dimensional structure of an H-superfamily conotoxin reveals a granulin fold arising from a common ICK cysteine framework. Journal of Biological Chemistry. 2019; 294 (22):8745-8759.

Chicago/Turabian Style

Lau D. Nielsen; Mads M. Foged; Anastasia Albert; Andreas B. Bertelsen; Cecilie L. Søltoft; Samuel D. Robinson; Steen V. Petersen; Anthony W. Purcell; Baldomero M. Olivera; Raymond S. Norton; Terje Vasskog; Helena Safavi-Hemami; Kaare Teilum; Lars Ellgaard. 2019. "The three-dimensional structure of an H-superfamily conotoxin reveals a granulin fold arising from a common ICK cysteine framework." Journal of Biological Chemistry 294, no. 22: 8745-8759.

Journal article
Published: 12 February 2019 in eLife
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The fish-hunting marine cone snail Conus geographus uses a specialized venom insulin to induce hypoglycemic shock in its prey. We recently showed that this venom insulin, Con-Ins G1, has unique characteristics relevant to the design of new insulin therapeutics. Here, we show that fish-hunting cone snails provide a rich source of minimized ligands of the vertebrate insulin receptor. Insulins from C. geographus, Conus tulipa and Conus kinoshitai exhibit diverse sequences, yet all bind to and activate the human insulin receptor. Molecular dynamics reveal unique modes of action that are distinct from any other insulins known in nature. When tested in zebrafish and mice, venom insulins significantly lower blood glucose in the streptozotocin-induced model of diabetes. Our findings suggest that cone snails have evolved diverse strategies to activate the vertebrate insulin receptor and provide unique insight into the design of novel drugs for the treatment of diabetes.

ACS Style

Peter Ahorukomeye; Maria M Disotuar; Joanna Gajewiak; Santhosh Karanth; Maren Watkins; Samuel Robinson; Paula Florez Salcedo; Nicholas Smith; Brian J Smith; Amnon Schlegel; Briony E Forbes; Baldomero Olivera; Danny Hung-Chieh Chou; Helena Safavi-Hemami. Fish-hunting cone snail venoms are a rich source of minimized ligands of the vertebrate insulin receptor. eLife 2019, 8, 1 .

AMA Style

Peter Ahorukomeye, Maria M Disotuar, Joanna Gajewiak, Santhosh Karanth, Maren Watkins, Samuel Robinson, Paula Florez Salcedo, Nicholas Smith, Brian J Smith, Amnon Schlegel, Briony E Forbes, Baldomero Olivera, Danny Hung-Chieh Chou, Helena Safavi-Hemami. Fish-hunting cone snail venoms are a rich source of minimized ligands of the vertebrate insulin receptor. eLife. 2019; 8 ():1.

Chicago/Turabian Style

Peter Ahorukomeye; Maria M Disotuar; Joanna Gajewiak; Santhosh Karanth; Maren Watkins; Samuel Robinson; Paula Florez Salcedo; Nicholas Smith; Brian J Smith; Amnon Schlegel; Briony E Forbes; Baldomero Olivera; Danny Hung-Chieh Chou; Helena Safavi-Hemami. 2019. "Fish-hunting cone snail venoms are a rich source of minimized ligands of the vertebrate insulin receptor." eLife 8, no. : 1.

Journal article
Published: 01 December 2018 in Toxins
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Cone snails (genus Conus) are venomous marine snails that inject prey with a lethal cocktail of conotoxins, small, secreted, and cysteine-rich peptides. Given the diversity and often high affinity for their molecular targets, consisting of ion channels, receptors or transporters, many conotoxins have become invaluable pharmacological probes, drug leads, and therapeutics. Transcriptome sequencing of Conus venom glands followed by de novo assembly and homology-based toxin identification and annotation is currently the state-of-the-art for discovery of new conotoxins. However, homology-based search techniques, by definition, can only detect novel toxins that are homologous to previously reported conotoxins. To overcome these obstacles for discovery, we have created ConusPipe, a machine learning tool that utilizes prominent chemical characters of conotoxins to predict whether a certain transcript in a Conus transcriptome, which has no otherwise detectable homologs in current reference databases, is a putative conotoxin. By using ConusPipe on RNASeq data of 10 species, we report 5148 new putative conotoxin transcripts that have no homologues in current reference databases. 896 of these were identified by at least three out of four models used. These data significantly expand current publicly available conotoxin datasets and our approach provides a new computational avenue for the discovery of novel toxin families.

ACS Style

Qing Li; Maren Watkins; Samuel D. Robinson; Helena Safavi-Hemami; Mark Yandell. Discovery of Novel Conotoxin Candidates Using Machine Learning. Toxins 2018, 10, 503 .

AMA Style

Qing Li, Maren Watkins, Samuel D. Robinson, Helena Safavi-Hemami, Mark Yandell. Discovery of Novel Conotoxin Candidates Using Machine Learning. Toxins. 2018; 10 (12):503.

Chicago/Turabian Style

Qing Li; Maren Watkins; Samuel D. Robinson; Helena Safavi-Hemami; Mark Yandell. 2018. "Discovery of Novel Conotoxin Candidates Using Machine Learning." Toxins 10, no. 12: 503.

Journal article
Published: 05 November 2018 in Toxins
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Assassin flies (Diptera: Asilidae) inject paralysing venom into insect prey during hunting, but their venoms are poorly characterised in comparison to those produced by spiders, scorpions, or hymenopteran insects. Here we investigated the composition of the venom of the giant Australian assassin fly Dolopus genitalis using a combination of insect microinjection assays, calcium imaging assays of mammalian sensory neurons, proteomics and transcriptomics. Injection of venom into blowflies (Lucilia cuprina) produced rapid contractile paralysis (PD50 at 1 min = 3.1 μg per fly) followed by death, and also caused immediate activation of mouse dorsal root ganglion neurons (at 50 ng/μL). These results are consistent with venom use for both prey capture and predator deterrence. Paragon searches of tandem mass spectra of venom against a translated thoracic gland RNA-Seq database identified 122 polypeptides present in the venom, including six linear and 21 disulfide-rich peptides. Some of these disulfide-rich peptides display sequence homology to peptide families independently recruited into other animal venoms, including inhibitor cystine knots, cystine-stabilised α/β defensins, Kazal peptides, and von Willebrand factors. Numerous enzymes are present in the venom, including 35 proteases of the S1 family, proteases of the S10, C1A, M12A, M14, and M17 families, and phosphatase, amylase, hydrolase, nuclease, and dehydrogenase-like proteins. These results highlight convergent molecular evolution between the assassin flies and other venomous animals, as well as the unique and rich molecular composition of assassin fly venom.

ACS Style

Andrew A. Walker; James Dobson; Jiayi Jin; Samuel D. Robinson; Volker Herzig; Irina Vetter; Glenn F. King; Bryan G. Fry. Buzz Kill: Function and Proteomic Composition of Venom from the Giant Assassin Fly Dolopus genitalis (Diptera: Asilidae). Toxins 2018, 10, 456 .

AMA Style

Andrew A. Walker, James Dobson, Jiayi Jin, Samuel D. Robinson, Volker Herzig, Irina Vetter, Glenn F. King, Bryan G. Fry. Buzz Kill: Function and Proteomic Composition of Venom from the Giant Assassin Fly Dolopus genitalis (Diptera: Asilidae). Toxins. 2018; 10 (11):456.

Chicago/Turabian Style

Andrew A. Walker; James Dobson; Jiayi Jin; Samuel D. Robinson; Volker Herzig; Irina Vetter; Glenn F. King; Bryan G. Fry. 2018. "Buzz Kill: Function and Proteomic Composition of Venom from the Giant Assassin Fly Dolopus genitalis (Diptera: Asilidae)." Toxins 10, no. 11: 456.

Preprint
Published: 29 September 2018
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Cone snails (genus Conus) are venomous marine snails that inject prey with a lethal cocktail of conotoxins, small, secreted, cysteine-rich peptides. Given the diversity and often high affinity for their molecular targets, consisting of ion channels, receptors or transporters, many conotoxins have become invaluable pharmacological probes, drug leads and therapeutics. Transcriptome sequencing of Conus venom glands followed by de novo assembly and homology-based toxin identification and annotation is currently the state-of-the-art for discovery of new conotoxins. However, homology-based search techniques, by definition, can only detect novel toxins that are homologous to previously reported conotoxins. To overcome these obstacles for discovery we have created ConusPipe, a machine learning tool that utilizes prominent chemical characters of conotoxins to predict whether a certain transcript in a Conus transcriptome, which has no otherwise detectable homologs in current reference databases, is a putative conotoxin. By using ConusPipe on RNASeq data of 10 species, we report 5,230 new putative conotoxin transcripts that have no homologues in current reference databases. 893 of these were identified by at least 3 out of 4 models used. These data significantly expand current publicly available conotoxin datasets and our approach provides a new computational avenue for the discovery of novel toxin families.

ACS Style

Qing Li; Maren Watkins; Samuel D. Robinson; Helena Safavi-Hemami; Mark Yandell. Discovery of Novel Conotoxin Candidates Using Machine Learning. 2018, 1 .

AMA Style

Qing Li, Maren Watkins, Samuel D. Robinson, Helena Safavi-Hemami, Mark Yandell. Discovery of Novel Conotoxin Candidates Using Machine Learning. . 2018; ():1.

Chicago/Turabian Style

Qing Li; Maren Watkins; Samuel D. Robinson; Helena Safavi-Hemami; Mark Yandell. 2018. "Discovery of Novel Conotoxin Candidates Using Machine Learning." , no. : 1.

Review
Published: 26 September 2018 in Toxicon
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The insects are a hyperdiverse class containing more species than all other animal groups combined—and many employ venom to capture prey, deter predators and micro-organisms, or facilitate parasitism or extra-oral digestion. However, with the exception of those made by Hymenoptera (wasps, ants and bees), little is known about insect venoms. Here, we review the current literature on insects that use venom for prey capture and predator deterrence, finding evidence for fourteen independent origins of venom usage among insects, mostly among the hyperdiverse holometabolan orders. Many lineages, including the True Bugs (Heteroptera), robber flies (Asilidae), and larvae of many Neuroptera, Coleoptera and Diptera, use mouthpart-associated venoms to paralyse and pre-digest prey during hunting. In contrast, some Hymenoptera and larval Lepidoptera, and one species of beetle, use non-mouthpart structures to inject venom in order to cause pain to deter potential predators. Several recently published insect venom proteomes indicate molecular convergence between insects and other venomous animal groups, with all insect venoms studied so far being potently bioactive cocktails containing both peptides and larger proteins, including novel peptide and protein families. This review summarises the current state of the field of entomo-venomics.

ACS Style

Andrew A. Walker; Samuel D. Robinson; David K. Yeates; Jiayi Jin; Kate Baumann; James Dobson; Bryan G. Fry; Glenn F. King. Entomo-venomics: The evolution, biology and biochemistry of insect venoms. Toxicon 2018, 154, 15 -27.

AMA Style

Andrew A. Walker, Samuel D. Robinson, David K. Yeates, Jiayi Jin, Kate Baumann, James Dobson, Bryan G. Fry, Glenn F. King. Entomo-venomics: The evolution, biology and biochemistry of insect venoms. Toxicon. 2018; 154 ():15-27.

Chicago/Turabian Style

Andrew A. Walker; Samuel D. Robinson; David K. Yeates; Jiayi Jin; Kate Baumann; James Dobson; Bryan G. Fry; Glenn F. King. 2018. "Entomo-venomics: The evolution, biology and biochemistry of insect venoms." Toxicon 154, no. : 15-27.

Journal article
Published: 21 September 2018 in Toxicon
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Members of Mas related G-protein coupled receptors (Mrgpr) are known to mediate itch. To date, several compounds have been shown to activate these receptors, including chloroquine, a common antimalarial drug, and peptides of the RF-amide family. However, specific ligands for these receptors are still lacking and there is a need for novel compounds that can be used to modulate the receptors in order to understand the cellular and molecular mechanism in which they mediate itch. Some cone snail venoms were previously shown to induce itch in mice. Here, we show that the venom of Conus textile induces itch through activation of itch-sensing sensory neurons, marked by their sensitivity to chloroquine. Two RF-amide peptides, CNF-Tx1 and CNF-Tx2, were identified in a C. textile venom gland transcriptome. These belong to the conorfamide family of peptides which includes previously described peptides from the venoms of Conus victoriae (CNF-Vc1) and Conus spurius (CNF-Sr1 and CNF-Sr2). We show that CNF-Vc1 and CNF-Sr1 activate MrgprC11 whereas CNF-Vc1 and CNF-Tx2 activate the human MrgprX1 (hMrgprX1). The peptides CNF-Tx1 and CNF-Sr2 do not activate MrgprC11 or hMrgprX1. Intradermal injection of CNF-Vc1 and CNF-Tx2 into the cheek of a transgenic mouse expressing hMrgprX1 instead of endogenous mouse Mrgprs resulted in itch-related scratching thus demonstrating the in vivo activity of these peptides. Using truncated analogues of CNF-Vc1, we identified amino acids at positions 7–18 as important for activity against hMrgprX1. The conopeptides reported here are tools that can be used to advance our understanding of the cellular and molecular mechanism of itch mediated by Mrgprs.

ACS Style

Samuel S. Espino; Samuel Robinson; Helena Safavi-Hemami; Joanna Gajewiak; Weishan Yang; Baldomero M. Olivera; Qin Liu. Conopeptides promote itch through human itch receptor hMgprX1. Toxicon 2018, 154, 28 -34.

AMA Style

Samuel S. Espino, Samuel Robinson, Helena Safavi-Hemami, Joanna Gajewiak, Weishan Yang, Baldomero M. Olivera, Qin Liu. Conopeptides promote itch through human itch receptor hMgprX1. Toxicon. 2018; 154 ():28-34.

Chicago/Turabian Style

Samuel S. Espino; Samuel Robinson; Helena Safavi-Hemami; Joanna Gajewiak; Weishan Yang; Baldomero M. Olivera; Qin Liu. 2018. "Conopeptides promote itch through human itch receptor hMgprX1." Toxicon 154, no. : 28-34.

Research article
Published: 12 September 2018 in Science Advances
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Ants (Hymenoptera: Formicidae) are diverse and ubiquitous, and their ability to sting is familiar to many of us. However, their venoms remain largely unstudied. We provide the first comprehensive characterization of a polypeptidic ant venom, that of the giant red bull ant, Myrmecia gulosa. We reveal a suite of novel peptides with a range of posttranslational modifications, including disulfide bond formation, dimerization, and glycosylation. One venom peptide has sequence features consistent with an epidermal growth factor fold, while the remaining peptides have features suggestive of a capacity to form amphipathic helices. We show that these peptides are derived from what appears to be a single, pharmacologically diverse, gene superfamily (aculeatoxins) that includes most venom peptides previously reported from the aculeate Hymenoptera. Two aculeatoxins purified from the venom were found to be capable of activating mammalian sensory neurons, consistent with the capacity to produce pain but via distinct mechanisms of action. Further investigation of the major venom peptide MIITX1-Mg1a revealed that it can also incapacitate arthropods, indicative of dual utility in both defense and predation. MIITX1-Mg1a accomplishes these functions by generating a leak in membrane ion conductance, which alters membrane potential and triggers neuronal depolarization. Our results provide the first insights into the evolution of the major toxin gene superfamily of the aculeate Hymenoptera and provide a new paradigm in the functional evolution of toxins from animal venoms.

ACS Style

Samuel D. Robinson; Alexander Mueller; Daniel Clayton; Hana Starobova; Brett R. Hamilton; Richard J. Payne; Irina Vetter; Glenn F. King; Eivind A. B. Undheim. A comprehensive portrait of the venom of the giant red bull ant, Myrmecia gulosa, reveals a hyperdiverse hymenopteran toxin gene family. Science Advances 2018, 4, eaau4640 .

AMA Style

Samuel D. Robinson, Alexander Mueller, Daniel Clayton, Hana Starobova, Brett R. Hamilton, Richard J. Payne, Irina Vetter, Glenn F. King, Eivind A. B. Undheim. A comprehensive portrait of the venom of the giant red bull ant, Myrmecia gulosa, reveals a hyperdiverse hymenopteran toxin gene family. Science Advances. 2018; 4 (9):eaau4640.

Chicago/Turabian Style

Samuel D. Robinson; Alexander Mueller; Daniel Clayton; Hana Starobova; Brett R. Hamilton; Richard J. Payne; Irina Vetter; Glenn F. King; Eivind A. B. Undheim. 2018. "A comprehensive portrait of the venom of the giant red bull ant, Myrmecia gulosa, reveals a hyperdiverse hymenopteran toxin gene family." Science Advances 4, no. 9: eaau4640.

Review
Published: 01 December 2017 in Neuropharmacology
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Diabetes mellitus is a chronic disease caused by a deficiency in production of insulin by the beta cells of the pancreas (type 1 diabetes, T1D), or by partial deficiency of insulin production and the ineffectiveness of the insulin produced (type 2 diabetes, T2D). Animal venoms are a unique source of compounds targeting ion channels and receptors in the nervous and cardiovascular systems. In recent years, several venom peptides have also emerged as pharmacological tools and therapeutics for T1D and T2D. Some of these peptides act directly as mimics of endogenous metabolic hormones while others act on ion channels expressed in pancreatic beta cells. Here, we provide an overview of the discovery of these venom peptides, their mechanisms of action in the context of diabetes, and their therapeutic potential for the treatment of this disease.

ACS Style

Samuel Robinson; Helena Safavi-Hemami. Venom peptides as pharmacological tools and therapeutics for diabetes. Neuropharmacology 2017, 127, 79 -86.

AMA Style

Samuel Robinson, Helena Safavi-Hemami. Venom peptides as pharmacological tools and therapeutics for diabetes. Neuropharmacology. 2017; 127 ():79-86.

Chicago/Turabian Style

Samuel Robinson; Helena Safavi-Hemami. 2017. "Venom peptides as pharmacological tools and therapeutics for diabetes." Neuropharmacology 127, no. : 79-86.

Review
Published: 13 September 2017 in Expert Review of Proteomics
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Introduction: Animal venoms are complex chemical arsenals. Most venoms are rich in bioactive peptides with proven potential as research tools, drug leads and drugs. Areas covered: We review recent advances in venom-peptide discovery, particularly the adoption of combined transcriptomic/proteomic approaches for the exploration of venom composition. Expert commentary: Advances in transcriptomics and proteomics have dramatically altered the manner and rate of venom-peptide discovery. The increasing trend towards a toxin-driven approach, as opposed to traditional target-based screening of venoms, is likely to expedite the discovery of venom-peptides with novel structures and new and unanticipated mechanisms of action. At the same time, these advances will drive the development of higher-throughput approaches for target identification. Taken together, these approaches should enhance our understanding of the natural ecological function of venom peptides and increase the rate of identification of novel venom-derived pharmacological tools, drug leads and drugs.

ACS Style

Samuel D. Robinson; Eivind Undheim; Beatrix Ueberheide; Glenn F. King. Venom peptides as therapeutics: advances, challenges and the future of venom-peptide discovery. Expert Review of Proteomics 2017, 14, 931 -939.

AMA Style

Samuel D. Robinson, Eivind Undheim, Beatrix Ueberheide, Glenn F. King. Venom peptides as therapeutics: advances, challenges and the future of venom-peptide discovery. Expert Review of Proteomics. 2017; 14 (10):931-939.

Chicago/Turabian Style

Samuel D. Robinson; Eivind Undheim; Beatrix Ueberheide; Glenn F. King. 2017. "Venom peptides as therapeutics: advances, challenges and the future of venom-peptide discovery." Expert Review of Proteomics 14, no. 10: 931-939.

Journal article
Published: 20 May 2017 in Marine Drugs
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The marine cone snail Conus gloriamaris is an iconic species. For over two centuries, its shell was one of the most prized and valuable natural history objects in the world. Today, cone snails have attracted attention for their remarkable venom components. Many conotoxins are proving valuable as research tools, drug leads, and drugs. In this article, we present the venom gland transcriptome of C. gloriamaris, revealing this species’ conotoxin repertoire. More than 100 conotoxin sequences were identified, representing a valuable resource for future drug discovery efforts.

ACS Style

Samuel D. Robinson; Qing Li; Aiping Lu; Pradip K. Bandyopadhyay; Mark Yandell; Baldomero M. Olivera; Helena Safavi-Hemami. The Venom Repertoire of Conus gloriamaris (Chemnitz, 1777), the Glory of the Sea. Marine Drugs 2017, 15, 145 .

AMA Style

Samuel D. Robinson, Qing Li, Aiping Lu, Pradip K. Bandyopadhyay, Mark Yandell, Baldomero M. Olivera, Helena Safavi-Hemami. The Venom Repertoire of Conus gloriamaris (Chemnitz, 1777), the Glory of the Sea. Marine Drugs. 2017; 15 (5):145.

Chicago/Turabian Style

Samuel D. Robinson; Qing Li; Aiping Lu; Pradip K. Bandyopadhyay; Mark Yandell; Baldomero M. Olivera; Helena Safavi-Hemami. 2017. "The Venom Repertoire of Conus gloriamaris (Chemnitz, 1777), the Glory of the Sea." Marine Drugs 15, no. 5: 145.