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Disulfide-rich peptides such as defensins play diverse roles in immunity and ion channel modulation, as well as constituting the bioactive components of many animal venoms. We investigated the structure and bioactivity of U-RDTX-Pp19, a peptide previously discovered in venom of the assassin bug Pristhesancus plagipennis. Recombinant Pp19 (rPp19) was found to possess insecticidal activity when injected into Drosophila melanogaster. A bioinformatic search revealed that domains homologous to Pp19 are produced by assassin bugs and diverse other arthropods. rPp19 co-eluted with native Pp19 isolated from P. plagipennis, which we found is more abundant in hemolymph than venom. We solved the three-dimensional structure of rPp19 using 2D 1 H NMR spectroscopy, finding that it adopts a disulfide-stabilized structure highly similar to known trans-defensins, with the same cystine connectivity as human α-defensin (I-VI, II-IV, and III-V). The structure of Pp19 is unique among reported structures of arthropod peptides., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Zygaenoidea is a superfamily of lepidopterans containing many venomous species, including the Limacodidae (nettle caterpillars) and Megalopygidae (asp caterpillars). Venom proteomes have been recently documented for several species from each of these families, but further data are required to understand the evolution of venom in Zygaenoidea. In this study, we examined the 'electric' caterpillar from North-Eastern Australia, a limacodid caterpillar densely covered in venomous spines. We used DNA barcoding to identify this caterpillar as the larva of the moth Comana monomorpha (Turner, 1904). We report the clinical symptoms of C. monomorpha envenomation, which include acute pain, and erythema and oedema lasting for more than a week. Combining transcriptomics of venom spines with proteomics of venom harvested from the spine tips revealed a venom markedly different in composition from previously examined limacodid venoms that are rich in peptides. In contrast, the venom of C. monomorpha is rich in aerolysin-like proteins similar to those found in venoms of asp caterpillars (Megalopygidae). Consistent with this composition, the venom potently permeabilises sensory neurons and human neuroblastoma cells. This study highlights the diversity of venom composition in Limacodidae., (© 2024. The Author(s).)

Larvae of the genus Megalopyge (Lepidoptera: Zygaenoidea: Megalopygidae), known as asp or puss caterpillars, produce defensive venoms that cause severe pain. Here, we present the anatomy, chemistry, and mode of action of the venom systems of caterpillars of two megalopygid species, the Southern flannel moth Megalopyge opercularis and the black-waved flannel moth Megalopyge crispata . We show that megalopygid venom is produced in secretory cells that lie beneath the cuticle and are connected to the venom spines by canals. Megalopygid venoms consist of large aerolysin-like pore-forming toxins, which we have named megalysins, and a small number of peptides. The venom system differs markedly from those of previously studied venomous zygaenoids of the family Limacodidae, suggestive of an independent origin. Megalopygid venom potently activates mammalian sensory neurons via membrane permeabilization and induces sustained spontaneous pain behavior and paw swelling in mice. These bioactivities are ablated by treatment with heat, organic solvents, or proteases, indicating that they are mediated by larger proteins such as the megalysins. We show that the megalysins were recruited as venom toxins in the Megalopygidae following horizontal transfer of genes from bacteria to the ancestors of ditrysian Lepidoptera. Megalopygids have recruited aerolysin-like proteins as venom toxins convergently with centipedes, cnidarians, and fish. This study highlights the role of horizontal gene transfer in venom evolution.

Limacodidae is a family of lepidopteran insects comprising >1500 species. More than half of these species produce pain-inducing defensive venoms in the larval stage, but little is known about their venom toxins. Recently, we characterised proteinaceous toxins from the Australian limacodid caterpillar Doratifera vulnerans, but it is unknown if the venom of this species is typical of other Limacodidae. Here, we use single animal transcriptomics and venom proteomics to investigate the venom of an iconic limacodid, the North American saddleback caterpillar Acharia stimulea. We identified 65 venom polypeptides, grouped into 31 different families. Neurohormones, knottins, and homologues of the immune signaller Diedel make up the majority of A.stimulea venom, indicating strong similarities to D. vulnerans venom, despite the large geographic separation of these caterpillars. One notable difference is the presence of RF-amide peptide toxins in A. stimulea venom. Synthetic versions of one of these RF-amide toxins potently activated the human neuropeptide FF1 receptor, displayed insecticidal activity when injected into Drosophila melanogaster, and moderately inhibited larval development of the parasitic nematode Haemonchus contortus. This study provides insights into the evolution and activity of venom toxins in Limacodidae, and provides a platform for future structure-function characterisation of A.stimulea peptide toxins., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

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., Competing Interests: The authors declare no competing interest.

Background: New disease modifying therapies (DMT) to control relapsing-remitting multiple sclerosis (RRMS) have been introduced to the market in the past few years and are now widely used in Australia., Objective: To analyse the dispensed use of government subsidised RRMS DMTs in Australia from 1996 to 2019., Methods: We obtained data of dispensed use of DMTs from the Australian Government's Pharmaceutical Benefits Scheme (PBS) administered by Medicare Australia. We measured use as defined daily dose (DDD) per 100,000 population per day. We obtained jurisdictional population data from the Australian Bureau of Statistics., Results: Total DMT use increased by an average of 18% annually, from 2.4 (in 1996) to 69.9 DDD/100,000/day in 2019. Interferon β1B was the most commonly used medicine between 1996 and 2000, Interferon β1A between 2001 and 2014, and fingolimod subsequently. Among Australian states, Tasmania (the southernmost state) had the highest dispensed DMT use of 94.6 DDD/100,000/day in 2019. Concession beneficiaries under the Government's PBS had both lower use and cost per patient than general beneficiaries did. Fingolimod and ocrelizumab accounted for 55% of total expenditure on MS drug therapy in 2019., Conclusion: The use of oral DMTs might increasingly replace parenteral treatments in the near future. Given the current substantial government expenditure on oral DMTs, it will be imperative to examine the real world effectiveness of DMTs., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective: We aimed to find the toxicoepidemiological indicators of tramadol poisoning in children and also the relationship of these indicators (such as demographic characteristics, and referral time) with the final therapeutic outcome., Methods: In this cross-sectional study with retrospective data collection, we included the records for all the patients under 18 that have been admitted due to tramadol poisoning between 2010 and 2015 to Noor and Ali-Asghar (PBUH) University hospital which serves as the referral medical center for acute poisonings management in the central part of Iran and is located in Isfahan. Demographic characteristics, ingested dose, dosage forms, clinical manifestations, coingested drugs, and the outcome of treatment for all pediatric patients were documented and descriptively analyzed., Findings: Demographic and clinical data of a total of 189 patients including 101 male (53.4%) with a mean age of 16.66 ± 2.64 years were abstracted and included in this study. The average time between tramadol ingestion and hospital admission was 3.39 ± 3.23 h. Mean duration of hospitalization was 12.3 ± 10.7 h. In all cases, the route of drug exposure was oral, and the most common form of drug dosage form was 100 mg tablets ( n = 122) proceeded by 200 mg tablets ( n = 32). The mean estimated dose of ingested tramadol was 1126 ± 1061 mg (median, 900 range, 50-7000 mg). 43.9% of the poisoned patients were high school students, and 23.3% had a high school diploma. Intentional intoxications were reported in 93.1% cases and 42.9% had coingestions. Activated charcoal (87.3%), gastric lavage (59.3%), oxygen therapy with mask (46.6%), naloxone (11.6%), anticonvulsants (13.2%), and intubation and ventilation (5.3%) were done as first-line therapeutic measures., Conclusion: Our results suggest that the trend of acute tramadol poisoning among children is decreasing, mostly accidental in adolescents and commonly intentional among young children. Proper education to improve emotional intelligence for young adults and to keep drugs out of reach of the children and safer packaging is recommended to reduce tramadol poisoning incidence in the pediatric population., Competing Interests: There are no conflicts of interest., (Copyright: © 2020 Journal of Research in Pharmacy Practice.)