The Experts below are selected from a list of 225 Experts worldwide ranked by ideXlab platform

William J Meggs - One of the best experts on this subject based on the ideXlab platform.

  • Long-term efficacy of pressure immobilization bandages in a porcine model of coral snake envenomation
    The American journal of emergency medicine, 2014
    Co-Authors: Mary E. Smyrnioudis, Kori L Brewer, Matthew D Rosenbaum, Dorcas O'rourke, William J Meggs
    Abstract:

    Abstract Background Pressure immobilization bandages delay mortality for 8 hours after coral snake envenomation, but long-term efficacy has not been established. Objective The objective of this study is to determine the long-term efficacy of pressure immobilization bandages after coral snake envenomation in the absence of antivenom therapy. Methods A randomized, observational pilot study was conducted. Ten pigs (17.3-25.6 kg) were sedated, intubated for 5 hours, and injected subcutaneously with 10 mg of lyophilized Micrurus fulvius venom resuspended in water. Pigs were randomly assigned to a control group (no treatment) or a treatment group (compression bandage and splint) approximately 1 minute after envenomation. Bandage pressure was not controlled. Pigs were monitored daily for 21 days for signs of respiratory depression, decreased oxygen saturations, and paralysis. In case of respiratory depression, pigs were humanely euthanized and time to death recorded. Statistical analysis was performed with Fisher exact test, Mann-Whitney U test, and Kaplan-Meier survival curve as appropriate. Results Median survival time of control animals was 307 minutes compared with 1172 minutes in treated animals ( P = .10). Sixty percent of pigs in the treatment group survived to 24 hours vs 0% of control pigs ( P = .08). Two of the treatment pigs survived to the end point of 21 days but showed necrosis of the distal lower extremity. Conclusions Long-term survival after coral snake envenomation is possible in the absence of antivenom with the use of pressure immobilization bandages. The applied pressure of the bandage is critical to allowing survival without necrosis. Future studies should be designed to accurately monitor the pressures applied.

  • trypsin and rosmarinic acid reduce the toxicity of Micrurus fulvius venom in mice
    Clinical Toxicology, 2014
    Co-Authors: Jennifer Parkercote, Kori L Brewer, Dorcas Orourke, Susan N Miller, Matthew D Rosenbaum, William J Meggs
    Abstract:

    AbstractContext. Antivenom is expensive and not always available, so alternative treatments are being investigated. Objective. The efficacy of trypsin or rosmarinic acid (RA) in treating Micrurus fulvius in a murine model is determined. Materials and methods. Design: randomized controlled blinded study. Subjects: Fifty mice (20–30 g). Study groups: Intraperitoneal injections of: 1) 2 mg/kg M. fulvius venom (approximately twice the LD50 for mice; n = 10); 2) 2 mg/kg M. fulvius venom incubated in vitro for 1 h prior to injection with RA at a 1:10 ratio (n = 17); 3) 2 mg/kg M. fulvius venom incubated in vitro for 1 h prior to injection with 1 mg of trypsin (n = 17); 4)1 mg trypsin IP without venom (n = 3); and 5) RA IP without venom (n = 3). Main outcome: time to toxicity (respiratory distress (< 25 breaths/min.), loss of spontaneous locomotor activity, or inability to upright self). Statistical analysis: Time to toxicity using Tukey–Kramer HSD; Survival to 4, 6, and 12 h using Chi-square analysis. Results. ...

  • A Localizing Circumferential Compression Device Delayed Death After Artificial Eastern Diamondback Rattlesnake Envenomation to the Torso of an Animal Model in a Pilot Study
    Journal of Medical Toxicology, 2010
    Co-Authors: Jason B Hack, Kori L Brewer, William J Meggs, Jocelyn M. Deguzman, Babatunde Orogbemi, Dorcas O’rourke
    Abstract:

    Nearly all prior studies to delay onset of systemic toxicity and death after snake bite use a model of distal extremity envenomation. In the first of a series of planned studies using snake venoms with different toxicity profiles, the application of a novel device in a new model of torso envenomation in the setting of Eastern Coral Snake ( Micrurus fulvius ) venom (a potent neurotoxin) envenomation showed promise by delaying systemic intoxication. In this pilot study, we investigated this novel localizing circumferential compression (LoCC) device’s ability to delay onset of life threatening systemic toxicity after Eastern Diamondback Rattlesnake ( Crotalus adamanteus ) envenomation, a potent hemotoxic and myotoxic venom. With university approval, four juvenile female pigs (22–25 kg) were anesthetized, sedated, and intubated but not paralyzed to allow for spontaneous respirations. Each animal was injected subcutaneously with 50 mg of C. adamanteus venom in identical preselected areas of the trunk. After 1 min, two treatment animals had the LoCC device applied; two control animals had no intervention. Vital signs were recorded every 10 min for the first 2 h and every 30 min thereafter. Endpoints included cardiovascular collapse (fatal arrhythmia, loss of mean arterial pressure, or pulse) or respiratory arrest (

  • A localizing circumferential compression device increases survival after coral snake envenomation to the torso of an animal model.
    The Journal of emergency medicine, 2010
    Co-Authors: Jason B Hack, Kori L Brewer, William J Meggs, Jocelyn M. Deguzman, Dorcas O'rourke
    Abstract:

    Background: Pressure immobilization bandages have been shown to delay onset of systemic toxicity after Eastern coral snake (Micrurus fulvius) envenomation to the distal extremity. Objectives: To assess the efficacy of a novel compression device in delaying onset of systemic toxicity after truncal envenomations with Eastern coral snake (Micrurus fulvius) venom in a porcine model. Methods: With University approval, nine juvenile pigs (11 kg to 22 kg) were sedated, anesthetized, and intubated but not paralyzed to ensure continuous spontaneous respirations in a university animal laboratory. Each animal was injected subcutaneously with 10 mg of M. fulvius venom in a pre-selected area of the trunk. After 1 min, six animals had the application of a novel, localizing circumferential compression (LoCC) device applied to the bite site (treatment group) and three animals had no treatment (control group). The device was composed of a rigid polymer clay form molded into a hollow fusiform shape with an internal dimension of 8 × 5 × 3 cm and an elastic belt wrapped around the animal securing the device in place. Vital signs were recorded at 30-min intervals. End points included a respiratory rate below 3 breaths/min, oxygen saturation < 80%, or survival to 8 h. Survival to 8 h was analyzed using Fisher's exact test, with p < 0.05 indicating significance. Survival analysis was performed using the Mantel-Cox test to assess time to death with outcomes represented in a Kaplan-Meier Cumulative survival plot. Results: Five of the six pigs in the treatment group survived 8 h (293–480 min). None of the control pigs survived to 8 h (Fisher's exact p = 0.04), with mean time of respiratory failure 322 min (272–382 min). Survival analysis showed a significant delay in time to event in the treatment group compared to the control group (p = 0.04). Conclusions: The LoCC device used in this study delayed the onset of systemic toxicity and significantly increased survival time after artificial truncal envenomation by Eastern coral snake venom.

  • pressure immobilization bandages delay toxicity in a porcine model of eastern coral snake Micrurus fulvius fulvius envenomation
    Annals of Emergency Medicine, 2005
    Co-Authors: Benjamin T German, Jason B Hack, Kori L Brewer, William J Meggs
    Abstract:

    Study objectives Pressure-immobilization bandages are used in countries where neurotoxic snake envenomations are common. They impede lymphatic egress from the bite site and delay systemic venom toxicity. The effectiveness of these devices has not been evaluated in coral snake envenomations. We investigated the efficacy of pressure-immobilization bandages in delaying the onset of systemic toxicity in a porcine model of coral snake envenomation. Methods A randomized controlled trial of pressure-immobilization bandages was conducted in a university animal care center. Subjects were 12 anesthetized, spontaneously breathing pigs, ranging from 9.1 to 11.4 kg. After injection with 10 mg of Micrurus fulvius fulvius venom in the subcutaneous tissue of the distal foreleg, subjects were randomized to receive no treatment or application of a pressure-immobilization bandage at 1 minute after injection. Treated animals had elastic bandages applied to the extremity and splinting for immobilization. Vital signs and quality of respirations were recorded. Outcome was the onset of respiratory failure or survival to 8 hours. Necropsies and histologic analysis of the envenomation site was performed. Results One animal from each group was removed because of the discovery of pre-existing respiratory pathology. Four of 5 pigs in the treatment group survived to 8 hours, but none in the control group survived. Mean time to onset of respiratory compromise was 170.4 ± 33.3 minutes in the control group. None of the pigs had histologic changes at the envenomation site consistent with ischemia or pressure-related injury. Conclusion Pressure-immobilization bandages delayed the onset of systemic toxicity in our porcine model of M fulvius envenomation.

José María Gutiérrez - One of the best experts on this subject based on the ideXlab platform.

  • delayed ly333013 oral and ly315920 intravenous reverse severe neurotoxicity and rescue juvenile pigs from lethal doses of Micrurus fulvius eastern coral snake venom
    Toxins, 2018
    Co-Authors: Matthew R. Lewin, Lyndi L. Gilliam, John Gilliam, Stephen P. Samuel, Tommaso C. Bulfone, Philip E. Bickler, José María Gutiérrez
    Abstract:

    There is a clear, unmet need for effective, lightweight, shelf-stable and economical snakebite envenoming therapies that can be given rapidly after the time of a snake’s bite and as adjuncts to antivenom therapies in the hospital setting. The sPLA2 inhibitor, {"type":"entrez-nucleotide","attrs":{"text":"LY315920","term_id":"1257380081","term_text":"LY315920"}}LY315920, and its orally bioavailable prodrug, {"type":"entrez-nucleotide","attrs":{"text":"LY333013","term_id":"1258032558","term_text":"LY333013"}}LY333013, demonstrate surprising efficacy and have the characteristics of an antidote with potential for both field and hospital use. The efficacy of the active pharmaceutical ingredient ({"type":"entrez-nucleotide","attrs":{"text":"LY315920","term_id":"1257380081","term_text":"LY315920"}}LY315920) and its prodrug ({"type":"entrez-nucleotide","attrs":{"text":"LY333013","term_id":"1258032558","term_text":"LY333013"}}LY333013) to treat experimental, lethal envenoming by Micrurus fulvius (Eastern coral snake) venom was tested using a porcine model. Inhibitors were administered by either intravenous or oral routes at different time intervals after venom injection. In some experiments, antivenom was also administered alone or in conjunction with {"type":"entrez-nucleotide","attrs":{"text":"LY333013","term_id":"1258032558","term_text":"LY333013"}}LY333013. 14 of 14 animals (100%) receiving either {"type":"entrez-nucleotide","attrs":{"text":"LY315920","term_id":"1257380081","term_text":"LY315920"}}LY315920 (intravenous) and/or {"type":"entrez-nucleotide","attrs":{"text":"LY333013","term_id":"1258032558","term_text":"LY333013"}}LY333013 (oral) survived to the 120 h endpoint despite, in some protocols, the presence of severe neurotoxic signs. The study drugs demonstrated the ability to treat, rescue, and re-rescue animals with advanced manifestations of envenoming. Low molecular mass sPLA2 inhibitors were highly effective in preventing lethality following experimental envenoming by M. fulvius. These findings suggest the plausibility of a new therapeutic approach to snakebite envenoming, in this example, for the treatment of a coral snake species for which there are limitations in the availability of effective antivenom.

  • Delayed LY333013 (Oral) and LY315920 (Intravenous) Reverse Severe Neurotoxicity and Rescue Juvenile Pigs from Lethal Doses of Micrurus fulvius (Eastern Coral Snake) Venom
    MDPI AG, 2018
    Co-Authors: Matthew R. Lewin, Lyndi L. Gilliam, John Gilliam, Stephen P. Samuel, Tommaso C. Bulfone, Philip E. Bickler, José María Gutiérrez
    Abstract:

    There is a clear, unmet need for effective, lightweight, shelf-stable and economical snakebite envenoming therapies that can be given rapidly after the time of a snake’s bite and as adjuncts to antivenom therapies in the hospital setting. The sPLA2 inhibitor, LY315920, and its orally bioavailable prodrug, LY333013, demonstrate surprising efficacy and have the characteristics of an antidote with potential for both field and hospital use. The efficacy of the active pharmaceutical ingredient (LY315920) and its prodrug (LY333013) to treat experimental, lethal envenoming by Micrurus fulvius (Eastern coral snake) venom was tested using a porcine model. Inhibitors were administered by either intravenous or oral routes at different time intervals after venom injection. In some experiments, antivenom was also administered alone or in conjunction with LY333013. 14 of 14 animals (100%) receiving either LY315920 (intravenous) and/or LY333013 (oral) survived to the 120 h endpoint despite, in some protocols, the presence of severe neurotoxic signs. The study drugs demonstrated the ability to treat, rescue, and re-rescue animals with advanced manifestations of envenoming. Low molecular mass sPLA2 inhibitors were highly effective in preventing lethality following experimental envenoming by M. fulvius. These findings suggest the plausibility of a new therapeutic approach to snakebite envenoming, in this example, for the treatment of a coral snake species for which there are limitations in the availability of effective antivenom

  • intravascular hemolysis induced by phospholipases a2 from the venom of the eastern coral snake Micrurus fulvius functional profiles of hemolytic and non hemolytic isoforms
    Toxicology Letters, 2017
    Co-Authors: Maria Laura Fernandez, José María Gutiérrez, Ruth Arcebejarano, Pablo Javier Yunes Quartino, Julian Fernandez, Luis F Camacho, Daniel Kuemmel, Gerardo D Fidelio, Bruno Lomonte
    Abstract:

    Abstract A unique feature of the venom of Micrurus fulvius (Eastern coral snake) is its ability to induce severe intravascular hemolysis in particular species, such as dogs or mice. This effect was previously shown to be induced by distinct phospholipase A2 (PLA2) isoforms which cause direct hemolysis in vitro, an uncommon finding for such enzymes. The functional profiles of PLA2-17, a direct hemolytic enzyme, and PLA2-12, a co-existing venom isoform lacking such effect, were compared. The enzymes differed not only in their ability to cause intravascular hemolysis: PLA2-17 additionally displayed lethal, myotoxic, and anticoagulant actions, whereas PLA2-12 lacked these effects. PLA2-12 was much more active in hydrolyzing a monodisperse synthetic substrate than PLA2-17, but the catalytic activity of latter was notably higher on a micellar substrate, or towards pure phospholipid artificial monolayers under controlled lateral pressures. Interestingly, PLA2-17 could hydrolyze substrate at a pressure of 20 mN m−1, in contrast to PLA2-12 or the non-toxic pancreatic PLA2. This suggests important differences in the monolayer penetrating power, which could be related to differences in toxicity. Comparative examination of primary structures and predicted three-dimensional folding of PLA2-12 and PLA2-17, revealed that differences concentrate in their N-terminal and central regions, leading to variations of the surface properties at the membrane interacting interface. PLA2-17 presents a less basic interfacial surface than PLA2-12, but more bulky aromatic residues, which could be associated to its higher membrane-penetrating strength. Altogether, these structural and functional comparative observations suggest that the ability of PLA2s to penetrate substrate interfaces could be a major determinant of toxicity, perhaps more important than protein surface charge.

  • intravascular hemolysis induced by the venom of the eastern coral snake Micrurus fulvius in a mouse model identification of directly hemolytic phospholipases a2
    Toxicon, 2014
    Co-Authors: Ruth Arcebejarano, Bruno Lomonte, José María Gutiérrez
    Abstract:

    Intravascular hemolysis has been described in envenomings by the Eastern coral snake, Micrurus fulvius, in dogs. An experimental model of intravascular hemolysis was developed in mice after intravenous (i.v.) injection of M. fulvius venom. Within one hr, there was prominent hemolysis, associated with a drastic drop in hematocrit, morphological alterations of erythrocytes, hemoglobinemia, and hemoglobinuria. Hemoglobin was identified in urine by mass spectrometry. Histological sections of kidney revealed abundant hyaline casts, probably corresponding to hemoglobin. This effect was abrogated by p-bromophenacyl bromide, indicating that it is caused by phospholipases A2 (PLA2). A monospecific anti-Micrurus nigrocinctus antivenom neutralized hemolytic activity in vivo. When tested in vitro with erythrocytes of various species, a clear difference in susceptibility was observed. Mouse and dog erythrocytes showed the highest susceptibility, whereas human and rabbit erythrocytes were not affected at the experimental conditions tested. The higher susceptibility of dog and mouse erythrocytes correlates with a high ratio of phosphatidylcholine/sphingomyelin in erythrocyte plasma membrane. When mouse erythrocytes were subjected to mechanical stress, after incubation with venom, hemolysis increased significantly, suggesting that both phospholipid hydrolysis by PLA2s and mechanical stress associated with rheological factors are likely to contribute to cell lysis in vivo. Several PLA2s isolated from this venom reproduced the hemolytic effect, and the complete amino acid sequence of one of them (fraction 17), which also induces myotoxicity, is reported. Since very few PLA2s inducing intravascular hemolysis have been described from snake venoms, this enzyme is a valuable tool to identify the structural determinants of hemolytic activity. The mouse model described in this study may be useful to explore the pathophysiology of intravascular hemolysis.

  • Preclinical assessment of the ability of polyvalent (Crotalinae) and anticoral (Elapidae) antivenoms produced in Costa Rica to neutralize the venoms of North American snakes.
    Toxicon : official journal of the International Society on Toxinology, 2003
    Co-Authors: Viviana Arce, Ermila Rojas, Charlotte L. Ownby, Gustavo Rojas, José María Gutiérrez
    Abstract:

    Polyvalent (Crotalinae) and anticoral (Elapidae) antivenoms produced by Instituto Clodomiro Picado, Costa Rica, were assessed for their ability to neutralize various toxic activities of the venoms of North American snakes of the genera Crotalus, Agkistrodon and Micrurus, in assays involving preincubation of venom and antivenom. When the intraperitoneal route of injection was utilized, polyvalent (Crotalinae) antivenom was effective in the neutralization of the venoms of Crotalus atrox, Crotalus adamanteus, Crotalus viridis viridis, Crotalus horridus atricaudatus, Agkistrodon contortrix contortrix and Agkistrodon piscivorus piscivorus, whereas the venom of Crotalus scutulatus was not neutralized. When the intravenous route was used, results differed depending on the "challenge dose" of venom employed. Polyvalent antivenom neutralized all venoms when mice were challenged with 2 LD(50)s of venom. When 5 LD(50)s were used, antivenom neutralized the venoms of C. atrox, C. adamanteus, C. v. viridis and C. h. atricaudatus, being ineffective in the neutralization of C. scutulatus, A. c. contortrix and A. p. piscivorus. Polyvalent antivenom was effective in the neutralization of hemorrhagic and myotoxic activities of all venoms studied. It also neutralized coagulant activity of C. adamanteus venom, whereas most of the venoms were devoid of clotting activity on plasma in vitro. Moreover, it neutralized defibrinating activity of the only three venoms that induced this effect (i.e. C. adamanteus, A. c. contortrix and A. p. piscivorus). Anticoral (Elapidae) antivenom neutralized lethality induced by the venom of Micrurus fulvius, using either the intravenous or the intraperitoneal routes of injection. Moreover, it neutralized myotoxic effect of this venom as well. It is concluded that polyvalent antivenom neutralizes lethality and other activities of most of the crotaline venoms tested. However, since it is ineffective in neutralizing the lethal effect of C. scutulatus venom, it is suggested that a venom containing presynaptically-active neurotoxic phospholipases A(2) related to "mojave toxin" needs to be introduced in the immunizing mixture in order to increase the neutralizing scope of this product in North America. Anticoral antivenom is highly effective in the neutralization of the venom of M. fulvius.

David W. Kikuchi - One of the best experts on this subject based on the ideXlab platform.

  • is the future already here the impact of climate change on the distribution of the eastern coral snake Micrurus fulvius
    PeerJ, 2018
    Co-Authors: Jennifer N Archis, David W. Kikuchi, Christopher K Akcali, Bryan L Stuart, Amanda J Chunco
    Abstract:

    Anthropogenic climate change is a significant global driver of species distribution change. Although many species have undergone range expansion at their poleward limits, data on several taxonomic groups are still lacking. A common method for studying range shifts is using species distribution models to evaluate current, and predict future, distributions. Notably, many sources of 'current' climate data used in species distribution modeling use the years 1950-2000 to calculate climatic averages. However, this does not account for recent (post 2000) climate change. This study examines the influence of climate change on the eastern coral snake (Micrurus fulvius). Specifically, we: (1) identified the current range and suitable environment of M. fulvius in the Southeastern United States, (2) investigated the potential impacts of climate change on the distribution of M. fulvius, and (3) evaluated the utility of future models in predicting recent (2001-2015) records. We used the species distribution modeling program Maxent and compared both current (1950-2000) and future (2050) climate conditions. Future climate models showed a shift in the distribution of suitable habitat across a significant portion of the range; however, results also suggest that much of the Southeastern United States will be outside the range of current conditions, suggesting that there may be no-analog environments in the future. Most strikingly, future models were more effective than the current models at predicting recent records, suggesting that range shifts may already be occurring. These results have implications for both M. fulvius and its Batesian mimics. More broadly, we recommend future Maxent studies consider using future climate data along with current data to better estimate the current distribution.

  • A Batesian mimic and its model share color production mechanisms
    Current Zoology, 2012
    Co-Authors: David W. Kikuchi
    Abstract:

    Batesian mimics are harmless prey species that resemble dangerous ones (models), and thus receive protection from predators. How such adaptive resemblances evolve is a classical problem in evolutionary biology. Mimicry is typically thought to be difficult to evolve, especially if the model and mimic produce the convergent phenotype through different proximate mechanisms. However, mimicry may evolve more readily if mimic and model share similar pathways for producing the convergent phenotype. In such cases, these pathways can be co-opted in ancestral mimic populations to produce high-fidelity mimicry without the need for major evolutionary innovations. Here, we show that a Batesian mimic, the scarlet kingsnake Lampropeltis elapsoides , produces its coloration using the same physiological mechanisms as does its model, the eastern coral snake Micrurus fulvius . Therefore, precise color mimicry may have been able to evolve easily in this system. Generally, we know relatively little about the proximate mechanisms underlying mimicry.

  • Predator Cognition Permits Imperfect Coral Snake Mimicry
    The American naturalist, 2010
    Co-Authors: David W. Kikuchi
    Abstract:

    Abstract: Batesian mimicry is often imprecise. An underexplored explanation for imperfect mimicry is that predators might not be able to use all dimensions of prey phenotype to distinguish mimics from models and thus permit imperfect mimicry to persist. We conducted a field experiment to test whether or not predators can distinguish deadly coral snakes (Micrurus fulvius) from nonvenomous scarlet kingsnakes (Lampropeltis elapsoides). Although the two species closely resemble one another, the order of colored rings that encircle their bodies differs. Despite this imprecise mimicry, we found that L. elapsoides that match coral snakes in other respects are not under selection to match the ring order of their model. We suggest that L. elapsoides have evolved only those signals necessary to deceive predators. Generally, imperfect mimicry might suffice if it exploits limitations in predator cognitive abilities.

  • Notes and Comments Predator Cognition Permits Imperfect Coral Snake Mimicry
    2010
    Co-Authors: David W. Kikuchi
    Abstract:

    Batesian mimicry is often imprecise. An underexplored explanation for imperfect mimicry is that predators might not be able to use all dimensions of prey phenotype to distinguish mimics from models and thus permit imperfect mimicry to persist. We con- ducted a field experiment to test whether or not predators can dis- tinguish deadly coral snakes (Micrurus fulvius) from nonvenomous scarlet kingsnakes (Lampropeltis elapsoides). Although thetwospecies closely resemble one another, the order of colored rings that encircle their bodies differs. Despite this imprecise mimicry, we found that L. elapsoides that match coral snakes in other respects are not under selection to match the ring order of their model. We suggest that L. elapsoides have evolved only those signals necessary to deceive pred- ators. Generally, imperfect mimicry might suffice if it exploits lim- itations in predator cognitive abilities.

  • High-model abundance may permit the gradual evolution of Batesian mimicry: an experimental test.
    Proceedings of the Royal Society B: Biological Sciences, 2009
    Co-Authors: David W. Kikuchi
    Abstract:

    In Batesian mimicry, a harmless species (the ‘mimic’) resembles a dangerous species (the ‘model’) and is thus protected from predators. It is often assumed that the mimetic phenotype evolves from a cryptic phenotype, but it is unclear how a population can transition through intermediate phenotypes; such intermediates may receive neither the benefits of crypsis nor mimicry. Here, we ask if selection against intermediates weakens with increasing model abundance. We also ask if mimicry has evolved from cryptic phenotypes in a mimetic clade. We first present an ancestral character-state reconstruction showing that mimicry of a coral snake (Micrurus fulvius) by the scarlet kingsnake (Lampropeltis elapsoides) evolved from a cryptic phenotype. We then evaluate predation rates on intermediate phenotypes relative to cryptic and mimetic phenotypes under conditions of both high- and low-model abundances. Our results indicate that where coral snakes are rare, intermediate phenotypes are attacked more often than cryptic and mimetic phenotypes, indicating the presence of an adaptive valley. However, where coral snakes are abundant, intermediate phenotypes are not attacked more frequently, resulting in an adaptive landscape without a valley. Thus, high-model abundance may facilitate the evolution of Batesian mimicry.

Darin R Rokyta - One of the best experts on this subject based on the ideXlab platform.

  • Contrasting Modes and Tempos of Venom Expression Evolution in Two Snake Species
    Genetics, 2014
    Co-Authors: Mark J Margres, Kenneth P Wray, James J. Mcgivern, Margaret Seavy, Jack Facente, Darin R Rokyta
    Abstract:

    Selection is predicted to drive diversification within species and lead to local adaptation, but understanding the mechanistic details underlying this process and thus the genetic basis of adaptive evolution requires the mapping of genotype to phenotype. Venom is complex and involves many genes, but the specialization of the venom gland toward toxin production allows specific transcripts to be correlated with specific toxic proteins, establishing a direct link from genotype to phenotype. To determine the extent of expression variation and identify the processes driving patterns of phenotypic diversity, we constructed genotype-phenotype maps and compared range-wide toxin-protein expression variation for two species of snake with nearly identical ranges: the eastern diamondback rattlesnake (Crotalus adamanteus) and the eastern coral snake (Micrurus fulvius). We detected significant expression variation in C. adamanteus, identified the specific loci associated with population differentiation, and found that loci expressed at all levels contributed to this divergence. Contrary to expectations, we found no expression variation in M. fulvius, suggesting that M. fulvius populations are not locally adapted. Our results not only linked expression variation at specific loci to divergence in a polygenic, complex trait but also have extensive conservation and biomedical implications. C. adamanteus is currently a candidate for federal listing under the Endangered Species Act, and the loss of any major population would result in the irrevocable loss of a unique venom phenotype. The lack of variation in M. fulvius has significant biomedical application because our data will assist in the development of effective antivenom for this species.

  • The venom-gland transcriptome of the eastern coral snake (Micrurus fulvius) reveals high venom complexity in the intragenomic evolution of venoms
    BMC Genomics, 2013
    Co-Authors: Mark J Margres, Karalyn Aronow, Jacob Loyacano, Darin R Rokyta
    Abstract:

    Background Snake venom is shaped by the ecology and evolution of venomous species, and signals of positive selection in toxins have been consistently documented, reflecting the role of venoms as an ecologically critical phenotype. New World coral snakes (Elapidae) are represented by three genera and over 120 species and subspecies that are capable of causing significant human morbidity and mortality, yet coral-snake venom composition is poorly understood in comparison to that of Old World elapids. High-throughput sequencing is capable of identifying thousands of loci, while providing characterizations of expression patterns and the molecular evolutionary forces acting within the venom gland. Results We describe the de novo assembly and analysis of the venom-gland transcriptome of the eastern coral snake ( Micrurus fulvius ). We identified 1,950 nontoxin transcripts and 116 toxin transcripts. These transcripts accounted for 57.1% of the total reads, with toxins accounting for 45.8% of the total reads. Phospholipases A_2 and three-finger toxins dominated expression, accounting for 86.0% of the toxin reads. A total of 15 toxin families were identified, revealing venom complexity previously unknown from New World coral snakes. Toxins exhibited high levels of heterozygosity relative to nontoxins, and overdominance may favor gene duplication leading to the fixation of advantageous alleles. Phospholipase A_2 expression was uniformly distributed throughout the class while three-finger toxin expression was dominated by a handful of transcripts, and phylogenetic analyses indicate that toxin divergence may have occurred following speciation. Positive selection was detected in three of the four most diverse toxin classes, suggesting that venom diversification is driven by recurrent directional selection. Conclusions We describe the most complete characterization of an elapid venom gland to date. Toxin gene duplication may be driven by heterozygote advantage, as the frequency of polymorphic toxin loci was significantly higher than that of nontoxins. Diversification among toxins appeared to follow speciation reflecting species-specific adaptation, and this divergence may be directly related to dietary shifts and is suggestive of a coevolutionary arms race.

  • the venom gland transcriptome of the eastern coral snake Micrurus fulvius reveals high venom complexity in the intragenomic evolution of venoms
    BMC Genomics, 2013
    Co-Authors: Mark J Margres, Karalyn Aronow, Jacob Loyacano, Darin R Rokyta
    Abstract:

    Background Snake venom is shaped by the ecology and evolution of venomous species, and signals of positive selection in toxins have been consistently documented, reflecting the role of venoms as an ecologically critical phenotype. New World coral snakes (Elapidae) are represented by three genera and over 120 species and subspecies that are capable of causing significant human morbidity and mortality, yet coral-snake venom composition is poorly understood in comparison to that of Old World elapids. High-throughput sequencing is capable of identifying thousands of loci, while providing characterizations of expression patterns and the molecular evolutionary forces acting within the venom gland.

Matthew R. Lewin - One of the best experts on this subject based on the ideXlab platform.

  • delayed ly333013 oral and ly315920 intravenous reverse severe neurotoxicity and rescue juvenile pigs from lethal doses of Micrurus fulvius eastern coral snake venom
    Toxins, 2018
    Co-Authors: Matthew R. Lewin, Lyndi L. Gilliam, John Gilliam, Stephen P. Samuel, Tommaso C. Bulfone, Philip E. Bickler, José María Gutiérrez
    Abstract:

    There is a clear, unmet need for effective, lightweight, shelf-stable and economical snakebite envenoming therapies that can be given rapidly after the time of a snake’s bite and as adjuncts to antivenom therapies in the hospital setting. The sPLA2 inhibitor, {"type":"entrez-nucleotide","attrs":{"text":"LY315920","term_id":"1257380081","term_text":"LY315920"}}LY315920, and its orally bioavailable prodrug, {"type":"entrez-nucleotide","attrs":{"text":"LY333013","term_id":"1258032558","term_text":"LY333013"}}LY333013, demonstrate surprising efficacy and have the characteristics of an antidote with potential for both field and hospital use. The efficacy of the active pharmaceutical ingredient ({"type":"entrez-nucleotide","attrs":{"text":"LY315920","term_id":"1257380081","term_text":"LY315920"}}LY315920) and its prodrug ({"type":"entrez-nucleotide","attrs":{"text":"LY333013","term_id":"1258032558","term_text":"LY333013"}}LY333013) to treat experimental, lethal envenoming by Micrurus fulvius (Eastern coral snake) venom was tested using a porcine model. Inhibitors were administered by either intravenous or oral routes at different time intervals after venom injection. In some experiments, antivenom was also administered alone or in conjunction with {"type":"entrez-nucleotide","attrs":{"text":"LY333013","term_id":"1258032558","term_text":"LY333013"}}LY333013. 14 of 14 animals (100%) receiving either {"type":"entrez-nucleotide","attrs":{"text":"LY315920","term_id":"1257380081","term_text":"LY315920"}}LY315920 (intravenous) and/or {"type":"entrez-nucleotide","attrs":{"text":"LY333013","term_id":"1258032558","term_text":"LY333013"}}LY333013 (oral) survived to the 120 h endpoint despite, in some protocols, the presence of severe neurotoxic signs. The study drugs demonstrated the ability to treat, rescue, and re-rescue animals with advanced manifestations of envenoming. Low molecular mass sPLA2 inhibitors were highly effective in preventing lethality following experimental envenoming by M. fulvius. These findings suggest the plausibility of a new therapeutic approach to snakebite envenoming, in this example, for the treatment of a coral snake species for which there are limitations in the availability of effective antivenom.

  • Delayed LY333013 (Oral) and LY315920 (Intravenous) Reverse Severe Neurotoxicity and Rescue Juvenile Pigs from Lethal Doses of Micrurus fulvius (Eastern Coral Snake) Venom
    MDPI AG, 2018
    Co-Authors: Matthew R. Lewin, Lyndi L. Gilliam, John Gilliam, Stephen P. Samuel, Tommaso C. Bulfone, Philip E. Bickler, José María Gutiérrez
    Abstract:

    There is a clear, unmet need for effective, lightweight, shelf-stable and economical snakebite envenoming therapies that can be given rapidly after the time of a snake’s bite and as adjuncts to antivenom therapies in the hospital setting. The sPLA2 inhibitor, LY315920, and its orally bioavailable prodrug, LY333013, demonstrate surprising efficacy and have the characteristics of an antidote with potential for both field and hospital use. The efficacy of the active pharmaceutical ingredient (LY315920) and its prodrug (LY333013) to treat experimental, lethal envenoming by Micrurus fulvius (Eastern coral snake) venom was tested using a porcine model. Inhibitors were administered by either intravenous or oral routes at different time intervals after venom injection. In some experiments, antivenom was also administered alone or in conjunction with LY333013. 14 of 14 animals (100%) receiving either LY315920 (intravenous) and/or LY333013 (oral) survived to the 120 h endpoint despite, in some protocols, the presence of severe neurotoxic signs. The study drugs demonstrated the ability to treat, rescue, and re-rescue animals with advanced manifestations of envenoming. Low molecular mass sPLA2 inhibitors were highly effective in preventing lethality following experimental envenoming by M. fulvius. These findings suggest the plausibility of a new therapeutic approach to snakebite envenoming, in this example, for the treatment of a coral snake species for which there are limitations in the availability of effective antivenom

  • varespladib ly315920 appears to be a potent broad spectrum inhibitor of snake venom phospholipase a2 and a possible pre referral treatment for envenomation
    Toxins, 2016
    Co-Authors: Matthew R. Lewin, Stephen P. Samuel, Janie Merkel, Philip E. Bickler
    Abstract:

    Snakebite remains a neglected medical problem of the developing world with up to 125,000 deaths each year despite more than a century of calls to improve snakebite prevention and care. An estimated 75% of fatalities from snakebite occur outside the hospital setting. Because phospholipase A2 (PLA2) activity is an important component of venom toxicity, we sought candidate PLA2 inhibitors by directly testing drugs. Surprisingly, varespladib and its orally bioavailable prodrug, methyl-varespladib showed high-level secretory PLA2 (sPLA2) inhibition at nanomolar and picomolar concentrations against 28 medically important snake venoms from six continents. In vivo proof-of-concept studies with varespladib had striking survival benefit against lethal doses of Micrurus fulvius and Vipera berus venom, and suppressed venom-induced sPLA2 activity in rats challenged with 100% lethal doses of M. fulvius venom. Rapid development and deployment of a broad-spectrum PLA2 inhibitor alone or in combination with other small molecule inhibitors of snake toxins (e.g., metalloproteases) could fill the critical therapeutic gap spanning pre-referral and hospital setting. Lower barriers for clinical testing of safety tested, repurposed small molecule therapeutics are a potentially economical and effective path forward to fill the pre-referral gap in the setting of snakebite.