Papers by Christina N Zdenek
Comparative biochemistry and physiology. Part C, Toxicology & pharmacology/Comparative biochemistry and physiology. Toxicology & pharmacology, Apr 1, 2024
In the ongoing evolutionary arms race between predators and prey, adaptive innovations often trig... more In the ongoing evolutionary arms race between predators and prey, adaptive innovations often trigger a reciprocal response. For instance, the emergence of α-neurotoxins in snake venom has driven prey species targeted by these snakes to evolve sophisticated defense mechanisms. This study zeroes in on the particular motifs within the orthosteric sites of post-synaptic nicotinic acetylcholine receptors (nAChR) that confer resistance to α-neurotoxins, often through structural alterations of nAChR. This research examined Australian agamid lizards, a primary prey group for Australian elapid snakes, which are subject to predatory selection pressures. We previously showed that Pogona vitticeps (Central bearded dragon) was resistant to α-neurotoxic snake venoms through a steric hindrance form resistance evolving within the nAChR orthosteric, specifically through the 187–189NVT motif resulting in the presence of N-glycosylation, with the branching carbohydrate chains impeding the binding by the neurotoxins. This adaptive trait is thought to be a compensatory mechanism for the lizard's limited escape capabilities. Despite the significance of this novel adaptation, the prevalence and evolutionary roots of such venom resistance in Australian agamids have not been thoroughly investigated. To fill this knowledge gap, we undertook a comprehensive sequencing analysis of the nAChR ligand-binding domain across the full taxonomical diversity of Australian agamid species. Our findings reveal that the N-glycosylation resistance mechanism is a trait unique to the Pogona genus and absent in other Australian agamids. This aligns with Pogona's distinctive morphology, which likely increases vulnerability to neurotoxic elapid snakes, thereby increasing selective pressures for resistance. In contrast, biolayer interferometry experiments with death adder (Acanthophis species) venoms did not indicate any resistance-related binding patterns in other agamids, suggesting a lack of similar resistance adaptations, consistent with these lineages either being fast-moving, covered with large defensive spines, or being arboreal. This research not only uncovers a novel α-neurotoxin resistance mechanism in Australian agamids but also highlights the complex dynamics of the predator-prey chemical arms race. It provides a deeper understanding of how evolutionary pressures shape the interactions between venomous snakes and their prey.
Comparative Biochemistry and Physiology C-toxicology & Pharmacology, Jul 1, 2021
What factors influence the evolution of a heavily selected functional trait in a diverse clade? T... more What factors influence the evolution of a heavily selected functional trait in a diverse clade? This study adopts rattlesnakes as a model group to investigate the evolutionary history of venom coagulotoxicity in the wider context of phylogenetics, natural history, and biology. Venom-induced clotting of human plasma and fibrinogen was determined and mapped onto the rattlesnake phylogenetic tree to reconstruct the evolution of coagulotoxicity across the group. Our results indicate that venom phenotype is often independent of phylogenetic relationships in rattlesnakes, suggesting the importance of diet and/or other environmental variables in driving venom evolution. Moreover, the striking inter- and intraspecific variability in venom activity on human blood highlights the considerable variability faced by physicians treating envenomation. This study is the most comprehensive effort to date to describe and characterize the evolutionary and biological aspects of coagulotoxins in rattlesnake venom. Further research at finer taxonomic levels is recommended to elucidate patterns of variation within species and lineages.
Toxicology Letters, Jul 1, 2020
Does the venom of Trimeresurus albolabris (white-lipped pit viper) differ between neonate and adu... more Does the venom of Trimeresurus albolabris (white-lipped pit viper) differ between neonate and adults? This species is responsible for most snakebites within south and southeast Asia, yet it is unknown whether ontogenetic variation in venom composition occurs in this species, or how this might affect antivenom efficacy. Using a coagulation analyser robot, we examined the anticoagulant activity of T. albolabris venom from eight individuals across multiple age classes. We then compared the efficacy of Thai Red Cross Green Pit Viper Antivenom across these age classes. Venoms from all age classes were equally potent in their pseudo-procoagulant, fibrinogenolytic activity, in that fibrinogen was cleaved to form weak, unstable fibrin clots that rapidly broke down, thus resulting in a net anticoagulant state. Similarly, this coagulotoxic activity was well neutralised by antivenom across all venoms. Given that coagulotoxicity is the primary serious pathology in T. albolabris envenomations, we conclude that Thai Red Cross Green Tree Pit Viper Antivenom is a valid treatment for envenomations by this species, regardless of age or sex of the offending snake. These results are relevant for clinical treatment of envenomations by T. albolabris.
Bioacoustics-the International Journal of Animal Sound and Its Recording, Aug 21, 2015
Parrots are renowned for their capacity for vocal learning and production of diverse sounds in ca... more Parrots are renowned for their capacity for vocal learning and production of diverse sounds in captivity, yet little is known about why such advanced vocal capabilities have evolved. Here, we provide a detailed description and statistical classification of the vocal repertoire of wild palm cockatoos Probosciger aterrimus and investigate the behavioural contexts of vocalizations. We show that palm cockatoos produce vocalizations that conform to most of the common vocalizations described for wild parrots, but also produce a variety of additional syllables in a phonological syntactic manner in the contexts of display and vocal-exchange with neighbouring individuals. These additional syllables are mainly produced by males and are often combined to form long, complex sequences. Unlike most parrots, palm cockatoos defend large multipurpose territories and we speculate that the large vocal repertoire and vocal assemblages of palm cockatoos may function in territorial defense.
Toxins, Feb 14, 2023
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
Frontiers in Immunology, Oct 7, 2021
African spitting cobras are unique among cobras for their potent anticoagulant venom activity ari... more African spitting cobras are unique among cobras for their potent anticoagulant venom activity arising from strong inhibition of Factor Xa. This anticoagulant effect is exerted by venom phospholipase A 2 (Group I PLA 2) toxins whose activity contributes to the lethality of these species. This anticoagulant toxicity is particularly problematic as it is not neutralized by current antivenoms. Previous work demonstrated this trait for Naja mossambica, N. nigricincta, N. nigricollis, and N. pallida. The present work builds upon previous research by testing across the full taxonomical range of African spitting cobras, demonstrating that N. ashei, N. katiensis, and N. nubiae are also potently anticoagulant through the inhibition of Factor Xa, and therefore the amplification of potent anticoagulant activity occurred at the base of the African spitting cobra radiation. Previous work demonstrated that the enzyme-inhibitor varespladib was able to neutralize this toxic action for N. mossambica, N. nigricincta, N. nigricollis, and N. pallida venoms. The current work demonstrates that varespladib was also able to neutralize N. ashei, N. katiensis, and N. nubiae. Thus varespladib is shown to have broad utility across the full range of African spitting cobras. In addition, we examined the cross-reactivity of the metalloprotease inhibitor prinomastat, which had been previously intriguingly indicated as being capable of neutralizing viperid venom PLA 2 (Group II PLA 2). In this study prinomastat inhibited the FXa-inhibiting PLA 2 toxins of all the African spitting cobras at the same concentration at which it has been shown to inhibit metalloproteases, and thus was comparably effective in its cross-reactivity. In addition we showed that the metalloproteaseinhibitor marimastat was also able to cross-neutralize PLA 2 but less effectively than prinomastat. Due to logistical (cold-chain requirement) and efficacy (cross-reactivity across snake species) limitations of traditional antivenoms, particularly in developing countries where snakebite is most common, these small molecule inhibitors (SMIs) might hold great promise as initial, field-based, treatments for snakebite envenoming as well as addressing fundamental limitations of antivenom in the clinical setting where certain toxin effects are unneutralized.
Angewandte Chemie, Mar 11, 2022
Knottins are topologically complex peptides that are stabilised by a cystine knot and have except... more Knottins are topologically complex peptides that are stabilised by a cystine knot and have exceptionally diverse functions, including protease inhibition. However, approaches for tuning their activity in situ are limited. Here, we demonstrate separate approaches for tuning the activity of knottin protease inhibitors using light or streptavidin. We show that the inhibitory activity and selectivity of an engineered knottin can be controlled with light by activating a second mode of action that switches the inhibitor ON against new targets. Guided by a knottin library screen, we also identify a position in the inhibitor's binding loop that permits insertion of a biotin tag without impairing activity. Using streptavidin, biotinylated knottins with nanomolar affinity can be switched OFF in activity assays, and the anticoagulant activity of a factor XIIa inhibitor can be rapidly switched OFF in human plasma. Our findings expand the scope of engineered knottins for precisely controlling protein function.
Neurotoxicity Research, Oct 4, 2022
The targeting of specific prey by snake venom toxins is a fascinating aspect of molecular and eco... more The targeting of specific prey by snake venom toxins is a fascinating aspect of molecular and ecological evolution. Neurotoxic targeting by elapid snakes dominates the literature in this regard; however, recent studies have revealed viper toxins also induce neurotoxic effect. While this effect is thought to primarily be driven by prey selectivity, no study has quantified the taxonomically specific neurotoxicity of the viper clade consisting of Daboia, Macrovipera, Montivipera, and Vipera genera. Here, we tested venom toxin binding from 28 species of vipers from the four genera on the alpha 1 neuronal nicotinic acetylcholine receptors (nAChRs) orthosteric sites of amphibian, avian, lizard, rodent, and human mimotopes (synthetic peptides) using the Octet HTX biolayer interferometry platform. Daboia siamensis and D. russelii had broad binding affinity towards all mimotopes, while D. palestinae had selectivity toward lizard. Macrovipera species, on the other hand, were observed to have a higher affinity for amphibian mimotopes except for M. schweizeri, which inclined more toward lizard mimotopes. All Montivipera and most Vipera species also had higher affinity toward lizard mimotopes. Vipera a. montandoni, V. latastei, V. nikolski, and V. transcaucasina had the least binding to any of the mimotopes of the study. While a wide range of affinity binding towards various mimotopes were observed within the clade, the lowest affinity occurred towards the human target. Daboia siamensis and Macrovipera lebetina exhibited the greatest affinity toward the human mimotope, albeit still the least targeted of the mimotopes within those species. Overlaying this toxin-targeting trait over phylogeny of this clade revealed multiple cases of amplification of this trait and several cases of secondary loss. Overall, our results reveal dynamic variation, amplification, and some secondary loss of the prey targeting trait by alpha-neurotoxins within the venoms of this clade, indicating evolutionary selection pressure shaping the basic biochemistry of these venoms. Our work illustrates the successful use of this biophysical assay to further research snake venom neurotoxins and emphasizes the risk of generalizing venom effects observed on laboratory animals to have similar effects on humans.
Toxins, Jan 22, 2021
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
Journal of Medicinal Chemistry, Nov 16, 2022
Science
Take students' questions seriously and answer them constructively. PIs who show students this res... more Take students' questions seriously and answer them constructively. PIs who show students this respect will stimulate their research motivation by demonstrating that the lab is a safe environment to express opinions.
Science
The future of scientific societies AAAS (the publisher of Science) turns 175 years old this year.... more The future of scientific societies AAAS (the publisher of Science) turns 175 years old this year. AAAS's mission is to advance science, engineering, and innovation throughout the world for the benefi t of all. To celebrate this milestone and explore AAAS's anniversary theme of "igniting progress for the next 175," we asked young scientists, "How have scientifi c societies aff ected your career, and how can societies best support scientists in the future?" Read a selection of the responses here. Follow NextGen Voices on Twitter with hashtag #NextGenSci.-Jennifer Sills Inclusion Scientific societies have given me the opportunity to attend events, enter contests, and start a science communication project. Ensuring more representation of neurodivergent researchers and other minorities in scientific societies is what drives me, as an autistic researcher, to pursue my goals. Scientific societies' most important role in the future will be inclusion. When scientific societies care about sharing the work and struggles of Black, LGBTQIA+, female, neurodivergent, and other underrepresented researchers, they create a more welcoming scientific community, which will encourage more individuals in minority groups to become scientists.
PLOS ONE
Evidence suggests that snakes can hear, but how snakes naturally respond to sound is still unclea... more Evidence suggests that snakes can hear, but how snakes naturally respond to sound is still unclear. We conducted 304 controlled experiment trials on 19 snakes across five genera in a sound-proof room (4.9 x 4.9 m) at 27ºC, observing the effects of three sounds on individual snake behavior, compared to controls. We quantified eight snake behaviors (body movement, body freezing, head-flicks, tongue-flicks, hissing, periscoping, head fixation, lower jaw drop) in response to three sounds, which were filtered pink-noise within the following frequency ranges: 0–150Hz (sound 1, which produced ground vibrations, as measured by an accelerometer), 150–300Hz (sound 2, which did not produced ground vibrations), 300–450Hz (sound 3, which did not produced ground vibrations). All snake responses were strongly genus dependent. Only one genus (Aspidites, Woma Pythons) significantly increased their probability of movement in response to sound, but three other genera (Acanthophis (Death Adders), Oxyur...
Neurotoxicity Research
The targeting of specific prey by snake venom toxins is a fascinating aspect of molecular and eco... more The targeting of specific prey by snake venom toxins is a fascinating aspect of molecular and ecological evolution. Neurotoxic targeting by elapid snakes dominates the literature in this regard; however, recent studies have revealed viper toxins also induce neurotoxic effect. While this effect is thought to primarily be driven by prey selectivity, no study has quantified the taxonomically specific neurotoxicity of the viper clade consisting of Daboia, Macrovipera, Montivipera, and Vipera genera. Here, we tested venom toxin binding from 28 species of vipers from the four genera on the alpha 1 neuronal nicotinic acetylcholine receptors (nAChRs) orthosteric sites of amphibian, avian, lizard, rodent, and human mimotopes (synthetic peptides) using the Octet HTX biolayer interferometry platform. Daboia siamensis and D. russelii had broad binding affinity towards all mimotopes, while D. palestinae had selectivity toward lizard. Macrovipera species, on the other hand, were observed to have ...
Australian Field Ornithology
Within Australia, the iconic Palm Cockatoo Probosciger arterrimus macgillivrayi occurs only on th... more Within Australia, the iconic Palm Cockatoo Probosciger arterrimus macgillivrayi occurs only on the Cape York Peninsula, Queensland, has recently been listed as Endangered, and requires large, old hollow-bearing trees for nesting. Surveys for these trees are crucial for management purposes. Typical surveys rely on following auditory (vocalisations) and visual (sightings) cues to determine the presence of birds or nests. However, nesting hollows can easily be inadvertently overlooked during such surveys because of false absences caused by biennial nesting, decreased vocal activity during nesting, and silent flushing from active nests when approached. We developed a systematic, grid-based transect methodology that maximises the likelihood of identifying potential, used, and confirmed Palm Cockatoo nest hollows and this has been implemented on western Cape York Peninsula since 2015. This method does not rely on bird presence at the time of surveys, but instead relies on multiple, specif...
Toxins
Despite coagulotoxicity being a primary weapon for prey capture by Bothrops species (lancehead pi... more Despite coagulotoxicity being a primary weapon for prey capture by Bothrops species (lancehead pit vipers) and coagulopathy being a major lethal clinical effect, a genus-wide comparison has not been undertaken. To fill this knowledge gap, we used thromboelastography to compare 37 venoms, from across the full range of geography, taxonomy, and ecology, for their action upon whole plasma and isolated fibrinogen. Potent procoagulant toxicity was shown to be the main venom effect of most of the species tested. However, the most basal species (B. pictus) was strongly anticoagulant; this is consistent with procoagulant toxicity being a novel trait that evolved within Bothrops subsequent to their split from anticoagulant American pit vipers. Intriguingly, two of the arboreal species studied (B. bilineatus and B. taeniatus) lacked procoagulant venom, suggesting differential evolutionary selection pressures. Notably, some terrestrial species have secondarily lost the procoagulant venom trait:...
Herpetological Conservation and Biology, Aug 1, 2021
<div><p>Parrots are renowned for their capacity for vocal learning and production of ... more <div><p>Parrots are renowned for their capacity for vocal learning and production of diverse sounds in captivity, yet little is known about why such advanced vocal capabilities have evolved. Here, we provide a detailed description and statistical classification of the vocal repertoire of wild palm cockatoos <i>Probosciger aterrimus</i> and investigate the behavioural contexts of vocalizations. We show that palm cockatoos produce vocalizations that conform to most of the common vocalizations described for wild parrots, but also produce a variety of additional syllables in a phonological syntactic manner in the contexts of display and vocal-exchange with neighbouring individuals. These additional syllables are mainly produced by males and are often combined to form long, complex sequences. Unlike most parrots, palm cockatoos defend large multipurpose territories and we speculate that the large vocal repertoire and vocal assemblages of palm cockatoos may function in territorial defense.</p></div
Frontiers in Immunology, 2021
Palearctic vipers are medically significant snakes in the genera Daboia, Macrovipera, Montivipera... more Palearctic vipers are medically significant snakes in the genera Daboia, Macrovipera, Montivipera, and Vipera which occur throughout Europe, Central Asia, Near and Middle East. While the ancestral condition is that of a small-bodied, lowland species, extensive diversification has occurred in body size, and niche specialization. Using 27 venom samples and a panel of in vitro coagulation assays, we evaluated the relative coagulotoxic potency of Palearctic viper venoms and compared their neutralization by three antivenoms (Insoserp Europe, VIPERFAV and ViperaTAb) and two metalloprotease inhibitors (prinomastat and DMPS). We show that variation in morphology parallels variation in the Factor X activating procoagulant toxicity, with the three convergent evolutions of larger body sizes (Daboia genus, Macrovipera genus, and Vipera ammodytes uniquely within the Vipera genus) were each accompanied by a significant increase in procoagulant potency. In contrast, the two convergent evolutions o...
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Papers by Christina N Zdenek