Oligoclonal mixtures of broadly-neutralizing antibodies can neutralize complex compositions of similar and dissimilar antigens, making them versatile tools for the treatment of e.g., infectious ...diseases and animal envenomations. However, these biotherapeutics are complicated to develop due to their complex nature. In this work, we describe the application of various strategies for the discovery of cross-neutralizing nanobodies against key toxins in coral snake venoms using phage display technology. We prepare two oligoclonal mixtures of nanobodies and demonstrate their ability to neutralize the lethality induced by two North American coral snake venoms in mice, while individual nanobodies fail to do so. We thus show that an oligoclonal mixture of nanobodies can neutralize the lethality of venoms where the clinical syndrome is caused by more than one toxin family in a murine challenge model. The approaches described may find utility for the development of advanced biotherapeutics against snakebite envenomation and other pathologies where multi-epitope targeting is beneficial.
The current outbreak of viral pneumonia in the city of Wuhan, China, was caused by a novel coronavirus designated 2019‐nCoV by the World Health Organization, as determined by sequencing the viral RNA ...genome. Many initial patients were exposed to wildlife animals at the Huanan seafood wholesale market, where poultry, snake, bats, and other farm animals were also sold. To investigate possible virus reservoir, we have carried out comprehensive sequence analysis and comparison in conjunction with relative synonymous codon usage (RSCU) bias among different animal species based on the 2019‐nCoV sequence. Results obtained from our analyses suggest that the 2019‐nCoV may appear to be a recombinant virus between the bat coronavirus and an origin‐unknown coronavirus. The recombination may occurred within the viral spike glycoprotein, which recognizes a cell surface receptor. Additionally, our findings suggest that 2019‐nCoV has most similar genetic information with bat coronovirus and most similar codon usage bias with snake. Taken together, our results suggest that homologous recombination may occur and contribute to the 2019‐nCoV cross‐species transmission.
Research Highlights
Taken together, our results suggest that homologous recombination may occur and contribute to the 2019‐nCoV cross‐species transmission.
Cardiovascular diseases (CVDs) are considered as a major cause of death worldwide. Therefore, identifying and developing therapeutic strategies to treat and reduce the prevalence of CVDs is a major ...medical challenge. Several drugs used for the treatment of CVDs, such as captopril, emerged from natural products, namely snake venoms. These venoms are complex mixtures of bioactive molecules, which, among other physiological networks, target the cardiovascular system, leading to them being considered in the development and design of new drugs. In this review, we describe some snake venom molecules targeting the cardiovascular system such as phospholipase A2 (PLA2), natriuretic peptides (NPs), bradykinin-potentiating peptides (BPPs), cysteine-rich secretory proteins (CRISPs), disintegrins, fibrinolytic enzymes, and three-finger toxins (3FTXs). In addition, their molecular targets, and mechanisms of action-vasorelaxation, inhibition of platelet aggregation, cardioprotective activities-are discussed. The dissection of their biological effects at the molecular scale give insights for the development of future snake venom-derived drugs.
We describe two geographically differentiated venom phenotypes across the wide distribution range of
Bothrops atrox, from the Colombian Magdalena Medio Valley through Puerto Ayacucho and El Paují, in ...the Venezuelan States of Amazonas and Orinoquia, respectively, and São Bento in the Brazilian State of Maranhão. Colombian and Venezuelan venoms show an ontogenetic toxin profile phenotype whereas Brazilian venoms exhibit paedomorphic phenotypes. Venoms from each of the 16 localities sampled contain both population-specific toxins and proteins shared by neighboring
B. atrox populations. Mapping the molecular similarity between conspecific populations onto a physical map of
B. atrox range provides clues for tracing dispersal routes that account for the current biogeographic distribution of the species. The proteomic pattern is consistent with a model of southeast and southwest dispersal and allopatric fragmentation northern of the Amazon Basin, and trans-Amazonian expansion through the Andean Corridor and across the Amazon river between Monte Alegre and Santarém. An antivenomic approach applied to assess the efficacy towards
B. atrox venoms of two antivenoms raised in Costa Rica and Brazil using
Bothrops venoms different than
B. atrox in the immunization mixtures showed that both antivenoms immunodepleted very efficiently the major toxins (PIII-SVMPs, serine proteinases, CRISP, LAO) of paedomorphic venoms from Puerto Ayacucho (Venezuelan Amazonia) through São Bento, but had impaired reactivity towards PLA
2 and P-I SVMP molecules abundantly present in ontogenetic venoms. The degree of immunodepletion achieved suggests that each of these antivenoms may be effective against envenomations by paedomorphic, and some ontogenetic,
B. atrox venoms.
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► Geographically differentiated venom phenotypes across the wide range of
B. atrox are described. ► Colombian and Venezuelan venoms show ontogenetic phenotypes. ► Brazilian venoms exhibit paedomorphic phenotypes. ► Venom phenotyping provides clues for tracing dispersal routes of
B. atrox. ► Costa Rican and Brazilian antivenoms effectively immunodeplete paedomorphic
B. atrox venoms.
Snakebite is a neglected tropical disease that causes high global rates of mortality and morbidity. Although snakebite can cause a variety of pathologies in victims, haemotoxic effects are ...particularly common and are typically characterised by haemorrhage and/or venom-induced consumption coagulopathy. Antivenoms are the mainstay therapeutic for treating the toxic effects of snakebite, but despite saving thousands of lives annually, these therapies are associated with limited cross-snake species efficacy due to venom variation, which ultimately restricts their therapeutic utility to particular geographical regions.
In this study we explored the feasibility of generating globally effective pathology-specific antivenoms to counteract the haemotoxic signs of snakebite envenoming. Two different immunogen mixtures, consisting of seven and twelve haemotoxic venoms sourced from geographically diverse and/or medically important snakes, were used to raise ovine polyclonal antibodies, prior to characterisation of their immunological binding characteristics and in vitro neutralisation profiles against each of the venoms. Despite variability of the immunogen mixtures, both experimental antivenoms exhibited broadly comparable in vitro venom binding and neutralisation profiles against the individual venom immunogens in immunological and functional assays. However, in vivo assessments using a murine preclinical model of antivenom efficacy revealed substantial differences in venom neutralisation. The experimental antivenom generated from the seven venom immunogen mixture outperformed the comparator, by providing protective effects against venom lethality caused by seven of the eight geographically diverse venoms tested, including three distinct venoms that were not used as immunogens to generate this antivenom. These findings suggest that a core set of venom immunogens may be sufficient to stimulate antibodies capable of broadly neutralising a geographically diverse array of haemotoxic snake venoms, and that adding additional venom immunogens may impact negatively on the dose efficacy of the resulting antivenom.
Although selection of appropriate immunogens that encapsulate venom toxin diversity without diluting antivenom potency remains challenging and further optimisation is required, the findings from this pilot study suggest that the generation of pathology-specific antivenoms with global utility is likely to feasible, thereby highlighting their promise as future modular treatments for the world's tropical snakebite victims.
The ecological origin of snakes remains amongst the most controversial topics in evolution, with three competing hypotheses: fossorial; marine; or terrestrial. Here we use a geometric morphometric ...approach integrating ecological, phylogenetic, paleontological, and developmental data for building models of skull shape and size evolution and developmental rate changes in squamates. Our large-scale data reveal that whereas the most recent common ancestor of crown snakes had a small skull with a shape undeniably adapted for fossoriality, all snakes plus their sister group derive from a surface-terrestrial form with non-fossorial behavior, thus redirecting the debate toward an underexplored evolutionary scenario. Our comprehensive heterochrony analyses further indicate that snakes later evolved novel craniofacial specializations through global acceleration of skull development. These results highlight the importance of the interplay between natural selection and developmental processes in snake origin and diversification, leading first to invasion of a new habitat and then to subsequent ecological radiations.
The highly derived morphology and astounding diversity of snakes has long inspired debate regarding the ecological and evolutionary origin of both the snake total-group (Pan-Serpentes) and crown ...snakes (Serpentes). Although speculation abounds on the ecology, behavior, and provenance of the earliest snakes, a rigorous, clade-wide analysis of snake origins has yet to be attempted, in part due to a dearth of adequate paleontological data on early stem snakes. Here, we present the first comprehensive analytical reconstruction of the ancestor of crown snakes and the ancestor of the snake total-group, as inferred using multiple methods of ancestral state reconstruction. We use a combined-data approach that includes new information from the fossil record on extinct crown snakes, new data on the anatomy of the stem snakes Najash rionegrina, Dinilysia patagonica, and Coniophis precedens, and a deeper understanding of the distribution of phenotypic apomorphies among the major clades of fossil and Recent snakes. Additionally, we infer time-calibrated phylogenies using both new 'tip-dating' and traditional node-based approaches, providing new insights on temporal patterns in the early evolutionary history of snakes.
Comprehensive ancestral state reconstructions reveal that both the ancestor of crown snakes and the ancestor of total-group snakes were nocturnal, widely foraging, non-constricting stealth hunters. They likely consumed soft-bodied vertebrate and invertebrate prey that was subequal to head size, and occupied terrestrial settings in warm, well-watered, and well-vegetated environments. The snake total-group - approximated by the Coniophis node - is inferred to have originated on land during the middle Early Cretaceous (~128.5 Ma), with the crown-group following about 20 million years later, during the Albian stage. Our inferred divergence dates provide strong evidence for a major radiation of henophidian snake diversity in the wake of the Cretaceous-Paleogene (K-Pg) mass extinction, clarifying the pattern and timing of the extant snake radiation. Although the snake crown-group most likely arose on the supercontinent of Gondwana, our results suggest the possibility that the snake total-group originated on Laurasia.
Our study provides new insights into when, where, and how snakes originated, and presents the most complete picture of the early evolution of snakes to date. More broadly, we demonstrate the striking influence of including fossils and phenotypic data in combined analyses aimed at both phylogenetic topology inference and ancestral state reconstruction.
The primary driver of nest failure for terrestrial birds is depredation, especially for ground-nesting species that arc vulnerable to a diverse guild of predators. However, descriptions of how ...complex predator-prey interactions happen, and ultimately lead to nest failures, are scarce. Herein, we provide observations collected from cameras stationed at nest sites as part of a larger study on Northern Bobwhite (Colinus virginianus) and Scaled Quail (Callipepla squamata) nesting behavior in the Oklahoma Panhandle during 2016. We observed 2 multi-episode (i.e.. multiple predator visits) diurnal nest depredation events at a nest of each species. In both instances, repeated nest depredation by hispid cotton rats (Sigmodon kispidus) as well as 2 different snake species resulted in nest abandonment. We observed that cotton rats routinely visited nest sites (up to 11 times in 1 diurnal period), and often entered the nest during oft' bouts (64% of off bouts) of the incubating females. By detailing interspecific interactions involved in nest depredation. we provide a glimpse into the complexity of the nesting ecology of ground-dwelling birds. These observations further reinforce the potential pitfalls of categorizing nest depredation events without camera data. Received 17 March 2022. Accepted 17 September 2022.
The Alto Juruá region, located in the extreme western part of the Brazilian Amazonia, possesses an indigenous and riverine population which is involved in agricultural and forest extraction ...activities, and is a region that stands out for its high incidence of snakebites.
To assess the attitudes of the victims, the characteristics of the snakes and the circumstances of the snakebites which occurred in a region where human populations are highly exposed to snakes.
The study was conducted at the Regional Hospital of Juruá in the Municipality of Cruzeiro do Sul (Acre), which regularly attends victims of snakebites in the Alto Juruá region. The snakes that caused the envenomations were identified from clinical and epidemiological diagnosis of the symptoms and signs that patients presented during hospital, and by enzyme immunoassay for venom detection using serum samples of the patients, or by identification of the snake responsible for the envenomation when it was taken to the hospital or photographed. People who suffered or witnessed the snakebite were interviewed to assess the circumstances of the bite, the attitude adopted after the accident and whether they recognized the species of snake that caused the envenomation.
There were 133 cases of snakebite (76.24/100.000 inhabitants), mainly involving male individuals living in the rural area and who had a low level of education. The most affected groups were farmers (48%) and children and teenagers (39%). It was observed that 8.3% of them presented a history of recurrence for bites. The lower limbs were the most affected anatomical region (84%). The Bothrops atrox snake, mainly small specimens (mostly juveniles), was the main species involved in the envenomations (83.4%). Snakebites occurred mainly in forest areas, backyards of houses in rural areas and near to aquatic environments, during activities (walking, farming, extractivism, hunting). Most of the time, the snake was on the ground and the bite occurred because of the approximation of the individual, either by trampling or by approximation of a hand. Half of the victims performed some kind of inadequate first aid (not drinking water, use of tourniquet, incision at the site of the bite, use of black stone, drinking a compound “Específico Pessoa”).
Snakebite is an important cause of morbidity in the Alto Juruá region. Bothrops bites are mostly caused by small-sized specimens, probably due to the greater abundance of B. atrox juveniles, and also because small snakes are more difficult for people to see. People are more often bitten on the lower limbs probably due to the size of B. atrox (small and medium) and because the snakes are usually on the ground in most situations. Many victims resort to ineffective actions that can cause complications and also delay serotherapy. A low level of education is a factor that may contribute to worse outcomes in snakebites since it is associated with a lack of knowledge of preventive and first aid measures.
•Snakebite is an important cause of morbidity in the Alto Juruá region.•Most snakebites occur in the rainy season when rivers are full and there is increased activity of snakes and their prey.•Small specimens of lancehead (Bothrops atrox) are responsible for most envenomations.•Half of the victims utilized some kind of inadequate first aid technique.
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