Because of significant differences in anatomy of the venom delivery system and distant phylogenetic relatedness, it had been long assumed that the venom systems of snakes and helodermatid lizards were independently evolved (1-3). However, both lineages were recently revealed to be members of a clade (Toxicofera) that also included several lineages of other lizards recently shown to be venomous (4, 5). In contrast to the hypothesis of independent origins, this new perspective revealed that lizard and snake venom systems are homologous but highly differentiated descendants of an early evolved venom system in squamates. The basal condition was incipient glands on both the mandibular and maxillary regions with snakes favoring the maxillary venom glands and secondarily losing the mandibular venom glands. However, the anguimorph lizards (anguids, helodermatids, and varanids) did the reverse, resulting in the modern condition seen today.The lizard venom delivery system is less sophisticated than the high pressure injection mechanism of the front fanged advanced snakes, and the vast majority of the species pose trivial direct medical risks to human (with the exception of helodermatids and large varanids such as Varanus komodoensis). However, the effects of envenomation from mediFrom the

The cytotoxicity of the venom of 25 species of Old World elapid snake was tested and compared with the morphological and behavioural adaptations of hooding and spitting. We determined that, contrary to previous assumptions, the venoms of spitting species are not consistently more cytotoxic than those of closely related non-spitting species. While this correlation between spitting and non-spitting was found among African cobras, it was not present among Asian cobras. On the other hand, a consistent positive correlation was observed between cytotoxicity and utilisation of the defensive hooding display that cobras are famous for. Hooding and spitting are widely regarded as defensive adaptations, but it has hitherto been uncertain whether cytotoxicity serves a defensive purpose or is somehow useful in prey subjugation. The results of this study suggest that cytotoxicity evolved primarily as a defensive innovation and that it has co-evolved twice alongside hooding behavior: once in the Hemachatus + Naja and again independently in the king cobras (Ophiophagus). There was a significant increase of cytotoxicity in the Asian Naja linked to the evolution of bold aposematic hood markings, reinforcing the link between hooding and the evolution of defensive cytotoxic venoms. In parallel, lineages with increased cytotoxicity but lacking bold hood patterns evolved aposematic markers in the form of high contrast body banding. The results also indicate that, secondary to the evolution of venom rich in cytotoxins, spitting has evolved three times independently: once within the African Naja, once within the Asian Naja, and once in the Hemachatus genus. The evolution of cytotoxic venom thus appears to facilitate the evolution of defensive spitting behaviour. In contrast, a secondary loss of cytotoxicity and reduction of the hood occurred in the water cobra Naja annulata, which possesses streamlined neurotoxic venom similar to that of other aquatic elapid snakes (e.g., hydrophiine sea snakes). The results of this study make an important contribution to our growing understanding of the selection pressures shaping the evolution of snake venom and its constituent toxins. The data also aid in elucidating the relationship between these selection pressures and the medical impact of human snakebite in the developing world, as cytotoxic cobras cause considerable morbidity including loss-of-function injuries that result in economic and social burdens in the tropics of Asia and sub-Saharan Africa.

Australian funnel-web spiders are infamous for causing human fatalities, which are induced by venom peptides known as δ-hexatoxins (δ-HXTXs). Humans and other primates did not feature in the prey or predator spectrum during evolution of these spiders, and consequently the primate lethality of δ-HXTXs remains enigmatic. Funnel-web envenomations are mostly inflicted by male spiders that wander from their burrow in search of females during the mating season, which suggests a role for δ-HXTXs in self-defense since male spiders rarely feed during this period. Although 35 species of Australian funnel-web spiders have been described, only nine δ-HXTXs from four species have been characterized, resulting in a lack of understanding of the ecological roles and molecular evolution of δ-HXTXs. Here, by profiling venom-gland transcriptomes of 10 funnel-web species, we report 22 δ-HXTXs. Phylogenetic and evolutionary assessments reveal a remarkable sequence conservation of δ-HXTXs despite their deep evolutionary origin within funnel-web spiders, consistent with a defensive role. We demonstrate that δ-HXTX-Ar1a, the lethal toxin from the Sydney funnel-web spider Atrax robustus, induces pain in mice by inhibiting inactivation of voltage-gated sodium (NaV) channels involved in nociceptive signaling. δ-HXTX-Ar1a also inhibited inactivation of cockroach NaV channels and was insecticidal to sheep blowflies. Considering their algogenic effects in mice, potent insecticidal effects, and high levels of sequence conservation, we propose that the δ-HXTXs were repurposed from an initial insecticidal predatory function to a role in defending against nonhuman vertebrate predators by male spiders, with their lethal effects on humans being an unfortunate evolutionary coincidence.

In 10 nonasthmatic subjects and 11 patients with asthma, we measured pulmonary resistance (RL), functional residual capacity (FRC), and specific conductance (sGaw) before, during, and after submaximal treadmill exercise. Nonasthmatic subjects did not change RL, FRC, or sGaw from base-line resting values during or after exercise. In patients with asthma, RL decreased significantly during exercise, both when exercise was begun from the control resting state and from conditions of elevated RL after a preceding period of exercise. When asthmatic patients inhaled a standardized dose of aerosolized histamine, the increase in RL during exercise was significantly less than the increase in RL when they breathed histamine at rest. When patients hyperventilated at rest with tidal volumes, breathing frequencies, and end-tidal CO2 tensions similar to those during exercise conditions, bronchodilatation also occurred, and the increase in RL following inhaled histamine during isocapnic hyperventilation was also less than at rest. Since bronchodilatation and inhibition of histamine-induced bronchoconstriction occur during both exercise and isocapnic hyperventilation, we suggest that the mechanism of bronchodilatation during exercise may not necessarily be related to metabolic factors associated with exercise.

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