Cysteine-Rich Secretory Proteins (CRISPs) From Venomous Snakes: An Overview of the Functional Diversity in A Large and Underappreciated Superfamily.

The CAP protein superfamily (Cysteine-rich secretory proteins (CRISPs), Antigen 5 (Ag5), and Pathogenesis-related 1 (PR-1) proteins) is widely distributed, but for toxinologists, snake venom CRISPs are the most familiar members. Although CRISPs are found in the majority of venoms, very few of these proteins have been functionally characterized, but those that have been exhibit diverse activities. Snake venom CRISPs (svCRISPs) inhibit ion channels and the growth of new blood vessels (angiogenesis). They also increase vascular permeability and promote inflammatory responses (leukocyte and neutrophil infiltration). Interestingly, CRISPs in lamprey buccal gland secretions also manifest some of these activities, suggesting an evolutionarily conserved function. As we strive to better understand the functions that CRISPs serve in venoms, it is worth considering the broad range of CRISP physiological activities throughout the animal kingdom. In this review, we summarize those activities, known crystal structures and sequence alignments, and we discuss predicted functional sites. CRISPs may not be lethal or major components of venoms, but given their almost ubiquitous occurrence in venoms and the accelerated evolution of svCRISP genes, these venom proteins are likely to have functions worth investigating.

Simulating the effect of sodium channel blockage on cardiac electromechanics.

There is growing interest to better understand drug-induced cardiovascular complications and to predict undesirable side effects at as early a stage in the drug development process as possible. The purpose of this paper is to investigate computationally the influence of sodium ion channel blockage on cardiac electromechanics. To do so, we implement a myofiber orientation dependent passive stress model (Holzapfel-Ogden) in the multiphysics solver Chaste to simulate an imaged physiological model of the human ventricles. A dosage of a sodium channel blocker was then applied and its inhibitory effects on the electrical propagation across ventricles were modeled. We employ the Kerckhoffs active stress model to generate electrically excited contractile behavior of myofibers. Our predictions indicate that a delay in the electrical activation of ventricular tissue caused by the sodium channel blockage translates to a delay in the mechanical biomarkers that were investigated. Moreover, sodium channel blockage was found to increase left ventricular twist. A multiphysics computational framework from the cell level to the organ level was thus used to predict the effect of sodium channel blocking drugs on cardiac electromechanics.