Plasticity in oligodendrocyte lineage progression: An OPC puzzle on our nerves.

Myelin deposition in the central nervous system has been shown to be responsive to experience, with sensory enrichment increasing myelination and sensory or social deprivation decreasing myelination. This process is referred to as "adaptive myelination" or "myelin plasticity" and signifies an essential component of new learning. However, whether these experience-driven adaptations are driven by (a) underlying changes in the generation of myelinating cells, (b) altered interactions between myelin sheath and axon, or (c) a combination of the above remains unclear. It has been suggested that myelination largely follows an "innate" and automatic programme, allowing for a predictable pattern of central nervous system myelin deposition over time. Adaptive myelination is thought to account for more nuanced alterations that do not dramatically shift this pattern, but ultimately drive functional responses. This makes the study of myelin plasticity particularly difficult, as it necessitates being able to clearly and specifically draw boundaries between the innate and adaptive programme. Thus, the field requires a holistic understanding of the remit of innate myelin development, prior to investigation of adaptive myelination. This review will collate literature regarding different aspects of oligodendrocyte and myelin development (namely, oligodendrocyte proliferation, differentiation, death and myelin sheath formation) in an innate context, before discussing how these parameters are proposed to change under adaptive conditions. It is the hope that this review will highlight the need for a comprehensive and integrated approach towards studying both innate and adaptive forms of myelination.

Molecular dissection of cobra venom highlights heparinoids as an antidote for spitting cobra envenoming.

Snakebites affect about 1.8 million people annually. The current standard of care involves antibody-based antivenoms, which can be difficult to access and are generally not effective against local tissue injury, the primary cause of morbidity. Here, we used a pooled whole-genome CRISPR knockout screen to define human genes that, when targeted, modify cell responses to spitting cobra venoms. A large portion of modifying genes that conferred resistance to venom cytotoxicity was found to control proteoglycan biosynthesis, including EXT1, B4GALT7, EXT2, EXTL3, XYLT2, NDST1, and SLC35B2, which we validated independently. This finding suggested heparinoids as possible inhibitors. Heparinoids prevented venom cytotoxicity through binding to three-finger cytotoxins, and the US Food and Drug Administration-approved heparinoid tinzaparin was found to reduce tissue damage in mice when given via a medically relevant route and dose. Overall, our systematic molecular dissection of cobra venom cytotoxicity provides insight into how we can better treat cobra snakebite envenoming.