https://www.selleckchem.com/ s as a principally vulnerable group do not appear to be hindered or reduced by legalization. Preliminary indicators on cannabis legalization in Canada show a mixed picture, some similar to US-based developments. While some use increases are observed, these do not necessarily represent indications of increases in cannabis-related harm, also since key (e.g., hospitalization or injury) data are lacking to date. There is a gradual embracing of legal supply sources of cannabis among users, which can be expected to serve public health and safety objectives. At the same time, cannabis use and access among under-age users as a principally vulnerable group do not appear to be hindered or reduced by legalization. Mammalian genomes contain millions of putative regulatory sequences, which are delineated by binding of multiple transcription factors. The degree to which spacing and orientation constraints among transcription factor binding sites contribute to the recognition and identity of regulatory sequence is an unresolved but important question that impacts our understanding of genome function and evolution. Global mechanisms that underlie phenomena including the size of regulatory sequences, their uniqueness, and their evolutionary turnover remain poorly described. Here, we ask whether models incorporating different degrees of spacing and orientation constraints among transcription factor binding sites are broadly consistent with several global properties of regulatory sequence. These properties include length, sequence diversity, turnover rate, and dominance of specific TFs in regulatory site identity and cell type specification. Models with and without spacing and orientation constraints are generally consistegulators may be, in part, a consequence of evolutionary pressure to limit the complexity and increase evolvability of regulatory sites. One of the most important protective health factors for children is breast-feeding, but the mechanisms