Universal ideals in local realities: online viewing in South Korea, Brazil and India

The potential of the internet to act as a global distribution outlet for screen content has long come into conflict with the nationally-focused strategies of producers, broadcasters, governments and internet service providers. Online viewing therefore acts as a useful case study for interrogating how tensions between ‘global’ and ‘local’ manifest within an increasingly digitized media landscape. This article examines the online viewing markets in three countries at different stages of digital maturity (South Korea, Brazil, India) to consider how online viewing has evolved in each. It then examines audience questionnaire and interview data generated in each country to explore how viewers are making sense of and valuing online viewing services. By interrogating all three samples before focusing specifically on India in more detail, it examines two tensions within the global expansion of online film and television distribution: between global trends and local infrastructures, and between the ideals of online viewing services and the grounded realities of their daily use

Binding to an unusual inactive kinase conformation by highly selective inhibitors of inositol-requiring enzyme 1a kinase-endoribonuclease

A series of imidazo[1,2-b]pyridazin-8-amine kinase inhibitors were discovered to allosterically inhibit the endoribonuclease function of the dual kinase-endoribonuclease inositol-requiring enzyme 1α (IRE1α), a key component of the unfolded protein response in mammalian cells and a potential drug target in multiple human diseases. Inhibitor optimization gave compounds with high kinome selectivity that prevented endoplasmic reticulum stress-induced IRE1α oligomerization and phosphorylation, and inhibited endoribonuclease activity in human cells. X-ray crystallography showed the inhibitors to bind to a previously unreported and unusually disordered conformation of the IRE1α kinase domain that would be incompatible with back-to-back dimerization of the IRE1α protein and activation of the endoribonuclease function. These findings increase the repertoire of known IRE1α protein conformations and can guide the discovery of highly selective ligands for the IRE1α kinase site that allosterically inhibit the endoribonuclease