Macromolecules, e.g., proteins, can enter the brain by vesicular transport, i.e., transcytosis, but this route is highly selective and actively suppressed by recently identified homeostatic mechanisms 5, 6. Most of them, however, including therapeutics, show negligible brain uptake due to rapid outward transport by efflux pumps to the bloodstream 3, 4. Diffusion of molecules across BECs is possible but restricted to low-molecular-weight hydrophobic compounds. The paracellular entry of molecules from the blood to the brain is barred by junctional complexes between adjoining brain endothelial cells (BEC) 2. The blood-brain barrier (BBB) is impermeable to most blood-borne substances, protecting the fragile brain environment from potentially harmful insults 1. Thus, post-capillary venules are the point-of-least resistance at the BBB, and compared to capillaries, provide a more feasible route for nanoparticle drug carriers into the brain. The vascular location of nanoparticle brain entry corresponds to the presence of perivascular space, which facilitates nanoparticle movement after transcytosis. The nanoparticles move unobstructed within endothelium, but transcytosis-mediated brain entry occurs mainly at post-capillary venules, and is negligible in capillaries. We show that transferrin receptor-targeted liposome nanoparticles are sequestered by the endothelium at capillaries and venules, but not at arterioles. Here, using two-photon microscopy in mice, we characterize the receptor-mediated transcytosis of nanoparticles at all steps of delivery to the brain in vivo. However, nanoparticle drug carriers explored for this purpose show negligible brain uptake, and the lack of basic understanding of nanoparticle-BBB interactions underlies many translational failures. This book guides decision-makers as they incorporate trust and social cohesion into the comprehensive reforms needed to address the region's most pernicious challenges.Effective treatments of neurodegenerative diseases require drugs to be actively transported across the blood-brain barrier (BBB). The good news is that governments can increase citizen trust with clearer promises of what citizens can expect from them, public sector reforms that enable them to keep their promises, and institutional reforms that strengthen the commitments that citizens make to each other. It keeps citizens from demanding better public services and infrastructure, from joining with others to control corruption, and from making the collective sacrifices that leave everyone better off. Mistrust distorts democratic decision-making. Trust inside private and public sector organizations is essential for collaboration and innovation. It suppresses growth and innovation: investment, entrepreneurship, and employment all flourish when firms and government, workers and employers, banks and borrowers, and consumers and producers trust each other. The economic and political consequences of mistrust ripple through society. Whether in others, in government, or in firms, trust is lower in the region than anywhere else in the world. Trust is the most pressing and yet least discussed problem confronting Latin America and the Caribbean.
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