Emerging therapeutic treatments based on the production of proteins by delivering mRNA have become increasingly important in recent times. While lipid nanoparticles (LNPs) are approved vehicles for small interfering RNA delivery, there are still challenges to use this formulation for mRNA delivery. LNPs are typically a mixture of a cationic lipid, distearoylphosphatidylcholine (DSPC), cholesterol, and a PEG-lipid. The structural characterization of mRNA-containing LNPs (mRNA-LNPs) is crucial for a full understanding of the way in which they function, but this information alone is not enough to predict their fate upon entering the bloodstream. The biodistribution and cellular uptake of LNPs are affected by their surface composition as well as by the extracellular proteins present at the site of LNP administration, e.g., apolipoproteinE (ApoE). ApoE, being responsible for fat transport in the body, plays a key role in the LNP’s plasma circulation time. In this work, we use small-angle neutron scattering, together with selective lipid, cholesterol, and solvent deuteration, to elucidate the structure of the LNP and the distribution of the lipid components in the absence and the presence of ApoE. While DSPC and cholesterol are found to be enriched at the surface of the LNPs in buffer, binding of ApoE induces a redistribution of the lipids at the shell and the core, which also impacts the LNP internal structure, causing release of mRNA. The rearrangement of LNP components upon ApoE incubation is discussed in terms of potential relevance to LNP endosomal escape.

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This paper addresses the development of effective heuristics for solving the vehicle routing and scheduling problem with time window constraints. Both tour construction and local search tour improvement heuristics are developed. A major premise of the paper is that embedding global tour improvement procedures within the tour construction process can lead to improved solutions. Computational results are reported on test problems from the literature as well as real world applications. The hybrid construction/improvement heuristic is more effective in reducing vehicle fleet size requirements than previously reported heuristics.

Communities in many parts of the world, especially in developing countries, face obstacles in supplying continuous water to household consumers. Authorities often cite water scarcity as the cause, but we demonstrate that environmental constraints constitute only one aspect of a multi-dimensional problem. By asking what causes intermittent domestic water supply, this literature review (129 articles) identifies 47 conditions of intermittent systems and the causal-consequential pathways between them that can reinforce intermittency. These pathways span several disciplines including engineering, government administration and anthropology, and when viewed together they (1) emphasize the human drivers of intermittency; (2) suggest generalized interventions; and (3) reveal a gap in the literature in terms of meaningful categorizations of the reliability of intermittent supplies. Based on the reliability of consumers' water access, we propose three categories of intermittency-predictable, irregular, and unreliable-to facilitate comparisons between case studies and transfers of solutions.

This paper examines a routing design probZem i n which