No abstract

An anti-candidiasis glycoconjugate vaccine was prepared via a tyrosine-selective alkynylation and a click chemistry mediated glycoconjugation sequence. It features a well-defined glycan, protein carrier, and connectivity. The construct, although with significantly lower carbohydrate loading and a shorter b-(1,3) glucan chain than the well-established anti-candidiasis vaccine derived from the random conjugation of laminarin at lysines, elicited a comparable level of specific IgG antibodies.

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This study investigates firms' R&D cooperation behavior in a supply chain where two firms first cooperate in R&D investments and then decide the production quantity according to a wholesale price contract. By using a concept named contribution level that measures a firm's technological contribution to the R&D cooperation in the supply chain, we show that both firms can achieve win–win via cartelization only if their contribution levels are Pareto matched, i.e., when each firm's contribution level is comparable to its partner's. When spillovers are endogenized, we further establish that an increasing spillover always benefits both firms without any R&D cooperation, but only benefits the firm whose contribution level is relatively low when under R&D cartels. Finally, we show that the path of first increasing spillovers to be perfect and then forming a cartel has a higher chance of achieving the best mode in terms of profitability.

Blockade of the hERG potassium channel prolongs the ventricular action potential (AP) and QT interval, and triggers early after depolarizations (EADs) and torsade de pointes (TdP) arrhythmia. Opinions differ as to the causal relationship between hERG blockade and TdP, the relative weighting of other contributing factors, definitive metrics of preclinical proarrhythmicity, and the true safety margin in humans. Here, we have used in silico techniques to characterize the effects of channel gating and binding kinetics on hERG occupancy, and of blockade on the human ventricular AP. Gating effects differ for compounds that are sterically compatible with closed channels (becoming trapped in deactivated channels) versus those that are incompatible with the closed/closing state, and expelled during deactivation. Occupancies of trappable blockers build to equilibrium levels, whereas those of non-trappable blockers build and decay during each AP cycle. Occupancies of ~83% (non-trappable) versus ~63% (trappable) of open/inactive channels caused EADs in our AP simulations. Overall, we conclude that hERG occupancy at therapeutic exposure levels may be tolerated for nontrappable, but not trappable blockers capable of building to the proarrhythmic occupancy level. Furthermore, the widely used Redfern safety index may be biased toward trappable blockers, overestimating the exposure-IC50 separation in nontrappable cases.