11 research outputs found

    Increasing the Potency and Breadth of an HIV Antibody by Using Structure-Based Rational Design

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    Antibodies against the CD4 binding site (CD4bs) on the HIV-1 spike protein gp120 can show exceptional potency and breadth. We determined structures of NIH45-46, a more potent clonal variant of VRC01, alone and bound to gp120. Comparisons with VRC01-gp120 revealed that a four-residue insertion in heavy chain complementarity–determining region 3 (CDRH3) contributed to increased interaction between NIH45-46 and the gp120 inner domain, which correlated with enhanced neutralization. We used structure-based design to create NIH45-46^(G54W), a single substitution in CDRH2 that increases contact with the gp120 bridging sheet and improves breadth and potency, critical properties for potential clinical use, by an order of magnitude. Together with the NIH45-46–gp120 structure, these results indicate that gp120 inner domain and bridging sheet residues should be included in immunogens to elicit CD4bs antibodies

    Econometric Forecasting

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    Several principles are useful for econometric forecasters: keep the model simple, use all the data you can get, and use theory (not the data) as a guide to selecting causal variables. But theory gives little guidance on dynamics, that is, on which lagged values of the selected variables to use. Early econometric models failed in comparison with extrapolative methods because they paid too little attention to dynamic structure. In a fairly simple way, the vector autoregression (VAR) approach that first appeared in the 1980s resolved the problem by shifting emphasis towards dynamics and away from collecting many causal variables. The VAR approach also resolves the question of how to make long-term forecasts where the causal variables themselves must be forecast. When the analyst does not need to forecast causal variables or can use other sources, he or she can use a single equation with the same dynamic structure. Ordinary least squares is a perfectly adequate estimation method. Evidence supports estimating the initial equation in levels, whether the variables are stationary or not. We recommend a general-to-specific model-building strategy: start with a large number of lags in the initial estimation, although simplifying by reducing the number of lags pays off. Evidence on the value of further simplification is mixed. If cointegration among variables, then error-correction models (ECMs) will do worse than equations in levels. But ECMs are only sometimes an improvement eve
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