HIV-1 evades antibody-mediated neutralization through conformational masking of receptor-binding sites

The ability of human immunodeficiency virus (HIV-1) to persist and cause AIDS is dependent on its avoidance of antibody-mediated neutralization. The virus elicits abundant, envelope-directed antibodies that have little neutralization capacity. This lack of neutralization is paradoxical, given the functional conservation and exposure of receptor-binding sites on the gp120 envelope glycoprotein, which are larger than the typical antibody footprint and should therefore be accessible for antibody binding. Because gp120-receptor interactions involve conformational reorganization, we measured the entropies of binding for 20 gp120-reactive antibodies. Here we show that recognition by receptor-binding-site antibodies induces conformational change. Correlation with neutralization potency and analysis of receptor-antibody thermodynamic cycles suggested a receptor-binding-site 'conformational masking' mechanism of neutralization escape. To understand how such an escape mechanism would be compatible with virus-receptor interactions, we tested a soluble dodecameric receptor molecule and found that it neutralized primary HIV-1 isolates with great potency, showing that simultaneous binding of viral envelope glycoproteins by multiple receptors creates sufficient avidity to compensate for such masking. Because this solution is available for cell-surface receptors but not for most antibodies, conformational masking enables HIV-1 to maintain receptor binding and simultaneously to resist neutralization.     

K-modes Clustering

0 norm (defined as the limit of an L_p norm as p approaches zero). In Monte Carlo simulations, both K-modes and the latent class procedures (e.g., Goodman 1974) performed with equal efficiency in recovering a known underlying cluster structure. However, K-modes is an order of magnitude faster than the latent class procedure in speed and suffers from fewer problems of local optima than do the latent class procedures. For data sets involving a large number of categorical variables, latent class procedures become computationally extremly slow and hence infeasible. We conjecture that, although in some cases latent class procedures might perform better than K-modes, it could out-perform latent class procedures in other cases. Hence, we recommend that these two approaches be used as "complementary" procedures in performing cluster analysis. We also present an empirical comparison of K-modes and latent class, where the former method prevails.     

Revisiting the enzymes stored in the laticifers of Carica papaya in the context of their possible participation in the plant defence mechanism

In the tropical species Carica papaya, the articulated and anastomosing laticifers form a dense network of vessels displayed in all aerial parts of the plant. Damaging the papaya tree inevitably severs its laticifers, eliciting an abrupt release of latex. Besides the well-known cysteine proteinases, papain, chymopapain, caricain and glycyl endopeptidase, papaya latex is also a rich source of other enzymes. Together, these enzymes could provide an important contribution to plant defence mechanisms by sanitising and sealing the wounded areas on the tree.     

Seasonality in large-scale macroeconometric models

Macroeconomic indicators are typically appraised in seasonally adjusted form, and forecasts are often presented in a similar way (as annual changes, for example). Moreover, the quarterly macroeconomic models used in forecasting are commonly estimated from seasonally adjusted data. Nevertheless, these models can generate forecasts with seasonal patterns, and this paper assesses the cause and cure of this phenomenon. It is found that forecast seasonality is induced by seasonality in the various inputs: exogenous variables, residual adjustments, the dynamic specification of certain equations, and annual changes in policy variables. Series changing annually but observed quarterly are termed ‘intercalated series’, and are simple examples of periodic processes. Forecast seasonality can be removed by appropriate adjustment of all these inputs. Models containing explicit future expectations variables solved in a model-consistent manner are also considered: numerical sensitivity to the terminal quarter may result from terminal conditions that require adjustment when seasonality is present.     

Rings of negatively charged amino acids determine the acetylcholine receptor channel conductance

The structure-function relationship of the nicotinic acetylcholine receptor (AChR) has been effectively studied by the combination of complementary DNA manipulation and single-channel current analysis. Previous work with chimaeras between the Torpedo californica and bovine AChR delta-subunits has shown that the region comprising the hydrophobic segment M2 and its vicinity contains an important determinant of the rate of ion transport through the AChR channel. It has also been suggested that this region is responsible for the reduction in channel conductance caused by divalent cations and that segment M2 contributes to the binding site of noncompetitive antagonists. To identify those amino acid residues that interact with permeating ions, we have introduced various point mutations into the Torpedo AChR subunit cDNAs to alter the net charge of the charged or glutamine residues around the proposed transmembrane segments. The single-channel conductance properties of these AChR mutants expressed in Xenopus laevis oocytes indicate that three clusters of negatively charged and glutamine residues neighbouring segment M2 of the alpha-, beta-, gamma- and delta-subunits, probably forming three anionic rings, are major determinants of the rate of ion transport.