The time dimension of neural network models

This review attempts to provide an insightful perspective on the role of time within neural network models and the use of neural networks for problems involving time. The most commonly used neural network models are defined and explained giving mention to important technical issues but avoiding great detail. The relationship between recurrent and feedforward networks is emphasised, along with the distinctions in their practical and theoretical abilities. Some practical examples are discussed to illustrate the major issues concerning the application of neural networks to data with various types of temporal structure, and finally some highlights of current research on the more difficult types of problems are presented

Optimal combinations of broadly neutralizing antibodies for prevention and treatment of HIV-1 clade C infection.

CAPRISA, 2016.Abstract available in PDF file

Genetic Signatures in the Envelope Glycoproteins of HIV-1 that Associate with Broadly Neutralizing Antibodies

A steady increase in knowledge of the molecular and antigenic structure of the gp120 and gp41 HIV-1 envelope glycoproteins (Env) is yielding important new insights for vaccine design, but it has been difficult to translate this information to an immunogen that elicits broadly neutralizing antibodies. To help bridge this gap, we used phylogenetically corrected statistical methods to identify amino acid signature patterns in Envs derived from people who have made potently neutralizing antibodies, with the hypothesis that these Envs may share common features that would be useful for incorporation in a vaccine immunogen. Before attempting this, essentially as a control, we explored the utility of our computational methods for defining signatures of complex neutralization phenotypes by analyzing Env sequences from 251 clonal viruses that were differentially sensitive to neutralization by the well-characterized gp120-specific monoclonal antibody, b12. We identified ten b12-neutralization signatures, including seven either in the b12-binding surface of gp120 or in the V2 region of gp120 that have been previously shown to impact b12 sensitivity. A simple algorithm based on the b12 signature pattern was predictive of b12 sensitivity/resistance in an additional blinded panel of 57 viruses. Upon obtaining these reassuring outcomes, we went on to apply these same computational methods to define signature patterns in Env from HIV-1 infected individuals who had potent, broadly neutralizing responses. We analyzed a checkerboard-style neutralization dataset with sera from 69 HIV-1-infected individuals tested against a panel of 25 different Envs. Distinct clusters of sera with high and low neutralization potencies were identified. Six signature positions in Env sequences obtained from the 69 samples were found to be strongly associated with either the high or low potency responses. Five sites were in the CD4-induced coreceptor binding site of gp120, suggesting an important role for this region in the elicitation of broadly neutralizing antibody responses against HIV-1

Recurrent Signature Patterns in HIV-1 B Clade Envelope Glycoproteins Associated with either Early or Chronic Infections

Here we have identified HIV-1 B clade Envelope (Env) amino acid signatures from early in infection that may be favored at transmission, as well as patterns of recurrent mutation in chronic infection that may reflect common pathways of immune evasion. To accomplish this, we compared thousands of sequences derived by single genome amplification from several hundred individuals that were sampled either early in infection or were chronically infected. Samples were divided at the outset into hypothesis-forming and validation sets, and we used phylogenetically corrected statistical strategies to identify signatures, systematically scanning all of Env. Signatures included single amino acids, glycosylation motifs, and multi-site patterns based on functional or structural groupings of amino acids. We identified signatures near the CCR5 co-receptor-binding region, near the CD4 binding site, and in the signal peptide and cytoplasmic domain, which may influence Env expression and processing. Two signatures patterns associated with transmission were particularly interesting. The first was the most statistically robust signature, located in position 12 in the signal peptide. The second was the loss of an N-linked glycosylation site at positions 413–415; the presence of this site has been recently found to be associated with escape from potent and broad neutralizing antibodies, consistent with enabling a common pathway for immune escape during chronic infection. Its recurrent loss in early infection suggests it may impact fitness at the time of transmission or during early viral expansion. The signature patterns we identified implicate Env expression levels in selection at viral transmission or in early expansion, and suggest that immune evasion patterns that recur in many individuals during chronic infection when antibodies are present can be selected against when the infection is being established prior to the adaptive immune response

An Investigation Of Exhaustive Learning

: An extended version of the Bayesian formalism is reviewed. We use this formalism to investigate the "exhaustive learning" scenario, first introduced by Schwartz et al. This scenario is perhaps the simplest possible supervised learning scenario. It is identical to the noise-free "Gibbs learning" scenario studied recently by Haussler et al., and can also be viewed as the zero-temperature limit of the "statistical mechanics" work of Tishby et al. We prove that the crucial "self-averaging " assumption invoked in the conventional analysis of exhaustive learning does not hold in the simplest non-trivial implementation of exhaustive learning. Therefore the central result of that analysis, that generalization accuracy necessarily rises as training set size is increased, is not generic. More importantly, we show that if one (reasonably) changes the definition of "generalization accuracy", to reflect only the error on inputs outside of the training set, then this central result does not hold e..