Analysis of the Contrasting Pathogenicities Induced by the D222G Mutation in 1918 and 2009 Pandemic Influenza A Viruses.

In 2009, the D222G mutation in the hemagglutinin (HA) glycoprotein of pandemic H1N1 influenza A virus was found to correlate with fatal and severe human infections. Previous static structural analysis suggested that, unlike the H1N1 viruses prevalent in 1918, the mutation did not compromise binding to human α2,6-linked glycan receptors, allowing it to transmit efficiently. Here we investigate the interconversion mechanism between two predicted binding modes in both 2009 and 1918 HAs, introducing a highly parallel intermediate network search scheme to construct kinetically relevant pathways efficiently. Accumulated mutations at positions 183 and 224 that alter the size of the binding pocket are identified with the fitness of the 2009 pandemic virus carrying the D222G mutation. This result suggests that the pandemic H1N1 viruses could gain binding affinity to the α2,3-linked glycan receptors in the lungs, usually associated with highly pathogenic avian influenza, without compromising viability.This work was supported by the ERC and the EPSRC.This is the final version of the article. It first appeared from ACS via http://pubs.acs.org/doi/abs/10.1021/ct5010565

Automatically Harnessing Sparse Acceleration

Sparse linear algebra is central to many scientific programs, yet compilers fail to optimize it well. High-performance libraries are available, but adoption costs are significant. Moreover, libraries tie programs into vendor-specific software and hardware ecosystems, creating non-portable code. In this paper, we develop a new approach based on our specification Language for implementers of Linear Algebra Computations (LiLAC). Rather than requiring the application developer to (re)write every program for a given library, the burden is shifted to a one-off description by the library implementer. The LiLAC-enabled compiler uses this to insert appropriate library routines without source code changes. LiLAC provides automatic data marshaling, maintaining state between calls and minimizing data transfers. Appropriate places for library insertion are detected in compiler intermediate representation, independent of source languages. We evaluated on large-scale scientific applications written in FORTRAN; standard C/C++ and FORTRAN benchmarks; and C++ graph analytics kernels. Across heterogeneous platforms, applications and data sets we show speedups of 1.1$\times$ to over 10$\times$ without user intervention.Comment: Accepted to CC 202

Research data supporting "Energy Landscapes and Persistent Minima"

Kinetic transition networks (databases of connected stationary points on the potential energy surface) for dialanine and tetraalanine peptides, the 38-atom Lennard-Jones cluster, a 60-atom binary Lennard-Jones mixture, a 69-bead model protein, binding modes for influenza virus, and a UUCG RNA tetraloop. These networks, obtained in previous work, are analysed here using topological persistence, to obtain subsets of local minima and hence a reduced description of the underlying energy landscape.This work was supported by the ERC [grant number 267369]

Virulence-Associated Substitution D222G in the Hemagglutinin of 2009 Pandemic Influenza A(H1N1) Virus Affects Receptor Binding

The clinical impact of the 2009 pandemic influenza A(H1N1) virus (pdmH1N1) has been relatively low. However, amino acid substitution D222G in the hemagglutinin of pdmH1N1 has been associated with cases of severe disease and fatalities. D222G was introduced in a prototype pdmH1N1 by reverse genetics, and the effect on virus receptor binding, replication, antigenic properties, and pathogenesis and transmission in animal models was investigated. pdmH1N1 with D222G caused ocular disease in mice without further indications of enhanced virulence in mice and ferrets. pdmH1N1 with D222G retained transmissibility via aerosols or respiratory droplets in ferrets and guinea pigs. The virus displayed changes in attachment to human respiratory tissues in vitro, in particular increased binding to macrophages and type II pneumocytes in the alveoli and to tracheal and bronchial submucosal glands. Virus attachment studies further indicated that pdmH1N1 with D222G acquired dual receptor specificity for complex alpha 2,3- and alpha 2,6-linked sialic acids. Molecular dynamics modeling of the hemagglutinin structure provided an explanation for the retention of alpha 2,6 binding. Altered receptor specificity of the virus with D222G thus affected interaction with cells of the human lower respiratory tract, possibly explaining the observed association with enhanced disease in human

Virulence-Associated Substitution D222G in the Hemagglutinin of 2009 Pandemic Influenza A(H1N1) Virus Affects Receptor Binding▿ ‡

The clinical impact of the 2009 pandemic influenza A(H1N1) virus (pdmH1N1) has been relatively low. However, amino acid substitution D222G in the hemagglutinin of pdmH1N1 has been associated with cases of severe disease and fatalities. D222G was introduced in a prototype pdmH1N1 by reverse genetics, and the effect on virus receptor binding, replication, antigenic properties, and pathogenesis and transmission in animal models was investigated. pdmH1N1 with D222G caused ocular disease in mice without further indications of enhanced virulence in mice and ferrets. pdmH1N1 with D222G retained transmissibility via aerosols or respiratory droplets in ferrets and guinea pigs. The virus displayed changes in attachment to human respiratory tissues in vitro, in particular increased binding to macrophages and type II pneumocytes in the alveoli and to tracheal and bronchial submucosal glands. Virus attachment studies further indicated that pdmH1N1 with D222G acquired dual receptor specificity for complex α2,3- and α2,6-linked sialic acids. Molecular dynamics modeling of the hemagglutinin structure provided an explanation for the retention of α2,6 binding. Altered receptor specificity of the virus with D222G thus affected interaction with cells of the human lower respiratory tract, possibly explaining the observed association with enhanced disease in humans

Analysis of the Contrasting Pathogenicities Induced by the D222G Mutation in 1918 and 2009 Pandemic Influenza A Viruses

This is the final version of the article. It first appeared from ACS via http://pubs.acs.org/doi/abs/10.1021/ct5010565.In 2009, the D222G mutation in the hemagglutinin (HA) glycoprotein of pandemic H1N1 influenza A virus was found to correlate with fatal and severe human infections. Previous static structural analysis suggested that, unlike the H1N1 viruses prevalent in 1918, the mutation did not compromise binding to human ?2,6-linked glycan receptors, allowing it to transmit efficiently. Here we investigate the interconversion mechanism between two predicted binding modes in both 2009 and 1918 HAs, introducing a highly parallel intermediate network search scheme to construct kinetically relevant pathways efficiently. Accumulated mutations at positions 183 and 224 that alter the size of the binding pocket are identified with the fitness of the 2009 pandemic virus carrying the D222G mutation. This result suggests that the pandemic H1N1 viruses could gain binding affinity to the ?2,3-linked glycan receptors in the lungs, usually associated with highly pathogenic avian influenza, without compromising viability.This work was supported by the ERC and the EPSRC