Biomedical subjects

Derek J Smith

Publications and source records attributed to Derek J Smith.

9 recordsLinked to original sources

PubMed2025

Near real-time data on the human neutralizing antibody landscape to influenza virus to inform vaccine-strain selection in September 2025.

The hemagglutinin of human influenza virus evolves rapidly to erode neutralizing antibody immunity. Twice per year, new vaccine strains are selected with the goal of providing maximum protection against the viruses that will be circulating when the vaccine is administered ~8-12 months in the future. To help inform this selection, here we quantify how the antibodies in recently collected human sera neutralize viruses with hemagglutinins from contemporary influenza strains. Specifically, we use a high-throughput sequencing-based neutralization assay to measure how 188 human sera collected from Oct 2024 to April 2025 neutralize 140 viruses representative of the H3N2 and H1N1 strains circulating in humans as of the summer of 2025. This data set, which encompasses 26,148 neutralization titer measurements, provides a detailed portrait of the current human neutralizing antibody landscape to influenza A virus. The full data set and accompanying visualizations are available for use in vaccine development and viral forecasting.

Journal Article↗

PubMed2006

The 1.8 A resolution structure of hydroxycinnamoyl-coenzyme A hydratase-lyase (HCHL) from Pseudomonas fluorescens, an enzyme that catalyses the transformation of feruloyl-coenzyme A to vanillin.

The crystal structure of hydroxycinnamoyl-CoA hydratase-lyase (HCHL) from Pseudomonas fluorescens AN103 has been solved to 1.8 A resolution. HCHL is a member of the crotonase superfamily and catalyses the hydration of the acyl-CoA thioester of ferulic acid [3-(4-hydroxy-3-methoxy-phenyl)prop-2-enoic acid] and the subsequent retro-aldol cleavage of the hydrated intermediate to yield vanillin (4-hydroxy-3-methoxy-benzaldehyde). The structure contains 12 molecules in the asymmetric unit, in which HCHL assumes a hexameric structure of two stacked trimers. The substrate, feruloyl-CoA, was modelled into the active site based on the structure of enoyl-CoA hydratase bound to the feruloyl-CoA-like substrate 4-(N,N-dimethylamino)-cinnamoyl-CoA (PDB code 1ey3). Feruloyl-CoA was bound in this model between helix 3 of the A subunit and helix 9 of the B subunit. A highly ordered structural water in the HCHL structure coincided with the thioester carbonyl of feruloyl-CoA in the model, suggesting that the oxyanion hole for stabilization of a thioester-derived enolate, characteristic of coenzyme-A dependent members of the crotonase superfamily, is conserved. The model also suggested that a strong hydrogen bond between the phenolic hydroxyl groups of feruloyl-CoA and BTyr239 may be an important determinant of the enzyme's ability to discriminate between the natural substrate and cinnamoyl-CoA, which is not a substrate.

Acyl Coenzyme A↗

PubMed2006

The crystal structure of superoxide dismutase from Plasmodium falciparum.

BACKGROUND: Superoxide dismutases (SODs) are important enzymes in defence against oxidative stress. In Plasmodium falciparum, they may be expected to have special significance since part of the parasite life cycle is spent in red blood cells where the formation of reactive oxygen species is likely to be promoted by the products of haemoglobin breakdown. Thus, inhibitors of P. falciparum SODs have potential as anti-malarial compounds. As a step towards their development we have determined the crystal structure of the parasite's cytosolic iron superoxide dismutase. RESULTS: The cytosolic iron superoxide dismutase from P. falciparum (PfFeSOD) has been overexpressed in E. coli in a catalytically active form. Its crystal structure has been solved by molecular replacement and refined against data extending to 2.5 A resolution. The structure reveals a two-domain organisation and an iron centre in which the metal is coordinated by three histidines, an aspartate and a solvent molecule. Consistent with ultracentrifugation analysis the enzyme is a dimer in which a hydrogen bonding lattice links the two active centres. CONCLUSION: The tertiary structure of PfFeSOD is very similar to those of a number of other iron-and manganese-dependent superoxide dismutases, moreover the active site residues are conserved suggesting a common mechanism of action. Comparison of the dimer interfaces of PfFeSOD with the human manganese-dependent superoxide dismutase reveals a number of differences, which may underpin the design of parasite-selective superoxide dismutase inhibitors.

Amino Acid Sequence↗

PubMed2006

Predictability and preparedness in influenza control.

The threat of pandemic human influenza looms as we survey the ongoing avian influenza pandemic and wonder if and when it will jump species. What are the risks and how can we plan? The nub of the problem lies in the inherent variability of the virus, which makes prediction difficult. However, it is not impossible; mathematical models can help determine and quantify critical parameters and thresholds in the relationships of those parameters, even if the relationships are nonlinear and obscure to simple reasoning. Mathematical models can derive estimates for the levels of drug stockpiles needed to buy time, how and when to modify vaccines, whom to target with vaccines and drugs, and when to enforce quarantine measures. Regardless, the models used for pandemic planning must be tested, and for this we must continue to gather data, not just for exceptional scenarios but also for seasonal influenza.

Antigenic Variation↗

PubMed2004

Preferential hydration and the exclusion of cosolvents from protein surfaces.

Protein stability is enhanced by the addition of osmolytes, such as sugars and polyols and inert crowders, such as polyethylene glycols. This stability enhancement has been quantified by the preferential hydration parameter which can be determined by experiments. To understand the mechanism of protein stability enhancement, we present a statistical mechanical analysis of the preferential hydration parameter based upon Kirkwood-Buff theory. Previously, the preferential hydration parameter was interpreted in terms of the number of hydration waters, as well as the cosolvent exclusion volume. It was not clear how accurate these interpretations were, nor what the relationship is between the two. By using the Kirkwood-Buff theory and experimental data, we conclude that the contribution from the cosolvent exclusion dominantly determines the preferential hydration parameters for crowders. For osmolytes, although the cosolvent exclusion largely determines the preferential hydration parameters, the contribution from hydration may not be negligible.

Computer Simulation↗

PubMed2004

Mapping the antigenic and genetic evolution of influenza virus.

The antigenic evolution of influenza A (H3N2) virus was quantified and visualized from its introduction into humans in 1968 to 2003. Although there was remarkable correspondence between antigenic and genetic evolution, significant differences were observed: Antigenic evolution was more punctuated than genetic evolution, and genetic change sometimes had a disproportionately large antigenic effect. The method readily allows monitoring of antigenic differences among vaccine and circulating strains and thus estimation of the effects of vaccination. Further, this approach offers a route to predicting the relative success of emerging strains, which could be achieved by quantifying the combined effects of population level immune escape and viral fitness on strain evolution.

Amino Acid Substitution↗

PubMed2004

Recognition of homo- and heterosubtypic variants of influenza A viruses by human CD8+ T lymphocytes.

In the present study, the recognition of epitope variants of influenza A viruses by human CTL was investigated. To this end, human CD8(+) CTL clones, specific for natural variants of the HLA-B*3501-restricted epitope in the nucleoprotein (NP(418-426)), were generated. As determined in (51)Cr release assays and by flow cytometry with HLA-B*3501-peptide tetrameric complexes, CTL clones were found to be specific for epitopes within one subtype or cross-reactive with heterosubtypic variants of the epitope. Using eight natural variants of the epitope, positions in the 9-mer important for T cell recognition and involved in escape from CTL immunity were identified and visualized using multidimensional scaling. It was shown that positions 4 and 5 in the 9-mer epitope were important determinants of T cell specificity. The in vivo existence of CD8(+) cells cross-reactive with homo- and heterosubtypic variants of the epitope was further confirmed using polyclonal T cell populations obtained after stimulation of PBMC with different influenza A viruses. Based on the observed recognition patterns of the clonal and polyclonal T cell populations and serology, it is hypothesized that consecutive infections with influenza viruses containing different variants of the epitope select for cross-reactive T cells in vivo.

Adult↗

PubMed2003

Applications of bioinformatics and computational biology to influenza surveillance and vaccine strain selection.

In recent years, collaborations often between mathematical and computational biologists and scientists in the World Health Organization (WHO) global influenza surveillance network, have resulted in a number of mathematical and computational advances including: increasing the resolution at which antigenic surveillance data can be analyzed, providing methods for genetic analysis and prediction, and an increased understanding of the determinants of repeated influenza vaccination. These advances increase the information extracted from influenza surveillance and increase the quantitative data available for the vaccine strain selection process. This mathematical and computational work is possible because of the wealth of information collected over many years by the WHO global influenza surveillance network, and further advances will be greatly facilitated by implementation of the proposed strengthening of virological and epidemiological surveillance in the WHO global agenda on influenza surveillance and control.

Computational Biology↗

PubMed2003

Mutations in the DNA mismatch repair proteins MutS and MutL of oxazolidinone-resistant or -susceptible Enterococcus faecium.

Mutations in mutS and mutL, which encode DNA mismatch repair (MMR) proteins, can confer hypermutator phenotypes and may facilitate the emergence of mutational antibiotic resistance in bacteria. Linezolid-resistant enterococci (LRE) rarely emerge during therapy and contain mutations in 23S rRNA genes. As enterococci with defective MMR could be prone to the development of oxazolidinone resistance mutations, we investigated 13 clinical isolates of Enterococcus faecium, including 2 LRE, for mutations in mutSL. A 4,944-bp fragment spanning mutSL was sequenced from two pairs of linezolid-resistant (MICs, 64 micro g/ml) and linezolid-susceptible (MICs, 2 micro g/ml) E. faecium isolates (one pair from Austria and one pair from the United Kingdom) identical by pulsed-field gel electrophoresis. The pairs represented distinct strains in which linezolid resistance had emerged during therapy. The MutSL peptides of all four isolates had amino acid substitutions compared with the sequence of E. faecium strain DO (used for genome sequencing). These were Val352Ile (one pair of isolates only) and Met628Leu in MutS and Leu387Pro, Tyr406Phe, Thr415Ser, Phe427Leu, and Phe565Ile in MutL. The significance of these changes remains unknown; these isolates did not show a demonstrable hypermutator phenotype. The same substitutions were found in two of nine geographically diverse linezolid-susceptible enterococcal isolates; the other seven isolates had MutSL sequences identical to that of strain DO. Multilocus sequence typing revealed that all isolates with alternate MutSL peptides belonged to a distinct lineage of a prevalent E. faecium clonal complex, designated CC17. Further studies are needed to investigate the prevalence of these MutSL mutations and their possible roles in the emergence of E. faecium strains resistant to oxazolidinones and other antibiotic classes.

Acetamides↗