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The site is located close to the fusion peptide and slightly hidden within the trimer interface but is distant from the epitope of major stalk-neutralizing mAbs. Our data suggests that the polymorphism has no major impact on binding or neutralization by human stalk-reactive antibodies and might be related to changing HA fusion activity.
Standardness and standard automorphisms of Chevalley groups, I: the case of rank at least two
Therefore, the selective pressure on this site might not be directly related to the human antibody response. While our stringent selection analyses uncovered fewer results than previous work, it was also more selective than those done previously 39 , 41 , 44 , 45 , 46 , We chose to look at sites that had a high number of polymorphisms at a given amino acid, not including those undergoing periodic evolution or abrupt fixation.
Choosing this type of selection method allowed for the evaluation of overall flexibility in the hemagglutinin head and stalk domains, and was a suitable complement to the evolutionary analyses that would evaluate how well the domains adapt to antibody pressures In any case, the analysis conducted here is based on virus sequences from the past. Any predictions about stalk evolution under enhanced pressure from anti-stalk immunity based on this data would therefore be speculation. However, the tolerance of the stalk domain to changes has been recently tested experimentally with two independent systems which either introduce five amino acid insertions or random mutations 44 , 45 , While the two experimental setups were radically different they both came to the conclusion that the stalk domain is highly intolerant of changes.
This might be explained by the function of the stalk during virus replication, where this domain completely refolds to induce fusion of viral and host endosomal membranes. The sequences were downloaded as a FASTA file containing: accession number, sequence ID, country of origin, and date of collection for each sequence. Once downloaded, any sequences that had a passage number above 1 were removed, along with incomplete sequences. The data sets were then sorted by date and separated by year. The alignments were then manually optimized to remove the non-coding regions before and after the HA protein sequence It has been shown that passaging of virus isolates before sequencing can introduce signals of positive selection compared to non-passaged isolates We first looked at correlating the mean dN values for each codon between the two datasets and found a correlation coefficient of 0.
Preliminary maximum likelihood phylogenetic trees were generated with RAxML Datasets were subsequently screened to remove identical sequences where the oldest unique sequence was maintained for subsequent analyses. The temporal signal was investigated using the ML trees produced above with TempEst v1. Sequences that fell outside the residual spread of Exact date of isolation was used to calibrate the clock. A GMRF Bayesian Skyride coalescent tree prior was chosen 65 to account for oscillations in the demographic history of the viral populations.
To estimate domain specific rate variation we used a structurally informed evolutionary model where a nucleotide substitution patterns could be co-estimated for each conserved domain This approach allows the substitution rate to vary according to its protein structure rather than unrealistically assuming a single rate across the entire gene. The likelihood is jointly estimated for each domain, given a single tree The Bayesian simulation integrates the posterior likelihood across all possible trees to account for phylogenetic uncertainty.
A uniform prior was applied to the relative rate parameter ranging from 0 to 1E The MCMC was set to million generations sampled every 10, steps and repeated 4 times. The data was analyzed under the amino acid substitution model FLU 67 with a strict clock model since only a portion of the gene was analyzed. The amino acids were mapped onto the nucleotide trees and the amino acid substitution rates for each antigenic site or mAb was estimated from repeated sampling of this empirical tree space. This analysis was repeated three times, each time with a new set of randomly selected trees.
The MCMC was set to 1 million with a log every The three runs were combined and the AA substitution rate estimates summarized. The data sets were randomly sub-sampled by year, using a random number generator, so that the total number of sequences in each sub-sample was less than but also ensured a minimum of 20 sequences per year if available. This sub-sampling was done three times per data set and all three subsamples were used for selection analysis.
Each sub-sample was uploaded to Data Monkey with a respective maximum likelihood tree. This analysis was run on each sub-sampled set of sequences for each virus dataset.
Only positive selection sites detected in all three of the subsamples were included in the results. The experimental setup was similar to previously published work Plasmids encoding human mAbs were obtained from Dr. Patrick Wilson University of Chicago Antibody was generated by transfecting ExpiF cells and purifying cell culture supernatant using a protein G column Plaque reduction assays were conducted as described previously 71 , Then the infection media was removed and replaced with an agarose overlay containing 2X MEM, 6. Then the plaques were visualized using immunostaining.
First, cells were fixed with 3. Plaques were manually counted and compared to an irrelevant IgG control mAb plate to calculate percent inhibition of the virus by the antibody.
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The rescue viruses were then plaque purified, sequenced, and used in plaque reduction neutralization assays. Fusion assays were performed with purified virus. The HA activity of each virus preparation was determined in an HA assay. Briefly, virus preps were serially diluted in 0. All viruses were then diluted to HAUs for the fusion assays.
Then, 4 times the diluted virus volume of 0. Statistical analysis was conducted using Prism 6 GraphPad software. The conditional probabilities used in the Bayes Factor Test to determine significance of rate variation in the head and stalk regions were calculated with Microsoft Excel. The data that support the findings of this study have partially been uploaded to github as indicated above and are available from the corresponding author upon request. Cox, N.
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General (g) versus Specific (s) Intelligences
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http://www.russianhockeyfans.com/wp-includes/rencontre-a-nice.php Margine, I. Hemagglutinin stalk-based universal vaccine constructs protect against group 2 influenza A viruses. Chimeric hemagglutinin influenza virus vaccine constructs elicit broadly protective stalk-specific antibodies. Nachbagauer, R. Schultz-Cherry — Kallewaard, N. Paules, C. Sui, J.