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Background: Seasonally prevalent H1N1 and H3N2 influenza A viruses have evolved by antigenic drift; this evolution has resulted in the acquisition of asparagine (N)-linked glycosylation sites (NGSs) in the globular head of hemagglutinin (HA), thereby affecting the antigenic and receptor-binding properties, as well as virulence. An epidemiological survey indicated that although the traditional seasonal H1N1 strain had disappeared, H3N2 became predominant again in the seasons (2010-11 and 2011-12) immediately following the H1N1 pandemic of 2009. Interestingly, although the 2009 pandemic H1N1 strain (H1N1pdm09) lacks additional NGSs, clinically isolated H3N2 strains obtained during these seasons gained N (Asn) residues at positions 45 and 144 of HA that forms additional NGSs.Methods: To investigate whether these NGSs are associated with re-emergence of H3N2 within the subtype, we tested the effect of amino acid substitutions on neutralizing activity by using the antisera raised against H3N2 strains with or without additional NGSs. Furthermore, because the N residue at position 144 of HA was identified as the site of mismatch between the vaccine and epidemic strains of 2011-2012, we generated mutant viruses by reverse genetics and tested the functional importance of this particular NGS for antibody-mediated neutralization by intranasal inoculation of mice.Results: The results indicated that amino acid substitution at residue 144 significantly affected neutralization activity, acting as an escape mutation.Conclusions: Our data suggest that the newly acquired NGSs in the HA globular head may play an important role in the re-emergence of endemic seasonal H3N2 strain by aiding the escape from humoral immunity. [ABSTRACT FROM AUTHOR]

The BRCA-1 associated protein gene (BRAP) was recently identified as a susceptibility gene for myocardial infarction (MI). In the present study we aimed to decipher the association between the BRAP polymorphism and carotid atherosclerosis and the mechanism underlying its proatherogenic effect. A total of 1749 stroke/MI-free volunteers received carotid ultrasonic examinations for the measurement of intima-medial thickness (IMT) and plaque. The promoter polymorphism rs11066001 was selected because it affects the transcription of BRAP. We found that the GG genotype was associated with a 1.58-fold increased risk for having at least one plaque compared to carrying the A allele (P = 0.021). When subjects were divided by the cutoff value of IMT above the mean plus 1 standard deviation, there was an overrepresentation of the GG genotype in the subjects with thicker IMT (P = 0.004). The expression of BRAP increased significantly when human aortic smooth muscle cells (HASMCs) were treated with lipopolysaccharide (LPS). HASMCs were transfected with small interfering RNA against BRAP or scrambled sequences before treatment with LPS. Knockdown of BRAP led to attenuated HASMC proliferation and reduced secretion of monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8) in response to LPS. Downregulation of BRAP did not affect the protein levels of nuclear factor-κB (NF-κB), but prohibited its nuclear translocation. Coimmunoprecipitation experiments confirmed an interaction between BRAP and the two major components of the IKK signalosome, lκBβ and IKKβ. Collectively, BRAP conferred a risk for carotid plaque and IMT. Inflammatory stimuli upregulated BRAP expression, and BRAP activated inflammatory cascades by regulating NF-κB nuclear translocation. [ABSTRACT FROM AUTHOR]

Background: Seasonally prevalent H1N1 and H3N2 influenza A viruses have evolved by antigenic drift; this evolution has resulted in the acquisition of asparagine (N)-linked glycosylation sites (NGSs) in the globular head of hemagglutinin (HA), thereby affecting the antigenic and receptor-binding properties, as well as virulence. An epidemiological survey indicated that although the traditional seasonal H1N1 strain had disappeared, H3N2 became predominant again in the seasons (2010-11 and 2011-12) immediately following the H1N1 pandemic of 2009. Interestingly, although the 2009 pandemic H1N1 strain (H1N1pdm09) lacks additional NGSs, clinically isolated H3N2 strains obtained during these seasons gained N (Asn) residues at positions 45 and 144 of HA that forms additional NGSs., Methods: To investigate whether these NGSs are associated with re-emergence of H3N2 within the subtype, we tested the effect of amino acid substitutions on neutralizing activity by using the antisera raised against H3N2 strains with or without additional NGSs. Furthermore, because the N residue at position 144 of HA was identified as the site of mismatch between the vaccine and epidemic strains of 2011-2012, we generated mutant viruses by reverse genetics and tested the functional importance of this particular NGS for antibody-mediated neutralization by intranasal inoculation of mice., Results: The results indicated that amino acid substitution at residue 144 significantly affected neutralization activity, acting as an escape mutation., Conclusions: Our data suggest that the newly acquired NGSs in the HA globular head may play an important role in the re-emergence of endemic seasonal H3N2 strain by aiding the escape from humoral immunity.

The BRCA-1 associated protein gene (BRAP) was recently identified as a susceptibility gene for myocardial infarction (MI). In the present study we aimed to decipher the association between the BRAP polymorphism and carotid atherosclerosis and the mechanism underlying its proatherogenic effect. A total of 1749 stroke/MI-free volunteers received carotid ultrasonic examinations for the measurement of intima-medial thickness (IMT) and plaque. The promoter polymorphism rs11066001 was selected because it affects the transcription of BRAP. We found that the GG genotype was associated with a 1.58-fold increased risk for having at least one plaque compared to carrying the A allele (P = 0.021). When subjects were divided by the cutoff value of IMT above the mean plus 1 standard deviation, there was an overrepresentation of the GG genotype in the subjects with thicker IMT (P = 0.004). The expression of BRAP increased significantly when human aortic smooth muscle cells (HASMCs) were treated with lipopolysaccharide (LPS). HASMCs were transfected with small interfering RNA against BRAP or scrambled sequences before treatment with LPS. Knockdown of BRAP led to attenuated HASMC proliferation and reduced secretion of monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8) in response to LPS. Downregulation of BRAP did not affect the protein levels of nuclear factor-κB (NF-κB), but prohibited its nuclear translocation. Coimmunoprecipitation experiments confirmed an interaction between BRAP and the two major components of the IKK signalosome, IκBβ and IKKβ. Collectively, BRAP conferred a risk for carotid plaque and IMT. Inflammatory stimuli upregulated BRAP expression, and BRAP activated inflammatory cascades by regulating NF-κB nuclear translocation.

Background: The strong linkage disequilibrium (LD) recently found in genic or exonic regions of the human genome demonstrated that LD can be increased by evolutionary mechanisms that select for functionally important loci. This suggests that LD might be stronger in regions conserved among species than in non-conserved regions, since regions exposed to natural selection tend to be conserved. To assess this hypothesis, we used genome-wide polymorphism data from the HapMap project and investigated LD within DNA sequences conserved between the human and mouse genomes., Results: Unexpectedly, we observed that LD was significantly weaker in conserved regions than in non-conserved regions. To investigate why, we examined sequence features that may distort the relationship between LD and conserved regions. We found that interspersed repeats, and not other sequence features, were associated with the weak LD tendency in conserved regions. To appropriately understand the relationship between LD and conserved regions, we removed the effect of repetitive elements and found that the high degree of sequence conservation was strongly associated with strong LD in coding regions but not with that in non-coding regions., Conclusion: Our work demonstrates that the degree of sequence conservation does not simply increase LD as predicted by the hypothesis. Rather, it implies that purifying selection changes the polymorphic patterns of coding sequences but has little influence on the patterns of functional units such as regulatory elements present in non-coding regions, since the former are generally restricted by the constraint of maintaining a functional protein product across multiple exons while the latter may exist more as individually isolated units.