39 research outputs found
High strain-rate material model validation for laser peening simulation
Finite element modeling can be a powerful tool for predicting residual stresses induced by laser peening; however the sign and magnitude of the stress predictions depend strongly on how the material model captures the high strain rate response. Although a Johnson-Cook formulation is often employed, its suitability for modeling phenomena at very high strain rates has not been rigorously evaluated. In this paper, we address the effectiveness of the Johnson-Cook model, with parameters developed from lower strain rate material data (∼10^3 s^–1), to capture the higher strain rate response (∼10^5–10^6 s^–1) encountered during the laser peening process. Published Johnson-Cook parameters extracted from split Hopkinson bar testing were used to predict the shock response of aluminum samples during high-impact flyer plate tests. Additional quasi-static and split Hopkinson bar tests were also conducted to study the model response in the lower strain rate regime. The overall objective of the research was to ascertain whether a material model based on conventional test data (quasi-static compression testing and split Hopkinson bar measurements) can credibly be used in FE simulations to predict laser peen-induced stresses
Weaker HLA footprints on HIV in the unique and highly genetically admixed host population of Mexico
HIV circumvents HLA class I-restricted CD8+ T-cell responses through selection of escape mutations that leave characteristic mutational “footprints,” also known as HLA-associated polymorphisms (HAPs), on HIV sequences at the population level. While many HLA footprints are universal across HIV subtypes and human populations, others can be region specific as a result of the unique immunogenetic background of each host population. Using a published probabilistic phylogenetically informed model, we compared HAPs in HIV Gag and Pol (PR-RT) in 1,612 subtype B-infected, antiretroviral treatment-naive individuals from Mexico and 1,641 individuals from Canada/United States. A total of 252 HLA class I allele subtypes were represented, including 140 observed in both cohorts, 67 unique to Mexico, and 45 unique to Canada/United States. At the predefined statistical threshold of a q value of <0.2, 358 HAPs (201 in Gag, 157 in PR-RT) were identified in Mexico, while 905 (534 in Gag and 371 in PR-RT) were identified in Canada/United States. HAPs identified in Mexico included both canonical HLA-associated escape pathways and novel associations, in particular with HLA alleles enriched in Amerindian and mestizo populations. Remarkably, HLA footprints on HIV in Mexico were not only fewer but also, on average, significantly weaker than those in Canada/United States, although some exceptions were noted. Moreover, exploratory analyses suggested that the weaker HLA footprint on HIV in Mexico may be due, at least in part, to weaker and/or less reproducible HLA-mediated immune pressures on HIV in this population. The implications of these differences for natural and vaccine-induced anti-HIV immunity merit further investigation
Transition density of states (TDOS) of the Si(100)2 × 1 surface derived from the L2,3VV Auger lineshape compared with cluster calculations
Evaluation of the mutagenic effects of SV40 in mouse, hamster, and mouse-human hybrid cells
We have examined the ability of SV40 to induce changes in drug or temperature resistance in mouse, hamster, and mouse-human hybrid cells. SV40 induced a substantial increase of cells resistant to 5-bromodeoxyuridine + trifluorothymidine in Balb/c 3T3 cells and induced an increase of hybrid cells resistant to 6-thioguanine. SV40 was found to be nonmutagenic or weakly mutagenic in other test systems. The 3T3 cells were T-antigen positive, exhibited a marked reduction in TK activity, were heterogeneous for [ 3 H]BrdU incorporation by autoradiography, and exhibited instability of the drug-resistance phenotype, suggesting that SV40 may be inducing resistance by an epigenetic process. SV40-induced 6-thioguanine resistance in the hybrids appears to occur predominantly by chromosome loss.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45539/1/11188_2005_Article_BF01233058.pd
Correlates of protective cellular immunity revealed by analysis of population-level immune escape pathways in HIV-1
HLA class I-associated polymorphisms identified at the population level mark viral sites under immune pressure by individual HLA alleles. As such, analysis of their distribution, frequency, location, statistical strength, sequence conservation, and other properties offers a unique perspective from which to identify correlates of protective cellular immunity. We analyzed HLA-associated HIV-1 subtype B polymorphisms in 1,888 treatment-naïve, chronically infected individuals using phylogenetically informed methods and identified characteristics of HLA-associated immune pressures that differentiate protective and nonprotective alleles. Over 2,100 HLA-associated HIV-1 polymorphisms were identified, approximately one-third of which occurred inside or within 3 residues of an optimally defined cytotoxic T-lymphocyte (CTL) epitope. Differential CTL escape patterns between closely related HLA alleles were common and increased with greater evolutionary distance between allele group members. Among 9-mer epitopes, mutations at HLA-specific anchor residues representedthe most frequently detected escape type: these occurred nearly 2-fold more frequently than expected by chance and were computationally predicted to reduce peptide-HLA binding nearly 10-fold on average. Characteristics associated with protective HLA alleles (defined using hazard ratios for progression to AIDS from natural history cohorts) included the potential to mount broad immune selection pressures across all HIV-1 proteins except Nef, the tendency to drive multisite and/or anchor residue escape mutations within known CTL epitopes, and the ability to strongly select mutations in conserved regions within HIV's structural and functional proteins. Thus, the factors defining protective cellular immune responsesmay be more complex than simply targeting conserved viral regions. The results provide new information to guide vaccine design and immunogenicity studies
Uncommon pathways of immune escape attenuate HIV-1 integrase replication capacity
An attenuation of the HIV-1 replication capacity (RC) has been observed for immune-mediated escape mutations in Gag restricted by protective HLA alleles. However, the extent to which escape mutations affect other viral proteins during natural infection is not well understood. We generated recombinant viruses encoding plasma HIV-1 RNA integrase sequences from antiretroviral-naive individuals with early (n = 88) and chronic (n = 304) infections and measured the in vitro RC of each. In contrast to data from previous studies of Gag, we observed little evidence that host HLA allele expression was associated with integrase RC. A modest negative correlation was observed between the number of HLA-B-associated integrase polymorphisms and RC in chronic infection (R = -0.2; P = 0.003); however, this effect was not driven by mutations restricted by protective HLA alleles. Notably, the integrase variants S119R, G163E, and I220L, which represent uncommon polymorphisms associated with HLA-C*05, -A*33, and -B*52, respectively, correlated with lower RC (all q < 0.2). We identified a novel C*05-restricted epitope (HTDNGSNF(114-121)) that likely contributes to the selection of the S119R variant, the polymorphism most significantly associated with lower RC in patient sequences. An NL4-3 mutant encoding the S119R polymorphism displayed a similar to 35%-reduced function that was rescued by a single compensatory mutation of A91E. Together, these data indicate that substantial HLA-driven attenuation of integrase is not a general phenomenon during HIV-1 adaptation to host immunity. However, uncommon polymorphisms selected by HLA alleles that are not conventionally regarded to be protective may be associated with impaired protein function. Vulnerable epitopes in integrase might therefore be considered for future vaccine strategies
HIV-1 residues under strong functional constraint are predicted by measures of evolutionary rather than population-level genetic conservation
No abstract availabl
HLA-associated mutations occur less frequently in HIV elite controllers than in chronically infected individuals
Background: HIV elite controllers (EC) are a rare group of persons who spontaneously control plasma viral load (pVL) to less than 50 RNA copies/ml without antiretroviral treatment. Mechanisms responsible for viral control remain unknown, but cytotoxic T lymphocytes (CTL) are believed to play a crucial role. CTL pressure can select for HLA-associated escape mutations, but a comprehensive analysis of the frequency of CTL escape mutations in EC has not been done.
Methods: A previously described list of HLA-associated polymorphisms in HIV subtype B, which represent likely CTL escape mutations, was used to compare the frequency of these polymorphisms in plasma viral sequences from EC and untreated chronic individuals. HLA-associated mutations in 54 Gag, 41 RT and 39 Nef sequences from EC were compared with 567 Gag, 531 RT, and 686 Nef sequences from chronic individuals. Statistical analyses were conducted using the Mann-Whitney U test.
Results: HLA alleles enriched among EC were associated with more HLA-associated polymorphisms in Gag (p ¼ 0.001), particularly in the p24 protein. Despite having undetectable pVL, HLAassociated polymorphisms were commonly observed in plasma virus from EC, but the proportion of HLA-associated codons exhibiting escape was significantly lower in EC than in chronic patients for Gag (0.375 vs 0.500; p < 0.001), RT (0.308 vs 0.400; p < 0.001) and Nef (0.421 vs 0.533; p < 0.001). Significant differences in the frequency of HLA-associated polymorphisms were seen for A*03, A*30, B*15, B*27, Cw*06 and Cw*07 in Gag, and for B*57, Cw*07 and Cw*12 in Nef.
Conclusion: These results indicate that HLA-associated polymorphisms are common in plasma viral sequences from EC, but are significantly less frequent during controlled than chronic infection. Larger studies of EC viruses will be necessary to examine the role of particular HLA-associated mutations in control of HIV viremia