Germline mutations within DNA-repair genes are implicated in susceptibility to multiple forms of cancer. For prostate cancer (PrCa), rare mutations in BRCA2 and BRCA1 give rise to moderately elevated ...risk, whereas two of B100 common, low-penetrance PrCa susceptibility variants identified so far by genome-wide association studies implicate RAD51B and RAD23B.
Genotype data from the iCOGS array were imputed to the 1000 genomes phase 3 reference panel for 21 780 PrCa cases and 21 727 controls from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium. We subsequently performed single variant, gene and pathway-level analyses using 81 303 SNPs within 20 Kb of a panel of 179 DNA-repair genes.
Single SNP analyses identified only the previously reported association with RAD51B. Gene-level analyses using the SKAT-C test from the SNP-set (Sequence) Kernel Association Test (SKAT) identified a significant association with PrCa for MSH5. Pathway-level analyses suggested a possible role for the translesion synthesis pathway in PrCa risk and Homologous recombination/Fanconi Anaemia pathway for PrCa aggressiveness, even though after adjustment for multiple testing these did not remain significant.
MSH5 is a novel candidate gene warranting additional follow-up as a prospective PrCa-risk locus. MSH5 has previously been reported as a pleiotropic susceptibility locus for lung, colorectal and serous ovarian cancers.
The diversity of HIV-1 is a confounding problem for vaccine design, as the human immune response appears to favor poor or strain-specific responses to any given HIV-1 virus strain. A significant ...portion of this diversity is manifested as sequence variability in the loops of HIV-1's surface envelope glycoprotein. Here we show that the most variable sequence positions in the third variable (V3) loop crown cluster to a small zone on the surface of one face of the V3 loop ss-hairpin conformation. These results provide a novel visualization of the gp120 V3 loop, specifically demonstrating a surprising preponderance of conserved three-dimensional structure in a highly sequence-variable region. From a structural point of view, there appears to be less diversity in this region of the HIV-1 "principle neutralizing domain" than previously appreciated.
A study found that late angiographic follow-up after Palmaz-Schatz stent implantation revealed continued patency of stented segments six months after the procedure.
The antigenic diversity of HIV-1 has long been an obstacle to vaccine design, and this diversity is especially pronounced in the V3 loop of the virus' surface envelope glycoprotein. Both sequence and ...structure vary between HIV strains in V3, but the molecular context of this variation is unclear. We developed a positional amino acid (AA) variability score and mapped sequence variability pattern on to the 3D structure of V3. The most variable positions were found to cluster to a small zone on the surface of one face of the V3 loop β-hairpin conformation. Furthermore, we ranked the breadth of neutralization for 7 monoclonal antibodies (mAbs) targeting known V3 epitopes and mapped the locations of these epitopes on the V3 structure. Comparison to the sequence variability map showed that the less broadly neutralizing mAbs engage the small variable zone, while broadly neutralizing mAbs avoid engaging this zone. Additionally, we developed a new structural analysis technique for dynamic antigenic viral segments like the V3 loop crown that we term 4D structural analysis by ab initio folding. In each of 3 test cases, 4D structural analysis by ab initio folding has been capable of detecting differences in flexibility and conformational preference between phenotypically different sets of V3 loop crowns. These differences could not have been detected by sequence analysis or crystallography. In each case, the results suggested viable new hypotheses that are in line with previously generated immunologic and virologic data. A complete 4D structural and antigenic picture of the V3 loop was thus achieved by our work, an advance that can be used to guide rational design of new anti-V3 HIV vaccines.
Epitopes, also known as antigenic determinants, are small clusters of specific atoms within macromolecules that are recognized by the immune system. Such epitopes can be targeted with vaccines ...designed to protect against specific pathogens. The third variable loop (V3 loop) of the HIV-1 pathogen's gp120 surface envelope glycoprotein can be a highly sensitive neutralization target. We derived sequence motifs for the V3 loop epitopes recognized by the human monoclonal antibodies (mAbs) 447-52D and 2219. Searching the HIV database for the occurrence of each epitope motif in worldwide viruses and correcting the results based on published WHO epidemiology reveal that the 447-52D epitope we defined occurs in 13% of viruses infecting patients worldwide: 79% of subtype B viruses, 1% of subtype C viruses, and 7% of subtype A/AG sequences. In contrast, the epitope we characterized for human anti-V3 mAb 2219 is present in 30% of worldwide isolates but is evenly distributed across the known HIV-1 subtypes: 48% of subtype B strains, 40% of subtype C, and 18% of subtype A/AG. Various assays confirmed that the epitopes corresponding to these motifs, when expressed in the SF162 Env backbone, were sensitively and specifically neutralized by the respective mAbs. The method described here is capable of accurately determining the worldwide occurrence and subtype distribution of any crystallographically resolved HIV-1 epitope recognized by a neutralizing antibody, which could be useful for multivalent vaccine design. More importantly, these calculations demonstrate that globally relevant, structurally conserved epitopes are present in the sequence variable V3 loop.
Abstract – This paper investigates the physical features that affect the learning process of students within the lecture halls in the Bahen centre. The impacts of any drawbacks or shortcomings due to ...structural design of the Bahen building on students’ learning qualities are considered. Primary research including physical measurements and opinion surveys of students and professors comprise the basis of discussion. Results indicate that a number of lecture halls do not meet the University's classroom design standards. Tutorial rooms fare better by design-standards but a lack of electrical access ignores the growing dependency on computers in the classrooms. The authors discuss a set of identified issues – from obstructed viewing angles to damaged accessibility equipment, and list recommendations to address learning challenges. Implementing some of the recommendation will require trivial effort, while future educational structures for others may be considered.
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