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18
نتائج ل
"Radford, M. P. (Mark P.)"
صنف حسب:
Genome-wide association meta-analyses combining multiple risk phenotypes provide insights into the genetic architecture of cutaneous melanoma susceptibility
Most genetic susceptibility to cutaneous melanoma remains to be discovered. Meta-analysis genome-wide association study (GWAS) of 36,760 cases of melanoma (67% newly genotyped) and 375,188 controls identified 54 significant (P < 5 × 10
) loci with 68 independent single nucleotide polymorphisms. Analysis of risk estimates across geographical regions and host factors suggests the acral melanoma subtype is uniquely unrelated to pigmentation. Combining this meta-analysis with GWAS of nevus count and hair color, and transcriptome association approaches, uncovered 31 potential secondary loci for a total of 85 cutaneous melanoma susceptibility loci. These findings provide insights into cutaneous melanoma genetic architecture, reinforcing the importance of nevogenesis, pigmentation and telomere maintenance, together with identifying potential new pathways for cutaneous melanoma pathogenesis.
Journal Article
Genome-wide meta-analysis identifies five new susceptibility loci for cutaneous malignant melanoma
Thirteen common susceptibility loci have been reproducibly associated with cutaneous malignant melanoma (CMM). We report the results of an international 2-stage meta-analysis of CMM genome-wide association studies (GWAS). This meta-analysis combines 11 GWAS (5 previously unpublished) and a further three stage 2 data sets, totaling 15,990 CMM cases and 26,409 controls. Five loci not previously associated with CMM risk reached genome-wide significance (P < 5 × 10(-8)), as did 2 previously reported but unreplicated loci and all 13 established loci. Newly associated SNPs fall within putative melanocyte regulatory elements, and bioinformatic and expression quantitative trait locus (eQTL) data highlight candidate genes in the associated regions, including one involved in telomere biology.
Journal Article
Instability, unfolding and aggregation of human lysozyme variants underlying amyloid fibrillogenesis
Tissue deposition of soluble proteins as amyloid fibrils underlies a range of fatal diseases. The two naturally occurring human lysozyme variants are both amyloidogenic, and are shown here to be unstable. They aggregate to form amyloid fibrils with transformation of the mainly helical native fold, observed in crystal structures, to the amyloid fibril cross-beta fold. Biophysical studies suggest that partly folded intermediates are involved in fibrillogenesis, and this may be relevant to amyloidosis generally.
Journal Article
Perturbing the folding energy landscape of the bacterial immunity protein Im7 by site-specific N-linked glycosylation
N-linked glycosylation modulates protein folding and stability through a variety of mechanisms. As such there is considerable interest in the development of general rules to predict the structural consequences of site-specific glycosylation and to understand how these effects can be exploited in the design and development of modified proteins with advantageous properties. In this study, expressed protein ligation is used to create site-specifically glycosylated variants of the bacterial immunity protein Im7 modified with the chitobiose disaccharide (GlcNAc-GlcNAc). Glycans were introduced at seven solvent exposed sites within the Im7 sequence and the kinetic and thermodynamic consequences of N-linked glycosylation analyzed. The ΔΔG° values for glycan incorporation were found to range from +5.2 to -3.8 kJ·mol⁻¹. In several cases, glycosylation influences folding by modulating the local conformational preferences of the glycosylated sequence. These locally mediated effects are most prominent in the center of α-helices where glycosylation negatively effects folding and in compact turn motifs between segments of ordered secondary structure where glycosylation promotes folding and enhances the overall stability of the native protein. The studies also provide insight into why glycosylation is commonly identified at the transition between different types of secondary structure and when glycosylation may be used to elaborate protein structure to protect disordered sequences from proteolysis or immune system recognition.
Journal Article
Overlapping genetic architecture between Parkinson disease and melanoma
Epidemiologic studies have reported inconsistent results regarding an association between Parkinson disease (PD) and cutaneous melanoma (melanoma). Identifying shared genetic architecture between these diseases can support epidemiologic findings and identify common risk genes and biological pathways. Here, we apply polygenic, linkage disequilibrium-informed methods to the largest available case–control, genome-wide association study summary statistic data for melanoma and PD. We identify positive and significant genetic correlation (correlation: 0.17, 95% CI 0.10–0.24;
P
= 4.09 × 10
−06
) between melanoma and PD. We further demonstrate melanoma and PD-inferred gene expression to overlap across tissues (correlation: 0.14, 95% CI 0.06 to 0.22;
P
= 7.87 × 10
−04
) and highlight seven genes including
PIEZO1
,
TRAPPC2L
, and
SOX6
as potential mediators of the genetic correlation between melanoma and PD. These findings demonstrate specific, shared genetic architecture between PD and melanoma that manifests at the level of gene expression.
Journal Article
Impact of 2019-2020 mega-fires on Australian fauna habitat
Australia's 2019-2020 mega-fires were exacerbated by drought, anthropogenic climate change and existing land-use management. Here, using a combination of remotely sensed data and species distribution models, we found these fires burnt ~97,000 km
of vegetation across southern and eastern Australia, which is considered habitat for 832 species of native vertebrate fauna. Seventy taxa had a substantial proportion (>30%) of habitat impacted; 21 of these were already listed as threatened with extinction. To avoid further species declines, Australia must urgently reassess the extinction vulnerability of fire-impacted species and assist the recovery of populations in both burnt and unburnt areas. Population recovery requires multipronged strategies aimed at ameliorating current and fire-induced threats, including proactively protecting unburnt habitats.
Journal Article
Slavoj Žižek, Rex Libris, and the Traumatic Real
Purpose
– The purpose of this paper is to use the work of philosopher Slavoj Žižek to gain insights into representations of the librarian and the library in contemporary popular culture.
Design/methodology/approach
– A psycho-analytic reading of the comic book series Rex Libris using Slavoj Žižek’s treatment of Jacques Lacan.
Findings
– Žižek’s approach can provide novel and previously unconsidered insights into the understanding of librarian stereotypes in particular and representations of the library in general.
Research limitations/implications
– This paper is limited to the representations of the librarian and the library in one comic book series. Its findings need to be generalized to representations in other forms of popular culture.
Originality/value
– As far as the authors know, this is the only paper that has applied the work of Žižek in the library and information science (LIS) literature. As such, not only are the insights into the representations of librarians and libraries important, this paper also acts as a valuable introduction to the work of Žižek for the LIS community of scholars.
Journal Article
Novel pleiotropic risk loci for melanoma and nevus density implicate multiple biological pathways
The total number of acquired melanocytic nevi on the skin is strongly correlated with melanoma risk. Here we report a meta-analysis of 11 nevus GWAS from Australia, Netherlands, UK, and USA comprising 52,506 individuals. We confirm known loci including MTAP, PLA2G6, and IRF4, and detect novel SNPs in KITLG and a region of 9q32. In a bivariate analysis combining the nevus results with a recent melanoma GWAS meta-analysis (12,874 cases, 23,203 controls), SNPs near GPRC5A, CYP1B1, PPARGC1B, HDAC4, FAM208B, DOCK8, and SYNE2 reached global significance, and other loci, including MIR146A and OBFC1, reached a suggestive level. Overall, we conclude that most nevus genes affect melanoma risk (KITLG an exception), while many melanoma risk loci do not alter nevus count. For example, variants in TERC and OBFC1 affect both traits, but other telomere length maintenance genes seem to affect melanoma risk only. Our findings implicate multiple pathways in nevogenesis.
Journal Article
Correction to: Overlapping genetic architecture between Parkinson disease and melanoma
The original version of this article unfortunately contained a mistake. Supplementary Tables 3 and 4 are not available with the rest of the supplementary material available online.
Journal Article