| 621. |
- Wang, Xinan, et al.
(författare)
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Impact of individual level uncertainty of lung cancer polygenic risk score (PRS) on risk stratification
- 2024
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Ingår i: Genome Medicine. - : BioMed Central (BMC). - 1756-994X .- 1756-994X. ; 16:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Although polygenic risk score (PRS) has emerged as a promising tool for predicting cancer risk from genome-wide association studies (GWAS), the individual-level accuracy of lung cancer PRS and the extent to which its impact on subsequent clinical applications remains largely unexplored.Methods: Lung cancer PRSs and confidence/credible interval (CI) were constructed using two statistical approaches for each individual: (1) the weighted sum of 16 GWAS-derived significant SNP loci and the CI through the bootstrapping method (PRS-16-CV) and (2) LDpred2 and the CI through posteriors sampling (PRS-Bayes), among 17,166 lung cancer cases and 12,894 controls with European ancestry from the International Lung Cancer Consortium. Individuals were classified into different genetic risk subgroups based on the relationship between their own PRS mean/PRS CI and the population level threshold.Results: Considerable variances in PRS point estimates at the individual level were observed for both methods, with an average standard deviation (s.d.) of 0.12 for PRS-16-CV and a much larger s.d. of 0.88 for PRS-Bayes. Using PRS-16-CV, only 25.0% of individuals with PRS point estimates in the lowest decile of PRS and 16.8% in the highest decile have their entire 95% CI fully contained in the lowest and highest decile, respectively, while PRS-Bayes was unable to find any eligible individuals. Only 19% of the individuals were concordantly identified as having high genetic risk (> 90th percentile) using the two PRS estimators. An increased relative risk of lung cancer comparing the highest PRS percentile to the lowest was observed when taking the CI into account (OR = 2.73, 95% CI: 2.12–3.50, P-value = 4.13 × 10−15) compared to using PRS-16-CV mean (OR = 2.23, 95% CI: 1.99–2.49, P-value = 5.70 × 10−46). Improved risk prediction performance with higher AUC was consistently observed in individuals identified by PRS-16-CV CI, and the best performance was achieved by incorporating age, gender, and detailed smoking pack-years (AUC: 0.73, 95% CI = 0.72–0.74). Conclusions: Lung cancer PRS estimates using different methods have modest correlations at the individual level, highlighting the importance of considering individual-level uncertainty when evaluating the practical utility of PRS.
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| 622. |
- Widemann, Thomas, et al.
(författare)
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Venus Evolution Through Time : Key Science Questions, Selected Mission Concepts and Future Investigations
- 2023
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Ingår i: Space Science Reviews. - : SPRINGER. - 0038-6308 .- 1572-9672. ; 219:7
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Forskningsöversikt (refereegranskat)abstract
- In this work we discuss various selected mission concepts addressing Venus evolution through time. More specifically, we address investigations and payload instrument concepts supporting scientific goals and open questions presented in the companion articles of this volume. Also included are their related investigations (observations & modeling) and discussion of which measurements and future data products are needed to better constrain Venus' atmosphere, climate, surface, interior and habitability evolution through time. A new fleet of Venus missions has been selected, and new mission concepts will continue to be considered for future selections. Missions under development include radar-equipped ESA-led EnVision M5 orbiter mission (European Space Agency 2021), NASA-JPL's VERITAS orbiter mission (Smrekar et al. 2022a), NASA-GSFC's DAVINCI entry probe/flyby mission (Garvin et al. 2022a). The data acquired with the VERITAS, DAVINCI, and EnVision from the end of this decade will fundamentally improve our understanding of the planet's long term history, current activity and evolutionary path. We further describe future mission concepts and measurements beyond the current framework of selected missions, as well as the synergies between these mission concepts, ground-based and space-based observatories and facilities, laboratory measurements, and future algorithmic or modeling activities that pave the way for the development of a Venus program that extends into the 2040s (Wilson et al. 2022).
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| 623. |
- Wojno, Jennifer, et al.
(författare)
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Chemical separation of disc components using RAVE
- 2016
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Ingår i: Monthly Notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 461:4, s. 4246-4255
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Tidskriftsartikel (refereegranskat)abstract
- We present evidence from the RAdial Velocity Experiment (RAVE) survey of chemically separated, kinematically distinct disc components in the solar neighbourhood.We apply probabilistic chemical selection criteria to separate our sample into a-low ('thin disc') and a-high ('thick disc') sequences. Using newly derived distances,which will be utilized in the upcoming RAVE DR5, we explore the kinematic trends as a function of metallicity for each of the disc components. For our a-low disc, we find a negative trend in the mean rotational velocity (Vf) as a function of iron abundance ([Fe/H]). We measure a positive gradient ∂Vφ/∂[Fe/H] for the a-high disc, consistent with results from high-resolution surveys.We also find differences between the a-low and a-high discs in all three components of velocity dispersion.We discuss the implications of an a-low, metal-rich population originating from the inner Galaxy, where the orbits of these stars have been significantly altered by radial mixing mechanisms in order to bring them into the solar neighbourhood. The probabilistic separation we propose can be extended to other data sets for which the accuracy in [a/Fe] is not sufficient to disentangle the chemical disc components a priori. For such data sets which will also have significant overlap with Gaia DR1, we can therefore make full use of the improved parallax and proper motion data as it becomes available to investigate kinematic trends in these chemical disc components.
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| 624. |
- Wojno, Jennifer, et al.
(författare)
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The selection function of the RAVE survey
- 2017
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Ingår i: Monthly Notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 468:3, s. 3368-3380
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Tidskriftsartikel (refereegranskat)abstract
- We characterize the selection function of RAdial Velocity Experiment (RAVE) using 2 Micron All Sky Survey (2MASS) as our underlying population, which we assume represents all stars that could have potentially been observed.We evaluate the completeness fraction as a function of position, magnitude and colour in two ways: first, on a field-by-field basis, and second, in equal-size areas on the sky. Then, we consider the effect of the RAVE stellar parameter pipeline on the final resulting catalogue, which in principle limits the parameter space over which our selection function is valid. Our final selection function is the product of the completeness fraction and the selection function of the pipeline. We then test if the application of the selection function introduces biases in the derived parameters. To do this, we compare a parent mock catalogue generated using GALAXIA with a mock-RAVE catalogue where the selection function of RAVE has been applied. We conclude that for stars brighter than I = 12, between 4000 < Teff < 8000K and 0.5 < log g < 5.0, RAVE is kinematically and chemically unbiased with respect to expectations from GALAXIA.
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| 625. |
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Women and Gender in Ancient Religions : Interdisciplinary Approaches
- 2010. - 1st
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Samlingsverk (redaktörskap) (övrigt vetenskapligt/konstnärligt)abstract
- Following a scholarly conference given in honor of Adela Yarbro Collins, this collection of essays offers focused studies on the wide range of ways that women and gender contribute to the religious landscape of the ancient world. Experts in Greek and Roman religions, Early Christianity, Ancient Judaism, and Ancient Christianity engage in literary, social, historical, and cultural analysis of various ancient texts, inscriptions, social phenomena, and cultic activity. These studies continue the welcomed trend in scholarship that expands the social location of women in ancient Mediterranean religion to include the public sphere and consciousness. The result is an important and lively book that deepens the understanding of ancient religion as a whole. With contributions by:Patricia D. Ahearne-Kroll, Loveday Alexander, Mary Rose D'Angelo, Stephen J. Davis, Robert Doran, Radcliffe G. Edmonds III, Carin M. C. Green, Fritz Graf, Jan Willem van Henten, Paul A. Holloway, Annette B. Huizenga, Jeremy F. Hultin, Sarah Iles Johnston, James A. Kelhoffer, Judith L. Kovacs, Outi Lehtipuu, Matt Jackson-McCabe, Candida R. Moss, Christopher N. Mount, Susan E. Myers, Clare K. Rothschild, Turid Karlsen Seim.
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| 626. |
- Zeden, Merve S., et al.
(författare)
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Metabolic reprogramming and altered cell envelope characteristics in a pentose phosphate pathway mutant increases MRSA resistance to β-lactam antibiotics
- 2023
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Ingår i: PLoS Pathogens. - : Public Library of Science (PLoS). - 1553-7366 .- 1553-7374. ; 19:7
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Tidskriftsartikel (refereegranskat)abstract
- Central metabolic pathways control virulence and antibiotic resistance, and constitute potential targets for antibacterial drugs. In Staphylococcus aureus the role of the pentose phosphate pathway (PPP) remains largely unexplored. Mutation of the 6-phosphogluconolactonase gene pgl, which encodes the only non-essential enzyme in the oxidative phase of the PPP, significantly increased MRSA resistance to β-lactam antibiotics, particularly in chemically defined media with physiologically-relevant concentrations of glucose, and reduced oxacillin (OX)-induced lysis. Expression of the methicillin-resistance penicillin binding protein 2a and peptidoglycan architecture were unaffected. Carbon tracing and metabolomics revealed extensive metabolic reprogramming in the pgl mutant including increased flux to glycolysis, the TCA cycle, and several cell envelope precursors, which was consistent with increased β-lactam resistance. Morphologically, pgl mutant cells were smaller than wild-type with a thicker cell wall and ruffled surface when grown in OX. The pgl mutation reduced resistance to Congo Red, sulfamethoxazole and oxidative stress, and increased resistance to targocil, fosfomycin and vancomycin. Levels of lipoteichoic acids (LTAs) were significantly reduced in pgl, which may limit cell lysis, while the surface charge of pgl cells was significantly more positive. A vraG mutation in pgl reversed the increased OX resistance phenotype, and partially restored wild-type surface charge, but not LTA levels. Mutations in vraF or graRS from the VraFG/GraRS complex that regulates DltABCD-mediated d-alanylation of teichoic acids (which in turn controls β-lactam resistance and surface charge), also restored wild-type OX susceptibility. Collectively these data show that reduced levels of LTAs and OX-induced lysis combined with a VraFG/GraRS-dependent increase in cell surface positive charge are accompanied by significantly increased OX resistance in an MRSA pgl mutant.
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| 627. |
- Zhang, Ruyang, et al.
(författare)
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A Large-Scale Genome-Wide Gene-Gene Interaction Study of Lung Cancer Susceptibility in Europeans With a Trans-Ethnic Validation in Asians
- 2022
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Ingår i: Journal of Thoracic Oncology. - : Elsevier. - 1556-0864 .- 1556-1380. ; 17:8, s. 974-990
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Although genome-wide association studies have been conducted to investigate genetic variation of lung tumorigenesis, little is known about gene-gene (G × G) interactions that may influence the risk of non-small cell lung cancer (NSCLC).Methods: Leveraging a total of 445,221 European-descent participants from the International Lung Cancer Consortium OncoArray project, Transdisciplinary Research in Cancer of the Lung and UK Biobank, we performed a large-scale genome-wide G × G interaction study on European NSCLC risk by a series of analyses. First, we used BiForce to evaluate and rank more than 58 billion G × G interactions from 340,958 single-nucleotide polymorphisms (SNPs). Then, the top interactions were further tested by demographically adjusted logistic regression models. Finally, we used the selected interactions to build lung cancer screening models of NSCLC, separately, for never and ever smokers.Results: With the Bonferroni correction, we identified eight statistically significant pairs of SNPs, which predominantly appeared in the 6p21.32 and 5p15.33 regions (e.g., rs521828C6orf10 and rs204999PRRT1, ORinteraction = 1.17, p = 6.57 × 10−13; rs3135369BTNL2 and rs2858859HLA-DQA1, ORinteraction = 1.17, p = 2.43 × 10−13; rs2858859HLA-DQA1 and rs9275572HLA-DQA2, ORinteraction = 1.15, p = 2.84 × 10−13; rs2853668TERT and rs62329694CLPTM1L, ORinteraction = 0.73, p = 2.70 × 10−13). Notably, even with much genetic heterogeneity across ethnicities, three pairs of SNPs in the 6p21.32 region identified from the European-ancestry population remained significant among an Asian population from the Nanjing Medical University Global Screening Array project (rs521828C6orf10 and rs204999PRRT1, ORinteraction = 1.13, p = 0.008; rs3135369BTNL2 and rs2858859HLA-DQA1, ORinteraction = 1.11, p = 5.23 × 10−4; rs3135369BTNL2 and rs9271300HLA-DQA1, ORinteraction = 0.89, p = 0.006). The interaction-empowered polygenetic risk score that integrated classical polygenetic risk score and G × G information score was remarkable in lung cancer risk stratification.Conclusions: Important G × G interactions were identified and enriched in the 5p15.33 and 6p21.32 regions, which may enhance lung cancer screening models.
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