| 1. |
- Campbell, PJ, et al.
(författare)
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Pan-cancer analysis of whole genomes
- 2020
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 578:7793, s. 82-
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Tidskriftsartikel (refereegranskat)abstract
- Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale1–3. Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4–5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter4; identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation5,6; analyses timings and patterns of tumour evolution7; describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity8,9; and evaluates a range of more-specialized features of cancer genomes8,10–18.
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| 2. |
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| 3. |
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| 4. |
- Vogel, Jacob W., et al.
(författare)
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Four distinct trajectories of tau deposition identified in Alzheimer’s disease
- 2021
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Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 27:5, s. 871-881
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer’s disease (AD) is characterized by the spread of tau pathology throughout the cerebral cortex. This spreading pattern was thought to be fairly consistent across individuals, although recent work has demonstrated substantial variability in the population with AD. Using tau-positron emission tomography scans from 1,612 individuals, we identified 4 distinct spatiotemporal trajectories of tau pathology, ranging in prevalence from 18 to 33%. We replicated previously described limbic-predominant and medial temporal lobe-sparing patterns, while also discovering posterior and lateral temporal patterns resembling atypical clinical variants of AD. These ‘subtypes’ were stable during longitudinal follow-up and were replicated in a separate sample using a different radiotracer. The subtypes presented with distinct demographic and cognitive profiles and differing longitudinal outcomes. Additionally, network diffusion models implied that pathology originates and spreads through distinct corticolimbic networks in the different subtypes. Together, our results suggest that variation in tau pathology is common and systematic, perhaps warranting a re-examination of the notion of ‘typical AD’ and a revisiting of tau pathological staging. © 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.
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| 5. |
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| 6. |
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| 7. |
- Hibar, Derrek P., et al.
(författare)
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Novel genetic loci associated with hippocampal volume
- 2017
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (r(g) = -0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness.
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| 8. |
- Abdalla, E., et al.
(författare)
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Cosmology intertwined : A review of the particle physics, astrophysics, and cosmology associated with the cosmological tensions and anomalies
- 2022
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Ingår i: Journal of High Energy Astrophysics. - : Elsevier BV. - 2214-4048 .- 2214-4056. ; 34, s. 49-211
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Tidskriftsartikel (refereegranskat)abstract
- The standard Λ Cold Dark Matter (ΛCDM) cosmological model provides a good description of a wide range of astrophysical and cosmological data. However, there are a few big open questions that make the standard model look like an approximation to a more realistic scenario yet to be found. In this paper, we list a few important goals that need to be addressed in the next decade, taking into account the current discordances between the different cosmological probes, such as the disagreement in the value of the Hubble constant H0, the σ8–S8 tension, and other less statistically significant anomalies. While these discordances can still be in part the result of systematic errors, their persistence after several years of accurate analysis strongly hints at cracks in the standard cosmological scenario and the necessity for new physics or generalisations beyond the standard model. In this paper, we focus on the 5.0σ tension between the Planck CMB estimate of the Hubble constant H0 and the SH0ES collaboration measurements. After showing the H0 evaluations made from different teams using different methods and geometric calibrations, we list a few interesting new physics models that could alleviate this tension and discuss how the next decade's experiments will be crucial. Moreover, we focus on the tension of the Planck CMB data with weak lensing measurements and redshift surveys, about the value of the matter energy density Ωm, and the amplitude or rate of the growth of structure (σ8,fσ8). We list a few interesting models proposed for alleviating this tension, and we discuss the importance of trying to fit a full array of data with a single model and not just one parameter at a time. Additionally, we present a wide range of other less discussed anomalies at a statistical significance level lower than the H0–S8 tensions which may also constitute hints towards new physics, and we discuss possible generic theoretical approaches that can collectively explain the non-standard nature of these signals. Finally, we give an overview of upgraded experiments and next-generation space missions and facilities on Earth that will be of crucial importance to address all these open questions.
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| 9. |
- Satizabal, Claudia L., et al.
(författare)
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Genetic architecture of subcortical brain structures in 38,851 individuals
- 2019
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 51:11, s. 1624-
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Tidskriftsartikel (refereegranskat)abstract
- Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.
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| 10. |
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| 11. |
- Zhou, XP, et al.
(författare)
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Non-coding variability at the APOE locus contributes to the Alzheimer's risk
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 3310-
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer’s disease (AD) is a leading cause of mortality in the elderly. While the coding change of APOE-ε4 is a key risk factor for late-onset AD and has been believed to be the only risk factor in the APOE locus, it does not fully explain the risk effect conferred by the locus. Here, we report the identification of AD causal variants in PVRL2 and APOC1 regions in proximity to APOE and define common risk haplotypes independent of APOE-ε4 coding change. These risk haplotypes are associated with changes of AD-related endophenotypes including cognitive performance, and altered expression of APOE and its nearby genes in the human brain and blood. High-throughput genome-wide chromosome conformation capture analysis further supports the roles of these risk haplotypes in modulating chromatin states and gene expression in the brain. Our findings provide compelling evidence for additional risk factors in the APOE locus that contribute to AD pathogenesis.
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| 12. |
- Weiner, D. J., et al.
(författare)
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Polygenic transmission disequilibrium confirms that common and rare variation act additively to create risk for autism spectrum disorders
- 2017
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 49:7
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Tidskriftsartikel (refereegranskat)abstract
- Autism spectrum disorder (ASD) risk is influenced by common polygenic and de novo variation. We aimed to clarify the influence of polygenic risk for ASD and to identify subgroups of ASD cases, including those with strongly acting de novo variants, in which polygenic risk is relevant. Using a novel approach called the polygenic transmission disequilibrium test and data from 6,454 families with a child with ASD, we show that polygenic risk for ASD, schizophrenia, and greater educational attainment is over-transmitted to children with ASD. These findings hold independent of proband IQ. We find that polygenic variation contributes additively to risk in ASD cases who carry a strongly acting de novo variant. Lastly, we show that elements of polygenic risk are independent and differ in their relationship with phenotype. These results confirm that the genetic influences on ASD are additive and suggest that they create risk through at least partially distinct etiologic pathways.
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| 13. |
- Thompson, Paul M., et al.
(författare)
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The ENIGMA Consortium : large-scale collaborative analyses of neuroimaging and genetic data
- 2014
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Ingår i: BRAIN IMAGING BEHAV. - : Springer Science and Business Media LLC. - 1931-7557 .- 1931-7565. ; 8:2, s. 153-182
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Tidskriftsartikel (refereegranskat)abstract
- The Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium is a collaborative network of researchers working together on a range of large-scale studies that integrate data from 70 institutions worldwide. Organized into Working Groups that tackle questions in neuroscience, genetics, and medicine, ENIGMA studies have analyzed neuroimaging data from over 12,826 subjects. In addition, data from 12,171 individuals were provided by the CHARGE consortium for replication of findings, in a total of 24,997 subjects. By meta-analyzing results from many sites, ENIGMA has detected factors that affect the brain that no individual site could detect on its own, and that require larger numbers of subjects than any individual neuroimaging study has currently collected. ENIGMA's first project was a genome-wide association study identifying common variants in the genome associated with hippocampal volume or intracranial volume. Continuing work is exploring genetic associations with subcortical volumes (ENIGMA2) and white matter microstructure (ENIGMA-DTI). Working groups also focus on understanding how schizophrenia, bipolar illness, major depression and attention deficit/hyperactivity disorder (ADHD) affect the brain. We review the current progress of the ENIGMA Consortium, along with challenges and unexpected discoveries made on the way.
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| 14. |
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| 15. |
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| 16. |
- Sampson, Joshua N., et al.
(författare)
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Analysis of Heritability and Shared Heritability Based on Genome-Wide Association Studies for 13 Cancer Types
- 2015
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 107:12
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Tidskriftsartikel (refereegranskat)abstract
- Background: Studies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the additive effects of common single-nucleotide polymorphisms (SNPs) for cancer at 13 anatomical sites. Methods: Between 2007 and 2014, the US National Cancer Institute has generated data from genome-wide association studies (GWAS) for 49 492 cancer case patients and 34 131 control patients. We apply novel mixed model methodology (GCTA) to this GWAS data to estimate the heritability of individual cancers, as well as the proportion of heritability attributable to cigarette smoking in smoking-related cancers, and the genetic correlation between pairs of cancers. Results: GWAS heritability was statistically significant at nearly all sites, with the estimates of array-based heritability, h(l)(2), on the liability threshold (LT) scale ranging from 0.05 to 0.38. Estimating the combined heritability of multiple smoking characteristics, we calculate that at least 24% (95% confidence interval [CI] = 14% to 37%) and 7% (95% CI = 4% to 11%) of the heritability for lung and bladder cancer, respectively, can be attributed to genetic determinants of smoking. Most pairs of cancers studied did not show evidence of strong genetic correlation. We found only four pairs of cancers with marginally statistically significant correlations, specifically kidney and testes (rho = 0.73, SE = 0.28), diffuse large B-cell lymphoma (DLBCL) and pediatric osteosarcoma (rho = 0.53, SE = 0.21), DLBCL and chronic lymphocytic leukemia (CLL) (rho = 0.51, SE = 0.18), and bladder and lung (rho = 0.35, SE = 0.14). Correlation analysis also indicates that the genetic architecture of lung cancer differs between a smoking population of European ancestry and a nonsmoking Asian population, allowing for the possibility that the genetic etiology for the same disease can vary by population and environmental exposures. Conclusion: Our results provide important insights into the genetic architecture of cancers and suggest new avenues for investigation.
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| 17. |
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| 18. |
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| 19. |
- Deming, Yuetiva, et al.
(författare)
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Sex-specific genetic predictors of Alzheimer’s disease biomarkers
- 2018
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Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 136:6, s. 857-872
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Tidskriftsartikel (refereegranskat)abstract
- Cerebrospinal fluid (CSF) levels of amyloid-β 42 (Aβ42) and tau have been evaluated as endophenotypes in Alzheimer’s disease (AD) genetic studies. Although there are sex differences in AD risk, sex differences have not been evaluated in genetic studies of AD endophenotypes. We performed sex-stratified and sex interaction genetic analyses of CSF biomarkers to identify sex-specific associations. Data came from a previous genome-wide association study (GWAS) of CSF Aβ42 and tau (1527 males, 1509 females). We evaluated sex interactions at previous loci, performed sex-stratified GWAS to identify sex-specific associations, and evaluated sex interactions at sex-specific GWAS loci. We then evaluated sex-specific associations between prefrontal cortex (PFC) gene expression at relevant loci and autopsy measures of plaques and tangles using data from the Religious Orders Study and Rush Memory and Aging Project. In Aβ42, we observed sex interactions at one previous and one novel locus: rs316341 within SERPINB1 (p = 0.04) and rs13115400 near LINC00290 (p = 0.002). These loci showed stronger associations among females (β = − 0.03, p = 4.25 × 10−8; β = 0.03, p = 3.97 × 10−8) than males (β = − 0.02, p = 0.009; β = 0.01, p = 0.20). Higher levels of expression of SERPINB1, SERPINB6, and SERPINB9 in PFC was associated with higher levels of amyloidosis among females (corrected p values < 0.02) but not males (p > 0.38). In total tau, we observed a sex interaction at a previous locus, rs1393060 proximal to GMNC (p = 0.004), driven by a stronger association among females (β = 0.05, p = 4.57 × 10−10) compared to males (β = 0.02, p = 0.03). There was also a sex-specific association between rs1393060 and tangle density at autopsy (pfemale = 0.047; pmale = 0.96), and higher levels of expression of two genes within this locus were associated with lower tangle density among females (OSTN p = 0.006; CLDN16 p = 0.002) but not males (p ≥ 0.32). Results suggest a female-specific role for SERPINB1 in amyloidosis and for OSTN and CLDN16 in tau pathology. Sex-specific genetic analyses may improve understanding of AD’s genetic architecture.
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| 20. |
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| 21. |
- Namjou, Bahram, et al.
(författare)
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High-density genotyping of STAT4 reveals multiple haplotypic associations with systemic lupus erythematosus in different racial groups
- 2009
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Ingår i: Arthritis and Rheumatism. - : Wiley. - 0004-3591 .- 1529-0131. ; 60:4, s. 1085-1095
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Systemic lupus erythematosus (SLE) is the prototypical systemic autoimmune disorder, with complex etiology and a strong genetic component. Recently, gene products involved in the interferon pathway have been under intense investigation in terms of the pathogenesis of SLE. STAT-1 and STAT-4 are transcription factors that play key roles in the interferon and Th1 signaling pathways, making them attractive candidates for involvement in SLE susceptibility. METHODS: Fifty-six single-nucleotide polymorphisms (SNPs) across STAT1 and STAT4 on chromosome 2 were genotyped using the Illumina platform, as part of an extensive association study in a large collection of 9,923 lupus patients and control subjects from different racial groups. DNA samples were obtained from the peripheral blood of patients with SLE and control subjects. Principal components analyses and population-based case-control association analyses were performed, and the P values, false discovery rate q values, and odds ratios with 95% confidence intervals were calculated. RESULTS: We observed strong genetic associations with SLE and multiple SNPs located within STAT4 in different ethnic groups (Fisher's combined P = 7.02 x 10(-25)). In addition to strongly confirming the previously reported association in the third intronic region of this gene, we identified additional haplotypic association across STAT4 and, in particular, a common risk haplotype that is found in multiple racial groups. In contrast, only a relatively weak suggestive association was observed with STAT1, probably due to its proximity to STAT4. CONCLUSION: Our findings indicate that STAT4 is likely to be a crucial component in SLE pathogenesis in multiple racial groups. Knowledge of the functional effects of this association, when they are revealed, might improve our understanding of the disease and provide new therapeutic targets.
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| 22. |
- Hagimoto, Masato, et al.
(författare)
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Bright extragalactic ALMA redshift survey (BEARS) III: detailed study of emission lines from 71 Herschel targets
- 2023
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Ingår i: Monthly Notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 521:4, s. 5508-5535
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Tidskriftsartikel (refereegranskat)abstract
- We analyse the molecular and atomic emission lines of 71 bright Herschel-selected galaxies between redshifts 1.4 and 4.6 detected by the Atacama Large Millimeter/submillimeter Array. These lines include a total of 156 CO, [C i], and H2O emission lines. For 46 galaxies, we detect two transitions of CO lines, and for these galaxies we find gas properties similar to those of other dusty star-forming galaxy (DSFG) samples. A comparison to photodissociation models suggests that most of Herschel-selected galaxies have similar interstellar medium conditions as local infrared-luminous galaxies and high-redshift DSFGs, although with denser gas and more intense far-ultraviolet radiation fields than normal star-forming galaxies. The line luminosities agree with the luminosity scaling relations across five orders of magnitude, although the star formation and gas surface density distributions (i.e. Schmidt-Kennicutt relation) suggest a different star formation phase in our galaxies (and other DSFGs) compared to local and low-redshift gas-rich, normal star-forming systems. The gas-to-dust ratios of these galaxies are similar to Milky Way values, with no apparent redshift evolution. Four of 46 sources appear to have CO line ratios in excess of the expected maximum (thermalized) profile, suggesting a rare phase in the evolution of DSFGs. Finally, we create a deep stacked spectrum over a wide rest-frame frequency (220-890 GHz) that reveals faint transitions from HCN and CH, in line with previous stacking experiments.
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| 23. |
- Kelly, P. L., et al.
(författare)
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SN REFSDAL : CLASSIFICATION AS A LUMINOUS AND BLUE SN 1987A-LIKE TYPE II SUPERNOVA
- 2016
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Ingår i: Astrophysical Journal. - 0004-637X .- 1538-4357. ; 831:2
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Tidskriftsartikel (refereegranskat)abstract
- We have acquired Hubble Space Telescope (HST) and Very Large Telescope near-infrared spectra and images of supernova (SN) Refsdal after its discovery as an Einstein cross in fall 2014. The HST light curve of SN Refsdal has a shape consistent with the distinctive, slowly rising light curves of SN. 1987A-like SNe, and we find strong evidence for a broad H alpha P-Cygni profile and Na I D absorption in the HST grism spectrum at the redshift (z = 1.49) of the spiral host galaxy. SNe. IIn, largely powered by circumstellar interaction, could provide a good match to the light curve of SN Refsdal, but the spectrum of a SN IIn would not show broad and strong H alpha and Na I D absorption. From the grism spectrum, we measure an H alpha expansion velocity consistent with those of SN. 1987A-like SNe at a similar phase. The luminosity, evolution, and Gaussian profile of the H alpha emission of the WFC3 and X-shooter spectra, separated by similar to 2.5 months in the rest frame, provide additional evidence that supports the SN. 1987A-like classification. In comparison with other examples of SN. 1987A-like SNe, photometry of SN Refsdal favors bluer B - V and V - R colors and one of the largest luminosities for the assumed range of potential magnifications. The evolution of the light curve at late times will provide additional evidence about the potential existence of any substantial circumstellar material. Using MOSFIRE and X-shooter spectra, we estimate a subsolar host-galaxy metallicity (8.3 +/- 0.1 dex and <8.4 dex, respectively) near the explosion site.
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| 24. |
- Abeysekara, A. U., et al.
(författare)
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A Luminous and Isolated Gamma-Ray Flare from the Blazar B2 1215+30
- 2017
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Ingår i: Astrophysical Journal. - : Institute of Physics Publishing (IOPP). - 0004-637X .- 1538-4357. ; 836:2
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Tidskriftsartikel (refereegranskat)abstract
- B2 1215+30 is a BL-Lac-type blazar that was first detected at TeV energies by the MAGIC atmospheric Cherenkov telescopes and subsequently confirmed by the Very Energetic Radiation Imaging Telescope Array System (VERITAS) observatory with data collected between 2009 and 2012. In 2014 February 08, VERITAS detected a large-amplitude flare from B2. 1215+30 during routine monitoring observations of the blazar 1ES. 1218+304, located in the same field of view. The TeV flux reached 2.4 times the Crab Nebula flux with a variability timescale of <3.6 hr. Multiwavelength observations with Fermi-LAT, Swift, and the Tuorla Observatory revealed a correlated high GeV flux state and no significant optical counterpart to the flare, with a spectral energy distribution where the gamma-ray luminosity exceeds the synchrotron luminosity. When interpreted in the framework of a onezone leptonic model, the observed emission implies a high degree of beaming, with Doppler factor delta > 10, and an electron population with spectral index p < 2.3.
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| 25. |
- Aliu, E., et al.
(författare)
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Constraints on Very High Energy Emission from GRB 130427A
- 2014
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Ingår i: Astrophysical Journal Letters. - 2041-8205 .- 2041-8213. ; 795:1
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Tidskriftsartikel (refereegranskat)abstract
- Prompt emission from the very fluent and nearby (z = 0.34) gamma-ray burst GRB 130427A was detected by several orbiting telescopes and by ground-based, wide-field-of-view optical transient monitors. Apart from the intensity and proximity of this GRB, it is exceptional due to the extremely long-lived high-energy (100 MeV to 100 GeV) gamma-ray emission, which was detected by the Large Area Telescope on the Fermi Gamma-Ray Space Telescope for ~70 ks after the initial burst. The persistent, hard-spectrum, high-energy emission suggests that the highest-energy gamma rays may have been produced via synchrotron self-Compton processes though there is also evidence that the high-energy emission may instead be an extension of the synchrotron spectrum. VERITAS, a ground-based imaging atmospheric Cherenkov telescope array, began follow-up observations of GRB 130427A ~71 ks (~20 hr) after the onset of the burst. The GRB was not detected with VERITAS; however, the high elevation of the observations, coupled with the low redshift of the GRB, make VERITAS a very sensitive probe of the emission from GRB 130427A for E > 100 GeV. The non-detection and consequent upper limit derived place constraints on the synchrotron self-Compton model of high-energy gamma-ray emission from this burst.
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| 26. |
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| 27. |
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| 28. |
- Hammond, Mark, et al.
(författare)
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Two-dimensional Eclipse Mapping of the Hot-Jupiter WASP-43b with JWST MIRI/LRS
- 2024
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Ingår i: Astronomical Journal. - 1538-3881 .- 0004-6256. ; 168:1
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Tidskriftsartikel (refereegranskat)abstract
- We present eclipse maps of the two-dimensional thermal emission from the dayside of the hot-Jupiter WASP-43b, derived from an observation of a phase curve with the JWST MIRI/LRS instrument. The observed eclipse shapes deviate significantly from those expected for a planet emitting uniformly over its surface. We fit a map to this deviation, constructed from spherical harmonics up to order ℓ max = 2 , alongside the planetary, orbital, stellar, and systematic parameters. This yields a map with a meridionally averaged eastward hot-spot shift of (7.75 ± 0.36)°, with no significant degeneracy between the map and the additional parameters. We show the latitudinal and longitudinal contributions of the dayside emission structure to the eclipse shape, finding a latitudinal signal of ∼200 ppm and a longitudinal signal of ∼250 ppm. To investigate the sensitivity of the map to the method, we fix the parameters not used for mapping and derive an “eigenmap” fitted with an optimized number of orthogonal phase curves, which yields a similar map to the ℓ max = 2 map. We also fit a map up to ℓ max = 3 , which shows a smaller hot-spot shift, with a larger uncertainty. These maps are similar to those produced by atmospheric simulations. We conclude that there is a significant mapping signal which constrains the spherical harmonic components of our model up to ℓ max = 2 . Alternative mapping models may derive different structures with smaller-scale features; we suggest that further observations of WASP-43b and other planets will drive the development of more robust methods and more accurate maps.
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| 29. |
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| 30. |
- Berndt, Sonja, I, et al.
(författare)
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Distinct germline genetic susceptibility profiles identified for common non-Hodgkin lymphoma subtypes
- 2022
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Ingår i: Leukemia. - : Springer Nature. - 0887-6924 .- 1476-5551. ; 36:12, s. 2835-2844
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Tidskriftsartikel (refereegranskat)abstract
- Lymphoma risk is elevated for relatives with common non-Hodgkin lymphoma (NHL) subtypes, suggesting shared genetic susceptibility across subtypes. To evaluate the extent of mutual heritability among NHL subtypes and discover novel loci shared among subtypes, we analyzed data from eight genome-wide association studies within the InterLymph Consortium, including 10,629 cases and 9505 controls. We utilized Association analysis based on SubSETs (ASSET) to discover loci for subsets of NHL subtypes and evaluated shared heritability across the genome using Genome-wide Complex Trait Analysis (GCTA) and polygenic risk scores. We discovered 17 genome-wide significant loci (P < 5 × 10−8) for subsets of NHL subtypes, including a novel locus at 10q23.33 (HHEX) (P = 3.27 × 10−9). Most subset associations were driven primarily by only one subtype. Genome-wide genetic correlations between pairs of subtypes varied broadly from 0.20 to 0.86, suggesting substantial heterogeneity in the extent of shared heritability among subtypes. Polygenic risk score analyses of established loci for different lymphoid malignancies identified strong associations with some NHL subtypes (P < 5 × 10−8), but weak or null associations with others. Although our analyses suggest partially shared heritability and biological pathways, they reveal substantial heterogeneity among NHL subtypes with each having its own distinct germline genetic architecture.
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| 31. |
- Berndt, Sonja I., et al.
(författare)
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Meta-analysis of genome-wide association studies discovers multiple loci for chronic lymphocytic leukemia
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Chronic lymphocytic leukemia (CLL) is a common lymphoid malignancy with strong heritability. To further understand the genetic susceptibility for CLL and identify common loci associated with risk, we conducted a meta-analysis of four genome-wide association studies (GWAS) composed of 3,100 cases and 7,667 controls with follow-up replication in 1,958 cases and 5,530 controls. Here we report three new loci at 3p24.1 (rs9880772, EOMES, P = 2.55 x 10(-11)), 6p25.2 (rs73718779, SERPINB6, P = 1.97 x 10(-8)) and 3q28 (rs9815073, LPP, P = 3.62 x 10(-8)), as well as a new independent SNP at the known 2q13 locus (rs9308731, BCL2L11, P = 1.00 x 10(-11)) in the combined analysis. We find suggestive evidence (P<5 x 10(-7)) for two additional new loci at 4q24 (rs10028805, BANK1, P = 7.19 x 10(-8)) and 3p22.2 (rs1274963, CSRNP1, P = 2.12 x 10(-7)). Pathway analyses of new and known CLL loci consistently show a strong role for apoptosis, providing further evidence for the importance of this biological pathway in CLL susceptibility.
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| 32. |
- Chen, J., et al.
(författare)
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Genome-wide association study identifies MAPT locus influencing human plasma tau levels
- 2017
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Ingår i: Neurology. - : Ovid Technologies (Wolters Kluwer Health). - 0028-3878 .- 1526-632X. ; 88:7, s. 669-676
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To identify genetic loci associated with plasma tau concentrations in healthy elders and individuals with Alzheimer disease. Methods: Four hundred sixty-three non-Hispanic white individuals exceeding quality control criteria were included from the Alzheimer's Disease Neuroimaging Initiative (ADNI-1) cohort. Association of plasma tau with genetic polymorphisms was performed with a linear regression model. Significant associations were validated in an independent replication cohort consisting of 431 healthy elders or individuals with mild cognitive impairment recruited from the University of California, San Francisco Memory and Aging Center. Results: The minor allele (A) of rs242557 in the microtubule-associated protein tau gene (MAPT) was associated with higher plasma tau levels at genome-wide significance (p = 4.85 x 10(-9), empiric family-wise error corrected p = 0.0024) in a dose-dependent fashion. This association was also observed in the replication cohort (p = 1.0 x 10(-5); joint analysis p = 1.2 x 10(-12)). Single nucleotide polymorphisms near PARK2 (rs2187213) (p = 6.15 x 10(-6)), IL2RA (rs7072793, rs7073236) (p = 7.89 x 10(-6)), and an intergenic locus on 9p21.3 (rs7047280) (p = 8.13 x 10(-6)) were identified as suggestive loci associated with plasma tau levels. Conclusions: MAPT H1c haplotype (rs242557) has previously been identified as a genetic risk factor for progressive supranuclear palsy and corticobasal degeneration. The current findings suggest that plasma tau concentration could be an endophenotype for identifying risk for 4-repeat tauopathies in older individuals.
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| 33. |
- Deters, K. D., et al.
(författare)
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Plasma Tau Association with Brain Atrophy in Mild Cognitive Impairment and Alzheimer's Disease
- 2017
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Ingår i: Journal of Alzheimers Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 58:4, s. 1245-1254
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Tidskriftsartikel (refereegranskat)abstract
- Background: Peripheral (plasma) and central (cerebrospinal fluid, CSF) measures of tau are higher in Alzheimer's disease (AD) relative to prodromal stages and controls. While elevated CSF tau concentrations have been shown to be associated with lower grey matter density (GMD) in AD-specific regions, this correlation has yet to be examined for plasma in a large study. Objective: Determine the neuroanatomical correlates of plasma tau using voxel-based analysis. Methods: Cross-sectional data for 508 ADNI participants were collected for clinical, plasma total-tau (t-tau), CSF amyloid (A beta(42)) and tau, and MRI variables. The relationship between plasma tau and GMD and between CSF t-tau and GMD were assessed on a voxel-by-voxel basis using regression models. Age, sex, APOE epsilon 4 status, diagnosis, and total intracranial volume were used as covariates where appropriate. Participants were defined as amyloid positive (A beta+) if CSF A beta(42) was <192 pg/mL. Results: Plasma tau was negatively correlated with GMD in the medial temporal lobe (MTL), precuneus, thalamus, and striatum. The associations with thalamus and striatum were independent of diagnosis. A negative correlation also existed between plasma tau and GMD in A beta+ participants in the MTL, precuneus, and frontal lobe. When compared to CSF t-tau, plasma tau showed a notably different associated brain atrophy pattern, with only small overlapping regions in the fusiform gyrus. Conclusion: Plasma tau may serve as a non-specific marker for neurodegeneration but is still relevant to AD considering low GMD was associated with plasma tau in A beta+ participants and not A beta-participants.
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| 34. |
- Gero, D., et al.
(författare)
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Defining Global Benchmarks in Bariatric Surgery A Retrospective Multicenter Analysis of Minimally Invasive Roux-en-Y Gastric Bypass and Sleeve Gastrectomy
- 2019
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Ingår i: Annals of Surgery. - : Ovid Technologies (Wolters Kluwer Health). - 0003-4932 .- 1528-1140. ; 270:5, s. 859-867
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To define "best possible'' outcomes for bariatric surgery (BS)(Roux-en-Y gastric bypass [RYGB] and sleeve gastrectomy [SG]). Background: Reference values for optimal surgical outcomes in welldefined low-risk bariatric patients have not been established so far. Consequently, outcome comparison across centers and over time is impeded by heterogeneity in case-mix. Methods: Out of 39,424 elective BS performed in 19 high-volume academic centers from 3 continents between June 2012 and May 2017, we identified 4120 RYGB and 1457 SG low-risk cases defined by absence of previous abdominal surgery, concomitant procedures, diabetes mellitus, sleep apnea, cardiopathy, renal insufficiency, inflammatory bowel disease, immunosuppression, anticoagulation, BMI>50 kg/m(2) and age>65 years. We chose clinically relevant endpoints covering the intra- and postoperative course. Complications were graded by severity using the comprehensive complication index. Benchmark values were defined as the 75th percentile of the participating centers' median values for respective quality indicators. Results: Patients were mainly females (78%), aged 38+/-11 years, with a baseline BMI 40.8 +/- 5.8 kg/m(2). Over 90 days, 7.2% of RYGB and 6.2% of SG patients presented at least 1 complication and no patients died (mortality in nonbenchmark cases: 0.06%). The most frequent reasons for readmission after 90-days following both procedures were symptomatic cholelithiasis and abdominal pain of unknown origin. Benchmark values for both RYGB and SG at 90-days postoperatively were 5.5% Clavien-Dindo grade >= IIIa complication rate, 5.5% readmission rate, and comprehensive complication index <= 33.73 in the subgroup of patients presenting at least 1 grade >= II complication. Conclusion: Benchmark cutoffs targeting perioperative outcomes in BS offer a new tool in surgical quality-metrics and may be implemented in qualityimprovement cycle. ClinicalTrials.gov Identifier NCT03440138
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| 35. |
- Grazian, A., et al.
(författare)
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Lyman continuum escape fraction of faint galaxies at z similar to 3.3 in the CANDELS/GOODS-North, EGS, and COSMOS fields with LBC
- 2017
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 602
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Tidskriftsartikel (refereegranskat)abstract
- Context. The reionization of the Universe is one of the most important topics of present-day astrophysical research. The most plausible candidates for the reionization process are star-forming galaxies, which according to the predictions of the majority of the theoretical and semi-analytical models should dominate the H I ionizing background at z greater than or similar to 3. Aims. We measure the Lyman continuum escape fraction, which is one of the key parameters used to compute the contribution of star-forming galaxies to the UV background. It provides the ratio between the photons produced at lambda <= 912 angstrom rest-frame and those that are able to reach the inter-galactic medium, i.e. that are not absorbed by the neutral hydrogen or by the dust of the galaxy's inter-stellar medium. Methods. We used ultra-deep U-band imaging (U = 30.2 mag at 1 sigma) from Large Binocular Camera at the Large Binocular Telescope (LBC/LBT) in the CANDELS/GOODS-North field and deep imaging in the COSMOS and EGS fields in order to estimate the Lyman continuum escape fraction of 69 star-forming galaxies with secure spectroscopic redshifts at 3.27 <= z <= 3.40 to faint magnitude limits (L = 0.2L*, or equivalently M-1500 similar to -19). The narrow redshift range implies that the LBC U-band filter exclusively samples the lambda <= 912 angstrom rest-frame wavelengths. Results. We measured through stacks a stringent upper limit (<1.7% at 1 sigma) for the relative escape fraction of H I ionizing photons from bright galaxies (L > L*), while for the faint population (L = 0.2L*) the limit to the escape fraction is less than or similar to 10%. We computed the contribution of star-forming galaxies to the observed UV background at z similar to 3 and find that it is not sufficient to keep the Universe ionized at these redshifts unless their escape fraction increases significantly (>= 10%) at low luminosities (M-1500 >= -19). Conclusions. We compare our results on the Lyman continuum escape fraction of high-z galaxies with recent estimates in the literature, and discuss future prospects to shed light on the end of the Dark Ages. In the future, strong gravitational lensing will be fundamental in order to measure the Lyman continuum escape fraction down to faint magnitudes (M-1500 similar to -16) that are inaccessible with the present instrumentation on blank fields. These results will be important in order to quantify the role of faint galaxies to the reionization budget.
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| 36. |
- Jack, C. R., et al.
(författare)
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Magnetic resonance imaging in Alzheimer's Disease Neuroimaging Initiative 2
- 2015
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Ingår i: Alzheimers & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 11:7, s. 740-756
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Alzheimer's Disease Neuroimaging Initiative (ADNI) is now in its 10th year. The primary objective of the magnetic resonance imaging (MRI) core of ADNI has been to improve methods for clinical trials in Alzheimer's disease (AD) and related disorders. Methods: We review the contributions of the MRI core from present and past cycles of ADNI (ADNI-1, -Grand Opportunity and -2). We also review plans for the future-ADNI-3. Results: Contributions of the MRI core include creating standardized acquisition protocols and quality control methods; examining the effect of technical features of image acquisition and analysis on outcome metrics; deriving sample size estimates for future trials based on those outcomes; and piloting the potential utility of MR perfusion, diffusion, and functional connectivity measures in multicenter clinical trials. Discussion: Over the past decade the MRI core of ADNI has fulfilled its mandate of improving methods for clinical trials in AD and will continue to do so in the future. (C) 2015 The Authors. Published by Elsevier Inc. on behalf of the Alzheimer's Association.
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| 37. |
- Kang, J. H., et al.
(författare)
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The Alzheimer's Disease Neuroimaging Initiative 2 Biomarker Core: A review of progress and plans
- 2015
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Ingår i: Alzheimers & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 11:7, s. 772-791
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: We describe Alzheimer's Disease Neuroimaging Initiative (ADNI) Biomarker Core progress including: the Biobank; cerebrospinal fluid (CSF) amyloid beta (A beta(1-42)), t-tau, and p-tau(181) analytical performance, definition of Alzheimer's disease (AD) profile for plaque, and tangle burden detection and increased risk for progression to AD; AD disease heterogeneity; progress in standardization; and new studies using ADNI biofluids. Methods: Review publications authored or coauthored by ADNI Biomarker core faculty and selected non-ADNI studies to deepen the understanding and interpretation ofCSFA beta(1-42), t-tau, and p-tau(181) data. Results: CSFAD biomarker measurements with the qualified AlzBio3 immunoassay detects neuropathologic AD hallmarks in preclinical and prodromal disease stages, based on CSF studies in nonADNI living subjects followed by the autopsy confirmation of AD. Collaboration across ADNI cores generated the temporal ordering model of AD biomarkers varying across individuals because of genetic/environmental factors that increase/decrease resilience to AD pathologies. Discussion: Further studies will refine this model and enable the use of biomarkers studied in ADNI clinically and in disease-modifying therapeutic trials. (C) 2015 Published by Elsevier Inc. on behalf of the Alzheimer's Association.
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| 38. |
- Liu, Y., et al.
(författare)
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Bandwidth scaling of phase-modulated CW comb through four-wave mixing on silicon nano-waveguide
- 2013
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Ingår i: 2013 Conference on Lasers and Electro-Optics, CLEO 2013; San Jose, CA; United States; 9 June 2013 through 14 June 2013. - 9781557529725 ; , s. Art. no. 6833039-
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Konferensbidrag (refereegranskat)abstract
- We demonstrate a scheme to scale the bandwidth of a frequency comb generated by phase modulation of CW lasers using four-wave mixing in a silicon nano-waveguides, resulting in >100 comb lines spaced by 10-GHz within 5-dB bandwidth.
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| 39. |
- Mattsson, Niklas, 1979, et al.
(författare)
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Emerging β-amyloid pathology and accelerated cortical atrophy
- 2014
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Ingår i: JAMA Neurology. - : American Medical Association (AMA). - 2168-6149. ; 71:6, s. 725-734
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Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE The effect of β-amyloid (Aβ) accumulation on regional structural brain changes in early stages of Alzheimer disease (AD) is not well understood. OBJECTIVE To test the hypothesis that the development of Aβ pathology is related to increased regional atrophy in the brains of cognitively normal (CN) persons. DESIGN, SETTING, AND PARTICIPANTS Longitudinal clinicobiomarker cohort study involving 47 CN control subjects and 15 patients with AD dementia. All participants underwent repeated cerebrospinal fluid Aβ42 and structural magnetic resonance imaging measurements for up to 4 years. Cognitively normal controls were classified using the longitudinal cerebrospinal fluid Aβ42 data and included 13 stable Aβ negative (normal baseline Aβ42 levels, with less than the median reduction over time), 13 declining Aβ negative (normal baseline Aβ42 levels, with greater than the median reduction over time), and 21 Aβ positive (pathologic baseline Aβ42 levels). All 15 patients with AD dementia were Aβ positive. MAIN OUTCOMES AND MEASURES Group effects on regional gray matter volumes at baseline and over time, tested by linear mixed-effects models. RESULTS Baseline gray matter volumes were similar among the CN Aβ groups, but atrophy rates were increased in frontoparietal regions in the declining Aβ-negative and Aβ-positive groups and in amygdala and temporal regions in the Aβ-positive group. Aβ-positive patients with AD dementia had further increased atrophy rates in hippocampus and temporal and cingulate regions. CONCLUSIONS AND RELEVANCE Emerging Aβ pathology is coupled to increased frontoparietal (but not temporal) atrophy rates. Atrophy rates peak early in frontoparietal regions but accelerate in hippocampus, temporal, and cingulate regions as the disease progresses to dementia. Early-stage Aβ pathologymay have mild effects on local frontoparietal cortical integrity while effects in temporal regions appear later and accelerate, leading to the atrophy pattern typically seen in AD. © 2014 American Medical Association.
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| 40. |
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| 41. |
- Andersson, Karin, 1972, et al.
(författare)
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Pathogenic Transdifferentiation of Th17 Cells Contribute to Perpetuation of Rheumatoid Arthritis during Anti-TNF Treatment.
- 2015
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Ingår i: Molecular medicine (Cambridge, Mass.). - : Springer Science and Business Media LLC. - 1528-3658 .- 1076-1551. ; 21, s. 536-43
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Tidskriftsartikel (refereegranskat)abstract
- T-helper cells producing interleukin (IL)-17A and IL-17F cytokines (Th17 cells) are considered the source of autoimmunity in rheumatoid arthritis (RA). In this study, we characterized specific pathogenic features of Th17 cells in RA. By using nano-string technology, we analyzed transcription of 419 genes in the peripheral blood CCR6(+)CXCR3(-) CD4(+) cells of 14 RA patients and 6 healthy controls and identified 109 genes discriminating Th17 cells of RA patients from the controls. Th17 cells of RA patients had an aggressive pathogenic profile and in addition to signature cytokines IL-17, IL-23 and IL-21, and transcriptional regulators RAR-related orphan receptor gamma of T cells (RORγt) and Janus kinase 2 (JAK2), they produced high levels of IL-23R, C-C chemokine ligand type 20 (CCL20), granulocyte-monocyte colony-stimulating factor (GM-CSF ) and transcription factor Tbet required for synovial homing. We showed that Th17 cells are enriched with Helios-producing Foxp3- and IL2RA-deficient cells, indicating altered regulatory profile. The follicular T-helper (Tfh) cells presented a functional profile of adaptor molecules, transcriptional regulator Bcl-6 and B-cell activating cytokines IL-21, IL-31 and leukemia inhibitory factor (LIF ). We observed that anti-tumor necrosis factor (TNF) treatment had a limited effect on the transcription signature of Th17 cells. Patients in remission retained the machinery of receptors (IL-23R and IL-1R1), proinflammatory cytokines (IL-17F, IL-23, IL-21 and TNF ) and adaptor molecules (C-X-C chemokine receptor 5 [CXCR5] and cytotoxic T-lymphocyte-associated protein 4 [CTLA-4]), essential for efficient transdifferentiation and accumulation of Th17 cells. This study convincingly shows that the peripheral blood CCR6(+)CXCR3(-) CD4(+) cells of RA patients harbor pathogenic subsets of Th17 and Tfh cells, which may transdifferentiate from Tregs and contribute to perpetuation of the disease.
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| 42. |
- Andersson, Karin, 1972, et al.
(författare)
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Survivin controls biogenesis of microRNA in smokers: A link to pathogenesis of rheumatoid arthritis.
- 2017
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Ingår i: Biochimica et biophysica acta. - : Elsevier BV. - 0006-3002. ; 1863:3, s. 663-673
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Tidskriftsartikel (refereegranskat)abstract
- MicroRNAs (miRs) represent a part of epigenetic control of autoimmunity gaining increasing attention in rheumatoid arthritis (RA). Since cigarette smoking plays important role in RA pathogenesis and reprograms transcriptional profile of miRNAs, we ask if the onco-protein survivin, a novel biomarker of RA, may provide a link between smoking and miRNA. Studying survivin expression in leukocytes of 144 female RA patients we observed that smoking patients had higher survivin transcription and a remarkable spreading of survivin isoforms. This was associated with restricted pattern and low production of miRs. Additionally, miRNA processing enzymes Dicer and DGRC8 were decreased in the patients with survivin isoform spreading. The direct contribution of survivin in miRs biogenesis was confirmed by a massive increase of miRs production following inhibition of survivin in leukocyte cultures. Dicer is shown to mediate these effects of survivin. Chromatin immunoprecipitation analysis demonstrated binding of survivin to the Dicer promoter region. Dicer expression increased 5-folds following survivin inhibition. Taken together, this study presents experimental evidence of a novel cellular function of survivin, control of miRs biogenesis. Up-regulation of survivin in smokers suggests its role as effector of the adverse epigenetic control in RA.
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| 43. |
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| 44. |
- Berndt, Sonja I., et al.
(författare)
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Genome-wide association study identifies multiple risk loci for chronic lymphocytic leukemia
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:8, s. 868-U202
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have previously identified 13 loci associated with risk of chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL). To identify additional CLL susceptibility loci, we conducted the largest meta-analysis for CLL thus far, including four GWAS with a total of 3,100 individuals with CLL (cases) and 7,667 controls. In the meta-analysis, we identified ten independent associated SNPs in nine new loci at 10q23.31 (ACTA2 or FAS (ACTA2/FAS), P = 1.22 x 10(-14)), 18q21.33 (BCL2, P = 7.76 x 10(-11)), 11p15.5 (C11orf21, P = 2.15 x 10(-10)), 4q25 (LEF1, P = 4.24 x 10(-10)), 2q33.1 (CASP10 or CASP8 (CASP10/CASP8), P = 2.50 x 10(-9)), 9p21.3 (CDKN2B-AS1, P = 1.27 x 10(-8)), 18q21.32 (PMAIP1, P = 2.51 x 10(-8)), 15q15.1 (BMF, P = 2.71 x 10(-10)) and 2p22.2 (QPCT, P = 1.68 x 10(-8)), as well as an independent signal at an established locus (2q13, ACOXL, P = 2.08 x 10(-18)). We also found evidence for two additional promising loci below genome-wide significance at 8q22.3 (ODF1, P = 5.40 x 10(-8)) and 5p15.33 (TERT, P = 1.92 x 10(-7)). Although further studies are required, the proximity of several of these loci to genes involved in apoptosis suggests a plausible underlying biological mechanism.
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| 45. |
- Casaletto, K. B., et al.
(författare)
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Tripartite Relationship Among Synaptic, Amyloid, and Tau Proteins An In Vivo and Postmortem Study
- 2021
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Ingår i: Neurology. - : Ovid Technologies (Wolters Kluwer Health). - 0028-3878 .- 1526-632X. ; 97:3
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Tidskriftsartikel (refereegranskat)abstract
- Objective To test the hypothesis that fundamental relationships along the amyloid, tau, and neurodegeneration (A/T/N) cascade depend on synaptic integrity in older adults in vivo and postmortem. Methods The 2 independent observational, cross-sectional cohorts included (1) in vivo community-dwelling, clinically normal adults from the University of California, San Francisco Memory and Aging Center who completed lumbar puncture and MRI (exclusion criteria, Clinical Dementia Rating score >0) and (2) postmortem decedents from the Rush Memory and Aging Project (exclusion criteria, inability to sign informed consent). In vivo measures included CSF synaptic proteins (synaptotagmin-1, synaptosome associated protein-25, neurogranin, and growth associated protein-43), beta-amyloid (A beta(42/40)), tau phosphorylated at amino acid 181 (ptau(181)), and MRI gray matter volume (GMV). Postmortem measures captured brain tissue levels of presynaptic proteins (complexin-I, complexin-II, vesicle associated membrane protein (VAMP), and SNARE complex) and neuritic plaque and neurofibrillary tangle (NFT) counts. Regression models tested statistical moderation of synaptic protein levels along the A/T/N cascade (synaptic proteins x amyloid on tau, and synaptic proteins x tau on GMV). Results Sixty-eight in vivo older adults (age 71 years, 43% female) and 633 decedents (age 90 years, 68% female, 34% clinically normal) were included. Each in vivo CSF synaptic protein moderated the relationship between A beta(42/40) and ptau(181) (-0.23 < beta < -0.12, p < 0.05) and the relationship between ptau(181) and GMV (-0.49
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| 46. |
- Cerhan, James R., et al.
(författare)
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Genome-wide association study identifies multiple susceptibility loci for diffuse large B cell lymphoma
- 2014
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 46:11, s. 1233-1238
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Tidskriftsartikel (refereegranskat)abstract
- Diffuse large B cell lymphoma (DLBCL) is the most common lymphoma subtype and is clinically aggressive. To identify genetic susceptibility loci for DLBCL, we conducted a meta-analysis of 3 new genome-wide association studies (GWAS) and 1 previous scan, totaling 3,857 cases and 7,666 controls of European ancestry, with additional genotyping of 9 promising SNPs in 1,359 cases and 4,557 controls. In our multi-stage analysis, five independent SNPs in four loci achieved genome-wide significance marked by rs116446171 at 6p25.3 (EXOC2; P = 2.33 x 10(-21)), rs2523607 at 6p21.33 (HLA-B; P = 2.40 x 10(-10)), rs79480871 at 2p23.3 (NCOA1; P = 4.23 x 10(-8)) and two independent SNPs, rs13255292 and rs4733601, at 8q24.21 (PVT1; P = 9.98 x 10(-13) and 3.63 x 10(-11), respectively). These data provide substantial new evidence for genetic susceptibility to this B cell malignancy and point to pathways involved in immune recognition and immune function in the pathogenesis of DLBCL.
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| 47. |
- Durazzo, T. C., et al.
(författare)
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History of cigarette smoking in cognitively-normal elders is associated with elevated cerebrospinal fluid biomarkers of oxidative stress
- 2014
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Ingår i: Drug and Alcohol Dependence. - : Elsevier BV. - 0376-8716. ; 142, s. 262-268
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Tidskriftsartikel (refereegranskat)abstract
- Background: Cigarette smoking in adults is associated with abnormalities in brain neurobiology. Smoking-induced central nervous system oxidative stress (OxS) is a potential mechanism associated with these abnormalities. The goal of this study was to compare cognitively-normal elders on cerebrospinal fluid (CSF) levels of F-2-isoprostane biomarkers of OxS. Methods: Elders with a lifetime history of smoking (smokers; n = 50; 75 +/- 5 years of age; 34 +/- 28 pack-years; approximately 12% were actively smoking at the time of study) were compared to never-smokers (n = 61; 76 +/- 6 years of age) on CSF iPF(2 alpha)-III and 8,12, iso-iPF(2 alpha)-VI F-2-isoprostanes levels. F-2-isoprostanes levels were quantitated with HPLC-atmospheric pressure chemical ionization-tandem mass spectrometry. Associations between F-2-isoprostanes levels, hippocampal volumes, and cigarette exposure measures were also evaluated. Results: Smokers showed higher iPF(2 alpha)-III level than never-smokers. An age x smoking status interaction was observed for 8,12, iso-iPF(2 alpha)-VI, where smokers demonstrate a significantly greater concentration with increasing age than never-smokers. In smokers only, higher 8,12, iso-iPF(2 alpha)-VI concentration was associated with smaller hippocampal volume, and greater iPF(2 alpha)-III level was related to greater pack years. Conclusions: This is the first study to demonstrate that a history of cigarette smoking in cognitively-normal elders was associated with significantly elevated CSF F-2-isoprostane levels and greater age-related increases in F-2-isoprostanes, and that higher F-2-isoprostane levels in smokers were related to smaller hippocampal volume. These findings provide additional novel evidence that a history of chronic smoking during adulthood is associated with adverse effects on the human brain that are potentially enduring even with extended smoking cessation.
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| 48. |
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| 49. |
- Fockler, J., et al.
(författare)
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Remote blood collection from older adults in the Brain Health Registry for plasma biomarker and genetic analysis
- 2022
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Ingår i: Alzheimer's and Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 18:12, s. 2627-2636
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Use of online registries to efficiently identify older adults with cognitive decline and Alzheimer's disease (AD) is an approach with growing evidence for feasibility and validity. Linked biomarker and registry data can facilitate AD clinical research. Methods: We collected blood for plasma biomarker and genetic analysis from older adult Brain Health Registry (BHR) participants, evaluated feasibility, and estimated associations between demographic variables and study participation. Results: Of 7150 participants invited to the study, 864 (12%) enrolled and 629 (73%) completed remote blood draws. Participants reported high study acceptability. Those from underrepresented ethnocultural and educational groups were less likely to participate. Discussion: This study demonstrates the challenges of remote blood collection from a large representative sample of older adults. Remote blood collection from>600 participants within a short timeframe demonstrates the feasibility of our approach, which can be expanded for efficient collection of plasma AD biomarker and genetic data. © 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.
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