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| 2. |
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| 3. |
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| 4. |
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| 5. |
- Klionsky, Daniel J., et al.
(author)
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Guidelines for the use and interpretation of assays for monitoring autophagy
- 2012
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In: Autophagy. - : Informa UK Limited. - 1554-8635 .- 1554-8627. ; 8:4, s. 445-544
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Research review (peer-reviewed)abstract
- In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
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| 6. |
- Singh, B., et al.
(author)
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Study of doubly strange systems using stored antiprotons
- 2016
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In: Nuclear Physics A. - : Elsevier. - 0375-9474 .- 1873-1554. ; 954, s. 323-340
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Journal article (peer-reviewed)abstract
- Bound nuclear systems with two units of strangeness are still poorly known despite their importance for many strong interaction phenomena. Stored antiprotons beams in the GeV range represent an unparalleled factory for various hyperon-antihyperon pairs. Their outstanding large production probability in antiproton collisions will open the floodgates for a series of new studies of systems which contain two or even more units of strangeness at the PANDA experiment at FAIR. For the first time, high resolution gamma-spectroscopy of doubly strange Lambda Lambda-hypernuclei will be performed, thus complementing measurements of ground state decays of Lambda Lambda-hypernuclei at J-PARC or possible decays of particle unstable hypernuclei in heavy ion reactions. High resolution spectroscopy of multistrange Xi(-) -atoms will be feasible and even the production of Omega(-) -atoms will be within reach. The latter might open the door to the vertical bar S vertical bar = 3 world in strangeness nuclear physics, by the study of the hadronic Omega(-) -nucleus interaction. For the first time it will be possible to study the behavior of Xi(+) in nuclear systems under well controlled conditions.
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| 7. |
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| 8. |
- Kattge, Jens, et al.
(author)
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TRY plant trait database - enhanced coverage and open access
- 2020
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In: Global Change Biology. - : Wiley-Blackwell. - 1354-1013 .- 1365-2486. ; 26:1, s. 119-188
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Journal article (peer-reviewed)abstract
- Plant traits-the morphological, anatomical, physiological, biochemical and phenological characteristics of plants-determine how plants respond to environmental factors, affect other trophic levels, and influence ecosystem properties and their benefits and detriments to people. Plant trait data thus represent the basis for a vast area of research spanning from evolutionary biology, community and functional ecology, to biodiversity conservation, ecosystem and landscape management, restoration, biogeography and earth system modelling. Since its foundation in 2007, the TRY database of plant traits has grown continuously. It now provides unprecedented data coverage under an open access data policy and is the main plant trait database used by the research community worldwide. Increasingly, the TRY database also supports new frontiers of trait-based plant research, including the identification of data gaps and the subsequent mobilization or measurement of new data. To support this development, in this article we evaluate the extent of the trait data compiled in TRY and analyse emerging patterns of data coverage and representativeness. Best species coverage is achieved for categorical traits-almost complete coverage for 'plant growth form'. However, most traits relevant for ecology and vegetation modelling are characterized by continuous intraspecific variation and trait-environmental relationships. These traits have to be measured on individual plants in their respective environment. Despite unprecedented data coverage, we observe a humbling lack of completeness and representativeness of these continuous traits in many aspects. We, therefore, conclude that reducing data gaps and biases in the TRY database remains a key challenge and requires a coordinated approach to data mobilization and trait measurements. This can only be achieved in collaboration with other initiatives.
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| 9. |
- Leal-Cidoncha, E., et al.
(author)
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Fission Fragment Angular Distribution measurements of 235U and 238U at CERN n_TOF facility
- 2016
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In: EPJ Web of Conferences. - : EDP Sciences. - 2100-014X.
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Conference paper (peer-reviewed)abstract
- Neutron-induced fission cross sections of U-238 and U-235 are used as standards in the fast neutron region up to 200 MeV. A high accuracy of the standards is relevant to experimentally determine other neutron reaction cross sections. Therefore, the detection efficiency should be corrected by using the angular distribution of the fission fragments (FFAD), which are barely known above 20 MeV. In addition, the angular distribution of the fragments produced in the fission of highly excited and deformed nuclei is an important observable to investigate the nuclear fission process. In order to measure the FFAD of neutron-induced reactions, a fission detection setup based on parallel-plate avalanche counters (PPACs) has been developed and successfully used at the CERN-n_TOF facility. In this work, we present the preliminary results on the analysis of new U-235(n,f) and U-238(n,f) data in the extended energy range up to 200 MeV compared to the existing experimental data.
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| 10. |
- Liu, Kui, et al.
(author)
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Kallikrein genes are associated with lupus and glomerular basement membrane-specific antibody-induced nephritis in mice and humans
- 2009
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In: Journal of Clinical Investigation. - 0021-9738 .- 1558-8238. ; 119:4, s. 911-923
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Journal article (peer-reviewed)abstract
- Immune-mediated nephritis contributes to disease in systemic lupus erythematosus, Goodpasture syndrome (caused by antibodies specific for glomerular basement membrane [anti-GBM antibodies]), and spontaneous lupus nephritis. Inbred mouse strains differ in susceptibility to anti-GBM antibody-induced and spontaneous lupus nephritis. This study sought to clarify the genetic and molecular factors that maybe responsible for enhanced immune-mediated renal disease in these models. When the kidneys of 3 mouse strains sensitive to anti-GBM antibody-induced nephritis were compared with those of 2 control strains using microarray analysis, one-fifth of the underexpressed genes belonged to the kallikrein gene family,which encodes serine esterases. Mouse strains that upregulated renal and urinary kallikreins exhibited less evidence of disease. Antagonizing the kallikrein pathway augmented disease, while agonists dampened the severity of anti-GBM antibody-induced nephritis. In addition, nephritis-sensitive mouse strains had kallikrein haplotypes that were distinct from those of control strains, including several regulatory polymorphisms,some of which were associated with functional consequences. Indeed, increased susceptibility to anti-GBM antibody-induced nephritis and spontaneous lupus nephritis was achieved by breeding mice with a genetic interval harboring the kallikrein genes onto a disease-resistant background. Finally, both human SLE and spontaneous lupus nephritis were found to be associated with kallikrein genes, particularly KLK1 and the KLK3 promoter, when DNA SNPs from independent cohorts of SLE patients and controls were compared. Collectively, these studies suggest that kallikreins are protective disease-associated genes in anti-GBM antibody-induced nephritis and lupus.
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| 11. |
- Machiela, Mitchell J., et al.
(author)
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Characterization of Large Structural Genetic Mosaicism in Human Autosomes
- 2015
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In: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 96:3, s. 487-497
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Journal article (peer-reviewed)abstract
- Analyses of genome-wide association study (GWAS) data have revealed that detectable genetic mosaicism involving large (>2 Mb) structural autosomal alterations occurs in a fraction of individuals. We present results for a set of 24,849 genotyped individuals (total GWAS set II [TGSII]) in whom 341 large autosomal abnormalities were observed in 168 (0.68%) individuals. Merging data from the new TGSII set with data from two prior reports (the Gene-Environment Association Studies and the total GWAS set I) generated a large dataset of 127,179 individuals; we then conducted a meta-analysis to investigate the patterns of detectable autosomal mosaicism (n = 1,315 events in 925 [0.73%] individuals). Restricting to events >2 Mb in size, we observed an increase in event frequency as event size decreased. The combined results underscore that the rate of detectable mosaicism increases with age (p value = 5.5 x 3 10(-31)) and is higher in men (p value = 0.002) but lower in participants of African ancestry (p value = 0.003). In a subset of 47 individuals from whom serial samples were collected up to 6 years apart, complex changes were noted over time and showed an overall increase in the proportion of mosaic cells as age increased. Our large combined sample allowed for a unique ability to characterize detectable genetic mosaicism involving large structural events and strengthens the emerging evidence of non-random erosion of the genome in the aging population.
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| 12. |
- Praena, J., et al.
(author)
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Preparation and characterization of 33S samples for 33S(n,alpha)30Si cross-section measurements at the n_TOF facility at CERN
- 2018
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In: Nuclear Instruments and Methods in Physics Research Section A. - : Elsevier BV. - 0168-9002 .- 1872-9576. ; 890, s. 142-147
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Journal article (peer-reviewed)abstract
- Thin 33S samples for the study of the 33S(n,alpha)30Si cross-section at the n_TOF facility at CERN were made by thermal evaporation of 33S powder onto a dedicated substrate made of kapton covered with thin layers of copper, chromium and titanium. This method has provided for the first time bare sulfur samples a few centimeters in diameter. The samples have shown an excellent adherence with no mass loss after few years and no sublimation in vacuum at room temperature. The determination of the mass thickness of 33S has been performed by means of Rutherford backscattering spectrometry. The samples have been successfully tested under neutron irradiation.
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| 13. |
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| 14. |
- Elsik, Christine G., et al.
(author)
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The Genome Sequence of Taurine Cattle : A Window to Ruminant Biology and Evolution
- 2009
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In: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 324:5926, s. 522-528
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Journal article (peer-reviewed)abstract
- To understand the biology and evolution of ruminants, the cattle genome was sequenced to about sevenfold coverage. The cattle genome contains a minimum of 22,000 genes, with a core set of 14,345 orthologs shared among seven mammalian species of which 1217 are absent or undetected in noneutherian (marsupial or monotreme) genomes. Cattle-specific evolutionary breakpoint regions in chromosomes have a higher density of segmental duplications, enrichment of repetitive elements, and species-specific variations in genes associated with lactation and immune responsiveness. Genes involved in metabolism are generally highly conserved, although five metabolic genes are deleted or extensively diverged from their human orthologs. The cattle genome sequence thus provides a resource for understanding mammalian evolution and accelerating livestock genetic improvement for milk and meat production.
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| 15. |
- Kuhle, J., et al.
(author)
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Conversion from clinically isolated syndrome to multiple sclerosis: A large multicentre study
- 2015
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In: Multiple Sclerosis Journal. - : SAGE Publications. - 1352-4585 .- 1477-0970. ; 21:8, s. 1013-1024
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Journal article (peer-reviewed)abstract
- Background and objective: We explored which clinical and biochemical variables predict conversion from clinically isolated syndrome (CIS) to clinically definite multiple sclerosis (CDMS) in a large international cohort. Methods: Thirty-three centres provided serum samples from 1047 CIS cases with at least two years' follow-up. Age, sex, clinical presentation, T2-hyperintense lesions, cerebrospinal fluid (CSF) oligoclonal bands (OCBs), CSF IgG index, CSF cell count, serum 25-hydroxyvitamin D3 (25-OH-D), cotinine and IgG titres against Epstein-Barr nuclear antigen 1 (EBNA-1) and cytomegalovirus were tested for association with risk of CDMS. Results: At median follow-up of 4.31 years, 623 CIS cases converted to CDMS. Predictors of conversion in multivariable analyses were OCB (HR = 2.18, 95% CI = 1.71-2.77, p < 0.001), number of T2 lesions (two to nine lesions vs 0/1 lesions: HR = 1.97, 95% CI = 1.52-2.55, p < 0.001; >9 lesions vs 0/1 lesions: HR = 2.74, 95% CI = 2.04-3.68, p < 0.001) and age at CIS (HR per year inversely increase = 0.98, 95% CI = 0.98-0.99, p < 0.001). Lower 25-OH-D levels were associated with CDMS in univariable analysis, but this was attenuated in the multivariable model. OCB positivity was associated with higher EBNA-1 IgG titres. Conclusions: We validated MRI lesion load, OCB and age at CIS as the strongest independent predictors of conversion to CDMS in this multicentre setting. A role for vitamin D is suggested but requires further investigation.
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| 16. |
- Sampson, Joshua N., et al.
(author)
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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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In: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 107:12
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Journal article (peer-reviewed)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. |
- Santangelo, James S., et al.
(author)
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Global urban environmental change drives adaptation in white clover
- 2022
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In: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 375
-
Journal article (peer-reviewed)abstract
- Urbanization transforms environments in ways that alter biological evolution. We examined whether urban environmental change drives parallel evolution by sampling 110,019 white clover plants from 6169 populations in 160 cities globally. Plants were assayed for a Mendelian antiherbivore defense that also affects tolerance to abiotic stressors. Urban-rural gradients were associated with the evolution of clines in defense in 47% of cities throughout the world. Variation in the strength of clines was explained by environmental changes in drought stress and vegetation cover that varied among cities. Sequencing 2074 genomes from 26 cities revealed that the evolution of urban-rural dines was best explained by adaptive evolution, but the degree of parallel adaptation varied among cities. Our results demonstrate that urbanization leads to adaptation at a global scale.
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| 18. |
- Cruz, Raquel, et al.
(author)
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Novel genes and sex differences in COVID-19 severity
- 2022
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In: Human Molecular Genetics. - : Oxford University Press. - 0964-6906 .- 1460-2083. ; 31:22, s. 3789-3806
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Journal article (peer-reviewed)abstract
- Here, we describe the results of a genome-wide study conducted in 11 939 coronavirus disease 2019 (COVID-19) positive cases with an extensive clinical information that were recruited from 34 hospitals across Spain (SCOURGE consortium). In sex-disaggregated genome-wide association studies for COVID-19 hospitalization, genome-wide significance (P < 5 × 10−8) was crossed for variants in 3p21.31 and 21q22.11 loci only among males (P = 1.3 × 10−22 and P = 8.1 × 10−12, respectively), and for variants in 9q21.32 near TLE1 only among females (P = 4.4 × 10−8). In a second phase, results were combined with an independent Spanish cohort (1598 COVID-19 cases and 1068 population controls), revealing in the overall analysis two novel risk loci in 9p13.3 and 19q13.12, with fine-mapping prioritized variants functionally associated with AQP3 (P = 2.7 × 10−8) and ARHGAP33 (P = 1.3 × 10−8), respectively. The meta-analysis of both phases with four European studies stratified by sex from the Host Genetics Initiative (HGI) confirmed the association of the 3p21.31 and 21q22.11 loci predominantly in males and replicated a recently reported variant in 11p13 (ELF5, P = 4.1 × 10−8). Six of the COVID-19 HGI discovered loci were replicated and an HGI-based genetic risk score predicted the severity strata in SCOURGE. We also found more SNP-heritability and larger heritability differences by age (<60 or ≥60 years) among males than among females. Parallel genome-wide screening of inbreeding depression in SCOURGE also showed an effect of homozygosity in COVID-19 hospitalization and severity and this effect was stronger among older males. In summary, new candidate genes for COVID-19 severity and evidence supporting genetic disparities among sexes are provided.
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| 19. |
- Docherty, Anna R, et al.
(author)
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GWAS Meta-Analysis of Suicide Attempt: Identification of 12 Genome-Wide Significant Loci and Implication of Genetic Risks for Specific Health Factors.
- 2023
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In: The American journal of psychiatry. - : American Psychiatric Association Publishing. - 1535-7228 .- 0002-953X. ; 180:10, s. 723-738
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Journal article (peer-reviewed)abstract
- Suicidal behavior is heritable and is a major cause of death worldwide. Two large-scale genome-wide association studies (GWASs) recently discovered and cross-validated genome-wide significant (GWS) loci for suicide attempt (SA). The present study leveraged the genetic cohorts from both studies to conduct the largest GWAS meta-analysis of SA to date. Multi-ancestry and admixture-specific meta-analyses were conducted within groups of significant African, East Asian, and European ancestry admixtures.This study comprised 22 cohorts, including 43,871 SA cases and 915,025 ancestry-matched controls. Analytical methods across multi-ancestry and individual ancestry admixtures included inverse variance-weighted fixed-effects meta-analyses, followed by gene, gene-set, tissue-set, and drug-target enrichment, as well as summary-data-based Mendelian randomization with brain expression quantitative trait loci data, phenome-wide genetic correlation, and genetic causal proportion analyses.Multi-ancestry and European ancestry admixture GWAS meta-analyses identified 12 risk loci at p values <5×10-8. These loci were mostly intergenic and implicated DRD2, SLC6A9, FURIN, NLGN1, SOX5, PDE4B, and CACNG2. The multi-ancestry SNP-based heritability estimate of SA was 5.7% on the liability scale (SE=0.003, p=5.7×10-80). Significant brain tissue gene expression and drug set enrichment were observed. There was shared genetic variation of SA with attention deficit hyperactivity disorder, smoking, and risk tolerance after conditioning SA on both major depressive disorder and posttraumatic stress disorder. Genetic causal proportion analyses implicated shared genetic risk for specific health factors.This multi-ancestry analysis of suicide attempt identified several loci contributing to risk and establishes significant shared genetic covariation with clinical phenotypes. These findings provide insight into genetic factors associated with suicide attempt across ancestry admixture populations, in veteran and civilian populations, and in attempt versus death.
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| 20. |
- Fresard, Laure, et al.
(author)
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Identification of rare-disease genes using blood transcriptome sequencing and large control cohorts
- 2019
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In: Nature Medicine. - : NATURE PUBLISHING GROUP. - 1078-8956 .- 1546-170X. ; 25:6, s. 911-919
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Journal article (peer-reviewed)abstract
- It is estimated that 350 million individuals worldwide suffer from rare diseases, which are predominantly caused by mutation in a single gene(1). The current molecular diagnostic rate is estimated at 50%, with whole-exome sequencing (WES) among the most successful approaches(2-5). For patients in whom WES is uninformative, RNA sequencing (RNA-seq) has shown diagnostic utility in specific tissues and diseases(6-8). This includes muscle biopsies from patients with undiagnosed rare muscle disorders(6,9), and cultured fibroblasts from patients with mitochondrial disorders(7). However, for many individuals, biopsies are not performed for clinical care, and tissues are difficult to access. We sought to assess the utility of RNA-seq from blood as a diagnostic tool for rare diseases of different pathophysiologies. We generated whole-blood RNA-seq from 94 individuals with undiagnosed rare diseases spanning 16 diverse disease categories. We developed a robust approach to compare data from these individuals with large sets of RNA-seq data for controls (n = 1,594 unrelated controls and n = 49 family members) and demonstrated the impacts of expression, splicing, gene and variant filtering strategies on disease gene identification. Across our cohort, we observed that RNA-seq yields a 7.5% diagnostic rate, and an additional 16.7% with improved candidate gene resolution.
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| 21. |
- Kehoe, Laura, et al.
(author)
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Make EU trade with Brazil sustainable
- 2019
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In: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 364:6438, s. 341-
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Journal article (other academic/artistic)
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| 22. |
- Mullins, Niamh, et al.
(author)
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Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors
- 2022
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In: Biological Psychiatry. - : Elsevier. - 0006-3223 .- 1873-2402. ; 91:3, s. 313-327
-
Journal article (peer-reviewed)abstract
- BACKGROUND: Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders.METHODS: We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors.RESULTS: Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged.CONCLUSIONS: Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.
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| 23. |
- Sumaila, U. Rashid, et al.
(author)
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WTO must ban harmful fisheries subsidies
- 2021
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In: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 374:6567, s. 544-544
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Journal article (other academic/artistic)
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| 24. |
- Grieser, M., et al.
(author)
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Storage ring at HIE-ISOLDE Technical design report
- 2012
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In: The European Physical Journal Special Topics. - : Springer Science and Business Media LLC. - 1951-6355 .- 1951-6401. ; 207:1, s. 1-117
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Research review (peer-reviewed)abstract
- We propose to install a storage ring at an ISOL-type radioactive beam facility for the first time. Specifically, we intend to setup the heavy-ion, low-energy ring TSR at the HIE-ISOLDE facility in CERN, Geneva. Such a facility will provide a capability for experiments with stored secondary beams that is unique in the world. The envisaged physics programme is rich and varied, spanning from investigations of nuclear ground-state properties and reaction studies of astrophysical relevance, to investigations with highly-charged ions and pure isomeric beams. The TSR might also be employed for removal of isobaric contaminants from stored ion beams and for systematic studies within the neutrino beam programme. In addition to experiments performed using beams recirculating within the ring, cooled beams can also be extracted and exploited by external spectrometers for high-precision measurements. The existing TSR, which is presently in operation at the Max-Planck Institute for Nuclear Physics in Heidelberg, is well-suited and can be employed for this purpose. The physics cases as well as technical details of the existing ring facility and of the beam and infrastructure requirements at HIE-ISOLDE are discussed in the present technical design report.
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| 25. |
- Grieser, M., et al.
(author)
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Storage ring at HIE-ISOLDE
- 2012
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In: European Physical Journal: Special Topics. - : Springer Science and Business Media LLC. - 1951-6401 .- 1951-6355. ; 207:1, s. 1-117
-
Journal article (peer-reviewed)abstract
- We propose to install a storage ring at an ISOL-type radioactive beam facility for the first time. Specifically, we intend to setup the heavy-ion, low-energy ring TSR at the HIE-ISOLDE facility in CERN, Geneva. Such a facility will provide a capability for experiments with stored secondary beams that is unique in the world. The envisaged physics programme is rich and varied, spanning from investigations of nuclear ground-state properties and reaction studies of astrophysical relevance, to investigations with highly-charged ions and pure isomeric beams. The TSR might also be employed for removal of isobaric contaminants from stored ion beams and for systematic studies within the neutrino beam programme. In addition to experiments performed using beams recirculating within the ring, cooled beams can also be extracted and exploited by external spectrometers for high-precision measurements. The existing TSR, which is presently in operation at the Max-Planck Institute for Nuclear Physics in Heidelberg, is well-suited and can be employed for this purpose. The physics cases as well as technical details of the existing ring facility and of the beam and infrastructure requirements at HIE-ISOLDE are discussed in the present technical design report.
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| 26. |
- Lu, R, et al.
(author)
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Genetic associations of LYN with systemic lupus erythematosus
- 2009
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In: Genes and Immunity. - : Springer Science and Business Media LLC. - 1466-4879 .- 1476-5470. ; 10:5, s. 397-403
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Journal article (peer-reviewed)abstract
- We targeted LYN, a src-tyosine kinase involved in B-cell activation, in case-control association studies using populations of European-American, African-American and Korean subjects. Our combined European-derived population, consisting of 2463 independent cases and 3131 unrelated controls, shows significant association with rs6983130 in a female-only analysis with 2254 cases and 2228 controls (P=1.1 x 10(-4), odds ratio (OR)=0.81 (95% confidence interval: 0.73-0.90)). This single nucleotide polymorphism (SNP) is located in the 5' untranslated region within the first intron near the transcription initiation site of LYN. In addition, SNPs upstream of the first exon also show weak and sporadic association in subsets of the total European-American population. Multivariate logistic regression analysis implicates rs6983130 as a protective factor for systemic lupus erythematosus (SLE) susceptibility when anti-dsDNA, anti-chromatin, anti-52 kDa Ro or anti-Sm autoantibody status were used as covariates. Subset analysis of the European-American female cases by American College of Rheumatology classification criteria shows a reduction in the risk of hematological disorder with rs6983130 compared with cases without hematological disorders (P=1.5 x 10(-3), OR=0.75 (95% CI: 0.62-0.89)). None of the 90 SNPs tested show significant association with SLE in the African American or Korean populations. These results support an association of LYN with European-derived individuals with SLE, especially within autoantibody or clinical subsets.
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| 27. |
- Machiela, Mitchell J, et al.
(author)
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Female chromosome X mosaicism is age-related and preferentially affects the inactivated X chromosome
- 2016
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In: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 7
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Journal article (peer-reviewed)abstract
- To investigate large structural clonal mosaicism of chromosome X, we analysed the SNP microarray intensity data of 38,303 women from cancer genome-wide association studies (20,878 cases and 17,425 controls) and detected 124 mosaic X events >2 Mb in 97 (0.25%) women. Here we show rates for X-chromosome mosaicism are four times higher than mean autosomal rates; X mosaic events more often include the entire chromosome and participants with X events more likely harbour autosomal mosaic events. X mosaicism frequency increases with age (0.11% in 50-year olds; 0.45% in 75-year olds), as reported for Y and autosomes. Methylation array analyses of 33 women with X mosaicism indicate events preferentially involve the inactive X chromosome. Our results provide further evidence that the sex chromosomes undergo mosaic events more frequently than autosomes, which could have implications for understanding the underlying mechanisms of mosaic events and their possible contribution to risk for chronic diseases.
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| 28. |
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| 29. |
- Seldin, M. F., et al.
(author)
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Amerindian ancestry in Argentina is associated with increased risk for systemic lupus erythematosus
- 2008
-
In: Genes and Immunity. - : Springer Science and Business Media LLC. - 1466-4879 .- 1476-5470. ; 9:4, s. 389-393
-
Journal article (peer-reviewed)abstract
- Previous studies have demonstrated that in admixed populations, West African ancestry is associated with an increased prevalence of systemic lupus erythematosus (SLE). In the current study, the effect of Amerindian ancestry in SLE was examined in an admixed population in Argentina. The Argentine population is predominantly European with approximately 20% Amerindian admixture, and a very small (<2%) contribution from West Africa. The results indicate that Amerindian admixture in this population is associated with a substantial increase in SLE susceptibility risk (Odds Ratio=7.94, P=0.00006). This difference was not due to known demographic factors, including site of collection, age and gender. In addition, there were trends towards significance for Amerindian ancestry influencing renal disease, age of onset and anti-SSA antibodies. These studies suggest that populations with Amerindian admixture, like those with West African admixture, should be considered in future studies to identify additional allelic variants that predispose to SLE.
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| 30. |
- Biurrun, Idoia, et al.
(author)
-
Benchmarking plant diversity of Palaearctic grasslands and other open habitats
- 2021
-
In: Journal of Vegetation Science. - Oxford : John Wiley & Sons. - 1100-9233 .- 1654-1103. ; 32:4
-
Journal article (peer-reviewed)abstract
- Journal of Vegetation Science published by John Wiley & Sons Ltd on behalf of International Association for Vegetation Science.Aims: Understanding fine-grain diversity patterns across large spatial extents is fundamental for macroecological research and biodiversity conservation. Using the GrassPlot database, we provide benchmarks of fine-grain richness values of Palaearctic open habitats for vascular plants, bryophytes, lichens and complete vegetation (i.e., the sum of the former three groups). Location: Palaearctic biogeographic realm. Methods: We used 126,524 plots of eight standard grain sizes from the GrassPlot database: 0.0001, 0.001, 0.01, 0.1, 1, 10, 100 and 1,000 m2 and calculated the mean richness and standard deviations, as well as maximum, minimum, median, and first and third quartiles for each combination of grain size, taxonomic group, biome, region, vegetation type and phytosociological class. Results: Patterns of plant diversity in vegetation types and biomes differ across grain sizes and taxonomic groups. Overall, secondary (mostly semi-natural) grasslands and natural grasslands are the richest vegetation type. The open-access file ”GrassPlot Diversity Benchmarks” and the web tool “GrassPlot Diversity Explorer” are now available online (https://edgg.org/databases/GrasslandDiversityExplorer) and provide more insights into species richness patterns in the Palaearctic open habitats. Conclusions: The GrassPlot Diversity Benchmarks provide high-quality data on species richness in open habitat types across the Palaearctic. These benchmark data can be used in vegetation ecology, macroecology, biodiversity conservation and data quality checking. While the amount of data in the underlying GrassPlot database and their spatial coverage are smaller than in other extensive vegetation-plot databases, species recordings in GrassPlot are on average more complete, making it a valuable complementary data source in macroecology. © 2021 The Authors.
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| 31. |
- Caciolli, A., et al.
(author)
-
Revision of the 15N(p, γ)16O reaction rate and oxygen abundance in H-burning zones
- 2011
-
In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 533
-
Journal article (peer-reviewed)abstract
- Context. The NO cycle takes place in the deepest layer of a H-burning core or shell, when the temperature exceeds T ≈ 30 × 106 K. The O depletion observed in some globular cluster giant stars, always associated with a Na enhancement, may be due to either a deep mixing during the red giant branch (RGB) phase of the star or to the pollution of the primordial gas by an early population of massive asymptotic giant branch (AGB) stars, whose chemical composition was modified by the hot bottom burning. In both cases, the NO cycle is responsible for the O depletion. Aims. The activation of this cycle depends on the rate of the 15N(p, γ)16O reaction. A precise evaluation of this reaction rate at temperatures as low as experienced in H-burning zones in stellar interiors is mandatory to understand the observed O abundances. Methods. We present a new measurement of the 15N(p, γ)16O reaction performed at LUNA covering for the first time the center of mass energy range 70-370 keV, which corresponds to stellar temperatures between 65 × 106 K and 780 × 106 K. This range includes the 15N(p, γ)16O Gamow-peak energy of explosive H-burning taking place in the external layer of a nova and the one of the hot bottom burning (HBB) nucleosynthesis occurring in massive AGB stars. Results. With the present data, we are also able to confirm the result of the previous R-matrix extrapolation. In particular, in the temperature range of astrophysical interest, the new rate is about a factor of 2 smaller than reported in the widely adopted compilation of reaction rates (NACRE or CF88) and the uncertainty is now reduced down to the 10% level. © 2011 ESO.
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| 32. |
- Clark, Andrew G., et al.
(author)
-
Evolution of genes and genomes on the Drosophila phylogeny
- 2007
-
In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 450:7167, s. 203-218
-
Journal article (peer-reviewed)abstract
- Comparative analysis of multiple genomes in a phylogenetic framework dramatically improves the precision and sensitivity of evolutionary inference, producing more robust results than single-genome analyses can provide. The genomes of 12 Drosophila species, ten of which are presented here for the first time (sechellia, simulans, yakuba, erecta, ananassae, persimilis, willistoni, mojavensis, virilis and grimshawi), illustrate how rates and patterns of sequence divergence across taxa can illuminate evolutionary processes on a genomic scale. These genome sequences augment the formidable genetic tools that have made Drosophila melanogaster a pre-eminent model for animal genetics, and will further catalyse fundamental research on mechanisms of development, cell biology, genetics, disease, neurobiology, behaviour, physiology and evolution. Despite remarkable similarities among these Drosophila species, we identified many putatively non-neutral changes in protein-coding genes, non-coding RNA genes, and cis-regulatory regions. These may prove to underlie differences in the ecology and behaviour of these diverse species.
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| 33. |
- Feng, Shaohong, et al.
(author)
-
Dense sampling of bird diversity increases power of comparative genomics
- 2020
-
In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 587:7833
-
Journal article (peer-reviewed)abstract
- Whole-genome sequencing projects are increasingly populating the tree of life and characterizing biodiversity(1-4). Sparse taxon sampling has previously been proposed to confound phylogenetic inference(5), and captures only a fraction of the genomic diversity. Here we report a substantial step towards the dense representation of avian phylogenetic and molecular diversity, by analysing 363 genomes from 92.4% of bird families-including 267 newly sequenced genomes produced for phase II of the Bird 10,000 Genomes (B10K) Project. We use this comparative genome dataset in combination with a pipeline that leverages a reference-free whole-genome alignment to identify orthologous regions in greater numbers than has previously been possible and to recognize genomic novelties in particular bird lineages. The densely sampled alignment provides a single-base-pair map of selection, has more than doubled the fraction of bases that are confidently predicted to be under conservation and reveals extensive patterns of weak selection in predominantly non-coding DNA. Our results demonstrate that increasing the diversity of genomes used in comparative studies can reveal more shared and lineage-specific variation, and improve the investigation of genomic characteristics. We anticipate that this genomic resource will offer new perspectives on evolutionary processes in cross-species comparative analyses and assist in efforts to conserve species. A dataset of the genomes of 363 species from the Bird 10,000 Genomes Project shows increased power to detect shared and lineage-specific variation, demonstrating the importance of phylogenetically diverse taxon sampling in whole-genome sequencing.
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| 34. |
- Marta, M., et al.
(author)
-
Precision study of ground state capture in the 14N(p,γ)15O reaction
- 2008
-
In: Physical Review C. Nuclear Physics. - 0556-2813 .- 1089-490X. ; 78:2
-
Journal article (peer-reviewed)abstract
- The rate of the hydrogen-burning carbon-nitrogen-oxygen (CNO) cycle is controlled by the slowest process, 14N(p,γ)15O, which proceeds by capture to the ground and several excited states in O15. Previous extrapolations for the ground state contribution disagreed by a factor 2, corresponding to 15% uncertainty in the total astrophysical S factor. At the Laboratory for Underground Nuclear Astrophysics (LUNA) 400 kV accelerator placed deep underground in the Gran Sasso facility in Italy, a new experiment on ground state capture has been carried out at 317.8, 334.4, and 353.3 keV center-of-mass energy. Systematic corrections have been reduced considerably with respect to previous studies by using a Clover detector and by adopting a relative analysis. The previous discrepancy has been resolved, and ground state capture no longer dominates the uncertainty of the total S factor. © 2008 The American Physical Society.
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| 35. |
- Marta, M., et al.
(author)
-
The N14(p,γ)O15 reaction studied with a composite germanium detector
- 2011
-
In: Physical Review C. Nuclear Physics. - 0556-2813 .- 1089-490X. ; 83:4
-
Journal article (peer-reviewed)abstract
- The rate of the carbon-nitrogen-oxygen (CNO) cycle of hydrogen burning is controlled by the N14(p,γ)O15 reaction. The reaction proceeds by capture to the ground states and several excited states in O15. In order to obtain a reliable extrapolation of the excitation curve to astrophysical energy, fits in the R-matrix framework are needed. In an energy range that sensitively tests such fits, new cross-section data are reported here for the four major transitions in the N14(p,γ)O15 reaction. The experiment has been performed at the Laboratory for Underground Nuclear Astrophysics (LUNA) 400-kV accelerator placed deep underground in the Gran Sasso facility in Italy. Using a composite germanium detector, summing corrections have been considerably reduced with respect to previous studies. The cross sections for capture to the ground state and to the 5181, 6172, and 6792 keV excited states in O15 have been determined at 359, 380, and 399 keV beam energy. In addition, the branching ratios for the decay of the 278-keV resonance have been remeasured. © 2011 American Physical Society.
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| 36. |
- Menkveld, Albert J., et al.
(author)
-
Nonstandard Errors
- 2024
-
In: JOURNAL OF FINANCE. - : Wiley-Blackwell. - 0022-1082 .- 1540-6261. ; 79:3, s. 2339-2390
-
Journal article (peer-reviewed)abstract
- In statistics, samples are drawn from a population in a data-generating process (DGP). Standard errors measure the uncertainty in estimates of population parameters. In science, evidence is generated to test hypotheses in an evidence-generating process (EGP). We claim that EGP variation across researchers adds uncertainty-nonstandard errors (NSEs). We study NSEs by letting 164 teams test the same hypotheses on the same data. NSEs turn out to be sizable, but smaller for more reproducible or higher rated research. Adding peer-review stages reduces NSEs. We further find that this type of uncertainty is underestimated by participants.
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| 37. |
- Nguyen, Thanh N, et al.
(author)
-
Global Impact of the COVID-19 Pandemic on Stroke Volumes and Cerebrovascular Events: A 1-Year Follow-up.
- 2023
-
In: Neurology. - 1526-632X. ; 100:4
-
Journal article (peer-reviewed)abstract
- Declines in stroke admission, IV thrombolysis (IVT), and mechanical thrombectomy volumes were reported during the first wave of the COVID-19 pandemic. There is a paucity of data on the longer-term effect of the pandemic on stroke volumes over the course of a year and through the second wave of the pandemic. We sought to measure the effect of the COVID-19 pandemic on the volumes of stroke admissions, intracranial hemorrhage (ICH), IVT, and mechanical thrombectomy over a 1-year period at the onset of the pandemic (March 1, 2020, to February 28, 2021) compared with the immediately preceding year (March 1, 2019, to February 29, 2020).We conducted a longitudinal retrospective study across 6 continents, 56 countries, and 275 stroke centers. We collected volume data for COVID-19 admissions and 4 stroke metrics: ischemic stroke admissions, ICH admissions, IVT treatments, and mechanical thrombectomy procedures. Diagnoses were identified by their ICD-10 codes or classifications in stroke databases.There were 148,895 stroke admissions in the 1 year immediately before compared with 138,453 admissions during the 1-year pandemic, representing a 7% decline (95% CI [95% CI 7.1-6.9]; p < 0.0001). ICH volumes declined from 29,585 to 28,156 (4.8% [5.1-4.6]; p < 0.0001) and IVT volume from 24,584 to 23,077 (6.1% [6.4-5.8]; p < 0.0001). Larger declines were observed at high-volume compared with low-volume centers (all p < 0.0001). There was no significant change in mechanical thrombectomy volumes (0.7% [0.6-0.9]; p = 0.49). Stroke was diagnosed in 1.3% [1.31-1.38] of 406,792 COVID-19 hospitalizations. SARS-CoV-2 infection was present in 2.9% ([2.82-2.97], 5,656/195,539) of all stroke hospitalizations.There was a global decline and shift to lower-volume centers of stroke admission volumes, ICH volumes, and IVT volumes during the 1st year of the COVID-19 pandemic compared with the prior year. Mechanical thrombectomy volumes were preserved. These results suggest preservation in the stroke care of higher severity of disease through the first pandemic year.This study is registered under NCT04934020.
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| 38. |
- Parma, Valentina, et al.
(author)
-
More Than Smell—COVID-19 Is Associated With Severe Impairment of Smell, Taste, and Chemesthesis
- 2020
-
In: Chemical Senses. - : Oxford University Press (OUP). - 0379-864X .- 1464-3553. ; 45:7, s. 609-622
-
Journal article (peer-reviewed)abstract
- Recent anecdotal and scientific reports have provided evidence of a link between COVID-19 and chemosensory impairments, such as anosmia. However, these reports have downplayed or failed to distinguish potential effects on taste, ignored chemesthesis, and generally lacked quantitative measurements. Here, we report the development, implementation, and initial results of a multilingual, international questionnaire to assess self-reported quantity and quality of perception in 3 distinct chemosensory modalities (smell, taste, and chemesthesis) before and during COVID-19. In the first 11 days after questionnaire launch, 4039 participants (2913 women, 1118 men, and 8 others, aged 19–79) reported a COVID-19 diagnosis either via laboratory tests or clinical assessment. Importantly, smell, taste, and chemesthetic function were each significantly reduced compared to their status before the disease. Difference scores (maximum possible change ±100) revealed a mean reduction of smell (−79.7 ± 28.7, mean ± standard deviation), taste (−69.0 ± 32.6), and chemesthetic (−37.3 ± 36.2) function during COVID-19. Qualitative changes in olfactory ability (parosmia and phantosmia) were relatively rare and correlated with smell loss. Importantly, perceived nasal obstruction did not account for smell loss. Furthermore, chemosensory impairments were similar between participants in the laboratory test and clinical assessment groups. These results show that COVID-19-associated chemosensory impairment is not limited to smell but also affects taste and chemesthesis. The multimodal impact of COVID-19 and the lack of perceived nasal obstruction suggest that severe acute respiratory syndrome coronavirus strain 2 (SARS-CoV-2) infection may disrupt sensory-neural mechanisms.
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| 39. |
- Phillips, Helen R. P., et al.
(author)
-
Global distribution of earthworm diversity
- 2019
-
In: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 366:6464, s. 480-
-
Journal article (peer-reviewed)abstract
- Soil organisms, including earthworms, are a key component of terrestrial ecosystems. However, little is known about their diversity, their distribution, and the threats affecting them. We compiled a global dataset of sampled earthworm communities from 6928 sites in 57 countries as a basis for predicting patterns in earthworm diversity, abundance, and biomass. We found that local species richness and abundance typically peaked at higher latitudes, displaying patterns opposite to those observed in aboveground organisms. However, high species dissimilarity across tropical locations may cause diversity across the entirety of the tropics to be higher than elsewhere. Climate variables were found to be more important in shaping earthworm communities than soil properties or habitat cover. These findings suggest that climate change may have serious implications for earthworm communities and for the functions they provide.
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| 40. |
- Tobias, Deirdre K, et al.
(author)
-
Second international consensus report on gaps and opportunities for the clinical translation of precision diabetes medicine
- 2023
-
In: Nature Medicine. - 1546-170X. ; 29:10, s. 2438-2457
-
Research review (peer-reviewed)abstract
- Precision medicine is part of the logical evolution of contemporary evidence-based medicine that seeks to reduce errors and optimize outcomes when making medical decisions and health recommendations. Diabetes affects hundreds of millions of people worldwide, many of whom will develop life-threatening complications and die prematurely. Precision medicine can potentially address this enormous problem by accounting for heterogeneity in the etiology, clinical presentation and pathogenesis of common forms of diabetes and risks of complications. This second international consensus report on precision diabetes medicine summarizes the findings from a systematic evidence review across the key pillars of precision medicine (prevention, diagnosis, treatment, prognosis) in four recognized forms of diabetes (monogenic, gestational, type 1, type 2). These reviews address key questions about the translation of precision medicine research into practice. Although not complete, owing to the vast literature on this topic, they revealed opportunities for the immediate or near-term clinical implementation of precision diabetes medicine; furthermore, we expose important gaps in knowledge, focusing on the need to obtain new clinically relevant evidence. Gaps include the need for common standards for clinical readiness, including consideration of cost-effectiveness, health equity, predictive accuracy, liability and accessibility. Key milestones are outlined for the broad clinical implementation of precision diabetes medicine.
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| 41. |
- Trautvetter, H P, et al.
(author)
-
Ground state capture in 14N(p,γ)15O studied above the 259 keV resonance at LUNA
- 2008
-
In: Journal of Physics G. - : IOP Publishing. - 0954-3899 .- 1361-6471. ; 35:1
-
Journal article (peer-reviewed)abstract
- We report on a new measurement of 14N(p,γ)15O for the ground state capture transition at Ep = 360, 380 and 400 keV, using the 400 kV LUNA accelerator. The true coincidence summing effect - the major source of error in the ground state capture determination - has been significantly reduced by using a Clover-type gamma detector. © 2008 IOP Publishing Ltd.
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| 42. |
- Dengler, Juergen, et al.
(author)
-
GrassPlot - a database of multi-scale plant diversity in Palaearctic grasslands
- 2018
-
In: Phytocoenologia. - : Schweizerbart. - 0340-269X. ; 48:3, s. 331-347
-
Journal article (peer-reviewed)abstract
- GrassPlot is a collaborative vegetation-plot database organised by the Eurasian Dry Grassland Group (EDGG) and listed in the Global Index of Vegetation-Plot Databases (GIVD ID EU-00-003). GrassPlot collects plot records (releves) from grasslands and other open habitats of the Palaearctic biogeographic realm. It focuses on precisely delimited plots of eight standard grain sizes (0.0001; 0.001;... 1,000 m(2)) and on nested-plot series with at least four different grain sizes. The usage of GrassPlot is regulated through Bylaws that intend to balance the interests of data contributors and data users. The current version (v. 1.00) contains data for approximately 170,000 plots of different sizes and 2,800 nested-plot series. The key components are richness data and metadata. However, most included datasets also encompass compositional data. About 14,000 plots have near-complete records of terricolous bryophytes and lichens in addition to vascular plants. At present, GrassPlot contains data from 36 countries throughout the Palaearctic, spread across elevational gradients and major grassland types. GrassPlot with its multi-scale and multi-taxon focus complements the larger international vegetationplot databases, such as the European Vegetation Archive (EVA) and the global database " sPlot". Its main aim is to facilitate studies on the scale-and taxon-dependency of biodiversity patterns and drivers along macroecological gradients. GrassPlot is a dynamic database and will expand through new data collection coordinated by the elected Governing Board. We invite researchers with suitable data to join GrassPlot. Researchers with project ideas addressable with GrassPlot data are welcome to submit proposals to the Governing Board.
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| 43. |
- Douglas, K. B., et al.
(author)
-
Complement receptor 2 polymorphisms associated with systemic lupus erythematosus modulate alternative splicing
- 2009
-
In: Genes and Immunity. - : Springer Science and Business Media LLC. - 1466-4879 .- 1476-5470. ; 10:5, s. 457-469
-
Journal article (peer-reviewed)abstract
- Genetic factors influence susceptibility to systemic lupus erythematosus (SLE). A recent family-based analysis in Caucasian and Chinese populations provided evidence for association of single-nucleotide polymorphisms (SNPs) in the complement receptor 2 (CR2/CD21) gene with SLE. Here we confirmed this result in a case-control analysis of an independent European-derived population including 2084 patients with SLE and 2853 healthy controls. A haplotype formed by the minor alleles of three CR2 SNPs (rs1048971, rs17615, rs4308977) showed significant association with decreased risk of SLE (30.4% in cases vs 32.6% in controls, P=0.016, OR=0.90 (0.82-0.98)). Two of these SNPs are in exon 10, directly 5' of an alternatively spliced exon preferentially expressed in follicular dendritic cells (FDC), and the third is in the alternatively spliced exon. Effects of these SNPs and a fourth SNP in exon 11 (rs17616) on alternative splicing were evaluated. We found that the minor alleles of these SNPs decreased splicing efficiency of exon 11 both in vitro and ex vivo. These findings further implicate CR2 in the pathogenesis of SLE and suggest that CR2 variants alter the maintenance of tolerance and autoantibody production in the secondary lymphoid tissues where B cells and FDCs interact.
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| 44. |
- Graham, Emily B., et al.
(author)
-
Microbes as Engines of Ecosystem Function : When Does Community Structure Enhance Predictions of Ecosystem Processes?
- 2016
-
In: Frontiers in Microbiology. - : Frontiers Media SA. - 1664-302X. ; 7
-
Journal article (peer-reviewed)abstract
- Microorganisms are vital in mediating the earth's biogeochemical cycles; yet, despite our rapidly increasing ability to explore complex environmental microbial communities, the relationship between microbial community structure and ecosystem processes remains poorly understood. Here, we address a fundamental and unanswered question in microbial ecology: 'When do we need to understand microbial community structure to accurately predict function?' We present a statistical analysis investigating the value of environmental data and microbial community structure independently and in combination for explaining rates of carbon and nitrogen cycling processes within 82 global datasets. Environmental variables were the strongest predictors of process rates but left 44% of variation unexplained on average, suggesting the potential for microbial data to increase model accuracy. Although only 29% of our datasets were significantly improved by adding information on microbial community structure, we observed improvement in models of processes mediated by narrow phylogenetic guilds via functional gene data, and conversely, improvement in models of facultative microbial processes via community diversity metrics. Our results also suggest that microbial diversity can strengthen predictions of respiration rates beyond microbial biomass parameters, as 53% of models were improved by incorporating both sets of predictors compared to 35% by microbial biomass alone. Our analysis represents the first comprehensive analysis of research examining links between microbial community structure and ecosystem function. Taken together, our results indicate that a greater understanding of microbial communities informed by ecological principles may enhance our ability to predict ecosystem process rates relative to assessments based on environmental variables and microbial physiology.
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| 45. |
- Kowal, Marta, et al.
(author)
-
Reasons for Facebook Usage : Data From 46 Countries
- 2020
-
In: Frontiers in Psychology. - : Frontiers Media SA. - 1664-1078. ; 11
-
Journal article (peer-reviewed)abstract
- Introduction: Seventy-nine percent of internet users use Facebook, and on average they access Facebook eight times a day (Greenwood et al., 2016). To put these numbers into perspective, according to Clement (2019), around 30% of the world's population uses this Online Social Network (OSN) site.Despite the constantly growing body of academic research on Facebook (Chou et al., 2009; Back et al., 2010; Kaplan and Haenlein, 2010; McAndrew and Jeong, 2012; Wilson et al., 2012; Krasnova et al., 2017), there remains limited research regarding the motivation behind Facebook use across different cultures. Our main goal was to collect data from a large cross-cultural sample of Facebook users to examine the roles of sex, age, and, most importantly, cultural differences underlying Facebook use.
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| 46. |
- Kuderna, Lukas F. K., et al.
(author)
-
Identification of constrained sequence elements across 239 primate genomes
- 2024
-
In: Nature. - : Springer Nature. - 0028-0836 .- 1476-4687. ; 625:7996, s. 735-742
-
Journal article (peer-reviewed)abstract
- Noncoding DNA is central to our understanding of human gene regulation and complex diseases1,2, and measuring the evolutionary sequence constraint can establish the functional relevance of putative regulatory elements in the human genome3,4,5,6,7,8,9. Identifying the genomic elements that have become constrained specifically in primates has been hampered by the faster evolution of noncoding DNA compared to protein-coding DNA10, the relatively short timescales separating primate species11, and the previously limited availability of whole-genome sequences12. Here we construct a whole-genome alignment of 239 species, representing nearly half of all extant species in the primate order. Using this resource, we identified human regulatory elements that are under selective constraint across primates and other mammals at a 5% false discovery rate. We detected 111,318 DNase I hypersensitivity sites and 267,410 transcription factor binding sites that are constrained specifically in primates but not across other placental mammals and validate their cis-regulatory effects on gene expression. These regulatory elements are enriched for human genetic variants that affect gene expression and complex traits and diseases. Our results highlight the important role of recent evolution in regulatory sequence elements differentiating primates, including humans, from other placental mammals.
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| 47. |
- Ladds, Marcus J. G. W., et al.
(author)
-
A DHODH inhibitor increases p53 synthesis and enhances tumor cell killing by p53 degradation blockage
- 2018
-
In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9
-
Journal article (peer-reviewed)abstract
- The development of non-genotoxic therapies that activate wild-type p53 in tumors is of great interest since the discovery of p53 as a tumor suppressor. Here we report the identification of over 100 small-molecules activating p53 in cells. We elucidate the mechanism of action of a chiral tetrahydroindazole (HZ00), and through target deconvolution, we deduce that its active enantiomer (R)-HZ00, inhibits dihydroorotate dehydrogenase (DHODH). The chiral specificity of HZ05, a more potent analog, is revealed by the crystal structure of the (R)-HZ05/DHODH complex. Twelve other DHODH inhibitor chemotypes are detailed among the p53 activators, which identifies DHODH as a frequent target for structurally diverse compounds. We observe that HZ compounds accumulate cancer cells in S-phase, increase p53 synthesis, and synergize with an inhibitor of p53 degradation to reduce tumor growth in vivo. We, therefore, propose a strategy to promote cancer cell killing by p53 instead of its reversible cell cycle arresting effect.
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| 48. |
- Lambert-Niclot, S., et al.
(author)
-
Antiretroviral resistance at virological failure in the NEAT 001/ANRS 143 trial: Raltegravir plus darunavir/ritonavir or tenofovir/emtricitabine plus darunavir/ritonavir as first-line ART
- 2016
-
In: Journal of Antimicrobial Chemotherapy. - : Oxford University Press (OUP). - 1460-2091 .- 0305-7453. ; 71:4, s. 1056-1062
-
Journal article (peer-reviewed)abstract
- Objectives: To describe the pattern of drug resistance at virological failure in the NEAT001/ANRS143 trial (first-line treatment with ritonavir-boosted darunavir plus either tenofovir/emtricitabine or raltegravir). Methods: Genotypic testing was performed at baseline for reverse transcriptase (RT) and protease genes and for RT, protease and integrase (IN) genes for patients with a confirmed viral load (VL) >50 copies/mL or any single VL >500 copies/mL during or after week 32. Results: A resistance test was obtained for 110/805 (13.7%) randomized participants qualifying for resistance analysis (61/401 of participants in the raltegravir arm and 49/404 of participants in the tenofovir/emtricitabine arm). No resistance-associated mutation (RAM) was observed in the tenofovir/emtricitabine plus darunavir/ritonavir arm, and all further analyses were limited to the raltegravir plus darunavir arm. In this group, 15/55 (27.3%) participants had viruses with IN RAMs (12 N155H alone, 1 N155H + Q148R, 1 F121Y and 1 Y143C), 2/53 (3.8%) with nucleotide analogue RT inhibitor RAMs (K65R, M41L) and 1/57 (1.8%) with primary protease RAM (L76V). The frequency of IN mutations at failure was significantly associated with baseline VL: 7.1% for a VL of TREND = 0.007). Of note, 4/15 participants with IN RAM had a VL <200 copies/mL at time of testing. Conclusions: In the NEAT001/ANRS143 trial, there was no RAM at virological failure in the standard tenofovir/emtricitabine plus darunavir/ritonavir regimen, contrasting with a rate of 29.5% (mostly IN mutations) in the raltegravir plus darunavir/ritonavir NRTI-sparing regimen. The cumulative risk of IN RAM after 96 weeks of follow-up in participants initiating ART with raltegravir plus darunavir/ritonavir was 3.9%.
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| 49. |
- Langefeld, Carl D., et al.
(author)
-
Transancestral mapping and genetic load in systemic lupus erythematosus
- 2017
-
In: Nature Communications. - : NATURE PUBLISHING GROUP. - 2041-1723. ; 8
-
Journal article (peer-reviewed)abstract
- Systemic lupus erythematosus (SLE) is an autoimmune disease with marked gender and ethnic disparities. We report a large transancestral association study of SLE using Immunochip genotype data from 27,574 individuals of European (EA), African (AA) and Hispanic Amerindian (HA) ancestry. We identify 58 distinct non-HLA regions in EA, 9 in AA and 16 in HA (similar to 50% of these regions have multiple independent associations); these include 24 novel SLE regions (P < 5 x 10(-8)), refined association signals in established regions, extended associations to additional ancestries, and a disentangled complex HLA multigenic effect. The risk allele count (genetic load) exhibits an accelerating pattern of SLE risk, leading us to posit a cumulative hit hypothesis for autoimmune disease. Comparing results across the three ancestries identifies both ancestry-dependent and ancestry-independent contributions to SLE risk. Our results are consistent with the unique and complex histories of the populations sampled, and collectively help clarify the genetic architecture and ethnic disparities in SLE.
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| 50. |
- Meeter, Lieke H.H., et al.
(author)
-
Clinical value of cerebrospinal fluid neurofilament light chain in semantic dementia
- 2019
-
In: Journal of Neurology, Neurosurgery and Psychiatry. - : BMJ. - 0022-3050 .- 1468-330X. ; 90:9, s. 997-1004
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Journal article (peer-reviewed)abstract
- Background: Semantic dementia (SD) is a neurodegenerative disorder characterised by progressive language problems falling within the clinicopathological spectrum of frontotemporal lobar degeneration (FTLD). The development of disease-modifying agents may be facilitated by the relative clinical and pathological homogeneity of SD, but we need robust monitoring biomarkers to measure their efficacy. In different FTLD subtypes, neurofilament light chain (NfL) is a promising marker, therefore we investigated the utility of cerebrospinal fluid (CSF) NfL in SD. Methods: This large retrospective multicentre study compared cross-sectional CSF NfL levels of 162 patients with SD with 65 controls. CSF NfL levels of patients were correlated with clinical parameters (including survival), neuropsychological test scores and regional grey matter atrophy (including longitudinal data in a subset). Results: CSF NfL levels were significantly higher in patients with SD (median: 2326 pg/mL, IQR: 1628-3593) than in controls (577 (446-766), p<0.001). Higher CSF NfL levels were moderately associated with naming impairment as measured by the Boston Naming Test (rs=-0.32, p=0.002) and with smaller grey matter volume of the parahippocampal gyri (rs=-0.31, p=0.004). However, cross-sectional CSF NfL levels were not associated with progression of grey matter atrophy and did not predict survival. Conclusion: CSF NfL is a promising biomarker in the diagnostic process of SD, although it has limited cross-sectional monitoring or prognostic abilities.
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