| 1. |
- Beal, Jacob, et al.
(författare)
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Robust estimation of bacterial cell count from optical density
- 2020
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Ingår i: Communications Biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 3:1
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Tidskriftsartikel (refereegranskat)abstract
- Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli. Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals <1.2-fold), is easily assessed for quality control, also assesses instrument effective linear range, and can be combined with fluorescence calibration to obtain units of Molecules of Equivalent Fluorescein (MEFL) per cell, allowing direct comparison and data fusion with flow cytometry measurements: in our study, fluorescence per cell measurements showed only a 1.07-fold mean difference between plate reader and flow cytometry data.
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| 2. |
- Abolfathi, Bela, et al.
(författare)
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The Fourteenth Data Release of the Sloan Digital Sky Survey : First Spectroscopic Data from the Extended Baryon Oscillation Spectroscopic Survey and from the Second Phase of the Apache Point Observatory Galactic Evolution Experiment
- 2018
-
Ingår i: Astrophysical Journal Supplement Series. - : IOP Publishing Ltd. - 0067-0049 .- 1538-4365. ; 235:2
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Tidskriftsartikel (refereegranskat)abstract
- The fourth generation of the Sloan Digital Sky Survey (SDSS-IV) has been in operation since 2014 July. This paper describes the second data release from this phase, and the 14th from SDSS overall (making this Data Release Fourteen or DR14). This release makes the data taken by SDSS-IV in its first two years of operation (2014-2016 July) public. Like all previous SDSS releases, DR14 is cumulative, including the most recent reductions and calibrations of all data taken by SDSS since the first phase began operations in 2000. New in DR14 is the first public release of data from the extended Baryon Oscillation Spectroscopic Survey; the first data from the second phase of the Apache Point Observatory (APO) Galactic Evolution Experiment (APOGEE-2), including stellar parameter estimates from an innovative data-driven machine-learning algorithm known as "The Cannon"; and almost twice as many data cubes from the Mapping Nearby Galaxies at APO (MaNGA) survey as were in the previous release (N = 2812 in total). This paper describes the location and format of the publicly available data from the SDSS-IV surveys. We provide references to the important technical papers describing how these data have been taken (both targeting and observation details) and processed for scientific use. The SDSS web site (www.sdss.org) has been updated for this release and provides links to data downloads, as well as tutorials and examples of data use. SDSS-IV is planning to continue to collect astronomical data until 2020 and will be followed by SDSS-V.
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| 3. |
- Frieler, Katja, et al.
(författare)
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Scenario setup and forcing data for impact model evaluation and impact attribution within the third round of the Inter-Sectoral Impact Model Intercomparison Project (ISIMIP3a)
- 2024
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Ingår i: Geoscientific Model Development. - : Copernicus Publications. - 1991-959X .- 1991-9603. ; 17:1, s. 1-51
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Tidskriftsartikel (refereegranskat)abstract
- This paper describes the rationale and the protocol of the first component of the third simulation round of the Inter-Sectoral Impact Model Intercomparison Project (ISIMIP3a, http://www.isimip.org, last access: 2 November 2023) and the associated set of climate-related and direct human forcing data (CRF and DHF, respectively). The observation-based climate-related forcings for the first time include high-resolution observational climate forcings derived by orographic downscaling, monthly to hourly coastal water levels, and wind fields associated with historical tropical cyclones. The DHFs include land use patterns, population densities, information about water and agricultural management, and fishing intensities. The ISIMIP3a impact model simulations driven by these observation-based climate-related and direct human forcings are designed to test to what degree the impact models can explain observed changes in natural and human systems. In a second set of ISIMIP3a experiments the participating impact models are forced by the same DHFs but a counterfactual set of atmospheric forcings and coastal water levels where observed trends have been removed. These experiments are designed to allow for the attribution of observed changes in natural, human, and managed systems to climate change, rising CH4 and CO2 concentrations, and sea level rise according to the definition of the Working Group II contribution to the IPCC AR6.
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| 4. |
- Kattge, Jens, et al.
(författare)
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TRY plant trait database - enhanced coverage and open access
- 2020
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Ingår i: Global Change Biology. - : Wiley-Blackwell. - 1354-1013 .- 1365-2486. ; 26:1, s. 119-188
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Tidskriftsartikel (refereegranskat)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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| 5. |
- Baeten, Lander, et al.
(författare)
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Identifying the tree species compositions that maximize ecosystem functioning in European forests
- 2019
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Ingår i: Journal of Applied Ecology. - : Wiley. - 0021-8901 .- 1365-2664. ; 56:3, s. 733-744
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Tidskriftsartikel (refereegranskat)abstract
- 1. Forest ecosystem functioning generally benefits from higher tree species richness, but variation within richness levels is typically large. This is mostly due to the contrasting performances of communities with different compositions. Evidence-based understanding of composition effects on forest productivity, as well as on multiple other functions will enable forest managers to focus on the selection of species that maximize functioning, rather than on diversity per se.2. We used a dataset of 30 ecosystem functions measured in stands with different species richness and composition in six European forest types. First, we quantified whether the compositions that maximize annual above-ground wood production (productivity) generally also fulfil the multiple other ecosystem functions (multifunctionality). Then, we quantified the species identity effects and strength of interspecific interactions to identify the "best" and "worst" species composition for multifunctionality. Finally, we evaluated the real-world frequency of occurrence of best and worst mixtures, using harmonized data from multiple national forest inventories.3. The most productive tree species combinations also tended to express relatively high multifunctionality, although we found a relatively wide range of compositions with high- or low-average multifunctionality for the same level of productivity. Monocultures were distributed among the highest as well as the lowest performing compositions. The variation in functioning between compositions was generally driven by differences in the performance of the component species and, to a lesser extent, by particular interspecific interactions. Finally, we found that the most frequent species compositions in inventory data were monospecific stands and that the most common compositions showed below-average multifunctionality and productivity.4. Synthesis and applications. Species identity and composition effects are essential to the development of high-performing production systems, for instance in forestry and agriculture. They therefore deserve great attention in the analysis and design of functional biodiversity studies if the aim is to inform ecosystem management. A management focus on tree productivity does not necessarily trade-off against other ecosystem functions; high productivity and multifunctionality can be combined with an informed selection of tree species and species combinations.
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| 6. |
- Bellenguez, Celine, et al.
(författare)
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Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke
- 2012
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 44:3, s. 141-328
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Tidskriftsartikel (refereegranskat)abstract
- Genetic factors have been implicated in stroke risk, but few replicated associations have been reported. We conducted a genome-wide association study (GWAS) for ischemic stroke and its subtypes in 3,548 affected individuals and 5,972 controls, all of European ancestry. Replication of potential signals was performed in 5,859 affected individuals and 6,281 controls. We replicated previous associations for cardioembolic stroke near PITX2 and ZFHX3 and for large vessel stroke at a 9p21 locus. We identified a new association for large vessel stroke within HDAC9 (encoding histone deacetylase 9) on chromosome 7p21.1 (including further replication in an additional 735 affected individuals and 28,583 controls) (rs11984041; combined P = 1.87 x 10(-11); odds ratio (OR) = 1.42, 95% confidence interval (CI) = 1.28-1.57). All four loci exhibited evidence for heterogeneity of effect across the stroke subtypes, with some and possibly all affecting risk for only one subtype. This suggests distinct genetic architectures for different stroke subtypes.
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| 7. |
- Beuttler, Julia, et al.
(författare)
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Targeting of Epidermal Growth Factor Receptor (EGFR)-Expressing Tumor Cells with Sterically Stabilized Affibody Liposomes (SAL)
- 2009
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Ingår i: Bioconjugate chemistry. - : American Chemical Society (ACS). - 1043-1802 .- 1520-4812. ; 20:6, s. 1201-1208
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Tidskriftsartikel (refereegranskat)abstract
- Affibody molecules are small and stable antigen-binding molecules derived from the B domain of protein A. We applied a bivalent, high-affinity epidermal growth factor receptor (EGFR)-specific affibody molecule for the generation of targeted PEGylated liposomes. These sterically stabilized affibody liposomes (SAL) were produced by chemical coupling of the cysteine-modified affibody molecule to maleimide-PEG(2000)-DSPE and subsequent insertion into PEGylated liposomes. These SAL showed strong and selective binding to EGFR-expressing tumor cell lines. Binding was dependent on the amount of inserted affibody molecule-lipid conjugates and could be blocked by soluble EGF. Approximately 30% of binding activity was still retained after 6 days of incubation in human plasma at 37 degrees C. Binding of SAL to cells led to efficient internalization of the liposomes. Using mitoxantrone-loaded liposomes, we observed for SAL, compared to untargeted liposomes, an enhanced cytotoxicity toward EGFR-expressing cells. In summary, we show that SAL can be easily prepared from affibody molecules and thus may be suitable for the development of carrier systems for targeted delivery of drugs.
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| 8. |
- Braunstein, Kerstin E., et al.
(författare)
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A point mutation in the dynein heavy chain gene leads to striatal atrophy and compromises neurite outgrowth of striatal neurons
- 2010
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 19:22, s. 4385-4398
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Tidskriftsartikel (refereegranskat)abstract
- The molecular motor dynein and its associated regulatory subunit dynactin have been implicated in several neurodegenerative conditions of the basal ganglia, such as Huntington's disease (HD) and Perry syndrome, an atypical Parkinson-like disease. This pathogenic role has been largely postulated from the existence of mutations in the dynactin subunit p150(Glued). However, dynactin is also able to act independently of dynein, and there is currently no direct evidence linking dynein to basal ganglia degeneration. To provide such evidence, we used here a mouse strain carrying a point mutation in the dynein heavy chain gene that impairs retrograde axonal transport. These mice exhibited motor and behavioural abnormalities including hindlimb clasping, early muscle weakness, incoordination and hyperactivity. In vivo brain imaging using magnetic resonance imaging showed striatal atrophy and lateral ventricle enlargement. In the striatum, altered dopamine signalling, decreased dopamine D1 and D2 receptor binding in positron emission tomography SCAN and prominent astrocytosis were observed, although there was no neuronal loss either in the striatum or substantia nigra. In vitro, dynein mutant striatal neurons displayed strongly impaired neuritic morphology. Altogether, these findings provide a direct genetic evidence for the requirement of dynein for the morphology and function of striatal neurons. Our study supports a role for dynein dysfunction in the pathogenesis of neurodegenerative disorders of the basal ganglia, such as Perry syndrome and HD.
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| 9. |
- Celutkiene, Jelena, et al.
(författare)
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Role of cardiovascular imaging in cancer patients receiving cardiotoxic therapies : a position statement on behalf of the Heart Failure Association (HFA), the European Association of Cardiovascular Imaging (EACVI) and the Cardio-Oncology Council of the European Society of Cardiology (ESC)
- 2020
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Ingår i: European Journal of Heart Failure. - : WILEY. - 1388-9842 .- 1879-0844. ; 22:9, s. 1504-1524
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Tidskriftsartikel (refereegranskat)abstract
- Cardiovascular (CV) imaging is an important tool in baseline risk assessment and detection of CV disease in oncology patients receiving cardiotoxic cancer therapies. This position statement examines the role of echocardiography, cardiac magnetic resonance, nuclear cardiac imaging and computed tomography in the management of cancer patients. The Imaging and Cardio-Oncology Study Groups of the Heart Failure Association (HFA) of the European Society of Cardiology (ESC) in collaboration with the European Association of Cardiovascular Imaging (EACVI) and the Cardio-Oncology Council of the ESC have evaluated the current evidence for the value of modern CV imaging in the cardio-oncology field. The most relevant echocardiographic parameters, including global longitudinal strain and three-dimensional ejection fraction, are proposed. The protocol for baseline pre-treatment evaluation and specific surveillance algorithms or pathways for anthracycline chemotherapy, HER2-targeted therapies such as trastuzumab, vascular endothelial growth factor tyrosine kinase inhibitors, BCr-Abl tyrosine kinase inhibitors, proteasome inhibitors and immune checkpoint inhibitors are presented. The indications for CV imaging after completion of oncology treatment are considered. The typical consequences of radiation therapy and the possibility of their identification in the long term are also summarized. Special populations are discussed including female survivors planning pregnancy, patients with carcinoid disease, patients with cardiac tumours and patients with right heart failure. Future directions and ongoing CV imaging research in cardio-oncology are discussed.
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| 10. |
- Clift, Roland, et al.
(författare)
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The Challenges of Applying Planetary Boundaries as a Basis for Strategic Decision-Making in Companies with Global Supply Chains
- 2017
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Ingår i: Sustainability. - : MDPI AG. - 2071-1050. ; 9:2
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Tidskriftsartikel (refereegranskat)abstract
- The Planetary Boundaries (PB) framework represents a significant advance in specifying the ecological constraints on human development. However, to enable decision-makers in business and public policy to respect these constraints in strategic planning, the PB framework needs to be developed to generate practical tools. With this objective in mind, we analyse the recent literature and highlight three major scientific and technical challenges in operationalizing the PB approach in decision-making: first, identification of thresholds or boundaries with associated metrics for different geographical scales; second, the need to frame approaches to allocate fair shares in the 'safe operating space' bounded by the PBs across the value chain and; third, the need for international bodies to co-ordinate the implementation of the measures needed to respect the Planetary Boundaries. For the first two of these challenges, we consider how they might be addressed for four PBs: climate change, freshwater use, biosphere integrity and chemical pollution and other novel entities. Four key opportunities are identified: (1) development of a common system of metrics that can be applied consistently at and across different scales; (2) setting 'distance from boundary' measures that can be applied at different scales; (3) development of global, preferably open-source, databases and models; and (4) advancing understanding of the interactions between the different PBs. Addressing the scientific and technical challenges in operationalizing the planetary boundaries needs be complemented with progress in addressing the equity and ethical issues in allocating the safe operating space between companies and sectors.
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| 11. |
- Fazey, Ioan, et al.
(författare)
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Transforming knowledge systems for life on Earth : Visions of future systems and how to get there
- 2020
-
Ingår i: Energy Research & Social Science. - : Elsevier. - 2214-6296 .- 2214-6326. ; 70
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Tidskriftsartikel (refereegranskat)abstract
- Formalised knowledge systems, including universities and research institutes, are important for contemporary societies. They are, however, also arguably failing humanity when their impact is measured against the level of progress being made in stimulating the societal changes needed to address challenges like climate change. In this research we used a novel futures-oriented and participatory approach that asked what future envisioned knowledge systems might need to look like and how we might get there. Findings suggest that envisioned future systems will need to be much more collaborative, open, diverse, egalitarian, and able to work with values and systemic issues. They will also need to go beyond producing knowledge about our world to generating wisdom about how to act within it. To get to envisioned systems we will need to rapidly scale methodological innovations, connect innovators, and creatively accelerate learning about working with intractable challenges. We will also need to create new funding schemes, a global knowledge commons, and challenge deeply held assumptions. To genuinely be a creative force in supporting longevity of human and non-human life on our planet, the shift in knowledge systems will probably need to be at the scale of the enlightenment and speed of the scientific and technological revolution accompanying the second World War. This will require bold and strategic action from governments, scientists, civic society and sustained transformational intent.
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| 12. |
- Golob-Schwarzi, Nicole, et al.
(författare)
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High Keratin 8/18 Ratio Predicts Aggressive Hepatocellular Cancer Phenotype
- 2019
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Ingår i: Translational Oncology. - : ELSEVIER SCIENCE INC. - 1944-7124 .- 1936-5233. ; 12:2, s. 256-268
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND amp; AIMS: Steatohepatitis (SH) and SH-associated hepatocellular carcinoma (HCC) are of considerable clinical significance. SH is morphologically characterized by steatosis, liver cell ballooning, cytoplasmic aggregates termedMallory-Denk bodies (MDBs), inflammation, and fibrosis at late stage. Disturbance of the keratin cytoskeleton and aggregation of keratins (KRTs) are essential for MDB formation. METHODS: Weanalyzed livers of aged Krt18(-/-) mice that spontaneously developed in the majority of cases SH-associated HCC independent of sex. Interestingly, the hepatic lipid profile in Krt18(-/-) mice, which accumulate KRT8, closely resembles human SH lipid profiles and shows that the excess of KRT8 over KRT18 determines the likelihood to develop SH-associated HCC linked with enhanced lipogenesis. RESULTS: Our analysis of the genetic profile of Krt18(-/-) mice with 26 human hepatoma cell lines and with data sets of amp;gt;300 patients with HCC, where Krt18(-/-) gene signatures matched human HCC. Interestingly, a high KRT8/18 ratio is associated with an aggressive HCC phenotype. CONCLUSIONS: We can prove that intermediate filaments and their binding partners are tightly linked to hepatic lipid metabolism and to hepatocarcinogenesis. We suggest KRT8/18 ratio as a novel HCC biomarker for HCC.
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| 13. |
- Graco-Roza, Caio, et al.
(författare)
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Distance decay 2.0 – A global synthesis of taxonomic and functional turnover in ecological communities
- 2022
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Ingår i: Global Ecology and Biogeography. - : Wiley. - 1466-822X .- 1466-8238. ; 31:7, s. 1399-1421
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Tidskriftsartikel (refereegranskat)abstract
- Aim: Understanding the variation in community composition and species abundances (i.e., beta-diversity) is at the heart of community ecology. A common approach to examine beta-diversity is to evaluate directional variation in community composition by measuring the decay in the similarity among pairs of communities along spatial or environmental distance. We provide the first global synthesis of taxonomic and functional distance decay along spatial and environmental distance by analysing 148 datasets comprising different types of organisms and environments.Location: Global.Time period: 1990 to present.Major taxa studied: From diatoms to mammals.Method: We measured the strength of the decay using ranked Mantel tests (Mantel r) and the rate of distance decay as the slope of an exponential fit using generalized linear models. We used null models to test whether functional similarity decays faster or slower than expected given the taxonomic decay along the spatial and environmental distance. We also unveiled the factors driving the rate of decay across the datasets, including latitude, spatial extent, realm and organismal features.Results: Taxonomic distance decay was stronger than functional distance decay along both spatial and environmental distance. Functional distance decay was random given the taxonomic distance decay. The rate of taxonomic and functional spatial distance decay was fastest in the datasets from mid-latitudes. Overall, datasets covering larger spatial extents showed a lower rate of decay along spatial distance but a higher rate of decay along environmental distance. Marine ecosystems had the slowest rate of decay along environmental distances.Main conclusions: In general, taxonomic distance decay is a useful tool for biogeographical research because it reflects dispersal-related factors in addition to species responses to climatic and environmental variables. Moreover, functional distance decay might be a cost-effective option for investigating community changes in heterogeneous environments.
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| 14. |
- Koenig, Julian, et al.
(författare)
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Cortical thickness and resting-state cardiac function across the lifespan : A cross-sectional pooled mega-analysis
- 2021
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Ingår i: Psychophysiology. - : Wiley. - 0048-5772 .- 1469-8986 .- 1540-5958. ; 58:7
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Tidskriftsartikel (refereegranskat)abstract
- Understanding the association between autonomic nervous system [ANS] function and brain morphology across the lifespan provides important insights into neurovisceral mechanisms underlying health and disease. Resting-state ANS activity, indexed by measures of heart rate [HR] and its variability [HRV] has been associated with brain morphology, particularly cortical thickness [CT]. While findings have been mixed regarding the anatomical distribution and direction of the associations, these inconsistencies may be due to sex and age differences in HR/HRV and CT. Previous studies have been limited by small sample sizes, which impede the assessment of sex differences and aging effects on the association between ANS function and CT. To overcome these limitations, 20 groups worldwide contributed data collected under similar protocols of CT assessment and HR/HRV recording to be pooled in a mega-analysis (N = 1,218 (50.5% female), mean age 36.7 years (range: 12–87)). Findings suggest a decline in HRV as well as CT with increasing age. CT, particularly in the orbitofrontal cortex, explained additional variance in HRV, beyond the effects of aging. This pattern of results may suggest that the decline in HRV with increasing age is related to a decline in orbitofrontal CT. These effects were independent of sex and specific to HRV; with no significant association between CT and HR. Greater CT across the adult lifespan may be vital for the maintenance of healthy cardiac regulation via the ANS—or greater cardiac vagal activity as indirectly reflected in HRV may slow brain atrophy. Findings reveal an important association between CT and cardiac parasympathetic activity with implications for healthy aging and longevity that should be studied further in longitudinal research.
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| 15. |
- Koettgen, Anna, et al.
(författare)
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Genome-wide association analyses identify 18 new loci associated with serum urate concentrations
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:2, s. 145-154
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Tidskriftsartikel (refereegranskat)abstract
- Elevated serum urate concentrations can cause gout, a prevalent and painful inflammatory arthritis. By combining data from >140,000 individuals of European ancestry within the Global Urate Genetics Consortium (GUGC), we identified and replicated 28 genome-wide significant loci in association with serum urate concentrations (18 new regions in or near TRIM46, INHBB, SEMBT1, TMEM171, VEGFA, BAZ1B, PRKAG2, STC1, HNF4G, A1CF, ATXN2, UBE2Q2, IGF1R, NFAT5, MAF, HLF, ACVR1B-ACVRL1 and B3GNT4). Associations for many of the loci were of similar magnitude in individuals of non-European ancestry. We further characterized these loci for associations with gout, transcript expression and the fractional excretion of urate. Network analyses implicate the inhibins-activins signaling pathways and glucose metabolism in systemic urate control. New candidate genes for serum urate concentration highlight the importance of metabolic control of urate production and excretion, which may have implications for the treatment and prevention of gout.
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| 16. |
- Lagou, Vasiliki, et al.
(författare)
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Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability
- 2021
-
Ingår i: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.
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| 17. |
- Leachman, Sancy A., et al.
(författare)
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Selection criteria for genetic assessment of patients with familial melanoma
- 2009
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Ingår i: Journal of American Academy of Dermatology. - : Elsevier BV. - 0190-9622. ; 61:4, s. 677-684
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Forskningsöversikt (refereegranskat)abstract
- Approximately 5% to 10% of melanoma may be hereditary in nature, and about 2% of melanoma can be specifically attributed to pathogenic germline mutations in cyclin-dependent kinase inhibitor 2A (CDKN2A). To appropriately identify the small proportion of patients Who benefit most from referral to a genetics specialist for consideration of genetic testing for CDKN2A, We have reviewed available published studies of CDKN2A mutation analysis in cohorts with invasive, cutaneous melanoma and found variability in the rate of CDKN2A mutations based on geography, ethnicity, and the type of study and eligibility criteria used. Except in regions of high melanoma incidence, such as Australia, we found higher rates of CDKN2A positivity in individuals with 3 or more primary invasive melanomas and/or families with at least one invasive melanoma and two or more other diagnoses of invasive melanoma and/or pancreatic cancer among first- or second-degree relatives on the same side of the family. The Work summarized in this review should help identify individuals who are appropriate candidates for referral for genetic consultation and possible testing. (J Am Acad Dermatol 2009;61:677-84.)
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| 18. |
- Margolskee, Alison, et al.
(författare)
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IMI - oral biopharmaceutics tools project - evaluation of bottom-up PBPK prediction success part 1 : Characterisation of the OrBiTo database of compounds
- 2017
-
Ingår i: European Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0928-0987 .- 1879-0720. ; 96, s. 598-609
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Tidskriftsartikel (refereegranskat)abstract
- Predicting oral bioavailability (F-oral) is of importance for estimating systemic exposure of orally administered drugs. Physiologically-based pharmacokinetic (PBPK) modelling and simulation have been applied extensively in biopharmaceutics recently. The Oral Biopharmaceutical Tools (OrBiTo) project (Innovative Medicines Initiative) aims to develop and improve upon biopharmaceutical tools, including PBPK absorption models. A large-scale evaluation of PBPK models may be considered the first step. Here we characterise the OrBiTo active pharmaceutical ingredient (API) database for use in a large-scale simulation study. The OrBiTo database comprised 83 APIs and 1475 study arms. The database displayed a median logP of 3.60 (2.40-4.58), human blood-to-plasma ratio of 0.62 (0.57-0.71), and fraction unbound in plasma of 0.05 (0.01-0.17). The database mainly consisted of basic compounds (48.19%) and Biopharmaceutics Classification System class II compounds (55.81%). Median human intravenous clearance was 16.9 L/h (interquartile range: 11.6-43.6 L/h; n = 23), volume of distribution was 80.8 L (54.5-239 L; n = 23). The majority of oral formulations were immediate release (IR: 87.6%). Human Foral displayed a median of 0.415 (0.203-0.724; n = 22) for IR formulations. The OrBiTo database was found to be largely representative of previously published datasets. 43 of the APIs were found to satisfy the minimum inclusion criteria for the simulation exercise, and many of these have significant gaps of other key parameters, which could potentially impact the interpretability of the simulation outcome. However, the OrBiTo simulation exercise represents a unique opportunity to perform a large-scale evaluation of the PBPK approach to predicting oral biopharmaceutics.
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| 19. |
- Mueller, Christian P., et al.
(författare)
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The Cortical Neuroimmune Regulator TANK Affects Emotional Processing and Enhances Alcohol Drinking : A Translational Study
- 2019
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Ingår i: Cerebral Cortex. - : OXFORD UNIV PRESS INC. - 1047-3211 .- 1460-2199. ; 29:4, s. 1736-1751
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Tidskriftsartikel (refereegranskat)abstract
- Alcohol abuse is a major public health problem worldwide. Understanding the molecular mechanisms that control regular drinking may help to reduce hazards of alcohol consumption. While immunological mechanisms have been related to alcohol drinking, most studies reported changes in immune function that are secondary to alcohol use. In this report, we analyse how the gene "TRAF family member-associated NF-kappa B activator" (TANK) affects alcohol drinking behavior. Based on our recent discovery in a large GWAS dataset that suggested an association of TANK, SNP rs197273, with alcohol drinking, we report that SNP rs197273 in TANK is associated both with gene expression (P = 1.16 x 10(-19)) and regional methylation (P = 5.90 x 10(-25)). A tank knock out mouse model suggests a role of TANK in alcohol drinking, anxiety-related behavior, as well as alcohol exposure induced activation of insular cortex NF-kappa B. Functional and structural neuroimaging studies among up to 1896 adolescents reveal that TANK is involved in the control of brain activity in areas of aversive interoceptive processing, including the insular cortex, but not in areas related to reinforcement, reward processing or impulsiveness. Our findings suggest that the cortical neuroimmune regulator TANK is associated with enhanced aversive emotional processing that better protects from the establishment of alcohol drinking behavior.
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| 20. |
- Nelson, G., et al.
(författare)
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QUAREP-LiMi: A community-driven initiative to establish guidelines for quality assessment and reproducibility for instruments and images in light microscopy
- 2021
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Ingår i: Journal of Microscopy. - : Wiley. - 0022-2720 .- 1365-2818. ; 284:1, s. 56-73
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Tidskriftsartikel (refereegranskat)abstract
- A modern day light microscope has evolved from a tool devoted to making primarily empirical observations to what is now a sophisticated , quantitative device that is an integral part of both physical and life science research. Nowadays, microscopes are found in nearly every experimental laboratory. However, despite their prevalent use in capturing and quantifying scientific phenomena, neither a thorough understanding of the principles underlying quantitative imaging techniques nor appropriate knowledge of how to calibrate, operate and maintain microscopes can be taken for granted. This is clearly demonstrated by the well-documented and widespread difficulties that are routinely encountered in evaluating acquired data and reproducing scientific experiments. Indeed, studies have shown that more than 70% of researchers have tried and failed to repeat another scientist's experiments, while more than half have even failed to reproduce their own experiments. One factor behind the reproducibility crisis of experiments published in scientific journals is the frequent underreporting of imaging methods caused by a lack of awareness and/or a lack of knowledge of the applied technique. Whereas quality control procedures for some methods used in biomedical research, such as genomics (e.g. DNA sequencing, RNA-seq) or cytometry, have been introduced (e.g. ENCODE), this issue has not been tackled for optical microscopy instrumentation and images. Although many calibration standards and protocols have been published, there is a lack of awareness and agreement on common standards and guidelines for quality assessment and reproducibility. In April 2020, the QUality Assessment and REProducibility for instruments and images in Light Microscopy (QUAREP-LiMi) initiative was formed. This initiative comprises imaging scientists from academia and industry who share a common interest in achieving a better understanding of the performance and limitations of microscopes and improved quality control (QC) in light microscopy. The ultimate goal of the QUAREP-LiMi initiative is to establish a set of common QC standards, guidelines, metadata models and tools, including detailed protocols, with the ultimate aim of improving reproducible advances in scientific research. This White Paper (1) summarizes the major obstacles identified in the field that motivated the launch of the QUAREP-LiMi initiative; (2) identifies the urgent need to address these obstacles in a grassroots manner, through a community of stakeholders including, researchers, imaging scientists, bioimage analysts, bioimage informatics developers, corporate partners, funding agencies, standards organizations, scientific publishers and observers of such; (3) outlines the current actions of the QUAREP-LiMi initiative and (4) proposes future steps that can be taken to improve the dissemination and acceptance of the proposed guidelines to manage QC. To summarize, the principal goal of the QUAREP-LiMi initiative is to improve the overall quality and reproducibility of light microscope image data by introducing broadly accepted standard practices and accurately captured image data metrics.
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| 21. |
- Ntalla, Ioanna, et al.
(författare)
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Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction
- 2020
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N=293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease. On the electrocardiogram, the PR interval reflects conduction from the atria to ventricles and also serves as risk indicator of cardiovascular morbidity and mortality. Here, the authors perform genome-wide meta-analyses for PR interval in multiple ancestries and identify 141 previously unreported genetic loci.
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| 22. |
- Panagopoulou, Paraskevi, et al.
(författare)
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Parental age and the risk of childhood acute myeloid leukemia : results from the Childhood Leukemia International Consortium
- 2019
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Ingår i: Cancer Epidemiology. - : Elsevier BV. - 1877-7821 .- 1877-783X. ; 59, s. 158-165
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Tidskriftsartikel (refereegranskat)abstract
- Background:Parental age has been associated with several childhood cancers, albeit the evidence is still inconsistent.Aim:To examine the associations of parental age at birth with acute myeloid leukemia (AML) among children aged 0-14 years using individual-level data from the Childhood Leukemia International Consortium (CLIC) and non-CLIC studies.Material/methods: We analyzed data of 3182 incident AML cases and 8377 controls from 17 studies [seven registry-based case-control (RCC) studies and ten questionnaire-based case-control (QCC) studies]. AML risk in association with parental age was calculated using multiple logistic regression, meta-analyses, and pooled-effect estimates. Models were stratified by age at diagnosis (infants < 1 year-old vs. children 1-14 years-old) and by study design, using five-year parental age increments and controlling for sex, ethnicity, birthweight, prematurity, multiple gestation, birth order, maternal smoking and education, age at diagnosis (cases aged 1-14 years), and recruitment time period.Results:Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) derived from RCC, but not from the QCC, studies showed a higher AML risk for infants of mothers >= 40-year-old (OR = 6.87; 95% CI: 2.12-22.25). There were no associations observed between any other maternal or paternal age group and AML risk for children older than one year.Conclusions:An increased risk of infant AML with advanced maternal age was found using data from RCC, but not from QCC studies; no parental age-AML associations were observed for older children.
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| 23. |
- Petridou, Eleni Th., et al.
(författare)
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Advanced parental age as risk factor for childhood acute lymphoblastic leukemia : results from studies of the Childhood Leukemia International Consortium
- 2018
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Ingår i: European Journal of Epidemiology. - : SPRINGER. - 0393-2990 .- 1573-7284. ; 33:10, s. 965-976
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Tidskriftsartikel (refereegranskat)abstract
- Advanced parental age has been associated with adverse health effects in the offspring including childhood (0-14 years) acute lymphoblastic leukemia (ALL), as reported in our meta-analysis of published studies. We aimed to further explore the association using primary data from 16 studies participating in the Childhood Leukemia International Consortium. Data were contributed by 11 case-control (CC) studies (7919 cases and 12,942 controls recruited via interviews) and five nested case-control (NCC) studies (8801 cases and 29,690 controls identified through record linkage of population-based health registries) with variable enrollment periods (1968-2015). Five-year paternal and maternal age increments were introduced in two meta-analyses by study design using adjusted odds ratios (OR) derived from each study. Increased paternal age was associated with greater ALL risk in the offspring (ORCC 1.05, 95% CI 1.00-1.11; ORNCC 1.04, 95% CI 1.01-1.07). A similar positive association with advanced maternal age was observed only in the NCC results (ORCC 0.99, 95% CI 0.91-1.07, heterogeneity I (2) = 58%, p = 0.002; ORNCC 1.05, 95% CI 1.01-1.08). The positive association between parental age and risk of ALL was most marked among children aged 1-5 years and remained unchanged following mutual adjustment for the collinear effect of the paternal and maternal age variables; analyses of the relatively small numbers of discordant paternal-maternal age pairs were not fully enlightening. Our results strengthen the evidence that advanced parental age is associated with increased childhood ALL risk; collinearity of maternal with paternal age complicates causal interpretation. Employing datasets with cytogenetic information may further elucidate involvement of each parental component and clarify underlying mechanisms.
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| 24. |
- Scott, Robert A., et al.
(författare)
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An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans
- 2017
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 66:11, s. 2888-2902
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Tidskriftsartikel (refereegranskat)abstract
- To characterize type 2 diabetes (T2D)-associated variation across the allele frequency spectrum, we conducted a meta-analysis of genome-wide association data from 26,676 T2D case and 132,532 control subjects of European ancestry after imputation using the 1000 Genomes multiethnic reference panel. Promising association signals were followed up in additional data sets (of 14,545 or 7,397 T2D case and 38,994 or 71,604 control subjects). We identified 13 novel T2D-associated loci (P < 5 x 10(-8)), including variants near the GLP2R, GIP, and HLA-DQA1 genes. Our analysis brought the total number of independent T2D associations to 128 distinct signals at 113 loci. Despite substantially increased sample size and more complete coverage of low-frequency variation, all novel associations were driven by common single nucleotide variants. Credible sets of potentially causal variants were generally larger than those based on imputation with earlier reference panels, consistent with resolution of causal signals to common risk haplotypes. Stratification of T2D-associated loci based on T2D-related quantitative trait associations revealed tissue-specific enrichment of regulatory annotations in pancreatic islet enhancers for loci influencing insulin secretion and in adipocytes, monocytes, and hepatocytes for insulin action-associated loci. These findings highlight the predominant role played by common variants of modest effect and the diversity of biological mechanisms influencing T2D pathophysiology.
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| 25. |
- Tavares, Julia, et al.
(författare)
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Basin-wide variation in tree hydraulic safety margins predicts the carbon balance of Amazon forests
- 2023
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Ingår i: Nature. - : Springer Nature. - 0028-0836 .- 1476-4687. ; 617:7959, s. 111-117
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Tidskriftsartikel (refereegranskat)abstract
- Tropical forests face increasing climate risk(1,2), yet our ability to predict their response to climate change is limited by poor understanding of their resistance to water stress. Although xylem embolism resistance thresholds (for example, ?(50)) and hydraulic safety margins (for example, HSM50) are important predictors of drought-induced mortality risk(3-5), little is known about how these vary across Earth's largest tropical forest. Here, we present a pan-Amazon, fully standardized hydraulic traits dataset and use it to assess regional variation in drought sensitivity and hydraulic trait ability to predict species distributions and long-term forest biomass accumulation. Parameters ?(50) and HSM50 vary markedly across the Amazon and are related to average long-term rainfall characteristics. Both ?(50) and HSM50 influence the biogeographical distribution of Amazon tree species. However, HSM50 was the only significant predictor of observed decadal-scale changes in forest biomass. Old-growth forests with wide HSM50 are gaining more biomass than are low HSM(50 )forests. We propose that this may be associated with a growth-mortality trade-off whereby trees in forests consisting of fast-growing species take greater hydraulic risks and face greater mortality risk. Moreover, in regions of more pronounced climatic change, we find evidence that forests are losing biomass, suggesting that species in these regions may be operating beyond their hydraulic limits. Continued climate change is likely to further reduce HSM50 in the Amazon(6,7), with strong implications for the Amazon carbon sink.
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