| 1. |
- Birney, Ewan, et al.
(författare)
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Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project
- 2007
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 447:7146, s. 799-816
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Tidskriftsartikel (refereegranskat)abstract
- We report the generation and analysis of functional data from multiple, diverse experiments performed on a targeted 1% of the human genome as part of the pilot phase of the ENCODE Project. These data have been further integrated and augmented by a number of evolutionary and computational analyses. Together, our results advance the collective knowledge about human genome function in several major areas. First, our studies provide convincing evidence that the genome is pervasively transcribed, such that the majority of its bases can be found in primary transcripts, including non-protein-coding transcripts, and those that extensively overlap one another. Second, systematic examination of transcriptional regulation has yielded new understanding about transcription start sites, including their relationship to specific regulatory sequences and features of chromatin accessibility and histone modification. Third, a more sophisticated view of chromatin structure has emerged, including its inter-relationship with DNA replication and transcriptional regulation. Finally, integration of these new sources of information, in particular with respect to mammalian evolution based on inter- and intra-species sequence comparisons, has yielded new mechanistic and evolutionary insights concerning the functional landscape of the human genome. Together, these studies are defining a path for pursuit of a more comprehensive characterization of human genome function.
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| 2. |
- Margulies, Elliott H, et al.
(författare)
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Analyses of deep mammalian sequence alignments and constraint predictions for 1% of the human genome
- 2007
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Ingår i: Genome Research. - : Cold Spring Harbor Laboratory. - 1088-9051 .- 1549-5469. ; 17:6, s. 760-774
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Tidskriftsartikel (refereegranskat)abstract
- A key component of the ongoing ENCODE project involves rigorous comparative sequence analyses for the initially targeted 1% of the human genome. Here, we present orthologous sequence generation, alignment, and evolutionary constraint analyses of 23 mammalian species for all ENCODE targets. Alignments were generated using four different methods; comparisons of these methods reveal large-scale consistency but substantial differences in terms of small genomic rearrangements, sensitivity (sequence coverage), and specificity (alignment accuracy). We describe the quantitative and qualitative trade-offs concomitant with alignment method choice and the levels of technical error that need to be accounted for in applications that require multisequence alignments. Using the generated alignments, we identified constrained regions using three different methods. While the different constraint-detecting methods are in general agreement, there are important discrepancies relating to both the underlying alignments and the specific algorithms. However, by integrating the results across the alignments and constraint-detecting methods, we produced constraint annotations that were found to be robust based on multiple independent measures. Analyses of these annotations illustrate that most classes of experimentally annotated functional elements are enriched for constrained sequences; however, large portions of each class (with the exception of protein-coding sequences) do not overlap constrained regions. The latter elements might not be under primary sequence constraint, might not be constrained across all mammals, or might have expendable molecular functions. Conversely, 40% of the constrained sequences do not overlap any of the functional elements that have been experimentally identified. Together, these findings demonstrate and quantify how many genomic functional elements await basic molecular characterization.
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| 3. |
- Moshontz, Hannah, et al.
(författare)
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The Psychological Science Accelerator: Advancing Psychology Through a Distributed Collaborative Network
- 2018
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Ingår i: Advances in Methods and Practices in Psychological Science. - : SAGE Publications. - 2515-2459 .- 2515-2467. ; 1:4, s. 501-515
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Tidskriftsartikel (refereegranskat)abstract
- Concerns about the veracity of psychological research have been growing. Many findings in psychological science are based on studies with insufficient statistical power and nonrepresentative samples, or may otherwise be limited to specific, ungeneralizable settings or populations. Crowdsourced research, a type of large-scale collaboration in which one or more research projects are conducted across multiple lab sites, offers a pragmatic solution to these and other current methodological challenges. The Psychological Science Accelerator (PSA) is a distributed network of laboratories designed to enable and support crowdsourced research projects. These projects can focus on novel research questions or replicate prior research in large, diverse samples. The PSA’s mission is to accelerate the accumulation of reliable and generalizable evidence in psychological science. Here, we describe the background, structure, principles, procedures, benefits, and challenges of the PSA. In contrast to other crowdsourced research networks, the PSA is ongoing (as opposed to time limited), efficient (in that structures and principles are reused for different projects), decentralized, diverse (in both subjects and researchers), and inclusive (of proposals, contributions, and other relevant input from anyone inside or outside the network). The PSA and other approaches to crowdsourced psychological science will advance understanding of mental processes and behaviors by enabling rigorous research and systematic examination of its generalizability.
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| 4. |
- Thors, Lina, 1981-, et al.
(författare)
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Biochanin A acts as a peripheral inhibitor of fatty acid amide hydrolase
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Inhibitors of fatty acid amide hydrolase (FAAH), the enzyme primarily responsible for the metabolism of the endogenous cannabinoid (CB) receptor ligand anandamide, are effective in animal models of inflammatory, cancer, visceral and neuropathic pain. No peripherallyrestricted FAAH inhibitors have yet been reported. The isoflavones are a class of naturallyoccurring compounds that show little brain penetration, and two of these, genistein and daidzein, inhibit FAAH at low micromolar concentrations. Here, we report that the related isoflavone biochanin A inhibits the hydrolysis of 0.5 μM anandamide by mouse, rat and human FAAH with IC50 values of 1.8, 1.4, and 2.4 μM, respectively. The inhibition of rat FAAH by biochanin A was mixed type in nature, with Ki slope and Ki intercept values of 1.1 and 8.2 μM, respectively. Anandamide hydrolysis was also inhibited in intact basophilic leukaemia cells at sub- to low- micromolar concentrations. The compound did not interact to any major extent with CB1 or CB2 receptors. In vivo, biochanin A (10 mg/kg i.v.) did not increase brain anandamide concentrations, but produced a modest potentiation of the effects of 10 mg/kg i.v. anandamide in the tetrad test. In anaesthetized mice, URB597 (30 μg/paw) and biochanin A (100 μg/paw) both inhibited the spinal phosphorylation of extracellular receptor kinase produced by the intraplantar injection of formalin. The effects of both compounds were significantly reduced by the CB1 receptor antagonist/inverse agonist AM251 (30 μg/paw). It is concluded that biochanin A may be useful as a template for the design of novel, peripherally-acting FAAH inhibitors.
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| 5. |
- Babulal, Ganesh M, et al.
(författare)
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Perspectives on ethnic and racial disparities in Alzheimer's disease and related dementias: Update and areas of immediate need.
- 2019
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Ingår i: Alzheimer's & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 15:2, s. 292-312
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer's disease and related dementias (ADRDs) are a global crisis facing the aging population and society as a whole. With the numbers of people with ADRDs predicted to rise dramatically across the world, the scientific community can no longer neglect the need for research focusing on ADRDs among underrepresented ethnoracial diverse groups. The Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment (ISTAART; alz.org/ISTAART) comprises a number of professional interest areas (PIAs), each focusing on a major scientific area associated with ADRDs. We leverage the expertise of the existing international cadre of ISTAART scientists and experts to synthesize a cross-PIA white paper that provides both a concise "state-of-the-science" report of ethnoracial factors across PIA foci and updated recommendations to address immediate needs to advance ADRD science across ethnoracial populations.
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| 6. |
- Bratman, Gregory N., et al.
(författare)
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Nature and mental health : An ecosystem service perspective
- 2019
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Ingår i: Science Advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 5:7
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Forskningsöversikt (refereegranskat)abstract
- A growing body of empirical evidence is revealing the value of nature experience for mental health. With rapid urbanization and declines in human contact with nature globally, crucial decisions must be made about how to preserve and enhance opportunities for nature experience. Here, we first provide points of consensus across the natural, social, and health sciences on the impacts of nature experience on cognitive functioning, emotional well-being, and other dimensions of mental health. We then show how ecosystem service assessments can be expanded to include mental health, and provide a heuristic, conceptual model for doing so.
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| 7. |
- Christmas, Matthew, et al.
(författare)
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Evolutionary constraint and innovation across hundreds of placental mammals
- 2023
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 380:6643
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Tidskriftsartikel (refereegranskat)abstract
- Zoonomia is the largest comparative genomics resource for mammals produced to date. By aligning genomes for 240 species, we identify bases that, when mutated, are likely to affect fitness and alter disease risk. At least 332 million bases (similar to 10.7%) in the human genome are unusually conserved across species (evolutionarily constrained) relative to neutrally evolving repeats, and 4552 ultraconserved elements are nearly perfectly conserved. Of 101 million significantly constrained single bases, 80% are outside protein-coding exons and half have no functional annotations in the Encyclopedia of DNA Elements (ENCODE) resource. Changes in genes and regulatory elements are associated with exceptional mammalian traits, such as hibernation, that could inform therapeutic development. Earth's vast and imperiled biodiversity offers distinctive power for identifying genetic variants that affect genome function and organismal phenotypes.
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| 8. |
- Jandrić, Petar, et al.
(författare)
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Teaching in the Age of Covid-19
- 2020
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Ingår i: Postdigital Science and Education. - : Springer Science and Business Media LLC. - 2524-4868 .- 2524-485X. ; 2:3, s. 1069-1230
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- A collection of 84 author's testimonies and workspace photographs between 18 March and 5 May 2020.
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| 9. |
- Jandrić, Petar, et al.
(författare)
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Teaching in the Age of Covid-19—1 Year Later
- 2021
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Ingår i: Postdigital Science and Education. - : Springer. - 2524-485X .- 2524-4868. ; 3:3, s. 1073-1223
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Tidskriftsartikel (refereegranskat)
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| 10. |
- Remme, Roy P., et al.
(författare)
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An ecosystem service perspective on urban nature, physical activity, and health
- 2021
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 118:22
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Tidskriftsartikel (refereegranskat)abstract
- Nature underpins human well-being in critical ways, especially in health. Nature provides pollination of nutritious crops, purification of drinking water, protection from floods, and climate security, among other well-studied health benefits. A crucial, yet challenging, research frontier is clarifying how nature promotes physical activity for its many mental and physical health benefits, particularly in densely populated cities with scarce and dwindling access to nature. Here we frame this frontier by conceptually developing a spatial decision-support tool that shows where, how, and for whom urban nature promotes physical activity, to inform urban greening efforts and broader health assessments. We synthesize what is known, present a model framework, and detail the model steps and data needs that can yield generalizable spatial models and an effective tool for assessing the urban nature-physical activity relationship. Current knowledge supports an initial model that can distinguish broad trends and enrich urban planning, spatial policy, and public health decisions. New, iterative research and application will reveal the importance of different types of urban nature, the different subpopulations who will benefit from it, and nature's potential contribution to creating more equitable, green, livable cities with active inhabitants.
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| 11. |
- Andrews, Timothy, et al.
(författare)
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On the Effect of Historical SST Patterns on Radiative Feedback
- 2022
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Ingår i: Journal of Geophysical Research - Atmospheres. - 2169-897X .- 2169-8996. ; 127:18
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Tidskriftsartikel (refereegranskat)abstract
- We investigate the dependence of radiative feedback on the pattern of sea-surface temperature (SST) change in 14 Atmospheric General Circulation Models (AGCMs) forced with observed variations in SST and sea-ice over the historical record from 1871 to near-present. We find that over 1871–1980, the Earth warmed with feedbacks largely consistent and strongly correlated with long-term climate sensitivity feedbacks (diagnosed from corresponding atmosphere-ocean GCM abrupt-4xCO2 simulations). Post 1980, however, the Earth warmed with unusual trends in tropical Pacific SSTs (enhanced warming in the west, cooling in the east) and cooling in the Southern Ocean that drove climate feedback to be uncorrelated with—and indicating much lower climate sensitivity than—that expected for long-term CO2 increase. We show that these conclusions are not strongly dependent on the Atmospheric Model Intercomparison Project (AMIP) II SST data set used to force the AGCMs, though the magnitude of feedback post 1980 is generally smaller in nine AGCMs forced with alternative HadISST1 SST boundary conditions. We quantify a “pattern effect” (defined as the difference between historical and long-term CO2 feedback) equal to 0.48 ± 0.47 [5%–95%] W m−2 K−1 for the time-period 1871–2010 when the AGCMs are forced with HadISST1 SSTs, or 0.70 ± 0.47 [5%–95%] W m−2 K−1 when forced with AMIP II SSTs. Assessed changes in the Earth's historical energy budget agree with the AGCM feedback estimates. Furthermore satellite observations of changes in top-of-atmosphere radiative fluxes since 1985 suggest that the pattern effect was particularly strong over recent decades but may be waning post 2014.
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| 12. |
- Robinson, Adam H., et al.
(författare)
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Multiscale characterisation of chimneys/pipes : Fluid escape structures within sedimentary basins
- 2021
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Ingår i: International Journal of Greenhouse Gas Control. - : Elsevier BV. - 1750-5836 .- 1878-0148. ; 106
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Tidskriftsartikel (refereegranskat)abstract
- Evaluation of seismic reflection data has identified the presence of fluid escape structures cross-cutting overburden stratigraphy within sedimentary basins globally. Seismically-imaged chimneys/pipes are considered to be possible pathways for fluid flow, which may hydraulically connect deeper strata to the seabed. The properties of fluid migration pathways through the overburden must be constrained to enable secure, long-term subsurface carbon dioxide (CO2) storage. We have investigated a site of natural active fluid escape in the North Sea, the Scanner pockmark complex, to determine the physical characteristics of focused fluid conduits, and how they control fluid flow. Here we show that a multi-scale, multi-disciplinary experimental approach is required for complete characterisation of fluid escape structures. Geophysical techniques are necessary to resolve fracture geometry and subsurface structure (e.g., multi-frequency seismics) and physical parameters of sediments (e.g., controlled source electromagnetics) across a wide range of length scales (m to km). At smaller (mm to cm) scales, sediment cores were sampled directly and their physical and chemical properties assessed using laboratory-based methods. Numerical modelling approaches bridge the resolution gap, though their validity is dependent on calibration and constraint from field and laboratory experimental data. Further, time-lapse seismic and acoustic methods capable of resolving temporal changes are key for determining fluid flux. Future optimisation of experiment resource use may be facilitated by the installation of permanent seabed infrastructure, and replacement of manual data processing with automated workflows. This study can be used to inform measurement, monitoring and verification workflows that will assist policymaking, regulation, and best practice for CO2 subsurface storage operations.
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| 13. |
- Sultana, M. Afifa, et al.
(författare)
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Downmodulation of Effector Functions in NK Cells upon Toxoplasma gondii Infection
- 2017
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Ingår i: Infection and Immunity. - 0019-9567 .- 1098-5522. ; 85:10
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Tidskriftsartikel (refereegranskat)abstract
- The obligate intracellular parasite Toxoplasma gondii can actively infect any nucleated cell type, including cells from the immune system. The rapid transfer of T. gondii from infected dendritic cells to effector natural killer (NK) cells may contribute to the parasite's sequestration and shielding from immune recognition shortly after infection. However, subversion of NK cell functions, such as cytotoxicity or production of proinflammatory cytokines, such as gamma interferon (IFN-γ), upon parasite infection might also be beneficial to the parasite. In the present study, we investigated the effects of T. gondii infection on NK cells. In vitro, infected NK cells were found to be poor at killing target cells and had reduced levels of IFN-γ production. This could be attributed in part to the inability of infected cells to form conjugates with their target cells. However, even upon NK1.1 cross-linking of NK cells, the infected NK cells also exhibited poor degranulation and IFN-γ production. Similarly, NK cells infected in vivo were also poor at killing target cells and producing IFN-γ. Increased levels of transforming growth factor β production, as well as increased levels of expression of SHP-1 in the cytosol of infected NK cells upon infection, were observed in infected NK cells. However, the phosphorylation of STAT4 was not altered in infected NK cells, suggesting that transcriptional regulation mediates the reduced IFN-γ production, which was confirmed by quantitative PCR. These data suggest that infection of NK cells by T. gondii impairs NK cell recognition of target cells and cytokine release, two mechanisms that independently could enhance T. gondii survival.
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