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| 2. |
- Mahajan, Anubha, et al.
(author)
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Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes
- 2018
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In: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 50:4, s. 559-571
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Journal article (peer-reviewed)abstract
- We aggregated coding variant data for 81,412 type 2 diabetes cases and 370,832 controls of diverse ancestry, identifying 40 coding variant association signals (P < 2.2 × 10−7); of these, 16 map outside known risk-associated loci. We make two important observations. First, only five of these signals are driven by low-frequency variants: even for these, effect sizes are modest (odds ratio ≤1.29). Second, when we used large-scale genome-wide association data to fine-map the associated variants in their regional context, accounting for the global enrichment of complex trait associations in coding sequence, compelling evidence for coding variant causality was obtained for only 16 signals. At 13 others, the associated coding variants clearly represent ‘false leads’ with potential to generate erroneous mechanistic inference. Coding variant associations offer a direct route to biological insight for complex diseases and identification of validated therapeutic targets; however, appropriate mechanistic inference requires careful specification of their causal contribution to disease predisposition.
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| 3. |
- North, R. L., et al.
(author)
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The state of Lake Simcoe (Ontario, Canada) : the effects of multiple stressors on phosphorus and oxygen dynamics
- 2013
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In: Inland Waters. - 2044-2041 .- 2044-205X. ; 3:1, s. 51-74
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Journal article (peer-reviewed)abstract
- Lake Simcoe, the largest lake in southern Ontario outside of the Laurentian Great Lakes, is affected by numerous stressors including eutrophication resulting from total phosphorus (TP) loading, climate change, and invasions of exotic species. We synthesized the long-term responses of Lake Simcoe to these stressors by assessing trends in water quality and biological composition over multiple trophic levels. Evidence for climate change included increasing thermal stability of the lake and changes in subfossil diatom communities over time. Although the deep water dissolved oxygen (O-2) minimum has increased significantly since TP load reductions, it is still below estimated historical values and the Lake Simcoe Protection Plan end-of-summer target level of 7 mg O-2 L-1. Low deep water O-2 concentrations corresponded with a decline in coldwater fish abundance. Since 1980, some nutrient concentrations have decreased (spring TP) while others have increased (silica), but many show no obvious changes (ice-free TP, nitrate, ammonium). Increases in water clarity, combined with declines in chlorophyll a and phytoplankton biovolumes in Cook's Bay, were temporally consistent with declines in TP loading and the lake-wide establishment of dreissenid mussels as a major component of the Lake Simcoe ecosystem. Using an investigative tool, we identified 2 periods when abrupt shifts potentially occurred in multiple parameters: 1986 and 1995-1997. Additional ecosystem level changes such as declines in zooplankton, declines in offshore benthic invertebrate abundance, and increased nearshore invertebrate abundance likely reflect the effects of invasive species. The interaction of these multiple stressors have significantly altered the Lake Simcoe ecosystem.
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| 4. |
- Azzoni, Emanuele, et al.
(author)
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The onset of circulation triggers a metabolic switch required for endothelial to hematopoietic transition
- 2021
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In: Cell Reports. - : Elsevier BV. - 2211-1247. ; 37:11
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Journal article (peer-reviewed)abstract
- Hematopoietic stem cells (HSCs) emerge during development from the vascular wall of the main embryonic arteries. The onset of circulation triggers several processes that provide critical external factors for HSC generation. Nevertheless, it is not fully understood how and when the onset of circulation affects HSC emergence. Here we show that in Ncx1−/− mouse embryos devoid of circulation the HSC lineage develops until the phenotypic pro-HSC stage. However, these cells reside in an abnormal microenvironment, fail to activate the hematopoietic program downstream of Runx1, and are functionally impaired. Single-cell transcriptomics shows that during the endothelial-to-hematopoietic transition, Ncx1−/− cells fail to undergo a glycolysis to oxidative phosphorylation metabolic switch present in wild-type cells. Interestingly, experimental activation of glycolysis results in decreased intraembryonic hematopoiesis. Our results suggest that the onset of circulation triggers metabolic changes that allow HSC generation to proceed.
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| 7. |
- Sasic Kalagasidis, Angela, 1968, et al.
(author)
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The International Building Physics Toolbox in Simulink
- 2007
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In: Energy and Buildings. - : Elsevier BV. - 0378-7788. ; 39:6, s. 665-674
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Journal article (peer-reviewed)abstract
- The International Building Physics Toolbox (IBPT) is a software library developed originally for heat, air and moisture system analysis in building physics. The toolbox is constructed as a modular structure of standard building elements, using the graphical programming language Simulink. To enable development of the toolbox, a common modelling platform is defined: a set of unique communication signals, material database and documentation protocol. The IBPT is an open source and available on the Internet. Any user can utilize, expand and develop the contents of the toolbox. This paper presents structure and essence of the library. Potential applications of the toolbox are illustrated through examples. (C) 2006 Elsevier B.V. All rights reserved.
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| 10. |
- Imaz-Rosshandler, Ivan, et al.
(author)
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Tracking early mammalian organogenesis - prediction and validation of differentiation trajectories at whole organism scale
- 2024
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In: DEVELOPMENT. - 0950-1991 .- 1477-9129. ; 151:3
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Journal article (peer-reviewed)abstract
- Early organogenesis represents a key step in animal development, during which pluripotent cells diversify to initiate organ formation. Here, we sampled 300,000 single-cell transcriptomes from mouse embryos between E8.5 and E9.5 in 6-h intervals and combined this new dataset with our previous atlas (E6.5-E8.5) to produce a densely sampled timecourse of >400,000 cells from early gastrulation to organogenesis. Computational lineage reconstruction identified complex waves of blood and endothelial development, including a new programme for somite-derived endothelium. We also dissected the E7.5 primitive streak into four adjacent regions, performed scRNA-seq and predicted cell fates computationally. Finally, we defined developmental state/ fate relationships by combining orthotopic grafting, microscopic analysis and scRNA-seq to transcriptionally determine cell fates of grafted primitive streak regions after 24 h of in vitro embryo culture. Experimentally determined fate outcomes were in good agreement with computationally predicted fates, demonstrating how classical grafting experiments can be revisited to establish high-resolution cell state/fate relationships. Such interdisciplinary approaches will benefit future studies in developmental biology and guide the in vitro production of cells for organ regeneration and repair.
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| 11. |
- Islar, Mine, et al.
(author)
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Diverse values of nature for sustainability
- 2022
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In: Nature. - 0028-0836 .- 1476-4687. ; 620, s. 813-823
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Journal article (peer-reviewed)abstract
- Twenty-five years since foundational publications on valuing ecosystem services for human well-being1,2, addressing the global biodiversity crisis3 still implies confronting barriers to incorporating nature’s diverse values into decision-making. These barriers include powerful interests supported by current norms and legal rules such as property rights, which determine whose values and which values of nature are acted on. A better understanding of how and why nature is (under)valued is more urgent than ever4. Notwithstanding agreements to incorporate nature’s values into actions, including the Kunming-Montreal Global Biodiversity Framework (GBF)5 and the UN Sustainable Development Goals6, predominant environmental and development policies still prioritize a subset of values, particularly those linked to markets, and ignore other ways people relate to and benefit from nature7. Arguably, a ‘values crisis’ underpins the intertwined crises of biodiversity loss and climate change8, pandemic emergence9 and socio-environmental injustices10. On the basis of more than 50,000 scientific publications, policy documents and Indigenous and local knowledge sources, the Intergovernmental Platform on Biodiversity and Ecosystem Services (IPBES) assessed knowledge on nature’s diverse values and valuation methods to gain insights into their role in policymaking and fuller integration into decisions7,11. Applying this evidence, combinations of values-centred approaches are proposed to improve valuation and address barriers to uptake, ultimately leveraging transformative changes towards more just (that is, fair treatment of people and nature, including inter- and intragenerational equity) and sustainable futures.
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| 12. |
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| 13. |
- Rode, C., et al.
(author)
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Moisture Buffer Value of Building Materials
- 2006
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Conference paper (peer-reviewed)abstract
- Building materials and furnishing used in contact with indoor air may have a positive effect to moderate the variations of indoor humidity seen in occupied buildings. Thus, very low humidity can be alleviated in winter, as well as can high indoor humidity in summer and during high occupancy loads. This way, materials can be used as a passive means of establishing indoor climatic conditions, which are comfortable for human occupancy, or for safe storing of artefacts which are sensible to humidity variation. But so far there has been a lack of a standardized figure to characterize the moisture buffering ability of materials. It has been the objective of a recent (ongoing until mid-2005) Nordic project to come up with such a definition, and to declare it in the form of a NORDTEST method. Apart from the definition of the term Moisture Buffer Value, there will also be a declaration of a test protocol which expresses how materials should be tested. Finally as a part of the project, some Round Robin Tests will be carried out on various typical building materials. The paper gives an account on the definition of the Moisture Buffer Value, it will outline the content of the test protocol, and it will give some examples of results from the Round Robin Tests.
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| 14. |
- Roeder, SS, et al.
(author)
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Evidence for postnatal neurogenesis in the human amygdala
- 2022
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In: Communications biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 5:1, s. 366-
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Journal article (peer-reviewed)abstract
- The human amygdala is involved in processing of memory, decision-making, and emotional responses. Previous studies suggested that the amygdala may represent a neurogenic niche in mammals. By combining two distinct methodological approaches, lipofuscin quantification and 14C-based retrospective birth dating of neurons, along with mathematical modelling, we here explored whether postnatal neurogenesis exists in the human amygdala. We investigated post-mortem samples of twelve neurologically healthy subjects. The average rate of lipofuscin-negative neurons was 3.4%, representing a substantial proportion of cells substantially younger than the individual. Mass spectrometry analysis of genomic 14C-concentrations in amygdala neurons compared with atmospheric 14C-levels provided evidence for postnatal neuronal exchange. Mathematical modelling identified a best-fitting scenario comprising of a quiescent and a renewing neuronal population with an overall renewal rate of >2.7% per year. In conclusion, we provide evidence for postnatal neurogenesis in the human amygdala with cell turnover rates comparable to the hippocampus.
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| 15. |
- Silvério-Alves, Rita, et al.
(author)
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GATA2 mitotic bookmarking is required for definitive haematopoiesis
- 2023
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In: Nature Communications. - 2041-1723. ; 14:1
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Journal article (peer-reviewed)abstract
- In mitosis, most transcription factors detach from chromatin, but some are retained and bookmark genomic sites. Mitotic bookmarking has been implicated in lineage inheritance, pluripotency and reprogramming. However, the biological significance of this mechanism in vivo remains unclear. Here, we address mitotic retention of the hemogenic factors GATA2, GFI1B and FOS during haematopoietic specification. We show that GATA2 remains bound to chromatin throughout mitosis, in contrast to GFI1B and FOS, via C-terminal zinc finger-mediated DNA binding. GATA2 bookmarks a subset of its interphase targets that are co-enriched for RUNX1 and other regulators of definitive haematopoiesis. Remarkably, homozygous mice harbouring the cyclin B1 mitosis degradation domain upstream Gata2 partially phenocopy knockout mice. Degradation of GATA2 at mitotic exit abolishes definitive haematopoiesis at aorta-gonad-mesonephros, placenta and foetal liver, but does not impair yolk sac haematopoiesis. Our findings implicate GATA2-mediated mitotic bookmarking as critical for definitive haematopoiesis and highlight a dependency on bookmarkers for lineage commitment.
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| 16. |
- Smith, Mike K., et al.
(author)
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Model Description Language (MDL) : A Standard for Modeling and Simulation
- 2017
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In: CPT. - : WILEY. - 2163-8306. ; 6:10, s. 647-650
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Journal article (peer-reviewed)abstract
- Recent work on Model Informed Drug Discovery and Development (MID3) has noted the need for clarity in model description used in quantitative disciplines such as pharmacology and statistics. 1-3 Currently, models are encoded in a variety of computer languages and are shared through publications that rarely include original code and generally lack reproducibility. The DDMoRe Model Description Language (MDL) has been developed primarily as a language standard to facilitate sharing knowledge and understanding of models.
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| 17. |
- Sobolev, Egor, et al.
(author)
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Megahertz single-particle imaging at the European XFEL
- 2020
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In: Communications Physics. - : Springer Science and Business Media LLC. - 2399-3650. ; 3:1
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Journal article (peer-reviewed)abstract
- The emergence of high repetition-rate X-ray free-electron lasers (XFELs) powered by superconducting accelerator technology enables the measurement of significantly more experimental data per day than was previously possible. The European XFEL is expected to provide 27,000 pulses per second, over two orders of magnitude more than any other XFEL. The increased pulse rate is a key enabling factor for single-particle X-ray diffractive imaging, which relies on averaging the weak diffraction signal from single biological particles. Taking full advantage of this new capability requires that all experimental steps, from sample preparation and delivery to the acquisition of diffraction patterns, are compatible with the increased pulse repetition rate. Here, we show that single-particle imaging can be performed using X-ray pulses at megahertz repetition rates. The results obtained pave the way towards exploiting high repetition-rate X-ray free-electron lasers for single-particle imaging at their full repetition rate.
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