| 1. |
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| 2. |
- Tabiri, S, et al.
(author)
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- 2021
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swepub:Mat__t
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| 3. |
- Bravo, L, et al.
(author)
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- 2021
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swepub:Mat__t
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| 4. |
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| 5. |
- Glasbey, JC, et al.
(author)
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- 2021
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swepub:Mat__t
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| 6. |
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| 7. |
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| 8. |
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| 9. |
- Dalton, A. S., et al.
(author)
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An updated radiocarbon-based ice margin chronology for the last deglaciation of the North American Ice Sheet Complex
- 2020
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In: Quaternary Science Reviews. - : Elsevier BV. - 0277-3791. ; 234
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Journal article (peer-reviewed)abstract
- The North American Ice Sheet Complex (NAISC; consisting of the Laurentide, Cordilleran and Innuitian ice sheets) was the largest ice mass to repeatedly grow and decay in the Northern Hemisphere during the Quaternary. Understanding its pattern of retreat following the Last Glacial Maximum is critical for studying many facets of the Late Quaternary, including ice sheet behaviour, the evolution of Holocene landscapes, sea level, atmospheric circulation, and the peopling of the Americas. Currently, the most up-to-date and authoritative margin chronology for the entire ice sheet complex is featured in two publications (Geological Survey of Canada Open File 1574 [Dyke et al., 2003]; 'Quaternary Glaciations - Extent and Chronology, Part II' [Dyke, 2004]). These often-cited datasets track ice margin recession in 36 time slices spanning 18 ka to 1 ka (all ages in uncalibrated radiocarbon years) using a combination of geomorphology, stratigraphy and radiocarbon dating. However, by virtue of being over 15 years old, the ice margin chronology requires updating to reflect new work and important revisions. This paper updates the aforementioned 36 ice margin maps to reflect new data from regional studies. We also update the original radiocarbon dataset from the 2003/2004 papers with 1541 new ages to reflect work up to and including 2018. A major revision is made to the 18 ka ice margin, where Banks and Eglinton islands (once considered to be glacial refugia) are now shown to be fully glaciated. Our updated 18 ka ice sheet increased in areal extent from 17.81 to 18.37 million km(2), which is an increase of 3.1% in spatial coverage of the NAISC at that time. Elsewhere, we also summarize, region-by-region, significant changes to the deglaciation sequence. This paper integrates new information provided by regional experts and radiocarbon data into the deglaciation sequence while maintaining consistency with the original ice margin positions of Dyke et al. (2003) and Dyke (2004) where new information is lacking; this is a pragmatic solution to satisfy the needs of a Quaternary research community that requires up-to-date knowledge of the pattern of ice margin recession of what was once the world's largest ice mass. The 36 updated isochrones are available in PDF and shapefile format, together with a spreadsheet of the expanded radiocarbon dataset (n = 5195 ages) and estimates of uncertainty for each interval. (C) 2020 Elsevier Ltd. All rights reserved.
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| 10. |
- Canelas, A.B., et al.
(author)
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Integrated multilaboratory systems biology reveals differences in protein metabolism between two reference yeast strains
- 2010
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723 .- 2041-1723. ; 1:9
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Journal article (peer-reviewed)abstract
- The field of systems biology is often held back by difficulties in obtaining comprehensive, high-quality, quantitative data sets. In this paper, we undertook an interlaboratory effort to generate such a data set for a very large number of cellular components in the yeast Saccharomyces cerevisiae, a widely used model organism that is also used in the production of fuels, chemicals, food ingredients and pharmaceuticals. With the current focus on biofuels and sustainability, there is much interest in harnessing this species as a general cell factory. In this study, we characterized two yeast strains, under two standard growth conditions. We ensured the high quality of the experimental data by evaluating a wide range of sampling and analytical techniques. Here we show significant differences in the maximum specific growth rate and biomass yield between the two strains. On the basis of the integrated analysis of the high-throughput data, we hypothesize that differences in phenotype are due to differences in protein metabolism.
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| 11. |
- Bracher, J. M., et al.
(author)
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The Penicillium chrysogenum transporter PcAraT enables high-affinity, glucose-insensitive l-arabinose transport in Saccharomyces cerevisiae
- 2018
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In: Biotechnology for Biofuels. - : BioMed Central. - 1754-6834. ; 11:1
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Journal article (peer-reviewed)abstract
- Background: l-Arabinose occurs at economically relevant levels in lignocellulosic hydrolysates. Its low-affinity uptake via the Saccharomyces cerevisiae Gal2 galactose transporter is inhibited by d-glucose. Especially at low concentrations of l-arabinose, uptake is an important rate-controlling step in the complete conversion of these feedstocks by engineered pentose-metabolizing S. cerevisiae strains. Results: Chemostat-based transcriptome analysis yielded 16 putative sugar transporter genes in the filamentous fungus Penicillium chrysogenum whose transcript levels were at least threefold higher in l-arabinose-limited cultures than in d-glucose-limited and ethanol-limited cultures. Of five genes, that encoded putative transport proteins and showed an over 30-fold higher transcript level in l-arabinose-grown cultures compared to d-glucose-grown cultures, only one (Pc20g01790) restored growth on l-arabinose upon expression in an engineered l-arabinose-fermenting S. cerevisiae strain in which the endogenous l-arabinose transporter, GAL2, had been deleted. Sugar transport assays indicated that this fungal transporter, designated as PcAraT, is a high-affinity (K m = 0.13 mM), high-specificity l-arabinose-proton symporter that does not transport d-xylose or d-glucose. An l-arabinose-metabolizing S. cerevisiae strain in which GAL2 was replaced by PcaraT showed 450-fold lower residual substrate concentrations in l-arabinose-limited chemostat cultures than a congenic strain in which l-arabinose import depended on Gal2 (4.2 × 10-3 and 1.8 g L-1, respectively). Inhibition of l-arabinose transport by the most abundant sugars in hydrolysates, d-glucose and d-xylose was far less pronounced than observed with Gal2. Expression of PcAraT in a hexose-phosphorylation-deficient, l-arabinose-metabolizing S. cerevisiae strain enabled growth in media supplemented with both 20 g L-1 l-arabinose and 20 g L-1 d-glucose, which completely inhibited growth of a congenic strain in the same condition that depended on l-arabinose transport via Gal2. Conclusion: Its high affinity and specificity for l-arabinose, combined with limited sensitivity to inhibition by d-glucose and d-xylose, make PcAraT a valuable transporter for application in metabolic engineering strategies aimed at engineering S. cerevisiae strains for efficient conversion of lignocellulosic hydrolysates.
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| 12. |
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| 13. |
- Nijkamp, J. F., et al.
(author)
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De novo sequencing, assembly and analysis of the genome of the laboratory strain Saccharomyces cerevisiae CEN.PK113-7D, a model for modern industrial biotechnology
- 2012
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In: Microbial Cell Factories. - : Springer Science and Business Media LLC. - 1475-2859. ; 11, s. Article Number: 36-
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Journal article (peer-reviewed)abstract
- Saccharomyces cerevisiae CEN.PK 113-7D is widely used for metabolic engineering and systems biology research in industry and academia. We sequenced, assembled, annotated and analyzed its genome. Single-nucleotide variations (SNV), insertions/deletions (indels) and differences in genome organization compared to the reference strain S. cerevisiae S288C were analyzed. In addition to a few large deletions and duplications, nearly 3000 indels were identified in the CEN.PK113-7D genome relative to S288C. These differences were overrepresented in genes whose functions are related to transcriptional regulation and chromatin remodelling. Some of these variations were caused by unstable tandem repeats, suggesting an innate evolvability of the corresponding genes. Besides a previously characterized mutation in adenylate cyclase, the CEN. PK113-7D genome sequence revealed a significant enrichment of non-synonymous mutations in genes encoding for components of the cAMP signalling pathway. Some phenotypic characteristics of the CEN. PK113-7D strains were explained by the presence of additional specific metabolic genes relative to S288C. In particular, the presence of the BIO1 and BIO6 genes correlated with a biotin prototrophy of CEN. PK113-7D. Furthermore, the copy number, chromosomal location and sequences of the MAL loci were resolved. The assembled sequence reveals that CEN. PK113-7D has a mosaic genome that combines characteristics of laboratory strains and wild-industrial strains.
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| 14. |
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| 15. |
- Bracher, J. M., et al.
(author)
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Laboratory evolution of a biotin-requiring Saccharomyces cerevisiae strain for full biotin prototrophy and identification of causal mutations
- 2017
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In: Applied and Environmental Microbiology. - : American Society for Microbiology. - 0099-2240 .- 1098-5336. ; 83:16
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Journal article (peer-reviewed)abstract
- Biotin prototrophy is a rare, incompletely understood, and industrially relevant characteristic of Saccharomyces cerevisiae strains. The genome of the haploid laboratory strain CEN.PK113-7D contains a full complement of biotin biosynthesis genes, but its growth in biotin-free synthetic medium is extremely slow (specific growth rate [μ] ≈ 0.01 h-1). Four independent evolution experiments in repeated batch cultures and accelerostats yielded strains whose growth rates (μ ≤ 0.36 h-1) in biotin-free and biotin-supplemented media were similar. Whole-genome resequencing of these evolved strains revealed up to 40-fold amplification of BIO1, which encodes pimeloyl-coenzyme A (CoA) synthetase. The additional copies of BIO1 were found on different chromosomes, and its amplification coincided with substantial chromosomal rearrangements. A key role of this gene amplification was confirmed by overexpression of BIO1 in strain CEN.PK113-7D, which enabled growth in biotin-free medium (μ= 0.15 h-1). Mutations in the membrane transporter genes TPO1 and/or PDR12 were found in several of the evolved strains. Deletion of TPO1 and PDR12 in a BIO1-overexpressing strain increased its specific growth rate to 0.25 h-1. The effects of null mutations in these genes, which have not been previously associated with biotin metabolism, were nonadditive. This study demonstrates that S. cerevisiae strains that carry the basic genetic information for biotin synthesis can be evolved for full biotin prototrophy and identifies new targets for engineering biotin prototrophy into laboratory and industrial strains of this yeast.
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| 16. |
- Marques, W. L., et al.
(author)
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Combined engineering of disaccharide transport and phosphorolysis for enhanced ATP yield from sucrose fermentation in Saccharomyces cerevisiae
- 2018
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In: Metabolic engineering. - : Academic Press Inc.. - 1096-7176 .- 1096-7184. ; 45, s. 121-133
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Journal article (peer-reviewed)abstract
- Anaerobic industrial fermentation processes do not require aeration and intensive mixing and the accompanying cost savings are beneficial for production of chemicals and fuels. However, the free-energy conservation of fermentative pathways is often insufficient for the production and export of the desired compounds and/or for cellular growth and maintenance. To increase free-energy conservation during fermentation of the industrially relevant disaccharide sucrose by Saccharomyces cerevisiae, we first replaced the native yeast α-glucosidases by an intracellular sucrose phosphorylase from Leuconostoc mesenteroides (LmSPase). Subsequently, we replaced the native proton-coupled sucrose uptake system by a putative sucrose facilitator from Phaseolus vulgaris (PvSUF1). The resulting strains grew anaerobically on sucrose at specific growth rates of 0.09 ± 0.02 h−1 (LmSPase) and 0.06 ± 0.01 h−1 (PvSUF1, LmSPase). Overexpression of the yeast PGM2 gene, which encodes phosphoglucomutase, increased anaerobic growth rates on sucrose of these strains to 0.23 ± 0.01 h−1 and 0.08 ± 0.00 h−1, respectively. Determination of the biomass yield in anaerobic sucrose-limited chemostat cultures was used to assess the free-energy conservation of the engineered strains. Replacement of intracellular hydrolase with a phosphorylase increased the biomass yield on sucrose by 31%. Additional replacement of the native proton-coupled sucrose uptake system by PvSUF1 increased the anaerobic biomass yield by a further 8%, resulting in an overall increase of 41%. By experimentally demonstrating an energetic benefit of the combined engineering of disaccharide uptake and cleavage, this study represents a first step towards anaerobic production of compounds whose metabolic pathways currently do not conserve sufficient free-energy.
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| 17. |
- Pilheden, M., et al.
(author)
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Duplex Sequencing Uncovers Recurrent Low-frequency Cancer-associated Mutations in Infant and Childhood KMT2A-rearranged Acute Leukemia
- 2022
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In: Hemasphere. - : Ovid Technologies (Wolters Kluwer Health). - 2572-9241. ; 6:10
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Journal article (peer-reviewed)abstract
- Infant acute lymphoblastic leukemia (ALL) with KMT2A-gene rearrangements (KMT2A-r) have few mutations and a poor prognosis. To uncover mutations that are below the detection of standard next-generation sequencing (NGS), a combination of targeted duplex sequencing and NGS was applied on 20 infants and 7 children with KMT2A-r ALL, 5 longitudinal and 6 paired relapse samples. Of identified nonsynonymous mutations, 87 had been previously implicated in cancer and targeted genes recurrently altered in KMT2A-r leukemia and included mutations in KRAS, NRAS, FLT3, TP53, PIK3CA, PAX5, PIK3R1, and PTPN11, with infants having fewer such mutations. Of identified cancer-associated mutations, 62% were below the resolution of standard NGS. Only 33 of 87 mutations exceeded 2% of cellular prevalence and most-targeted PI3K/RAS genes (31/33) and typically KRAS/NRAS. Five patients only had low-frequency PI3K/RAS mutations without a higher-frequency signaling mutation. Further, drug-resistant clones with FLT3(D835H) or NRAS(G13D/G12S) mutations that comprised only 0.06% to 0.34% of diagnostic cells, expanded at relapse. Finally, in longitudinal samples, the relapse clone persisted as a minor subclone from diagnosis and through treatment before expanding during the last month of disease. Together, we demonstrate that infant and childhood KMT2A-r ALL harbor low-frequency cancer-associated mutations, implying a vast subclonal genetic landscape.
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| 18. |
- Juergens, H., et al.
(author)
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Evaluation of a novel cloud-based software platform for structured experiment design and linked data analytics
- 2018
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In: Scientific Data. - : Nature Publishing Groups. - 2052-4463. ; 5
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Journal article (peer-reviewed)abstract
- Open data in science requires precise definition of experimental procedures used in data generation, but traditional practices for sharing protocols and data cannot provide the required data contextualization. Here, we explore implementation, in an academic research setting, of a novel cloud-based software system designed to address this challenge. The software supports systematic definition of experimental procedures as visual processes, acquisition and analysis of primary data, and linking of data and procedures in machine-computable form. The software was tested on a set of quantitative microbial-physiology experiments. Though time-intensive, definition of experimental procedures in the software enabled much more precise, unambiguous definitions of experiments than conventional protocols. Once defined, processes were easily reusable and composable into more complex experimental flows. Automatic coupling of process definitions to experimental data enables immediate identification of correlations between procedural details, intended and unintended experimental perturbations, and experimental outcomes. Software-based experiment descriptions could ultimately replace terse and ambiguous ‘Materials and Methods’ sections in scientific journals, thus promoting reproducibility and reusability of published studies.
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| 19. |
- Lee, Bruce Y., et al.
(author)
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Research gaps and opportunities in precision nutrition : an NIH workshop report
- 2022
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In: The American journal of clinical nutrition. - : Elsevier BV. - 1938-3207 .- 0002-9165. ; 116:6, s. 1877-1900
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Journal article (peer-reviewed)abstract
- Precision nutrition is an emerging concept that aims to develop nutrition recommendations tailored to different people's circumstances and biological characteristics. Responses to dietary change and the resulting health outcomes from consuming different diets may vary significantly between people based on interactions between their genetic backgrounds, physiology, microbiome, underlying health status, behaviors, social influences, and environmental exposures. On 11-12 January 2021, the National Institutes of Health convened a workshop entitled "Precision Nutrition: Research Gaps and Opportunities" to bring together experts to discuss the issues involved in better understanding and addressing precision nutrition. The workshop proceeded in 3 parts: part I covered many aspects of genetics and physiology that mediate the links between nutrient intake and health conditions such as cardiovascular disease, Alzheimer disease, and cancer; part II reviewed potential contributors to interindividual variability in dietary exposures and responses such as baseline nutritional status, circadian rhythm/sleep, environmental exposures, sensory properties of food, stress, inflammation, and the social determinants of health; part III presented the need for systems approaches, with new methods and technologies that can facilitate the study and implementation of precision nutrition, and workforce development needed to create a new generation of researchers. The workshop concluded that much research will be needed before more precise nutrition recommendations can be achieved. This includes better understanding and accounting for variables such as age, sex, ethnicity, medical history, genetics, and social and environmental factors. The advent of new methods and technologies and the availability of considerably more data bring tremendous opportunity. However, the field must proceed with appropriate levels of caution and make sure the factors listed above are all considered, and systems approaches and methods are incorporated. It will be important to develop and train an expanded workforce with the goal of reducing health disparities and improving precision nutritional advice for all Americans.
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| 20. |
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| 21. |
- Versluys, A. B., et al.
(author)
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Hematopoietic cell transplant in pediatric acute myeloid leukemia after similar upfront therapy; a comparison of conditioning regimens
- 2021
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In: Bone Marrow Transplantation. - : Springer Science and Business Media LLC. - 0268-3369 .- 1476-5365. ; 56:6, s. 1426-1432
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Journal article (peer-reviewed)abstract
- The impact of conditioning regimen prior to hematopoietic cell transplant (HCT) in pediatric AML-patients is not well studied. We retrospectively analyzed the impact of Busulfan-Cyclophosphamide (BuCy), Busulfan-Cyclophosphamide-Melphalan (BuCyMel) and Clofarabine-Fludarabine-Busulfan (CloFluBu) in pediatric AML-patients, with similar upfront leukemia treatment (NOPHO-DBHconsortium), receiving an HCT between 2010 and 2015. Outcomes of interest were LFS, relapse, TRM and GvHD. 103 patients were included; 30 received BuCy, 37 BuCyMel, and 36 CloFluBu. The 5-years LFS was 43.3% (SE +/- 9.0) in the BuCy group, 59.2 % (SE +/- 8.1) after BuCyMel, and 66.7 % (SE +/- 7.9) after CloFluBu. Multivariable Cox regression analysis showed a trend to lower LFS after BuCy compared to CloFluBu (p = 0.07). BuCy was associated with a higher relapse incidence compared to the other regimens (p = 0.06). Younger age was a predictor for relapse (p = 0.02). A strong correlation between Busulfan Therapeutic Drug Monitoring (TDM) and lower incidence of aGvHD (p < 0.001) was found. In conclusion, LFS after BuCyMel and CloFluBu was comparable, lower LFS was found after BuCy, due to higher relapse incidence. CloFluBu was associated with lower incidence of aGvHD, suggesting lower toxicity with this type of conditioning. This finding is also explained by the impact of Busulfan monitoring.
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| 22. |
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| 23. |
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| 24. |
- Attema, Joanne, et al.
(author)
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Hematopoietic stem cell ageing is uncoupled from p16 INK4A-mediated senescence
- 2009
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In: Oncogene. - : Nature Publishing Group. - 0950-9232 .- 1476-5594. ; 28:22, s. 2238-2243
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Journal article (peer-reviewed)abstract
- Somatic stem cells are ultimately responsible for mediating appropriate organ homeostasis and have therefore been proposed to represent a cellular origin of the ageing process-a state often characterized by inappropriate homeostasis. Specifically, it has been suggested that ageing stem cells might succumb to replicative senescence by a mechanism involving the cyclin-dependent kinase inhibitor p16(INK4A). Here, we tested multiple functional and molecular parameters indicative of p16(INK4A) activity in primary aged murine hematopoietic stem cells (HSCs). We found no evidence that replicative senescence accompanies stem cell ageing in vivo, and in line with p16(INK4A) being a critical determinant of such processes, most aged HSCs (>99%) failed to express p16(INK4A) at the mRNA level. Moreover, whereas loss of epigenetically guided repression of the INK4A/ARF locus accompanied replicative senescent murine embryonic fibroblasts, such repression was maintained in aged stem cells. Taken together, these studies indicate that increased senescence as mediated by the p16(INK4A) tumor suppressor has only a minor function as an intrinsic regulator of steady-state HSC ageing in vivo.
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| 25. |
- Bachiller, S., et al.
(author)
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Early-life stress elicits peripheral and brain immune activation differently in wild type and 5xFAD mice in a sex-specific manner
- 2022
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In: Journal of Neuroinflammation. - : Springer Science and Business Media LLC. - 1742-2094. ; 19
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Journal article (peer-reviewed)abstract
- BackgroundThe risk of developing Alzheimer’s disease (AD) is modulated by genetic and environmental factors. Early-life stress (ELS) exposure during critical periods of brain development can impact later brain function and health, including increasing the risk of developing AD. Microglial dysfunction and neuroinflammation have been implicated as playing a role in AD pathology and may be modulated by ELS. To complicate matters further, sex-specific effects have been noted in response to ELS and in the incidence and progression of AD.MethodsHere, we subjected male and female mice with either a wild type or 5xFAD familial AD-model background to maternal separation (MS) from postnatal day 2 to 14 to induce ELS.ResultsWe detected hippocampal neuroinflammatory alterations already at postnatal day 15. By 4 months of age, MS mice presented increased immobility time in the forced swim test and a lower discrimination index in the novel object recognition memory test compared to controls. We found altered Bdnf and Arc expression in the hippocampus and increased microglial activation in the prefrontal cortex due to MS in a sex-dependent manner. In 5xFAD mice specifically, MS exacerbated amyloid-beta deposition, particularly in females. In the periphery, the immune cell population was altered by MS exposure.ConclusionOverall, our results demonstrate that MS has both short- and long-term effects on brain regions related to memory and on the inflammatory system, both in the brain and periphery. These ELS-related effects that are detectable even in adulthood may exacerbate pathology and increase the risk of developing AD via sex-specific mechanisms.
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| 26. |
- Kazemi Seresht, Ali, 1980, et al.
(author)
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Long-Term Adaptation of Saccharomyces cerevisiae to the Burden of Recombinant Insulin Production
- 2013
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In: Biotechnology and Bioengineering. - : Wiley. - 0006-3592 .- 1097-0290. ; 110:10, s. 2749-2763
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Journal article (peer-reviewed)abstract
- High-level production of heterologous proteins is likely to impose a metabolic burden on the host cell and can thus affect various aspects of cellular physiology. A data-driven approach was applied to study the secretory production of a human insulin analog precursor (IAP) in Saccharomyces cerevisiae during prolonged cultivation (80 generations) in glucose-limited aerobic chemostat cultures. Physiological characterization of the recombinant cells involved a comparison with cultures of a congenic reference strain that did not produce IAP, and time-course analysis of both strains aimed at identifying the metabolic adaptation of the cells towards the burden of IAP production. All cultures were examined at high cell density conditions (30g/L dry weight) to increase the industrial relevance of the results. The burden of heterologous protein production in the recombinant strain was explored by global transcriptome analysis and targeted metabolome analysis, including the analysis of intracellular amino acid pools, glycolytic metabolites, and TCA intermediates. The cellular re-arrangements towards IAP production were categorized in direct responses, for example, enhanced metabolism of amino acids as precursors for the formation of IAP, as well as indirect responses, for example, changes in the central carbon metabolism. As part of the long-term adaptation, a metabolic re-modeling of the IAP-expressing strain was observed, indicating an augmented negative selection pressure on glycolytic overcapacity, and the emergence of mitochondrial dysfunction. The evoked metabolic re-modeling of the cells led to less optimal conditions with respect to the expression and processing of the target protein and thus decreased the cellular expression capacity for the secretory production of IAP during prolonged cultivation.
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| 27. |
- Lilljebjörn, Henrik, et al.
(author)
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Identification of ETV6-RUNX1-like and DUX4-rearranged subtypes in paediatric B-cell precursor acute lymphoblastic leukaemia
- 2016
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In: Nature Communications. - : NATURE PUBLISHING GROUP. - 2041-1723. ; 7:11790
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Journal article (peer-reviewed)abstract
- Fusion genes are potent driver mutations in cancer. In this study, we delineate the fusion gene landscape in a consecutive series of 195 paediatric B-cell precursor acute lymphoblastic leukaemia (BCP ALL). Using RNA sequencing, we find in-frame fusion genes in 127 (65%) cases, including 27 novel fusions. We describe a subtype characterized by recurrent IGH-DUX4 or ERG-DUX4 fusions, representing 4% of cases, leading to overexpression of DUX4 and frequently co-occurring with intragenic ERG deletions. Furthermore, we identify a subtype characterized by an ETV6-RUNX1-like gene-expression profile and coexisting ETV6 and IKZF1 alterations. Thus, this study provides a detailed overview of fusion genes in paediatric BCP ALL and adds new pathogenetic insights, which may improve risk stratification and provide therapeutic options for this disease.
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| 28. |
- Norddahl, Gudmundur, et al.
(author)
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Accumulating mitochondrial DNA mutations drive premature hematopoietic aging phenotypes distinct from physiological stem cell aging
- 2011
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In: Cell Stem Cell. - Cambridge Mass. : Cell Press. - 1934-5909 .- 1875-9777. ; 8:5, s. 499-510
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Journal article (peer-reviewed)abstract
- Somatic stem cells mediate tissue maintenance for the lifetime of an organism. Despite the well-established longevity that is a prerequisite for such function, accumulating data argue for compromised stem cell function with age. Identifying the mechanisms underlying age-dependent stem cell dysfunction is therefore key to understanding the aging process. Here, using a model carrying a proofreading-defective mitochondrial DNA polymerase, we demonstrate hematopoietic defects reminiscent of premature HSC aging, including anemia, lymphopenia, and myeloid lineage skewing. However, in contrast to physiological stem cell aging, rapidly accumulating mitochondrial DNA mutations had little functional effect on the hematopoietic stem cell pool, and instead caused distinct differentiation blocks and/or disappearance of downstream progenitors. These results show that intact mitochondrial function is required for appropriate multilineage stem cell differentiation, but argue against mitochondrial DNA mutations per se being a primary driver of somatic stem cell aging.
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| 29. |
- Papapetridis, Ioannis, et al.
(author)
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Laboratory evolution for forced glucose-xylose co-consumption enables identification of mutations that improve mixed-sugar fermentation by xylose-fermenting Saccharomyces cerevisiae
- 2018
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In: FEMS yeast research (Print). - : Oxford University Press. - 1567-1356 .- 1567-1364. ; 18:6
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Journal article (peer-reviewed)abstract
- Simultaneous fermentation of glucose and xylose can contribute to improved productivity and robustness of yeast-based processes for bioethanol production from lignocellulosic hydrolysates. This study explores a novel laboratory evolution strategy for identifying mutations that contribute to simultaneous utilisation of these sugars in batch cultures of Saccharomyces cerevisiae. To force simultaneous utilisation of xylose and glucose, the genes encoding glucose-6-phosphate isomerase (PGI1) and ribulose-5-phosphate epimerase (RPE1) were deleted in a xylose-isomerase-based xylose-fermenting strain with a modified oxidative pentose-phosphate pathway. Laboratory evolution of this strain in serial batch cultures on glucose-xylose mixtures yielded mutants that rapidly co-consumed the two sugars. Whole-genome sequencing of evolved strains identified mutations in HXK2, RSP5 and GAL83, whose introduction into a non-evolved xylose-fermenting S. cerevisiae strain improved co-consumption of xylose and glucose under aerobic and anaerobic conditions. Combined deletion of HXK2 and introduction of a GAL83(G673T) allele yielded a strain with a 2.5-fold higher xylose and glucose co-consumption ratio than its xylose-fermenting parental strain. These two modifications decreased the time required for full sugar conversion in anaerobic bioreactor batch cultures, grown on 20 g L-1 glucose and 10 g L-1 xylose, by over 24 h. This study demonstrates that laboratory evolution and genome resequencing of microbial strains engineered for forced co-consumption is a powerful approach for studying and improving simultaneous conversion of mixed substrates.
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| 30. |
- Pronk, Cornelis J. H., et al.
(author)
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Elucidation of the phenotypic, functional, and molecular topography of a myeloerythroid progenitor cell hierarchy
- 2007
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In: Cell Stem Cell. - : Elsevier (Cell Press). - 1934-5909 .- 1875-9777. ; 1:4, s. 428-442
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Journal article (peer-reviewed)abstract
- The major myeloid blood cell lineages are generated from hematopoietic stem cells by differentiation through a series of increasingly committed progenitor cells. Precise characterization of intermediate progenitors is important for understanding fundamental differentiation processes and a variety of disease states, including leukemia. Here, we evaluated the functional in vitro and in vivo potentials of a range of prospectively isolated myeloid precursors with differential expression of CD150, Endoglin, and CD41. Our studies revealed a hierarchy of myeloerythroid progenitors with distinct lineage potentials. The global gene expression signatures of these subsets were consistent with their functional capacities, and hierarchical clustering analysis suggested likely lineage relationships. These studies provide valuable tools for understanding myeloid lineage commitment, including isolation of an early erythroid-restricted precursor, and add to existing models of hematopoietic differentiation by suggesting that progenitors of the innate and adaptive immune system can separate late, following the divergence of megakaryocytic/erythroid potential.
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| 31. |
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| 32. |
- Shahsavani, M, et al.
(author)
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An in vitro model of lissencephaly : expanding the role of DCX during neurogenesis
- 2018
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In: Molecular Psychiatry. - : Nature Publishing Group. - 1359-4184 .- 1476-5578. ; 23:7, s. 1674-1684
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Journal article (peer-reviewed)abstract
- Lissencephaly comprises a spectrum of brain malformations due to impaired neuronal migration in the developing cerebral cortex. Classical lissencephaly is characterized by smooth cerebral surface and cortical thickening that result in seizures, severe neurological impairment and developmental delay. Mutations in the X-chromosomal gene DCX, encoding doublecortin, is the main cause of classical lissencephaly. Much of our knowledge about DCX-associated lissencephaly comes from post-mortem analyses of patient's brains, mainly since animal models with DCX mutations do not mimic the disease. In the absence of relevant animal models and patient brain specimens, we took advantage of induced pluripotent stem cell (iPSC) technology to model the disease. We established human iPSCs from two males with mutated DCX and classical lissencephaly including smooth brain and abnormal cortical morphology. The disease was recapitulated by differentiation of iPSC into neural cells followed by expression profiling and dissection of DCX-associated functions. Here we show that neural stem cells, with absent or reduced DCX protein expression, exhibit impaired migration, delayed differentiation and deficient neurite formation. Hence, the patient-derived iPSCs and neural stem cells provide a system to further unravel the functions of DCX in normal development and disease.Molecular Psychiatry advance online publication, 19 September 2017; doi:10.1038/mp.2017.175.
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| 33. |
- Slaats, D., et al.
(author)
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Donor and Recipient Perspectives on Anonymity in Kidney Donation From Live Donors: A Multicenter Survey Study
- 2018
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In: American Journal of Kidney Diseases. - : Elsevier BV. - 0272-6386. ; 71:1, s. 52-64
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Journal article (peer-reviewed)abstract
- Background: Maintaining anonymity is a requirement in the Netherlands and Sweden for kidney donation from live donors in the context of nondirected (or unspecified) and paired exchange (or specified indirect) donation. Despite this policy, some donors and recipients express the desire to know one another. Little empirical evidence informs the debate on anonymity. This study explored the experiences, preferences, and attitudes of donors and recipients toward anonymity. Study Design: Retrospective observational multicenter study using both qualitative and quantitative methods. Setting & Participants: 414 participants from Dutch and Swedish transplantation centers who received or donated a kidney anonymously (nondirected or paired exchange) completed a questionnaire about anonymity. Participation was a median of 31 months after surgery. Factors: Country of residence, donor/recipient status, transplant type, time since surgery. Results: Most participants were satisfied with their experience of anonymity before and aftersurgery. A minority would have liked to have met the other party before (donors, 7%; recipients, 15%) or after (donors, 22%; recipients, 31%) surgery. Significantly more recipients than donors wanted to meet the other party. Most study participants were open to meeting the other party if the desire was mutual (donors, 58%; recipients, 60%). Donors agree significantly more with the principle of anonymity before and after surgery than recipients. Donors and recipients thought that if both parties agreed, it should be permissible to meet before or after surgery. There were few associations between country or time since surgery and experiences or attitudes. The pros and cons of anonymity reported by participants were clustered into relational and emotional, ethical, and practical and logistical domains. Limitations: The relatively low response rate of recipients may have reduced generalizability. Recall bias was possible given the time lag between transplantation and data collection. Conclusions: This exploratory study illustrated that although donors and recipients were usually satisfied with anonymity, the majority viewed a strict policy on anonymity as unnecessary. These results may inform policy and education on anonymity.
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| 34. |
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| 35. |
- Verhoeven, Maarten D., et al.
(author)
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Laboratory evolution of a glucose-phosphorylation-deficient, arabinose-fermenting S. cerevisiae strain reveals mutations in GAL2 that enable glucose-insensitive L-arabinose uptake
- 2018
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In: FEMS yeast research (Print). - : Oxford University Press. - 1567-1356 .- 1567-1364. ; 18:6
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Journal article (peer-reviewed)abstract
- Cas9-assisted genome editing was used to construct an engineered glucose-phosphorylation-negative S. cerevisiae strain, expressing the Lactobacillus plantarum L-arabinose pathway and the Penicillium chrysogenum transporter PcAraT. This strain, which showed a growth rate of 0.26 h(-1) on L-arabinose in aerobic batch cultures, was subsequently evolved for anaerobic growth on L-arabinose in the presence of D-glucose and D-xylose. In four strains isolated from two independent evolution experiments the galactose-transporter gene GAL2 had been duplicated, with all alleles encoding Gal2(N376T) or Gal(2N376I) substitutions. In one strain, a single GAL2 allele additionally encoded a Gal2(T89I) substitution, which was subsequently also detected in the independently evolved strain IMS0010. In C-14-sugar-transport assays, Gal2(N376S), Gal2(N376T) and Gal(2N376I) substitutions showed a much lower glucose sensitivity of L-arabinose transport and a much higher Km for D-glucose transport than wild-type Gal2. Introduction of the Gal2(N376I) substitution in a non-evolved strain enabled growth on L-arabinose in the presence of D-glucose. Gal2(N376T), T89I and Gal2(T89I) variants showed a lower K-m for L-arabinose and a higher K-m for D-glucose than wild-type Gal2, while reverting Gal2(N376T), T89I to Gal2(N376) in an evolved strain negatively affected anaerobic growth on L-arabinose. This study indicates that optimal conversion of mixed-sugar feedstocks may require complex 'transporter landscapes', consisting of sugar transporters with complementary kinetic and regulatory properties.
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| 36. |
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| 37. |
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| 38. |
- Arad-Cohen, Nira, et al.
(author)
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Supportive care in pediatric acute myeloid leukemia:Expert-based recommendations of the NOPHO-DB-SHIP consortium
- 2022
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In: Expert Review of Anticancer Therapy. - : Taylor & Francis Group. - 1473-7140 .- 1744-8328. ; 22:11, s. 1183-1196
-
Research review (peer-reviewed)abstract
- Introduction Pediatric acute myeloid leukemia (AML) is the second most common type of pediatric leukemia. Patients with AML are at high risk for several complications such as infections, typhlitis, and acute and long-term cardiotoxicity. Despite this knowledge, there are no definite supportive care guidelines as to what the best approach is to manage or prevent these complications. Area covered The NOPHO-DB-SHIP (Nordic-Dutch-Belgian-Spain-Hong-Kong-Israel-Portugal) consortium, in preparation for a new trial in pediatric AML patients, had dedicated meetings for supportive care. In this review, the authors discuss the available data and outline recommendations for the management of children and adolescents with AML with an emphasis on hyperleukocytosis, tumor lysis syndrome, coagulation abnormalities and bleeding, infection, typhlitis, malnutrition, cardiotoxicity, and fertility preservation. Expert opinion Improved supportive care has significantly contributed to increased cure rates. Recommendations on supportive care are an essential part of treatment for this highly susceptible population and will further improve their outcome.
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| 39. |
- Bisschops, Mark, 1985, et al.
(author)
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Oxygen availability strongly affects chronological lifespan and thermotolerance in batch cultures of Saccharomyces cerevisiae
- 2015
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In: Microbial Cell. - : Shared Science Publishers OG. - 2311-2638. ; 2:11, s. 429-444
-
Journal article (peer-reviewed)abstract
- Stationary-phase (SP) batch cultures of Saccharomyces cerevisiae, in which growth has been arrested by carbon-source depletion, are widely applied to study chronological lifespan, quiescence and SP-associated robustness. Based on this type of experiments, typically performed under aerobic conditions, several roles of oxygen in aging have been proposed. However, SP in anaerobic yeast cultures has not been investigated in detail. Here, we use the unique capability of S. cerevisiae to grow in the complete absence of oxygen to directly compare SP in aerobic and anaerobic bioreactor cultures. This comparison revealed strong positive effects of oxygen availability on adenylate energy charge, longevity and thermotolerance during SP. A low thermotolerance of anaerobic batch cultures was already evident during the exponential growth phase and, in contrast to the situation in aerobic cultures, was not substantially increased during transition into SP. A combination of physiological and transcriptome analysis showed that the slow post-diauxic growth phase on ethanol, which precedes SP in aerobic, but not in anaerobic cultures, endowed cells with the time and resources needed for inducing longevity and thermotolerance. When combined with literature data on acquisition of longevity and thermotolerance in retentostat cultures, the present study indicates that the fast transition from glucose excess to SP in anaerobic cultures precludes acquisition of longevity and thermotolerance. Moreover, this study demonstrates the importance of a preceding, calorie-restricted conditioning phase in the acquisition of longevity and stress tolerance in SP yeast cultures, irrespective of oxygen availability.
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| 40. |
- Eguíluz-Gracia, Ibon, et al.
(author)
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Long-Term persistence of human donor alveolar macrophages in lung transplant recipients
- 2016
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In: Thorax. - : BMJ. - 0040-6376 .- 1468-3296. ; 71:11, s. 1006-1011
-
Journal article (peer-reviewed)abstract
- Background Alveolar macrophages (AMFs) are critical regulators of lung function, and may participate in graft rejection following lung transplantation. Recent studies in experimental animals suggest that most AMFs are self-maintaining cells of embryonic origin, but knowledge about the ontogeny and life span of human AMFs is scarce. Methods To follow the origin and longevity of AMFs in patients with lung transplantation for more than 100â €..weeks, we obtained transbronchial biopsies from 10 gender-mismatched patients with lung transplantation. These were subjected to combined in situ hybridisation for X/Y chromosomes and immunofluorescence staining for macrophage markers. Moreover, development of AMFs in humanised mice reconstituted with CD34+ umbilical cord-derived cells was assessed. Results The number of donor-derived AMFs was unchanged during the 2â €..year post-Transplantation period. A fraction of the AMFs proliferated locally, demonstrating that at least a subset of human AMFs have the capacity to self-renew. Lungs of humanised mice were found to abundantly contain populations of human AMFs expressing markers compatible with a monocyte origin. Moreover, in patients with lung transplantation we found that recipient monocytes seeded the alveoli early after transplantation, and showed subsequent phenotypical changes consistent with differentiation into proliferating mature AMFs. This resulted in a stable mixed chimerism between donor and recipient AMFs throughout the 2-year period. Conclusions The finding that human AMFs are maintained in the lung parenchyma for several years indicates that pulmonary macrophage transplantation can be a feasible therapeutic option for patients with diseases caused by dysfunctional AMFs. Moreover, in a lung transplantation setting, long-Term persistence of donor AMFs may be important for the development of chronic graft rejection.
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| 41. |
- Ekholm, Jennifer, et al.
(author)
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Full-scale aerobic granular sludge for municipal wastewater treatment – granule formation, microbial succession, and process performance
- 2022
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In: Environmental Science: Water Research & Technology. - 2053-1419. ; :8, s. 3138-3154
-
Journal article (peer-reviewed)abstract
- Aerobic granular sludge (AGS) plants have gained growing interest and application due to their low energy demand, small footprint, and low operational costs. However, the fulfilment of strict discharge limits for nitrogen and phosphorus, vast seasonal temperature variations, and large peaks in influent flows may pose challenges to the implementation of AGS. Moreover, the knowledge about microbial community assembly and process performance under varying environmental conditions in full-scale reactors is still limited. In this study, the first implementation of the AGS process in the Nordic countries was assessed. In two full-scale AGS reactors with different seeding sludges, the start-up was associated with rapid changes in microbial community composition in both, but only successful granulation in one. As a consequence, the non-granulated reactor was eventually reseeded with biomass from the better granulated reactor. This resulted in a convergence of the microbial communities in the two reactors with the maintenance of stable sludge concentrations (6–8 g L−1) with large granules (50–80% with diameter >2 mm) and fast settling of biomass (SVI30/SVI10 of 0.9–1). Immigration from the influent wastewater was a minor factor affecting the microbial community once the granules had formed, while the seasonal variations in environmental factors were identified as important. Key guilds of AOB (Nitrosomonas), NOB (mainly Ca. Nitrotoga), PAOs (mainly Tetrasphaera), and GAOs (mainly Ca. Competibacter) varied considerably in abundance throughout the study period. After 15 months, stable organic matter, nitrogen, and phosphorus removal were attained with low effluent concentrations. During the start-up, the BOD7/N ratio, influent flow, and temperature were important factors influencing the performance of the AGS.
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| 42. |
- Ekholm, Jennifer, 1992, et al.
(author)
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Full-scale aerobic granular sludge for municipal wastewater treatment - granule formation, microbial succession, and process performance
- 2022
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In: Environmental Science: Water Research and Technology. - : Royal Society of Chemistry (RSC). - 2053-1419 .- 2053-1400. ; 8:12, s. 3138-3154
-
Journal article (peer-reviewed)abstract
- Aerobic granular sludge (AGS) plants have gained growing interest and application due to their low energy demand, small footprint, and low operational costs. However, the fulfilment of strict discharge limits for nitrogen and phosphorus, vast seasonal temperature variations, and large peaks in influent flows may pose challenges to the implementation of AGS. Moreover, the knowledge about microbial community assembly and process performance under varying environmental conditions in full-scale reactors is still limited. In this study, the first implementation of the AGS process in the Nordic countries was assessed. In two full-scale AGS reactors with different seeding sludges, the start-up was associated with rapid changes in microbial community composition in both, but only successful granulation in one. As a consequence, the non-granulated reactor was eventually reseeded with biomass from the better granulated reactor. This resulted in a convergence of the microbial communities in the two reactors with the maintenance of stable sludge concentrations (6-8 g L-1) with large granules (50-80% with diameter >2 mm) and fast settling of biomass (SVI30/SVI10 of 0.9-1). Immigration from the influent wastewater was a minor factor affecting the microbial community once the granules had formed, while the seasonal variations in environmental factors were identified as important. Key guilds of AOB (Nitrosomonas), NOB (mainly Ca. Nitrotoga), PAOs (mainly Tetrasphaera), and GAOs (mainly Ca. Competibacter) varied considerably in abundance throughout the study period. After 15 months, stable organic matter, nitrogen, and phosphorus removal were attained with low effluent concentrations. During the start-up, the BOD7/N ratio, influent flow, and temperature were important factors influencing the performance of the AGS.
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| 43. |
- Espersen, A. D. L., et al.
(author)
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Acute myeloid leukemia (AML) with t(7;12)(q36;p13) is associated with infancy and trisomy 19: Data from Nordic Society for Pediatric Hematology and Oncology (NOPHO-AML) and review of the literature
- 2018
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In: Genes Chromosomes & Cancer. - : Wiley. - 1045-2257 .- 1098-2264. ; 57:7, s. 359-365
-
Journal article (peer-reviewed)abstract
- The t(7;12)(q36;p13) (MNX1/ETV6) is not included in the WHO classification but has been described in up to 30% of acute myeloid leukemia (AML) in children <2 years and associated with a poor prognosis. We present the clinical and cytogenetics characteristics of AML cases with t(7;12)(p36;p13). A literature review identified 35 patients with this translocation, published between 2000 and 2015. Outcome data were available in 22 cases. The NOPHO-AML (Nordic Society for Pediatric Hematology and Oncology) database contained 651 patients with AML from 1993 to 2014 and seven (1.1%) had the translocation. The t(7;12) was only present in patients <2 years of age (median age 6 months) but none was diagnosed as newborn. These patients constituted 4.3% of the patients <2 years of age. There was a strong association with trisomy 19 (literature: 86%, NOPHO: 100%) and +8 (literature: 19%, NOPHO: 14%). Seventeen of 22 patients from the literature with t(7;12) and four of seven patients from the NOPHO database suffered from relapse. The patients with t(7;12) had a 3-year event free survival of 24% (literature) vs. 43% (NOPHO) and a 3-year overall survival of 42% (literature) vs. 100% (NOPHO). None of the NOPHO patients was treated with hematopoietic stem cell transplantation (HSCT) in first complete remission. Relapse was frequent but the salvage rate using HSCT was high. We conclude that t(7;12)(q36;13) is a unique subgroup of childhood AML with presentation before 2 years of age with most cases being associated with +19.
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| 44. |
- Heggarty, Paul, et al.
(author)
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Language trees with sampled ancestors support a hybrid model for the origin of Indo-European languages
- 2023
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In: Science. - 0036-8075 .- 1095-9203. ; 381:6656
-
Journal article (peer-reviewed)abstract
- Languages of the Indo-European family are spoken by almost half of the world’s population, but their origins and patterns of spread are disputed. Heggarty et al. present a database of 109 modern and 52 time-calibrated historical Indo-European languages, which they analyzed with models of Bayesian phylogenetic inference. Their results suggest an emergence of Indo-European languages around 8000 years before present. This is a deeper root date than previously thought, and it fits with an initial origin south of the Caucasus followed by a branch northward into the Steppe region. These findings lead to a “hybrid hypothesis” that reconciles current linguistic and ancient DNA evidence from both the eastern Fertile Crescent (as a primary source) and the steppe (as a secondary homeland).
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| 45. |
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| 46. |
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| 47. |
- Jansen, Mickel LA, et al.
(author)
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Saccharomyces cerevisiae strains for second-generation ethanol production : from academic exploration to industrial implementation
- 2017
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In: FEMS Yeast Research. - : Oxford University Press. - 1567-1364. ; 17:5
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Journal article (peer-reviewed)abstract
- The recent start-up of several full-scale 'second generation' ethanol plants marks a major milestone in the development of Saccharomyces cerevisiae strains for fermentation of lignocellulosic hydrolysates of agricultural residues and energy crops. After a discussion of the challenges that these novel industrial contexts impose on yeast strains, this minireview describes key metabolic engineering strategies that have been developed to address these challenges. Additionally, it outlines how proof-of-concept studies, often developed in academic settings, can be used for the development of robust strain platforms that meet the requirements for industrial application. Fermentation performance of current engineered industrial S. cerevisiae strains is no longer a bottleneck in efforts to achieve the projected outputs of the first large-scale second-generation ethanol plants. Academic and industrial yeast research will continue to strengthen the economic value position of second-generation ethanol production by further improving fermentation kinetics, product yield and cellular robustness under process conditions.
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| 48. |
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| 49. |
- Karlsson, Lene, et al.
(author)
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Characteristics and outcome of primary resistant disease in paediatric acute myeloid leukaemia
- 2023
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In: British Journal of Haematology. - : Wiley. - 0007-1048 .- 1365-2141. ; 201:4, s. 757-765
-
Journal article (peer-reviewed)abstract
- A significant proportion of events in paediatric acute myeloid leukaemia (AML) are caused by resistant disease (RD). We investigated clinical and biological characteristics in 66 patients with RD from 1013 children with AML registered and treated according to the NOPHO-AML 93, NOPHO-AML 2004, DB AML-01 and NOPHO-DBH AML 2012 protocols. Risk factors for RD were age10 years or older and a white-blood-cell count (WBC) of 100 x 10(9)/L or more at diagnosis. The five-year overall survival (OS) was 38% (95% confidence interval [CI]: 28%-52%). Of the 63 children that received salvage therapy with chemotherapy, 59% (N = 37) achieved complete remission (CR) with OS 57% (95% CI: 42%-75%) compared to 12% (95% CI: 4%-35%) for children that did not achieve CR. Giving more than two salvage chemotherapy courses did not increase CR rates. OS for all 43 patients receiving allogeneic haematopoietic stem cell transplantation (HSCT) was 49% (95% CI: 36%-66%). Those achieving CR and proceeding to HSCT had an OS of 56% (95% CI: 41%-77%, N = 30). This study showed that almost 40% of children with primary resistant AML can be cured with salvage therapy followed by HSCT. Children that did not achieve CR after two salvage courses with chemotherapy did not benefit from additional chemotherapy.
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| 50. |
- Lam, Matti, et al.
(author)
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Single cell analysis of autism patient with bi-allelic NRXN1-alpha deletion reveals skewed fate choice in neural progenitors and impaired neuronal functionality
- 2019
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In: Experimental Cell Research. - : Elsevier BV. - 0014-4827 .- 1090-2422. ; 383:1
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Journal article (peer-reviewed)abstract
- We generated human iPS derived neural stem cells and differentiated cells from healthy control individuals and an individual with autism spectrum disorder carrying bi-allelic NRXN1-alpha deletion. We investigated the expression of NRXN1-alpha during neural induction and neural differentiation and observed a pivotal role for NRXN1-alpha during early neural induction and neuronal differentiation. Single cell RNA-seq pinpointed neural stem cells carrying NRXN1-alpha deletion shifting towards radial glia-like cell identity and revealed higher proportion of differentiated astroglia. Furthermore, neuronal cells carrying NRXN1-alpha deletion were identified as immature by single cell RNA-seq analysis, displayed significant depression in calcium signaling activity and presented impaired maturation action potential profile in neurons investigated with electrophysiology. Our observations propose NRXN1-alpha plays an important role for the efficient establishment of neural stem cells, in neuronal differentiation and in maturation of functional excitatory neuronal cells.
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