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| 4. |
- Benatar, Michael, et al.
(författare)
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Safety and efficacy of arimoclomol in patients with early amyotrophic lateral sclerosis (ORARIALS-01) : a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial
- 2024
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Ingår i: Lancet Neurology. - : Elsevier. - 1474-4422 .- 1474-4465. ; 23:7, s. 687-699
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Tidskriftsartikel (refereegranskat)abstract
- Background: Amyotrophic lateral sclerosis is a progressive neurodegenerative disorder leading to muscle weakness and respiratory failure. Arimoclomol, a heat-shock protein-70 (HSP70) co-inducer, is neuroprotective in animal models of amyotrophic lateral sclerosis, with multiple mechanisms of action, including clearance of protein aggregates, a pathological hallmark of sporadic and familial amyotrophic lateral sclerosis. We aimed to evaluate the safety and efficacy of arimoclomol in patients with amyotrophic lateral sclerosis.Methods: ORARIALS-01 was a multinational, randomised, double-blind, placebo-controlled, parallel-group trial done at 29 centres in 12 countries in Europe and North America. Patients were eligible if they were aged 18 years or older and met El Escorial criteria for clinically possible, probable, probable laboratory-supported, definite, or familial amyotrophic lateral sclerosis; had an ALS Functional Rating Scale-Revised score of 35 or more; and had slow vital capacity at 70% or more of the value predicted on the basis of the participant's age, height, and sex. Patients were randomly assigned (2:1) in blocks of 6, stratified by use of a stable dose of riluzole or no riluzole use, to receive oral arimoclomol citrate 1200 mg/day (400 mg three times per day) or placebo. The Randomisation sequence was computer generated centrally. Investigators, study personnel, and study participants were masked to treatment allocation. The primary outcome was the Combined Assessment of Function and Survival (CAFS) rank score over 76 weeks of treatment. The primary outcome and safety were analysed in the modified intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT03491462, and is completed.Findings: Between July 31, 2018, and July 17, 2019, 287 patients were screened, 245 of whom were enrolled in the trial and randomly assigned. The modified intention-to-treat population comprised 239 patients (160 in the arimoclomol group and 79 in the placebo group): 151 (63%) were male and 88 (37%) were female; mean age was 57·6 years (SD 10·9). CAFS score over 76 weeks did not differ between groups (mean 0·51 [SD 0·29] in the arimoclomol group vs 0·49 [0·28] in the placebo group; p=0·62). Cliff's delta comparing the two groups was 0·039 (95% CI –0·116 to 0·194). Proportions of participants who died were similar between the treatment groups: 29 (18%) of 160 patients in the arimoclomol group and 18 (23%) of 79 patients in the placebo group. Most deaths were due to disease progression. The most common adverse events were gastrointestinal. Adverse events were more often deemed treatment-related in the arimoclomol group (104 [65%]) than in the placebo group (41 [52%]) and more often led to treatment discontinuation in the arimoclomol group (26 [16%]) than in the placebo group (four [5%]).Interpretation: Arimoclomol did not improve efficacy outcomes compared with placebo. Although available biomarker data are insufficient to preclude future strategies that target the HSP response, safety data suggest that a higher dose of arimoclomol would not have been tolerated.Funding: Orphazyme.
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| 7. |
- Dieval, Catherine, et al.
(författare)
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A case study of proton precipitation at Mars : Mars Express observations and hybrid simulations
- 2012
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Ingår i: Journal of Geophysical Research. - 0148-0227 .- 2156-2202. ; 117
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Tidskriftsartikel (refereegranskat)abstract
- Using the data from the Analyzer of Space Plasma and Energetic Atoms (ASPERA-3) experiment on board Mars Express and hybrid simulations, we have investigated the entry of protons into the Martian induced magnetosphere. We discuss one orbit on the dayside with observations of significant proton fluxes at altitudes down to 260 km on 27 February 2004. The protons observed below the induced magnetosphere boundary at an altitude of less than 700 km have energies of a few keV, travel downward, and precipitate onto the atmosphere. The measured energy flux and particle flux are 108–109 eV cm−2 s−1 and 105–106 H+ cm−2 s−1, respectively. The proton precipitation occurs because the Martian magnetosheath is small with respect to the heated proton gyroradius in the subsolar region. The data suggest that the precipitation is not permanent but may occur when there are transient increases in the magnetosheath proton temperature. The higher-energy protons penetrate deeper because of their larger gyroradii. The proton entry into the induced magnetosphere is simulated using a hybrid code. A simulation using a fast solar wind as input can reproduce the high energies of the observed precipitating protons. The model shows that the precipitating protons originate from both the solar wind and the planetary exosphere. The precipitation extends over a few thousand kilometers along the orbit of the spacecraft. The proton precipitation does not necessarily correlate with the crustal magnetic anomalies.
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| 8. |
- Edberg, Niklas J. T., et al.
(författare)
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Solar wind interaction with comet 67P : Impacts of corotating interaction regions
- 2016
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Ingår i: Journal of Geophysical Research - Space Physics. - 2169-9380 .- 2169-9402. ; 121:2, s. 949-965
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Tidskriftsartikel (refereegranskat)abstract
- We present observations from the Rosetta Plasma Consortium of the effects of stormy solar wind on comet 67P/Churyumov-Gerasimenko. Four corotating interaction regions (CIRs), where the first event has possibly merged with a coronal mass ejection, are traced from Earth via Mars (using Mars Express and Mars Atmosphere and Volatile EvolutioN mission) to comet 67P from October to December 2014. When the comet is 3.1-2.7AU from the Sun and the neutral outgassing rate approximate to 10(25)-10(26)s(-1), the CIRs significantly influence the cometary plasma environment at altitudes down to 10-30km. The ionospheric low-energy (approximate to 5eV) plasma density increases significantly in all events, by a factor of >2 in events 1 and 2 but less in events 3 and 4. The spacecraft potential drops below -20V upon impact when the flux of electrons increases. The increased density is likely caused by compression of the plasma environment, increased particle impact ionization, and possibly charge exchange processes and acceleration of mass-loaded plasma back to the comet ionosphere. During all events, the fluxes of suprathermal (approximate to 10-100eV) electrons increase significantly, suggesting that the heating mechanism of these electrons is coupled to the solar wind energy input. At impact the magnetic field strength in the coma increases by a factor of 2-5 as more interplanetary magnetic field piles up around the comet. During two CIR impact events, we observe possible plasma boundaries forming, or moving past Rosetta, as the strong solar wind compresses the cometary plasma environment. We also discuss the possibility of seeing some signatures of the ionospheric response to tail disconnection events.
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| 10. |
- Gunell, H., et al.
(författare)
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Plasma penetration of the dayside magnetopause
- 2012
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Ingår i: Physics of Plasmas. - Melville, NY : AIP Publishing. - 1070-664X .- 1089-7674. ; 19:7, s. 072906-
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Tidskriftsartikel (refereegranskat)abstract
- Data from the Cluster spacecraft during their magnetopause crossing on 25 January 2002 are presented. The magnetopause was in a state of slow non-oscillatory motion during the observational period. Coherent structures of magnetosheath plasma, here typified as plasmoids, were seen on closed magnetic field lines on the inside of the magnetopause. Using simultaneous measurements on two spacecraft, the inward motion of the plasmoids is followed from one spacecraft to the next, and it is found to be in agreement with the measured ion velocity. The plasma characteristics and the direction of motion of the plasmoids show that they have penetrated the magnetopause, and the observations are consistent with the concept of impulsive penetration, as it is known from theory, simulations, and laboratory experiments. The mean flux across the magnetopause observed was 0.2%-0.5% of the solar wind flux at the time, and the peak values of the flux inside the plasmoids reached approximately 20% of the solar wind flux.
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| 11. |
- Lundström, Staffan, et al.
(författare)
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In-plane permeability measurements : a Nordic round-robin study
- 2000
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Ingår i: Composites. Part A, Applied science and manufacturing. - 1359-835X .- 1878-5840. ; 31:1, s. 29-43
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Tidskriftsartikel (refereegranskat)abstract
- Three methods to measure the in-plane permeability are compared. The methods are based on the wetting and saturated parallel flow techniques and the wetting radial flow technique. It is found that the stability of all three methods is very good. The best repeatability in the results is obtained with the wetting parallel flow technique. A main drawback of this method is, however, that the samples are not saturated hence, the saturated parallel flow method is suggested for continued evaluation. The standard deviation from repeatable measurements of this method is 14 and 20% for the two fabrics tested. By a round-robin comparison at three laboratories it is found that the reproducibility of the saturated parallel flow technique is in the same range as the repeatability of the method. Furthermore, it is shown that the liquid tested and the pressure applied have very small influence on the results. It is clear that most of the scatter is due to the sample preparation and variations in the material. Accordingly, a continued work should be concentrated on improvements of the sample preparation, and development of methods to reduce the influence, from small errors, in sample preparation on the results.
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| 12. |
- Lundström, Staffan, et al.
(författare)
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In-plane permeability measurements : stability, repeatability and reproducibility
- 1999
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Ingår i: ICCM-12 Europe. - Tours : ICCM. - 2951452624
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Konferensbidrag (refereegranskat)abstract
- Three methods to measure the in-plane permeability have been compared by theoretical analysis and repeated measurements. Based on this comparison the saturated parallel flow technique is suggested for continued evaluation. The stability of this method is better than 1%. However when doing repeatable measurements with new samples the averaged standard deviation increases to 14 % and 20 % for the two fabrics tested. By a round-robin comparison at three laboratories it is found that the reproducibility of the saturated parallel flow technique is in the same range as the repeatability of the method. It is clear that the scatter is due to the sample preparation, variations in the material and the method of loading the sample. Accordingly, a continued work should be concentrated on improvements of the sample preparation, and developments of methods to reduce the influence, from small errors, in sample preparation and sample loading on the results.
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| 13. |
- Nilsson, Hans, et al.
(författare)
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Evolution of the ion environment of comet 67P/Churyumov-Gerasimenko
- 2015
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 583
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Tidskriftsartikel (refereegranskat)abstract
- Context. The Rosetta spacecraft is escorting comet 67P/Churyumov-Gerasimenko from a heliocentric distance of >3.6 AU, where the comet activity was low, until perihelion at 1.24 AU. Initially, the solar wind permeates the thin comet atmosphere formed from sublimation. Aims. Using the Rosetta Plasma Consortium Ion Composition Analyzer (RPC-ICA), we study the gradual evolution of the comet ion environment, from the first detectable traces of water ions to the stage where cometary water ions accelerated to about 1 keV energy are abundant. We compare ion fluxes of solar wind and cometary origin. Methods. RPC-ICA is an ion mass spectrometer measuring ions of solar wind and cometary origins in the 10 eV-40 keV energy range. Results. We show how the flux of accelerated water ions with energies above 120 eV increases between 3.6 and 2.0 AU. The 24 h average increases by 4 orders of magnitude, mainly because high-flux periods become more common. The water ion energy spectra also become broader with time. This may indicate a larger and more uniform source region. At 2.0 AU the accelerated water ion flux is frequently of the same order as the solar wind proton flux. Water ions of 120 eV-few keV energy may thus constitute a significant part of the ions sputtering the nucleus surface. The ion density and mass in the comet vicinity is dominated by ions of cometary origin. The solar wind is deflected and the energy spectra broadened compared to an undisturbed solar wind. Conclusions. The flux of accelerated water ions moving from the upstream direction back toward the nucleus is a strongly nonlinear function of the heliocentric distance.
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| 14. |
- Rees, R. M., et al.
(författare)
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Nitrous oxide emissions from European agriculture; an analysis of variability and drivers of emissions from field experiments
- 2012
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Ingår i: Biogeosciences Discussions. - : Copernicus GmbH. - 1810-6277. ; 9:7, s. 9259-9288
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Tidskriftsartikel (refereegranskat)abstract
- Nitrous oxide emissions from a network of agricultural experiments in Europe and Zimbabwe were used to explore the relative importance of site and management controls of emissions. At each site, a selection of management interventions were compared 5 within replicated experimental designs in plot based experiments. Arable experiments were conducted at Beano in Italy, El Encin in Spain, Foulum in Denmark, Logården in Sweden, Maulde in Belgium, Paulinenaue in Germany, Harare in Zimbabwe and Tulloch in the UK. Grassland experiments were conducted at Crichton, Nafferton and Peaknaze in the UK, Gödöllö in Hungary, Rzecin in Poland, Zarnekow in Germany and 10 Theix in France. Nitrous oxide emissions were measured at each site over a period of at least two years using static chambers. Emissions varied widely between sites and as a result of manipulation treatments. Average site emissions (throughout the study period) varied between 0.04 and 21.21 kg N2O-N ha−1 yr−1, with the largest fluxes and variability associated with the grassland sites. Total nitrogen addition was found to be 15 the single most important determinant of emissions, accounting for 15% of the variance (using linear regression) in the data from the arable sites (p < 0.0001), and 77% in the grassland sites. The annual emissions from arable sites were significantly greater than those that would be predicted by IPCC default emission factors. Variability in N2O within sites that occurred as a result of manipulation treatments was greater than that 20 resulting from site to site and year to year variation, highlighting the importance of management interventions in contributing to greenhouse gas mitigation.
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| 15. |
- Rees, R. M., et al.
(författare)
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Nitrous oxide emissions from European agriculture - an analysis of variability and drivers of emissions from field experiments
- 2013
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Ingår i: Biogeosciences. - : Copernicus GmbH. - 1726-4170 .- 1726-4189. ; 10:4, s. 2671-2682
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Tidskriftsartikel (refereegranskat)abstract
- Nitrous oxide emissions from a network of agricultural experiments in Europe and Zimbabwe were used to explore the relative importance of site and management controls of emissions. At each site, a selection of management interventions were compared within replicated experimental designs in plot based experiments. Arable experiments were conducted at Beano in Italy, El Encin in Spain, Foulum in Denmark, Logården in Sweden, Maulde in Belgium, Paulinenaue in Germany, Harare in Zimbabwe and Tulloch in the UK. Grassland experiments were conducted at Crichton, Nafferton and Peaknaze in the UK, Gödöllö in Hungary, Rzecin in Poland, Zarnekow in Germany and Theix in France. Nitrous oxide emissions were measured at each site over a period of at least two years using static chambers. Emissions varied widely between sites and as a result of manipulation treatments. Average site emissions (throughout the study period) varied between 0.04 and 21.21 kg N2O-N ha−1 yr−1, with the largest fluxes and variability associated with the grassland sites. Total nitrogen addition was found to be the single most important determinant of emissions, accounting for 15% of the variance (using linear regression) in the data from the arable sites (p < 0.0001), and 77% in the grassland sites. The annual emissions from arable sites were significantly greater than those that would be predicted by IPCC default emission factors. Variability in N2O within sites that occurred as a result of manipulation treatments was greater than that resulting from site to site and year to year variation, highlighting the importance of management interventions in contributing to greenhouse gas mitigation.
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| 18. |
- Arvidsson, Kristina, et al.
(författare)
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A hydrogeological study of the Nhandugue River, Mozambique - A major groundwater recharge zone
- 2010
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Ingår i: Procs. WaterNet 2010.
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Konferensbidrag (refereegranskat)abstract
- The Nhandugue River flows over the western margin of the Urema Rift, the southernmost extension of the East African Rift System, and marks the north-western border of Gorongosa National Park, Mozambique. It constitutes one of the major indispensable water resources for the ecosystem that the park protects. Our study focused on the hydrogeological conditions at the western rift margin by resistivity measurements, soil sampling and discharge measurements. The resistivity results suggest that the area is heavily faulted and constitutes a major groundwater recharge zone. East of the rift margin the resistivity indicate that solid gneiss is fractured and weathered, and is overlain by sandstone and alluvial sediments. The top 10-15 m of the alluvial sequence is interpreted as sand. The sand layer extends back to the rift margin thus also covering the gneiss. The sandstone outcrops a few kilometers from the rift margin and dips towards east/south-east. Further into the rift valley, the sand is underlain by lenses of silt and clay on top of sand mixed with finer matter. In the lower end of the investigated area the lenses of silt and clay appears as a more or less continuous layer between the two sand units. The topmost alluvial sand constitutes an unconfined aquifer under which the solid gneiss forms a hydraulic boundary and the fractured gneiss an unconfined aquifer. The sandstone is an unconfined aquifer in the west, becoming semi-confined down dip. The lenses of silt and clay forms an aquitard and the underlying sand mixed with finer matter a semi-confined aquifer. The surface runoff decreases downstream and it is therefore concluded that surface water infiltrates as recharge to the aquifers and moves as groundwater in an east/south-eastward direction. (C) 2011 Elsevier Ltd. All rights reserved.
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| 20. |
- Brindefalk, B., et al.
(författare)
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Bacterial composition in Swedish raw drinking water reveals three major interacting ubiquitous metacommunities
- 2022
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Ingår i: Microbiologyopen. - : Wiley. - 2045-8827. ; 11:5
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Tidskriftsartikel (refereegranskat)abstract
- Background Surface raw water used as a source for drinking water production is a critical resource, sensitive to contamination. We conducted a study on Swedish raw water sources, aiming to identify mutually co-occurring metacommunities of bacteria, and environmental factors driving such patterns. Methods The water sources were different regarding nutrient composition, water quality, and climate characteristics, and displayed various degrees of anthropogenic impact. Water inlet samples were collected at six drinking water treatment plants over 3 years, totaling 230 samples. The bacterial communities of DNA sequenced samples (n = 175), obtained by 16S metabarcoding, were analyzed using a joint model for taxa abundance. Results Two major groups of well-defined metacommunities of microorganisms were identified, in addition to a third, less distinct, and taxonomically more diverse group. These three metacommunities showed various associations to the measured environmental data. Predictions for the well-defined metacommunities revealed differing sets of favored metabolic pathways and life strategies. In one community, taxa with methanogenic metabolism were common, while a second community was dominated by taxa with carbohydrate and lipid-focused metabolism. Conclusion The identification of ubiquitous persistent co-occurring bacterial metacommunities in freshwater habitats could potentially facilitate microbial source tracking analysis of contamination issues in freshwater sources.
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| 21. |
- Cameron, Sarina R., et al.
(författare)
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PTE, a novel module to target Polycomb Repressive Complex 1 to the human cyclin D2 (CCND2) oncogene
- 2018
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Ingår i: Journal of Biological Chemistry. - : American Society for Biochemistry and Molecular Biology. - 0021-9258 .- 1083-351X. ; 293:37, s. 14342-14358
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Tidskriftsartikel (refereegranskat)abstract
- Polycomb group proteins are essential epigenetic repressors. They form multiple protein complexes of which two kinds, PRC1 and PRC2, are indispensable for repression. Although much is known about their biochemical properties, how mammalian PRC1 and PRC2 are targeted to specific genes is poorly understood. Here, we establish the cyclin D2 (CCND2) oncogene as a simple model to address this question. We provide the evidence that the targeting of PRC1 to CCND2 involves a dedicated PRC1-targeting element (PTE). The PTE appears to act in concert with an adjacent cytosine-phosphate-guanine (CpG) island to arrange for the robust binding of PRC1 and PRC2 to repressed CCND2. Our findings pave the way to identify sequence-specific DNA-binding proteins implicated in the targeting of mammalian PRC1 complexes and provide novel link between polycomb repression and cancer.
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| 23. |
- D'Angiolo, M., et al.
(författare)
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A yeast living ancestor reveals the origin of genomic introgressions
- 2020
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 587, s. 420-425
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Tidskriftsartikel (refereegranskat)abstract
- A yeast clonal descendant of an ancient hybridization event is identified and sheds light on the early evolution of the Saccharomyces cerevisiae Alpechin lineage and its abundant Saccharomyces paradoxus introgressions. Genome introgressions drive evolution across the animal(1), plant(2) and fungal(3) kingdoms. Introgressions initiate from archaic admixtures followed by repeated backcrossing to one parental species. However, how introgressions arise in reproductively isolated species, such as yeast(4), has remained unclear. Here we identify a clonal descendant of the ancestral yeast hybrid that founded the extant Saccharomyces cerevisiae Alpechin lineage(5), which carries abundant Saccharomyces paradoxus introgressions. We show that this clonal descendant, hereafter defined as a 'living ancestor', retained the ancestral genome structure of the first-generation hybrid with contiguous S. cerevisiae and S. paradoxus subgenomes. The ancestral first-generation hybrid underwent catastrophic genomic instability through more than a hundred mitotic recombination events, mainly manifesting as homozygous genome blocks generated by loss of heterozygosity. These homozygous sequence blocks rescue hybrid fertility by restoring meiotic recombination and are the direct origins of the introgressions present in the Alpechin lineage. We suggest a plausible route for introgression evolution through the reconstruction of extinct stages and propose that genome instability allows hybrids to overcome reproductive isolation and enables introgressions to emerge.
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| 25. |
- de Peppo, G.M., et al.
(författare)
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Human Embryonic Mesodermal Progenitors Highly Resemble Human Mesenchymal Stem Cells and Display High Potential for Tissue Engineering Applications
- 2010
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Ingår i: Tissue Engineering. Part A. - : Mary Ann Liebert. - 1937-3341 .- 1937-335X. ; 16:7, s. 2161-2182
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Tidskriftsartikel (refereegranskat)abstract
- Adult stem cells, such as human mesenchymal stem cells (hMSCs), show limited proliferative capacity and, after long-term culture, lose their differentiation capacity and are therefore not an optimal cell source for tissue engineering. Human embryonic stem cells (hESCs) constitute an important new resource in this field, but one major drawback is the risk of tumor formation in the recipients. One alternative is to use progenitor cells derived from hESCs which are more lineage restricted but do not form teratomas. We have recently derived a cell line from hESCs denoted human embryonic stem cell-derived mesodermal progenitors (hESMPs) and here, using genome wide microarray analysis, report that the process of hES-MPs derivation results in a significantly altered expression of hESCs characteristic genes to an expression level highly similar to that of hMSCs. However, hES-MPs displayed a significantly higher proliferative capacity and longer telomeres. Interestingly, the hES-MPs also demonstrated a lower expression of HLA class II proteins before and after interferon-γ treatment, indicating that these cells may somewhat be immunoprivileged and potentially used for HLA-incompatible transplantation. The hES-MPs are thus an appealing alternative to hMSCs in tissue engineering applications and stem cell-based therapies for mesodermal tissues.
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