| 1. |
- Loza, M. J., et al.
(författare)
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Validated and longitudinally stable asthma phenotypes based on cluster analysis of the ADEPT study
- 2016
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Ingår i: Respiratory Research. - : Springer Nature. - 1465-9921 .- 1465-993X. ; 17:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Asthma is a disease of varying severity and differing disease mechanisms. To date, studies aimed at stratifying asthma into clinically useful phenotypes have produced a number of phenotypes that have yet to be assessed for stability and to be validated in independent cohorts. The aim of this study was to define and validate, for the first time ever, clinically driven asthma phenotypes using two independent, severe asthma cohorts: ADEPT and U-BIOPRED. Methods: Fuzzy partition-around-medoid clustering was performed on pre-specified data from the ADEPT participants (n = 156) and independently on data from a subset of U-BIOPRED asthma participants (n = 82) for whom the same variables were available. Models for cluster classification probabilities were derived and applied to the 12-month longitudinal ADEPT data and to a larger subset of the U-BIOPRED asthma dataset (n = 397). High and low type-2 inflammation phenotypes were defined as high or low Th2 activity, indicated by endobronchial biopsies gene expression changes downstream of IL-4 or IL-13. Results: Four phenotypes were identified in the ADEPT (training) cohort, with distinct clinical and biomarker profiles. Phenotype 1 was "mild, good lung function, early onset", with a low-inflammatory, predominantly Type-2, phenotype. Phenotype 2 had a "moderate, hyper-responsive, eosinophilic" phenotype, with moderate asthma control, mild airflow obstruction and predominant Type-2 inflammation. Phenotype 3 had a "mixed severity, predominantly fixed obstructive, non-eosinophilic and neutrophilic" phenotype, with moderate asthma control and low Type-2 inflammation. Phenotype 4 had a "severe uncontrolled, severe reversible obstruction, mixed granulocytic" phenotype, with moderate Type-2 inflammation. These phenotypes had good longitudinal stability in the ADEPT cohort. They were reproduced and demonstrated high classification probability in two subsets of the U-BIOPRED asthma cohort. Conclusions: Focusing on the biology of the four clinical independently-validated easy-to-assess ADEPT asthma phenotypes will help understanding the unmet need and will aid in developing tailored therapies. Trial registration:NCT01274507(ADEPT), registered October 28, 2010 and NCT01982162(U-BIOPRED), registered October 30, 2013.
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| 2. |
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- 2019
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Tidskriftsartikel (refereegranskat)
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| 3. |
- Lindblad-Toh, Kerstin, et al.
(författare)
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Genome sequence, comparative analysis and haplotype structure of the domestic dog.
- 2005
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 438:7069, s. 803-19
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Tidskriftsartikel (refereegranskat)abstract
- Here we report a high-quality draft genome sequence of the domestic dog (Canis familiaris), together with a dense map of single nucleotide polymorphisms (SNPs) across breeds. The dog is of particular interest because it provides important evolutionary information and because existing breeds show great phenotypic diversity for morphological, physiological and behavioural traits. We use sequence comparison with the primate and rodent lineages to shed light on the structure and evolution of genomes and genes. Notably, the majority of the most highly conserved non-coding sequences in mammalian genomes are clustered near a small subset of genes with important roles in development. Analysis of SNPs reveals long-range haplotypes across the entire dog genome, and defines the nature of genetic diversity within and across breeds. The current SNP map now makes it possible for genome-wide association studies to identify genes responsible for diseases and traits, with important consequences for human and companion animal health.
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| 4. |
- Persson, Agneta, 1963, et al.
(författare)
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Differences in Specific Mass Density Between Dinoflagellate Life Stages and Relevance to Accumulation by Hydrodynamic Processes
- 2021
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Ingår i: Journal of Phycology. - : Wiley. - 0022-3646 .- 1529-8817. ; 57:5, s. 1492-1503
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Tidskriftsartikel (refereegranskat)abstract
- One previously unstudied aspect of differences between sexual and asexual life stages in large-scale transport and accumulation is density (mass per unit volume) of cells in each life stage. The specific density was determined for Scrippsiella lachrymosa cells in medium with and without nitrogen (N) enrichment through density-gradient centrifugation. Growth medium without N addition is often called "encystment medium" when used for the purpose of resting cyst formation in cyst-forming dinoflagellates; mating gametes are usually seen after 2-3 days. Significant differences in specific density were found after 2 days in encystment medium simultaneously with the observation of typical gamete swimming behavior and mating. The specific density of cells in encystment medium was 1.06 g center dot cm(-3); whereas, the specific density of cells in growth medium was 1.11 g center dot cm(-3). Cells in encystment medium were found to have significantly increased lipid content, reduced chlorophyll content, and reduced internal complexity. The findings may explain differential transport of less dense and chemotactically aggregating gametes into surface blooms in contrast to denser vegetative cells that perform daily vertical migration and do not aggregate. Passive accumulation of non-migrating gametes into layers in stagnant water also can be explained, as well as sinking of zygotes when the storage of highly dense starch increases. Resting cysts had a density of over 1.14 g center dot cm(-3) and would sink to become part of the silt fraction of the sediment. We suggest that differences in behavior and buoyancy between sexual and asexual life stages cause differences in cell accumulation, and therefore large-scale, environmental transport could be directly dependent upon life-cycle transitions.
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| 5. |
- Chatron, N., et al.
(författare)
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Bi-allelic GAD1 variants cause a neonatal onset syndromic developmental and epileptic encephalopathy
- 2020
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Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 143:5, s. 1447-1461
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Tidskriftsartikel (refereegranskat)abstract
- Developmental and epileptic encephalopathies are a heterogeneous group of early-onset epilepsy syndromes dramatically impairing neurodevelopment. Modern genomic technologies have revealed a number of monogenic origins and opened the door to therapeutic hopes. Here we describe a new syndromic developmental and epileptic encephalopathy caused by bi-allelic loss-of-function variants in GAD1, as presented by 11 patients from six independent consanguineous families. Seizure onset occurred in the first 2 months of life in all patients. All 10 patients, from whom early disease history was available, presented with seizure onset in the first month of life, mainly consisting of epileptic spasms or myoclonic seizures. Early EEG showed suppression-burst or pattern of burst attenuation or hypsarrhythmia if only recorded in the post-neonatal period. Eight patients had joint contractures and/or pes equinovarus. Seven patients presented a cleft palate and two also had an omphalocele, reproducing the phenotype of the knockout Gad1(-/-) mouse model. Four patients died before 4 years of age. GAD1 encodes the glutamate decarboxylase enzyme GAD67, a critical actor of the c-aminobutyric acid (GABA) metabolism as it catalyses the decarboxylation of glutamic acid to form GABA. Our findings evoke a novel syndrome related to GAD67 deficiency, characterized by the unique association of developmental and epileptic encephalopathies, cleft palate, joint contractures and/or omphalocele.
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| 6. |
- Persson, Agneta, 1963, et al.
(författare)
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Differences in swimming pattern between life cycle stages of the toxic dinoflagellate Alexandrium fundyense
- 2013
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Ingår i: Harmful Algae. - : Elsevier BV. - 1568-9883. ; 21-22, s. 36-43
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Tidskriftsartikel (refereegranskat)abstract
- Different life stages of Alexandrium fundyense have different swimming behavior; gametes often are said to "swarm" or "dance" before mating. This behavior was studied, and quantitative measures of these motility patterns in two-dimensions were generated using motion-analysis software applied to video records of individual-cell movements. Behavior, swimming patterns, and growth were studied in two strains of A. fundyense and compared in encystment medium and growth medium. Vegetative cells swam straight, rotating around the apical axis until they hit something and then swam straight in a different direction. Gamete swimming behavior was slower and characterized by frequent direction changes and circular motion. Gametes contacted other cells frequently (>5 cell contacts min(-1) cell(-1)). Zygotes swam slowly when newly formed and later became nearly immobile; these cells continued to contact other cells and also surfaces. The results are in accordance with field observations of long swimming distances for vegetative cells, accumulation in thin layers of gametes, and sinking of developing resting cysts attached to marine snow for zygotes. (C) 2012 Elsevier B.V. All rights reserved.
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| 7. |
- Persson, Agneta, 1963, et al.
(författare)
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Dinoflagellate gamete formation and environmental cues: Observations, theory, and synthesis
- 2008
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Ingår i: Harmful Algae. - : Elsevier BV. - 1568-9883. ; 7:6, s. 798-801
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Tidskriftsartikel (refereegranskat)abstract
- For some species of cyst-producing dinoflagellates, the sexual life cycle is well studied in laboratory cultures. Dinoflagellate blooms in stratified waters, vertical migration of vegetative cells, and the accumulation of populations within thin layers are well-documented phenomena in nature. We propose a conceptual model that places these phenomena in a functional, ecological context: vegetative cells of a dinoflagellate population display vertical migration, but at the end of the bloom, environmental or internal cues shift the cell cycle to gamete formation. Then the vertical migrations cease, and cells accumulate in a layer at the pycnocline where gametes fuse to form zygotes, which then sink to the sediment as resting cysts. We support this conceptual model with experimental and environmental evidence. (C) 2008 Elsevier B.V. All rights reserved.
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| 8. |
- Persson, Agneta, 1963, et al.
(författare)
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Toxin content differs between life stages of Alexandrium fundyense (Dinophyceae)
- 2012
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Ingår i: Harmful Algae. - : Elsevier BV. - 1568-9883. ; 19:-, s. 101-107
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Tidskriftsartikel (refereegranskat)abstract
- Different life stages of two mating-compatible clones of the paralytic shellfish toxin (PST)-producing dinoflagellate Alexandrium fundyense Balech were separated using a combination of techniques; culturing and sampling methods were used to separate vegetative cells and gametes, and sorting flow cytometry was used to separate zygotes. PST profiles were significantly different between life stages; the two gonyautoxins GTX1 and 2 were present in vegetative and senescent cells, but disappeared from gametes and zygotes. Toxin-profile changes were shown to occur very quickly in both strains when pellicle cyst formation was induced by shaking (four minutes) followed by rinsing on a screen. These pellicle cysts produced from exponentially-growing, vegetative cells lost GTX1 and 2 completely. Rapid toxin epimerization of GTX1 to GTX4 and GTX2 to GTX3 is one possible explanation, although the biological advantage of this remains unclear. Another possible explanation is that during the mating phase of a bloom or when cells are disturbed, GTX1 and GTX2 are released into the surrounding water. It may be advantageous for a dinoflagellate bloom to be surrounded by free toxins in the water. (c) 2012 Elsevier B.V. All rights reserved.
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| 9. |
- Smith, B. C., et al.
(författare)
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Dinoflagellate cell density limits explored using Scrippsiella lachrymosa cultured in flow-through cages
- 2023
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Ingår i: Journal of Applied Phycology. - : Springer Science and Business Media LLC. - 0921-8971 .- 1573-5176. ; 35, s. 613-623
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Tidskriftsartikel (refereegranskat)abstract
- Dinoflagellates constitute one of the most important groups of primary producers and micro-zooplankton on earth, common in both marine and freshwater environments. Despite their prominent position among phytoplankton, they are difficult to grow into dense cultures in the laboratory. This discrepancy between field and laboratory indicates serious limitations caused by the laboratory culturing conditions. A difficult to study but important factor is the constraints of enclosure in a limited volume of water. We conducted an experiment wherein the dinoflagellate Scrippsiella lachrymosa was grown in "flow cells" - 100 cm(3) cylindrical cages constructed from plankton net, inserted in larger volumes of growth medium, allowing an exchange of medium without dilution of the culture. Cell numbers far exceeding the normal for culturing of this species and dinoflagellates in general were attained, even though the experiment was terminated before cultures reached stationary phase. A cell number ten times higher than under regular batch culturing was achieved (up to 340,000 cells mL(-1)). Pattern formation was distinct in cultures when cells were plentiful and water movements caused cell accumulation, not dispersion. High cell density concurrent with access to new growth medium promoted induction of the sexual cell cycle. The results indicate serious limitations to growth set by enclosure in a limited water volume in laboratory experiments; thus, maximum growth rates of dinoflagellates in favourable field conditions may be vastly underestimated. Cell accumulation behavior of dinoflagellates during the sexual life cycle may together with physical transport by larger forces in nature explain sudden bloom occurrences.
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| 10. |
- Smith, B.C., et al.
(författare)
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Toxin profile change in vegetative cells and pellicle cysts of Alexandrium fundyense after gut passage in the eastern oyster Crassostrea virginica
- 2011
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Ingår i: Aquatic biology. - : Inter-Research Science Center. - 1864-7790 .- 1864-7782. ; 13:2, s. 193-201
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Tidskriftsartikel (refereegranskat)abstract
- Abstract: Vegetative cells and pellicle cysts of the toxic dinoflagellate Alexandrium fundyense Balech were fed to the eastern oyster Crassostrea virginica Gmelin under controlled conditions. Para lytic shellfish toxins (PSTs) were measured in vegetative cells and pellicle cysts prior to feeding and directly after passage through the oyster alimentary canal and defecation as intact cells. Oysters fed with vegetative cells and those fed with pellicle cysts accumulated toxins. One experimental treatment tested for direct uptake of toxins from the water (oysters and A. fundyense cells were separated by a screen); PSTs were not accumulated from the water by the oysters. There were no significant changes in total, per-cell toxicity after passage through the oyster alimentary canal, suggesting limited transfer of toxins from intact cells to the oysters. However, there were statistically significant changes in the toxin composition of cells following gut passage. Vegetative cells and pellicle cysts from feces had increased amounts of saxitoxin (STX) and decreased amounts of gonyautoxin 4 (GTX4) per cell, compared to amounts prior to gut passage. Following gut passage, pellicle cysts showed better survival in the feces than vegetative cells, which is consistent with the view of pellicle-cyst formation as a successful survival strategy against adverse conditions.
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