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1.	Haas, Jan, et al. (author) Atlas of the clinical genetics of human dilated cardiomyopathy 2015 In: European Heart Journal. - : Oxford University Press. - 0195-668X .- 1522-9645. ; 36:18, s. 1123-U43 Journal article (peer-reviewed)abstract Aim: We were able to show that targeted Next-Generation Sequencing is well suited to be applied in clinical routine diagnostics, substantiating the ongoing paradigm shift from low- to high-throughput genomics in medicine. By means of our atlas of the genetics of human DCM, we aspire to soon be able to apply our findings to the individual patient with cardiomyopathy in daily clinical practice. Numerous genes are known to cause dilated cardiomyopathy (DCM). However, until now technological limitations have hindered elucidation of the contribution of all clinically relevant disease genes to DCM phenotypes in larger cohorts. We now utilized next-generation sequencing to overcome these limitations and screened all DCM disease genes in a large cohort. Methods and results: In this multi-centre, multi-national study, we have enrolled 639 patients with sporadic or familial DCM. To all samples, we applied a standardized protocol for ultra-high coverage next-generation sequencing of 84 genes, leading to 99.1% coverage of the target region with at least 50-fold and a mean read depth of 2415. In this well characterized cohort, we find the highest number of known cardiomyopathy mutations in plakophilin-2, myosin-binding protein C-3, and desmoplakin. When we include yet unknown but predicted disease variants, we find titin, plakophilin-2, myosin-binding protein-C 3, desmoplakin, ryanodine receptor 2, desmocollin-2, desmoglein-2, and SCN5A variants among the most commonly mutated genes. The overlap between DCM, hypertrophic cardiomyopathy (HCM), and channelopathy causing mutations is considerably high. Of note, we find that >38% of patients have compound or combined mutations and 12.8% have three or even more mutations. When comparing patients recruited in the eight participating European countries we find remarkably little differences in mutation frequencies and affected genes. Conclusion: This is to our knowledge, the first study that comprehensively investigated the genetics of DCM in a large-scale cohort and across a broad gene panel of the known DCM genes. Our results underline the high analytical quality and feasibility of Next-Generation Sequencing in clinical genetic diagnostics and provide a sound database of the genetic causes of DCM.
2.	Kehoe, Laura, et al. (author) Make EU trade with Brazil sustainable 2019 In: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 364:6438, s. 341- Journal article (other academic/artistic)
3.	Aladro, Rebeca, 1979, et al. (author) Molecular gas in the northern nucleus of Mrk 273: Physical and chemical properties of the disc and its outflow 2018 In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 617 Journal article (peer-reviewed)abstract Aiming to characterise the properties of the molecular gas in the ultra-luminous infrared galaxy Mrk 273 and its outflow, we used the NOEMA interferometer to image the dense-gas molecular tracers HCN, HCO+, HNC, HOC+ and HC3N at similar to 86 GHz and similar to 256 GHz with angular resolutions of 4.'' 9 x 4.'' 5 (similar to 3.7 x 3.4 kpc) and 0.'' 61 x 0.'' 55 (similar to 460 x 420 pc). We also modelled the flux of several H2O lines observed with Herschel using a radiative transfer code that includes excitation by collisions and far-infrared photons. The disc of the Mrk 273 north nucleus has two components with decoupled kinematics. The gas in the outer parts (R similar to 1.5 kpc) rotates with a south-east to north-west direction, while in the inner disc (R similar to 300 pc) follows a north-east to south-west rotation. The central 300 pc, which hosts a compact starburst region, is filled with dense and warm gas, and contains a dynamical mass of (4-5) x 10(9) M-circle dot, a luminosity of L'HCN = (3-4) x 10(8) K km s(-1) pc(2), and a dust temperature of 55 K. At the very centre, a compact core with R similar to 50 pc has a luminosity of LIR = 4 x 10(11) L-circle dot (30% of the total infrared luminosity), and a dust temperature of 95 K. The core is expanding at low velocities similar to 50-100 km s(-1), probably affected by the outflowing gas. We detect the blue-shifted component of the outflow, while the red-shifted counterpart remains undetected in our data. Its cold and dense phase reaches fast velocities up to similar to 1000 km s(-1), while the warm outflowing gas has more moderate maximum velocities of similar to 600 km s(-1). The outflow is compact, being detected as far as 460 pc from the centre in the northern direction, and has a mass of dense gas <= 8 x 10(8) M-circle dot. The difference between the position angles of the inner disc (similar to 70 degrees) and the outflow (similar to 10 degrees) indicates that the outflow is likely powered by the AGN, and not by the starburst. Regarding the chemistry in Mrk 273, we measure an extremely low HCO+/HOC+ ratio of 10 +/- 5 in the inner disc of Mrk 273.
4.	Alimena, Juliette, et al. (author) Searching for long-lived particles beyond the Standard Model at the Large Hadron Collider 2020 In: Journal of Physics G. - : IOP Publishing. - 0954-3899 .- 1361-6471. ; 47:9 Journal article (peer-reviewed)abstract Particles beyond the Standard Model (SM) can generically have lifetimes that are long compared to SM particles at the weak scale. When produced at experiments such as the Large Hadron Collider (LHC) at CERN, these long-lived particles (LLPs) can decay far from the interaction vertex of the primary proton-proton collision. Such LLP signatures are distinct from those of promptly decaying particles that are targeted by the majority of searches for new physics at the LHC, often requiring customized techniques to identify, for example, significantly displaced decay vertices, tracks with atypical properties, and short track segments. Given their non-standard nature, a comprehensive overview of LLP signatures at the LHC is beneficial to ensure that possible avenues of the discovery of new physics are not overlooked. Here we report on the joint work of a community of theorists and experimentalists with the ATLAS, CMS, and LHCb experiments-as well as those working on dedicated experiments such as MoEDAL, milliQan, MATHUSLA, CODEX-b, and FASER-to survey the current state of LLP searches at the LHC, and to chart a path for the development of LLP searches into the future, both in the upcoming Run 3 and at the high-luminosity LHC. The work is organized around the current and future potential capabilities of LHC experiments to generally discover new LLPs, and takes a signature-based approach to surveying classes of models that give rise to LLPs rather than emphasizing any particular theory motivation. We develop a set of simplified models; assess the coverage of current searches; document known, often unexpected backgrounds; explore the capabilities of proposed detector upgrades; provide recommendations for the presentation of search results; and look towards the newest frontiers, namely high-multiplicity 'dark showers', highlighting opportunities for expanding the LHC reach for these signals.
5.	Berndt, Sonja I., et al. (author) Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture 2013 In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:5, s. 501-U69 Journal article (peer-reviewed)abstract Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.
6.	Fischer, Silvia, et al. (author) Extracellular RNA Liberates Tumor Necrosis Factor-alpha to Promote Tumor Cell Trafficking and Progression 2013 In: Cancer Research. - 0008-5472 .- 1538-7445. ; 73:16, s. 5080-5089 Journal article (peer-reviewed)abstract Extracellular RNA (eRNA) released from injured cells promotes tissue permeability, thrombosis, and inflammation in vitro and in vivo, and RNase1 pretreatment can reduce all these effects. In this study, we investigated the role of the eRNA/RNase1 system in tumor progression and metastasis. Under quiescent and stimulatory conditions, tumor cells released much higher levels of endogenous extracellular RNA (eRNA) than nontumor cells. In glioblastomas, eRNA was detected at higher levels in tumors than nontumor tissue. eRNA induced tumor cells to adhere to and migrate through human cerebral microvascular endothelial cells (HCMEC/D3), in a manner requiring activation of VEGF signaling. In addition, eRNA liberated TNF-alpha from macrophages in a manner requiring activation of the TNF-alpha-converting enzyme TACE. Accordingly, supernatants derived from eRNA-treated macrophages enhanced tumor cell adhesion to HCMEC/D3. TNF-alpha release evoked by eRNA relied upon signaling activation of mitogen-activated protein kinases and the NF-kappa B pathway. In subcutaneous xenograft models of human cancer, administration of RNase1 but not DNase decreased tumor volume and weight. Taken together, these results suggest that eRNA released from tumor cells has the capacity to promote tumor cell invasion through endothelial barriers by both direct and indirect mechanisms, including through a mechanism involving TNF-alpha release from tumor-infiltrating monocytes/macrophages. Our findings establish a crucial role for eRNA in driving tumor progression, and they suggest applications for extracellular RNase1 as an antiinvasive regimen for cancer treatment.
7.	Fischer, Sabine, et al. (author) Zebrafish Ext2 is necessary for Fgf and Wnt signaling, but not for Hh signaling 2011 In: BMC Developmental Biology. - 1471-213X. ; 11, s. 53- Journal article (peer-reviewed)abstract Background: Heparan sulfate (HS) biosynthesis is tightly regulated during vertebrate embryo development. However, potential roles for HS biosynthesis in regulating the function of paracrine signaling molecules that bind to HS are incompletely understood.Results: In this report we have studied Fgf, Wnt and Hedgehog (Hh) signaling in ext2 mutants, where heparan sulfate content is low. We found that Fgf targeted gene expression is reduced in ext2 mutants and that the remaining expression is readily inhibited by SU5402, an FGF receptor inhibitor. In the ext2 mutants, Fgf signaling is shown to be affected during nervous system development and reduction of Fgf ligands in the mutants affects tail development. Also, Wnt signaling is affected in the ext2 mutants, as shown by a stronger phenotype in ext2 mutants injected with morpholinos that partially block translation of Wnt11 or Wnt5b, compared to injected wild type embryos. In contrast, Hh dependent signaling is apparently unaffected in the ext2 mutants; Hh targeted gene expression is not reduced, the Hh inhibitor cyclopamine is not more affective in the mutants and Hh dependent cell differentiation in the retina and in the myotome are normal in ext2 mutants. In addition, no genetic interaction between ext2 and shha during development could be detected.Conclusion: We conclude that ext2 is involved in Fgf and Wnt signaling but not in Hh signaling, revealing an unexpected specificity for ext2 in signaling pathways during embryonic development. Thus, our results support the hypothesis that regulation of heparan sulfate biosynthesis has distinct instructive functions for different signaling factors.
8.	Hochhausl, Sophie, et al. (author) Architecture and the Environment 2018 In: Architectural Histories. - : Open Library of the Humanities. - 2050-5833. ; 6:1 Journal article (peer-reviewed)abstract These Field Notes, on the topic of Architecture and the Environment, elucidate how problems raised in the environmental humanities have informed architectural history, and in turn, what architectural history has to contribute to this emerging field. The short essays explore specific 'positions' in the overarching debate, identifying a radical return to critical theory and the embrace of the fundamentally transdisciplinary nature of environmental humanities and architectural history. While the positions advocate for a serious investigation of architects' texts and ideas on environmental issues, the collection also champions a broader engagement with Anthropocene questions and proposes to adopt the environment as an intellectual perspective from which to look upon the world.
9.	Kennedy, Vanessa E., et al. (author) Mast cell leukemia : clinical and molecular features and survival outcomes of patients in the ECNM Registry 2023 In: Blood Advances. - : American Society of Hematology. - 2473-9529 .- 2473-9537. ; 7:9, s. 1713-1724 Journal article (peer-reviewed)abstract Mast cell leukemia (MCL) is a rare subtype of systemic mastocytosis defined by >= 20% mast cells (MC) on a bone marrow aspirate. We evaluated 92 patients with MCL from the European Competence Network on Mastocytosis registry. Thirty-one (34%) patients had a diagnosis of MCL with an associated hematologic neoplasm (MCL-AHN). Chronic MCL (lack of C-findings) comprised 14% of patients, and only 4.5% had "leukemic MCL" (>= 10% circulating MCs). KIT D816V was found in 62/85 (73%) evaluable patients; 9 (11%) individuals exhibited alternative KIT mutations, and no KIT variants were detected in 14 (17%) subjects. Ten evaluable patients (17%) had an abnormal karyotype and the poor-risk SRSF2, ASXL1, and RUNX1 (S/A/R) mutations were identified in 16/36 (44%) patients who underwent next-generation sequencing. Midostaurin was the most common therapy administered to 65% of patients and 45% as first-line therapy. The median overall survival (OS) was 1.6 years. In multivariate analysis (S/A/R mutations excluded owing to low event rates), a diagnosis of MCL-AHN (hazard ratio [HR], 4.7; 95% confidence interval [CI], 1.7-13.0; P = .001) and abnormal karyotype (HR, 5.6; 95% CI, 1.4-13.3; P = .02) were associated with inferior OS; KIT D816V positivity (HR, 0.33; 95% CI, 0.11-0.98; P = .04) and midostaurin treatment (HR, 0.32; 95% CI, 0.08-0.72; P = .008) were associated with superior OS. These data provide the most comprehensive snapshot of the clinicopathologic, molecular, and treatment landscape of MCL to date, and should help further inform subtyping and prognostication of MCL.
10.	Kluin-Nelemans, Hanneke C., et al. (author) Cytogenetic and molecular aberrations and worse outcome for male patients in systemic mastocytosis 2021 In: Theranostics. - : Ivyspring International Publisher. - 1838-7640. ; 11:1, s. 292-303 Journal article (peer-reviewed)abstract In systemic mastocytosis (SM), the clinical features and survival vary greatly. Patient-related factors determining the outcome in SM are largely unknown. Methods: We examined the impact of sex on the clinical features, progression-free survival (PFS), and overall survival (OS) in 3403 patients with mastocytosis collected in the registry of the European Competence Network on Mastocytosis (ECNM). The impact of cytogenetic and molecular genetic aberrations on sex differences was analyzed in a subset of patients. Results: Of all patients enrolled, 55.3% were females. However, a male predominance was found in a subset of advanced SM (AdvSM) patients, namely SM with an associated hematologic neoplasm (SM-AHN, 70%; p < 0.001). Correspondingly, organomegaly (male: 23% vs. female: 13%, p = 0.007) was more, whereas skin involvement (male: 71% vs. female: 86%, p = 0.001) was less frequent in males. In all patients together, OS (p < 0.0001) was significantly inferior in males, and also within the WHO sub-categories indolent SM, aggressive SM (ASM) and SM-AHN. PFS was significantly (p = 0.0002) worse in males when all patients were grouped together; due to low numbers of events, this significance persisted only in the subcategory smoldering SM. Finally, prognostically relevant cytogenetic abnormalities (10% vs. 5%, p = 0.006) or molecular aberrations (SRSF2/ASXLI/RUNXI profile; 63% vs. 40%, p = 0.003) were more frequently present in males. Conclusions: Male sex has a major impact on clinical features, disease progression, and survival in mastocytosis. Male patients have an inferior survival, which seems related to the fact that they more frequently develop a multi-mutated AdvSM associated with a high-risk molecular background.
11.	Koenig, Julian, et al. (author) Cortical thickness and resting-state cardiac function across the lifespan : A cross-sectional pooled mega-analysis 2021 In: Psychophysiology. - : Wiley. - 0048-5772 .- 1469-8986 .- 1540-5958. ; 58:7 Journal article (peer-reviewed)abstract Understanding the association between autonomic nervous system [ANS] function and brain morphology across the lifespan provides important insights into neurovisceral mechanisms underlying health and disease. Resting-state ANS activity, indexed by measures of heart rate [HR] and its variability [HRV] has been associated with brain morphology, particularly cortical thickness [CT]. While findings have been mixed regarding the anatomical distribution and direction of the associations, these inconsistencies may be due to sex and age differences in HR/HRV and CT. Previous studies have been limited by small sample sizes, which impede the assessment of sex differences and aging effects on the association between ANS function and CT. To overcome these limitations, 20 groups worldwide contributed data collected under similar protocols of CT assessment and HR/HRV recording to be pooled in a mega-analysis (N = 1,218 (50.5% female), mean age 36.7 years (range: 12–87)). Findings suggest a decline in HRV as well as CT with increasing age. CT, particularly in the orbitofrontal cortex, explained additional variance in HRV, beyond the effects of aging. This pattern of results may suggest that the decline in HRV with increasing age is related to a decline in orbitofrontal CT. These effects were independent of sex and specific to HRV; with no significant association between CT and HR. Greater CT across the adult lifespan may be vital for the maintenance of healthy cardiac regulation via the ANS—or greater cardiac vagal activity as indirectly reflected in HRV may slow brain atrophy. Findings reveal an important association between CT and cardiac parasympathetic activity with implications for healthy aging and longevity that should be studied further in longitudinal research.
12.	Lübke, Johannes, et al. (author) Prognostic Impact of Organomegaly in Mastocytosis : An Analysis of the European Competence Network on Mastocytosis 2023 In: Journal of Allergy and Clinical Immunology. - : Elsevier. - 2213-2198 .- 2213-2201. ; 11:2, s. 581-590 Journal article (peer-reviewed)abstract BACKGROUND: Organomegaly, including splenomegaly, hepatomegaly, and/or lymphadenopathy, are important diagnostic and prognostic features in patients with cutaneous mastocytosis (CM) or systemic mastocytosis (SM).OBJECTIVES: To investigate the prevalence and prognostic impact of 1 or more organomegalies on clinical course and survival in patients with CM/SM.METHODS: Therefore, 3155 patients with CM (n = 1002 [32%]) or SM (n = 2153 [68%]) enrolled within the registry of the European Competence Network on Mastocytosis were analyzed. RESULTS: Overall survival (OS) was adversely affected by the number of organomegalies (OS: #0 vs #1 hazard ratio [HR], 4.9; 95% CI, 3.4-7.1, P < .001; #1 vs #2 HR, 2.1, 95% CI, 1.4-3.1, P < .001; #2 vs #3 HR, 1.7, 95% CI, 1.2-2.5, P = .004). Lymphadenopathy was frequently detected in patients with smoldering SM (SSM, 18 of 60 [30%]) or advanced SM (AdvSM, 137 of 344 [40%]). Its presence confered an inferior outcome in patients with AdvSM compared with patients with AdvSM without lymphadenopathy (median OS, 3.8 vs 2.6 years; HR, 1.6; 95% CI, 1.2-2.2; P = .003). OS was not different between patients having organomegaly with either ISM or SSM (median, 25.5 years vs not reached; P = .435). At time of disease progression, a new occurrence of any organomegaly was observed in 17 of 40 (43%) patients with ISM, 4 of 10 (40%) patients with SSM, and 33 of 86 (38%) patients with AdvSM, respectively.CONCLUSIONS: Organomegalies including lymphadenopathy are often found in SSM and AdvSM. ISM with organomegaly has a similar course and prognosis compared with SSM. The number of organomegalies is adversely associated with OS. A new occurrence of organomegaly in all variants of SM may indicate disease progression.
13.	Lübke, Johannes, et al. (author) Serum chemistry profiling and prognostication in systemic mastocytosis : a registry-based study of the ECNM and GREM 2024 In: Blood Advances. - : American Society of Hematology. - 2473-9529 .- 2473-9537. ; 8:11, s. 2890-2900 Journal article (peer-reviewed)abstract Certain laboratory abnormalities correlate with subvariants of systemic mastocytosis (SM) and are often prognostically relevant. To assess the diagnostic and prognostic value of individual serum chemistry parameters in SM, 2607 patients enrolled within the European Competence Network on Mastocytosis and 575 patients enrolled within the German Registry on Eosinophils and Mast Cells were analyzed. For screening and diagnosis of SM, tryptase was identified as the most speci fic serum parameter. For differentiation between indolent and advanced SM (AdvSM), the following serum parameters were most relevant: tryptase, alkaline phosphatase, beta 2-microglobulin, lactate dehydrogenase (LDH), albumin, vitamin B12, and C-reactive protein (P < .001). With regard to subvariants of AdvSM, an elevated LDH of ≥ 260 U/L was associated with multilineage expansion (leukocytosis, r = 0.37, P < .001; monocytosis, r = 0.26, P < .001) and the presence of an associated myeloid neoplasm (P < .001), whereas tryptase levels were highest in mast cell leukemia (MCL) vs non-MCL (308 μg/L vs 146 μg/L, P = .003). Based on multivariable analysis, the hazard-risk weighted assignment of 1 point to LDH (hazard ratio [HR], 2.1; 95% confidence interval [CI], 1.1-4.0; P = .018) and 1.5 points each to β2-microglobulin (HR, 2.7; 95% CI, 1.4-5.4; P = .004) and albumin (HR, 3.3; 95% CI, 1.7-6.5; P = .001) delineated a highly predictive 3-tier risk classification system (0 points, 8.1 years vs 1 point, 2.5 years; ≥1.5 points, 1.7 years; P < .001). Moreover, serum chemistry parameters enabled further stratification of patients classified as having an International Prognostic Scoring System for Mastocytosis-AdvSM1/2 risk score (P = .027). In conclusion, serum chemistry pro filing is a crucial tool in the clinical practice supporting diagnosis and prognostication of SM and its subvariants.
14.	Moser, Lydia, et al. (author) A low-luminosity type-1 QSO sample. IV. Molecular gas contents and conditions of star formation in three nearby Seyfert galaxies 2016 In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 587, s. A137- Journal article (peer-reviewed)abstract We present a pilot study of ~3'' resolution observations of low CO transitions with the Submillimeter Array in three nearby Seyfert galaxies, which are part of the low-luminosity quasi-stellar object (LLQSOs) sample consisting of 99 nearby (z = 0.06) type-1 active galactic nuclei (AGN) taken from the Hamburg/ESO quasi-stellar object (QSO) survey. Two sources were observed in 12CO(2-1) and 13CO(2-1) and the third in 12CO(3-2) and HCO+(4-3). None of the sources is detected in continuum emission. More than 80% of the 12CO detected molecular gas is concentrated within a diameter (FWHM) 1.5 × 109M⊙ and for the dust masses of Mdust> 1.6 × 106M⊙. The R21 = 12CO/13CO(2-1) line luminosity ratios show Galactic values of R21 ~ 5-7 in the outskirts and R21 ≳ 20 in the central region, similar to starbursts and (ultra)luminous infrared galaxies ((U)LIRGs; i.e. LIRGs and ULIRGs), implying higher temperatures and stronger turbulence. All three sources show indications of 12CO(2-1)/12CO(1-0) ratios of ~0.5, suggesting a cold or diffuse gas phase. Strikingly, the 12CO(3-2)/(1-0) ratio of ~1 also indicates a higher excited phase. Since these galaxies have high infrared luminosities of LIR ≥ 1011L⊙ and seem to contain a circumnuclear starburst with minimum surface densities of gas and star formation rate (SFR) around Σmol = 50-550 M⊙pc-2 and ΣSFR = 1.1-3.1 M⊙ kpc-2 yr-1, we conclude that the interstellar medium in the centers of these LIRG Seyferts is strongly affected by violent star formation and better described by the ULIRG mass conversion factor.
15.	Osoegawa, Kazutoyo, et al. (author) Quality control project of NGS HLA genotyping for the 17th International HLA and Immunogenetics Workshop 2019 In: Human Immunology. - : ELSEVIER SCIENCE INC. - 0198-8859 .- 1879-1166. ; 80:4, s. 228-236 Journal article (peer-reviewed)abstract The 17th International HLA and Immunogenetics Workshop (IHIW) organizers conducted a Pilot Study (PS) in which 13 laboratories (15 groups) participated to assess the performance of the various sequencing library preparation protocols, NGS platforms and software in use prior to the workshop. The organizers sent 50 cell lines to each of the 15 groups, scored the 15 independently generated sets of NGS HLA genotyping data, and generated "consensus" HLA genotypes for each of the 50 cell lines. Proficiency Testing (PT) was subsequently organized using four sets of 24 cell lines, selected from 48 of 50 PS cell lines, to validate the quality of NGS HLA typing data from the 34 participating IHIW laboratories. Completion of the PT program with a minimum score of 95% concordance at the HLA-A, HLA-B, HLA-C, HLA-DRB1 and HLA-DQB1 loci satisfied the requirements to submit NGS HLA typing data for the 17th IHIW projects. Together, these PS and PT efforts constituted the 17th IHIW Quality Control project. Overall PT concordance rates for HLA-A, HLA-B, HLA-C, HLA-DPA1, HLA-DPB1, HLA-DQA1, HLA-DQB1, HLA-DRB1, HLA-DRB3, HLA-DRB4 and HLA-DRB5 were 98.1%, 97.0% and 98.1%, 99.0%, 98.6%, 98.8%, 97.6%, 96.0%, 99.1%, 90.0% and 91.7%, respectively. Across all loci, the majority of the discordance was due to allele dropout. The high cost of NGS HLA genotyping per experiment likely prevented the retyping of initially failed HLA loci. Despite the high HLA genotype concordance rates of the software, there remains room for improvement in the assembly of more accurate consensus DNA sequences by NGS HLA genotyping software.
16.	Patterson, Nick, et al. (author) Large-scale migration into Britain during the Middle to Late Bronze Age 2022 In: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; , s. 588-594 Journal article (peer-reviewed)abstract Present-day people from England and Wales harbour more ancestry derived from Early European Farmers (EEF) than people of the Early Bronze Age1. To understand this, we generated genome-wide data from 793 individuals, increasing data from the Middle to Late Bronze and Iron Age in Britain by 12-fold, and Western and Central Europe by 3.5-fold. Between 1000 and 875 BC, EEF ancestry increased in southern Britain (England and Wales) but not northern Britain (Scotland) due to incorporation of migrants who arrived at this time and over previous centuries, and who were genetically most similar to ancient individuals from France. These migrants contributed about half the ancestry of Iron Age people of England and Wales, thereby creating a plausible vector for the spread of early Celtic languages into Britain. These patterns are part of a broader trend of EEF ancestry becoming more similar across central and western Europe in the Middle to Late Bronze Age, coincident with archaeological evidence of intensified cultural exchange2-6. There was comparatively less gene flow from continental Europe during the Iron Age, and Britain's independent genetic trajectory is also reflected in the rise of the allele conferring lactase persistence to ~50% by this time compared to ~7% in central Europe where it rose rapidly in frequency only a millennium later. This suggests that dairy products were used in qualitatively different ways in Britain and in central Europe over this period.
17.	Roellig, Marlene, et al. (author) Post Hoc Assessment of Stand Structure Across European Wood-Pastures : Implications for Land Use Policy 2018 In: Rangeland Ecology & Management. - : Elsevier BV. - 1550-7424 .- 1551-5028. ; 71:5, s. 526-535 Journal article (peer-reviewed)abstract Europe's woodland and savanna rangelands, often part of silvopastoral systems known as wood-pastures, are deteriorating because of abandonment that leads to return to a forested state or lack of tree regeneration from overgrazing or tree and shrub removal. Despite numerous local studies, there has been no broader survey of the stand structure of European wood-pastures showing which systems are at risk of losing their semiopen character. This overview aims to 1) show some of the differences and similarities in wood-pastures from landscapes across Europe and 2) identify which of these wood-pastures are at risk of losing their semiopen character. We collated a dataset of 13 693 trees from 390 plots in wood-pastures from eight different European regions (western Estonia, eastern Greece, northern Germany, Hungary, northern Italy, southern Portugal, central Romania, and southern Sweden), including tree diameters at breast height, tree density, management type, and tree species composition. On the basis of their structural characteristics, we classified wood-pastures using principal component analysis (PCA) and cluster analysis. The PCA showed a gradient from dense wood-pastures with high levels of regeneration (e.g., in Estonia) to sparse wood-pastures with large trees but a lack of regeneration (e.g., in Romania). Along this gradient, we identified three main groups of wood-pastures: 1) sparse wood-pastures with mostly big trees; 2) dense wood-pastures composed of small trees, and 3) wood-pastures containing a wide range of tree ages. Our results show a large structural gradient in European wood-pastures, as well as regeneration problems varying in their severity, highlighting the importance of social-ecological context for wood-pasture conditions. To maintain the ecological and cultural integrity of European wood-pastures, we suggest 1) more comprehensively considering them in European policies such as the Common Agricultural Policy and EU Habitats Directive, while 2) taking into account their structural characteristics and social-ecological backgrounds.
18.	Speliotes, Elizabeth K., et al. (author) Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index 2010 In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:11, s. 937-948 Journal article (peer-reviewed)abstract Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ~2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 × 10−8), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.
19.	Stolt-Bergner, Peggy, et al. (author) Baculovirus-driven protein expression in insect cells : A benchmarking study 2018 In: Journal of Structural Biology. - : Elsevier BV. - 1047-8477. ; 203:2, s. 71-80 Journal article (peer-reviewed)abstract Baculovirus-insect cell expression system has become one of the most widely used eukaryotic expression systems for heterologous protein production in many laboratories. The availability of robust insect cell lines, serum-free media, a range of vectors and commercially-packaged kits have supported the demand for maximizing the exploitation of the baculovirus-insect cell expression system. Naturally, this resulted in varied strategies adopted by different laboratories to optimize protein production. Most laboratories have preference in using either the E. coli transposition-based recombination bacmid technology (e.g. Bac-to-Bac®) or homologous recombination transfection within insect cells (e.g. flashBAC™). Limited data is presented in the literature to benchmark the protocols used for these baculovirus vectors to facilitate the selection of a system for optimal production of target proteins. Taking advantage of the Protein Production and Purification Partnership in Europe (P4EU) scientific network, a benchmarking initiative was designed to compare the diverse protocols established in thirteen individual laboratories. This benchmarking initiative compared the expression of four selected intracellular proteins (mouse Dicer-2, 204 kDa; human ABL1 wildtype, 126 kDa; human FMRP, 68 kDa; viral vNS1-H1, 76 kDa). Here, we present the expression and purification results on these proteins and highlight the significant differences in expression yields obtained using different commercially-packaged baculovirus vectors. The highest expression level for difficult-to-express intracellular protein candidates were observed with the EmBacY baculovirus vector system.
20.	Tsuchiya, Takafumi, et al. (author) Association of the calpain-10 gene with type 2 diabetes in Europeans: Results of pooled and meta-analyses 2006 In: Molecular Genetics and Metabolism. - : Elsevier BV. - 1096-7192. ; 89:1-2, s. 174-184 Journal article (peer-reviewed)abstract We conducted pooled and meta-analyses of the association of the calpain-10 gene (CAPN10) polymorphisms SNP-43, Indel-19 and SNP-63 individually and as haplotypes with type 2 diabetes (T2D) in 3237 patients and 2935 controls of European ancestry. In the pooled analyses, the common SNP-43G allele was associated with modest but statistically significant increased risk of T2D (odds ratio (OR) = 1.11 (95% confidence interval (0), 1.02-1.20), P = 0.01). Two haplotype combinations were associated with increased risk of T2D) (1-2-1/1-2-1, OR = 1.20 (1.03-1.41), P = 0.02; and 1-1-2/1-2-1, OR = 1.26 (1.01-1.59), P = 0.04) and one with decreased risk (1-1-1/2-2-1, OR = 0.86 (0.75-0.99), P = 0.03). The meta-analysis also showed a significant effect of the 1-2-1/1-2-1 haplogenotype on risk (OR = 1.25 (1.05-1.50), P = 0.01). However, there was evidence for heterogeneity with respect to this effect (P = 0.06). The heterogeneity appeared to be due to data sets in which the cases were selected from samples used in linkage studies of T2D. Using only the population-based case-control samples removed the heterogeneity (P = 0.89) and strengthened the evidence for association with T2D) in both the pooled (SNP-43G, OR = 1.19 (1.07-1.32), P = 0.001; 1-2-1/1-2-1 haplogenotype, OR = 1.46 (1.19-1.78), P = 0.0003; 1-1-2/1-2-1 haplogenotype, OR = 1.52 (1.12-2.06), P = 0.007; and 1-1-1/2-2-1 haplogenotype, OR = 0.83 (0.70-0.99), P = 0.03) and the meta-analysis (SNP-43*G, OR = 1.18 (1.05-1.32), P = 0.005; 1-2-1/1-2-1 haplogenotype, OR = 1.68 (1.33-2.11), P = 0.00001). The pooled and meta-analyses as well as the linkage disequilibrium and haplotype diversity studies suggest a role for genetic variation in CAPN10 affecting risk of T2D in Europeans. (c) 2006 Elsevier Inc. All rights reserved.
21.	Vinnepand, Mathias, et al. (author) Decoding geochemical signals of the Schwalbenberg Loess-Palaeosol-Sequences — A key to Upper Pleistocene ecosystem responses to climate changes in western Central Europe 2022 In: Catena. - : Elsevier BV. - 0341-8162. ; 212 Journal article (peer-reviewed)abstract Loess deposits are the most extent continental archives of climatic- and environmental change and represent important components of local and global dust systems. Consequently, their geochemistry provides an excellent basis for studying climate oscillations on land and how these affect processes in the terrestrial system. It is, however, challenging to assess information archived in loess records due to complexities in their formation, causing interfering geochemical signatures. In particular, the use of element ratios to derive weathering indices may be complicated since dust sources change through time, and since ecosystems respond differently to changing conditions. Whilst this complexity appears as limiting factor, the explanatory potential of proxies increases when the diversity of geochemical processes is acknowledged. To make use of this potential, we integrate the decadic logarithm of element ratios indicative for provenance shifts, mineral sorting during transport and sediment reworking as well as weathering into multivariate statistical analysis. We test, if the sensitivity of Principal Component Analyses (PCA) and Linear Discriminant Analysis (LDA) can be increased by applying both to sub-datasets of diagnostic Stratigraphic Units (SU) of the Schwalbenberg Loess-Palaeosol-Sequences (Middle Rhine valley, Germany). The selected site recorded sub-millennial Upper Pleistocene ecological changes in an unprecedented resolution for Central European LPS. Differences in operating functions of PCA and LDA and our age model highlight timing and intensity of provenance shifts, sediment relocation, decalcification, redox dynamic and clay-mineral formation associated with Atlantic-driven climate oscillations. Based on this we provide evidence for the accretionary character of interstadial palaeosols caused by a close interplay of dust input and soil formation. Automated re-detection of SU across the site using LDA functions contributes important insights into slope dynamics through regional erosion events. Overall, our approach provides a key for tracing ecological changes during climate oscillations across continents.
22.	Wilczek, Sabine, et al. (author) Microbial activity within a subaqueous dune in a large lowland river (River Elbe, Germany) 2004 In: AQUATIC MICROBIAL ECOLOGY. ; 36:, s. 83–97- Journal article (peer-reviewed)abstract Microbial processes within subaqueous dunes of large rivers are important for organicmatter retention and decomposition but have rarely been examined. We investigated 3 morphodynamicallydefined zones (stoss side, crestal plateau, and lee side) within a subaqueous dune in the8th-order River Elbe. Analysis of flow velocity, vertical hydraulic gradient, concentration of mobilefine interstitial particles, and the quantity and biochemical quality of sedimentary organic matterindicated that the stoss and the lee sides of the dune were focal zones of particulate matter retentiondue to infiltration and sedimentation processes. Bacterial abundance and most measures of microbialactivity (sediment community respiration and activities of the extracellular enzymes β-glucosidase,leucine aminopeptidase, β-xylosidase, and exo-1,4-β-glucanase) were significantly higher in thesezones than in the plateau. Increases in bacterial abundance and microbial activity were closely correlatedwith protein, carbohydrates, nitrogen and phaeopigments associated with high-quality particulateorganic matter. Our findings showed that the morphodynamic differentiation of the subaqueousdune resulted in the formation of distinct functional zones in the sediment. The underlyingmechanisms can be conceptually summarized by a 2-stage regulatory hierarchy. Microbial activitieswere controlled directly by the input of dissolved oxygen and easily degradable microbial substrates,and indirectly by hydromorphological processes. We conclude that the subaqueous dune functionedas an efficient filter of particulate organic matter, and that the stoss and the lee sides of this river bedformwere focal sites of microbial carbon mineralisation in the large river ecosystem.
23.	Yang, Jian, et al. (author) FTO genotype is associated with phenotypic variability of body mass index 2012 In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 490:7419, s. 267-272 Journal article (peer-reviewed)abstract There is evidence across several species for genetic control of phenotypic variation of complex traits(1-4), such that the variance among phenotypes is genotype dependent. Understanding genetic control of variability is important in evolutionary biology, agricultural selection programmes and human medicine, yet for complex traits, no individual genetic variants associated with variance, as opposed to the mean, have been identified. Here we perform a meta-analysis of genome-wide association studies of phenotypic variation using similar to 170,000 samples on height and body mass index (BMI) in human populations. We report evidence that the single nucleotide polymorphism (SNP) rs7202116 at the FTO gene locus, which is known to be associated with obesity (as measured by mean BMI for each rs7202116 genotype)(5-7), is also associated with phenotypic variability. We show that the results are not due to scale effects or other artefacts, and find no other experiment-wise significant evidence for effects on variability, either at loci other than FTO for BMI or at any locus for height. The difference in variance for BMI among individuals with opposite homozygous genotypes at the FTO locus is approximately 7%, corresponding to a difference of similar to 0.5 kilograms in the standard deviation of weight. Our results indicate that genetic variants can be discovered that are associated with variability, and that between-person variability in obesity can partly be explained by the genotype at the FTO locus. The results are consistent with reported FTO by environment interactions for BMI8, possibly mediated by DNA methylation(9,10). Our BMI results for other SNPs and our height results for all SNPs suggest that most genetic variants, including those that influence mean height or mean BMI, are not associated with phenotypic variance, or that their effects on variability are too small to detect even with samples sizes greater than 100,000.
24.	Zanotti, Roberta, et al. (author) Refined diagnostic criteria for bone marrow mastocytosis : a proposal of the European competence network on mastocytosis 2022 In: Leukemia. - : Springer Nature. - 0887-6924 .- 1476-5551. ; 36:2, s. 516-524 Journal article (peer-reviewed)abstract In the current classification of the World Health Organization (WHO), bone marrow mastocytosis (BMM) is a provisional variant of indolent systemic mastocytosis (ISM) defined by bone marrow involvement and absence of skin lesions. However, no additional diagnostic criteria for BMM have been proposed. Within the registry dataset of the European Competence Network on Mastocytosis, we compared characteristics and outcomes of 390 patients with BMM and 1175 patients with typical ISM. BMM patients were significantly older, predominantly male, had lower tryptase and lower burden of neoplastic mast cells, and displayed a higher frequency of allergic reactions, mainly triggered by Hymenoptera, than patients with typical ISM. The estimated 10-year progression-free survival of BMM and typical ISM was 95.9% and 92.6%, respectively. In BMM patients defined by WHO-based criteria, the presence of one B-Finding and tryptase level >= 125 ng/mL were identified as risk factors for progression in multivariate analyses. BMM patients without any of these risk factors were found to have better progression-free survival (p < 0.05) and better overall survival (p < 0.05) than other ISM patients. These data support the proposal to define BMM as a separate SM variant characterized by SM criteria, absence of skin lesions, absence of B-Findings, and tryptase levels <125 ng/mL.

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