| 1. |
- Antonarakis, S. E., et al.
(author)
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Factor VIII gene inversions in severe hemophilia A : Results of an international consortium study
- 1995
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In: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 86:6, s. 2206-2212
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Journal article (peer-reviewed)abstract
- Twenty-two molecular diagnostic laboratories from 14 countries participated in a consortium study to estimate the impact of Factor VIII gene inversions in severe hemophilia A. A total of 2,093 patients with severe hemophilia A were studied; of those, 740 (35%) had a type 1 (distal) factor VIII inversion, and 140 (7%) showed a type 2 (proximal) inversion. In 25 cases, the molecular analysis showed additional abnormal or polymorphic patterns. Ninety-eight percent of 532 mothers of patients with inversions were carriers of the abnormal factor VIII gene; when only mothers of nonfamilial cases were studied, 9 de novo inversions in maternal germ cells ware observed among 225 cases (≃ 1 de novo maternal origin of the inversion in 25 mothers of sporadic cases). When the maternal grandparental origin was examined, the inversions occurred de novo in male germ cells in 69 cases and female germ cells in 1 case. The presence of factor VIII inversions is not a major predisposing factor for the development of factor VIII inhibitors; however, slightly more patients with severe hemophilia A and factor VIII inversions develop inhibitors (130 of 642 [20%]) than patients with severe hemophilia A without inversions (131 of 821 [16%]).
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| 2. |
- Kehoe, Laura, et al.
(author)
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Make EU trade with Brazil sustainable
- 2019
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In: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 364:6438, s. 341-
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Journal article (other academic/artistic)
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| 3. |
- Budde, U, et al.
(author)
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Detailed von Willebrand factor multimer analysis in patients with von Willebrand disease in the European study, molecular and clinical markers for the diagnosis and management of type 1 von Willebrand disease (MCMDM-1VWD)
- 2008
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In: Journal of Thrombosis and Haemostasis. - : Elsevier BV. - 1538-7933 .- 1538-7836. ; 6:5, s. 762-771
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Journal article (peer-reviewed)abstract
- Background: Type 1 von Willebrand disease (VWD) is a congenital bleeding disorder characterized by a partial quantitative deficiency of plasma von Willebrand factor (VWF) in the absence of structural and/or functional VWF defects. Accurate assessment of the quantity and quality of plasma VWF is difficult but is a prerequisite for correct classification. Objective: To evaluate the proportion of misclassification of patients historically diagnosed with type 1 VWD using detailed analysis of the VWF multimer structure. Patients and methods: Previously diagnosed type 1 VWD families and healthy controls were recruited by 12 expert centers in nine European countries. Phenotypic characterization comprised plasma VWF parameters and multimer analysis using low- and intermediate-resolution gels combined with an optimized visualization system. VWF genotyping was performed in all index cases (ICs). Results: Abnormal multimers were present in 57 out of 150 ICs; however, only 29 out of these 57 (51%) had VWF ristocetin cofactor to antigen ratio below 0.7. In most cases multimer abnormalities were subtle, and only two cases had a significant loss of the largest multimers. Conclusions: Of the cases previously diagnosed as type 1 VWD, 38% showed abnormal multimers. Depending on the classification criteria used, 22 out of these 57 cases (15% of the total cohort) may be reclassified as type 2, emphasizing the requirement for multimer analysis compared with a mere ratio of VWF functional parameters and VWF:Ag. This is further supported by the finding that even slightly aberrant multimers are highly predictive for the presence of VWF mutations.
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| 4. |
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| 5. |
- Tosetto, A., et al.
(author)
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Impact of plasma von Willebrand factor levels in the diagnosis of type 1 von Willebrand disease: results from a multicenter European study (MCMDM-1VWD)
- 2007
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In: Journal of Thrombosis and Haemostasis. - : Elsevier BV. - 1538-7933 .- 1538-7836. ; 5:4, s. 715-721
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Journal article (peer-reviewed)abstract
- Background: Presence of bleeding symptoms, inheritance and reduced von Willebrand factor (VWF) contribute to the diagnosis of type 1 von Willebrand disease (VWD). However, quantitative analysis of the importance of VWF antigen (VWF:Ag) and ristocetin cofactor activity (VWF:RCo) levels in the diagnosis is lacking. Objectives: To evaluate the relative contribution of VWF measurement to the diagnosis of VWD. Patients and methods: From the MCMDM-1VWD study cohort, 204 subjects (considered as affected by VWD based on the enrolling Center diagnoses and the presence of linkage with the VWF locus) were compared with 1155 normal individuals. Sensitivity, specificity and diagnostic positive likelihood ratios (LR) of VWF:Ag and VWF:RCo were computed. Results: ABO blood group was the variable most influencing VWF levels, but adjustment of the lower reference limit for the ABO group did not improve sensitivity and specificity of VWF:Ag or VWF:RCo. The lower reference limit (2.5th percentile) was 47 IU dL(-1) for both VWF:Ag and VWF:RCo and showed similar diagnostic performance [receiver-operator curve area: 0.962 and 0.961 for VWF:Ag and VWF:RCo, respectively; P = 0.81]. The probability of VWD was markedly increased only for values below 40 IU dL(-1) (positive LR: 95.1 for VWF:Ag), whereas intermediate values (40 to 60 IU dL(-1)) of VWF only marginally indicated the probability of VWD. Conclusions: Although the conventional 2.5 lower percentile has good sensitivity and specificity, only VWF:Ag or VWF:RCo values below 40 IU dL(-1) appear to significantly indicate the likelihood of type 1 VWD. The LR profile of VWF level could be used in a diagnostic algorithm.
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| 6. |
- Salojarvi, Jarkko, et al.
(author)
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Genome sequencing and population genomic analyses provide insights into the adaptive landscape of silver birch
- 2017
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In: Nature Genetics. - : NATURE PUBLISHING GROUP. - 1061-4036 .- 1546-1718. ; 49:6, s. 904-912
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Journal article (peer-reviewed)abstract
- Silver birch (Betula pendula) is a pioneer boreal tree that can be induced to flower within 1 year. Its rapid life cycle, small (440-Mb) genome, and advanced germplasm resources make birch an attractive model for forest biotechnology. We assembled and chromosomally anchored the nuclear genome of an inbred B. pendula individual. Gene duplicates from the paleohexaploid event were enriched for transcriptional regulation, whereas tandem duplicates were overrepresented by environmental responses. Population resequencing of 80 individuals showed effective population size crashes at major points of climatic upheaval. Selective sweeps were enriched among polyploid duplicates encoding key developmental and physiological triggering functions, suggesting that local adaptation has tuned the timing of and cross-talk between fundamental plant processes. Variation around the tightly-linked light response genes PHYC and FRS10 correlated with latitude and longitude and temperature, and with precipitation for PHYC. Similar associations characterized the growth-promoting cytokinin response regulator ARR1, and the wood development genes KAK and MED5A.
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| 7. |
- Ansell, Brendan R. E., et al.
(author)
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Divergent Transcriptional Responses to Physiological and Xenobiotic Stress in Giardia duodenalis
- 2016
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In: Antimicrobial Agents and Chemotherapy. - 0066-4804 .- 1098-6596. ; 60:10, s. 6034-6045
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Journal article (peer-reviewed)abstract
- Understanding how parasites respond to stress can help to identify essential biological processes. Giardia duodenalis is a parasitic protist that infects the human gastrointestinal tract and causes 200 to 300 million cases of diarrhea annually. Metronidazole, a major antigiardial drug, is thought to cause oxidative damage within the infective trophozoite form. However, treatment efficacy is suboptimal, due partly to metronidazole-resistant infections. To elucidate conserved and stress-specific responses, we calibrated sublethal metronidazole, hydrogen peroxide, and thermal stresses to exert approximately equal pressure on trophozoite growth and compared transcriptional responses after 24 h of exposure. We identified 252 genes that were differentially transcribed in response to all three stressors, including glycolytic and DNA repair enzymes, a mitogen-activated protein (MAP) kinase, high-cysteine membrane proteins, flavin adenine dinucleotide (FAD) synthetase, and histone modification enzymes. Transcriptional responses appeared to diverge according to physiological or xenobiotic stress. Downregulation of the antioxidant system and alpha-giardins was observed only under metronidazole-induced stress, whereas upregulation of GARP-like transcription factors and their subordinate genes was observed in response to hydrogen peroxide and thermal stressors. Limited evidence was found in support of stress-specific response elements upstream of differentially transcribed genes; however, antisense derepression and differential regulation of RNA interference machinery suggest multiple epigenetic mechanisms of transcriptional control.
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| 8. |
- Wahl, Simone, et al.
(author)
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Epigenome-wide association study of body mass index, and the adverse outcomes of adiposity
- 2017
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In: Nature. - : NATURE PUBLISHING GROUP. - 0028-0836 .- 1476-4687. ; 541:7635, s. 81-
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Journal article (peer-reviewed)abstract
- Approximately 1.5 billion people worldwide are overweight or affected by obesity, and are at risk of developing type (2) diabetes, cardiovascular disease and related metabolic and inflammatory disturbances(1,2). Although the mechanisms linking adiposity to associated clinical conditions are poorly understood, recent studies suggest that adiposity may influence DNA methylation(3-6), a key regulator of gene expression and molecular phenotype(7). Here we use epigenome-wide association to show that body mass index (BMI; a key measure of adiposity) is associated with widespread changes in DNA methylation (187 genetic loci with P < 1 x 10(-7), range P = 9.2 x 10(-8) to 6.0 x 10(-46); n = 10,261 samples). Genetic association analyses demonstrate that the alterations in DNA methylation are predominantly the consequence of adiposity, rather than the cause. We find that methylation loci are enriched for functional genomic features in multiple tissues (P < 0.05), and show that sentinel methylation markers identify gene expression signatures at 38 loci (P < 9.0 x 10(-6), range P = 5.5 x 10(-6) to 6.1 x 10(-35), n = 1,785 samples). The methylation loci identify genes involved in lipid and lipoprotein metabolism, substrate transport and inflammatory pathways. Finally, we show that the disturbances in DNA methylation predict future development of type 2 diabetes (relative risk per 1 standard deviation increase in methylation risk score: 2.3 (2.07-2.56); P = 1.1 x 10(-54)). Our results provide new insights into the biologic pathways influenced by adiposity, and may enable development of new strategies for prediction and prevention of type 2 diabetes and other adverse clinical consequences of obesity.
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| 9. |
- Yu, Changxun, et al.
(author)
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Iron behavior in a northern estuary: Large pools of non-sulfidized Fe(II) associated with organic matter
- 2015
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In: Chemical Geology. - : Elsevier BV. - 0009-2541 .- 1872-6836. ; 413, s. 73-85
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Journal article (peer-reviewed)abstract
- The estuaries of the Northern Baltic Sea (Gulf of Bothnia) receive an abundance of diagenetically reactive catchment-derived Fe, which is to a large degree complexed with organicmatter or present as Fe (hydr-) oxides. However, our understanding of sedimentary Fe diagenesis in these estuaries is limited. To address this limitation, the present study examines Fe geochemistry in a 3.5-m-thick estuarine benthic mud layer and three samples of suspended particulate matter of a catchment on the eastern Gulf of Bothnia. The age-depth model of the mud, constructed on the basis of sedimentary features as well as Cs-137 and aquatic plant C-14 determinations, revealed a high average rate of sedimentation (5 cm . yr(-1)) for the upper mud unit (0-182.5 cm, corresponding to 1973-2011), in response to intensive land-use (ditching) in the catchment since the 1960s and 1970s. The intensive land-use has resulted in a strong increase in the Fe accumulation rates, but has not caused a recognizable impact on the diagenetic processes of Fe including features such as degree of sulfidization and solid-phase partitioning. Iron X-ray absorption spectroscopy (XAS) indicated that in the suspended particulate matter, large proportions (47-58%) of Fe occur as Fe(III)-organic complexes and 2-line ferrihydrite. In the mud, the former is completely reduced, and reactive Fe (defined via extraction with 1 MHCl) was high throughout (52-68%, median = 61%) and strongly dominated by Fe(II). This reactive Fe(II) pool was sulfidized to only a limited extent (degree of reactive sulfidization = 11-26%, median = 17%). This phenomenon is attributed to the brackish-water conditions (i.e. low in sulfate) and the abundant input of reactive Fe(III) from the catchment, leading to a surplus of dissolved Fe2+ over dissolved sulfide in the sediment. The low availability of dissolved sulfide, in combination with the high average sedimentation rate, limits the formation of intermediate reduced sulfur compounds at the water-sediment interface, thereby retarding the conversion of FeS into pyrite (ratios of pyrite-S to AVS = 0.17-1.73, median = 0.37; degree of pyritization = 1-17%, median = 3%). Iron XAS, in combination with wavelet transform analysis, of representative sediment segments from the upper and lower mud units suggests that the non-sulfidized Fe(II) pool is dominantly complexed by organic matter, with the remaining Fe(II) occurring as mackinawite. This has implications for the understanding of early Fe diagenesis in settings with a high input of organic matter and relatively low supply of sulfate. (C) 2015 Elsevier B.V. All rights reserved.
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| 10. |
- Yu, Changxun, et al.
(author)
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Manganese accumulation and solid-phase speciation in a 3.5 m thick mud sequence from the estuary of an acidic and Mn-rich creek, northern Baltic Sea
- 2016
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In: Chemical Geology. - : Elsevier BV. - 0009-2541 .- 1872-6836. ; 437, s. 56-66
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Journal article (peer-reviewed)abstract
- In sediments, manganese (Mn) is typically enriched in the form of authigenic Mn hydroxides at the water-sediment interface where intensive redox cycling of Mn occurs. Here we show, based on existing hydrochemical and geochemical (sediment core) data and new detailed chemical and mineralogical characterization of a 3.5 m long sediment core from a Boreal estuary, that the behavior of Mn can be profoundly different and more complex in estuarine settings receiving an abundance of terrestrial Mn. The most notable feature in the 3.5 m long sediment core is two depth intervals (60-155 cm and 181-230 cm) where there are strong fine-scale variations in Mn concentrations with peaks episodically reaching up to 10-25 g kg(-1) and 6.7-12 g kg(-1), respectively. X-ray absorption spectroscopy and sequential chemical extraction show that Mn occurs mainly as authigenic rhodochrosite at these two depth intervals and is mainly surface-sorbed in other sections with relatively low and stable Mn concentrations. The data suggests that the strong fine-scale variations in Mn concentrations are a reflection of the extent of formation and settling of Mn hydroxides, the precursors of the authigenic rhodochrosite (and also of the surface-sorbed Mn), rather than Mn input to the estuary or redox-related Mn translocation within the sediment. There was agreement between the results of linear combination fitting of extended X-ray absorption fine structure data and a 7-step sequential chemical extraction (SCE) in terms of quantification of surface-sorbed Mn species, whereas the SCE experiment failed to fractionate a majority of rhodochrosite into SCE step-2 (1M NH4-acetate at pH 6), which is frequently employed to dissolve carbonate. We ascribe this discrepancy to only partial dissolution of rhodochrosite in the weakly acidic (pH = 6) NH4-acetate leach.
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