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- 2019
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Tidskriftsartikel (refereegranskat)
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| 2. |
- Hancock, Dana B, et al.
(författare)
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Genome-Wide Joint Meta-Analysis of SNP and SNP-by-Smoking Interaction Identifies Novel Loci for Pulmonary Function
- 2012
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Ingår i: PLoS genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 8:12, s. e1003098-
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies have identified numerous genetic loci for spirometic measures of pulmonary function, forced expiratory volume in one second (FEV1), and its ratio to forced vital capacity (FEV1/FVC). Given that cigarette smoking adversely affects pulmonary function, we conducted genome-wide joint meta-analyses (JMA) of single nucleotide polymorphism (SNP) and SNP-by-smoking (ever-smoking or pack-years) associations on FEV1 and FEV1/FVC across 19 studies (total N = 50,047). We identified three novel loci not previously associated with pulmonary function. SNPs in or near DNER (smallest PJMA = 5.00×10−11), HLA-DQB1 and HLA-DQA2 (smallest PJMA = 4.35×10−9), and KCNJ2 and SOX9 (smallest PJMA = 1.28×10−8) were associated with FEV1/FVC or FEV1 in meta-analysis models including SNP main effects, smoking main effects, and SNP-by-smoking (ever-smoking or pack-years) interaction. The HLA region has been widely implicated for autoimmune and lung phenotypes, unlike the other novel loci, which have not been widely implicated. We evaluated DNER, KCNJ2, and SOX9 and found them to be expressed in human lung tissue. DNER and SOX9 further showed evidence of differential expression in human airway epithelium in smokers compared to non-smokers. Our findings demonstrated that joint testing of SNP and SNP-by-environment interaction identified novel loci associated with complex traits that are missed when considering only the genetic main effects.
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| 3. |
- Köttgen, Anna, et al.
(författare)
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New loci associated with kidney function and chronic kidney disease
- 2010
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:5, s. 376-384
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Tidskriftsartikel (refereegranskat)abstract
- Chronic kidney disease (CKD) is a significant public health problem, and recent genetic studies have identified common CKD susceptibility variants. The CKDGen consortium performed a meta-analysis of genome-wide association data in 67,093 individuals of European ancestry from 20 predominantly population-based studies in order to identify new susceptibility loci for reduced renal function as estimated by serum creatinine (eGFRcrea), serum cystatin c (eGFRcys) and CKD (eGFRcrea < 60 ml/min/1.73 m2; n = 5,807 individuals with CKD (cases)). Follow-up of the 23 new genome-wide–significant loci (P < 5 × 10−8) in 22,982 replication samples identified 13 new loci affecting renal function and CKD (in or near LASS2, GCKR, ALMS1, TFDP2, DAB2, SLC34A1, VEGFA, PRKAG2, PIP5K1B, ATXN2, DACH1, UBE2Q2 and SLC7A9) and 7 loci suspected to affect creatinine production and secretion (CPS1, SLC22A2, TMEM60, WDR37, SLC6A13, WDR72 and BCAS3). These results further our understanding of the biologic mechanisms of kidney function by identifying loci that potentially influence nephrogenesis, podocyte function, angiogenesis, solute transport and metabolic functions of the kidney.
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| 4. |
- Armstrong, Paul W., et al.
(författare)
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Efficacy and safety of unfractionated heparin versus enoxaparin : a pooled analysis of ASSENT-3 and -3 PLUS data
- 2006
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Ingår i: CMJA. Canadian Medical Association Journal. Onlineutg. Med tittel. - : CMA Joule Inc.. - 0820-3946 .- 1488-2329. ; 174:10, s. 1421-1426
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The optimal antithrombotic therapy to accompany tenecteplase in cases of acute ST-segment elevation myocardial infarction (STEMI) remains unclear. We undertook a prespecified pooled analysis of data from the ASSENT-3 and ASSENT-3 PLUS trials. METHODS: We created a combined database of the 2040 and 818 patients who received enoxaparin in ASSENT-3 and ASSENT-3 PLUS, respectively, and compared them with the 2038 and 821 patients who received unfractionated heparin. RESULTS: The efficacy end point (a composite of 30-day mortality, reinfarction or refractory ischemia) was 12.2% with enoxaparin versus 16.0% with unfractionated heparin (p < 0.001); the combined end point of efficacy plus safety (a composite of 30-day mortality, reinfarction, refractory ischemia, intracranial hemorrhage [ICH] or major systemic bleeding) was 15.0% versus 18.0%, respectively (p = 0.003) [corrected] The 1049 patients urgently revascularized had greater benefit from enoxaparin (15.4% v. 10.1%, p = 0.013), yet the excess in major systemic bleeding evident with enoxaparin (3.3% v. 2.4%, p = 0.01) was largely confined to the 3492 patients without or before revascularization. Although ICH rates in the groups were similar (1.3% v. 0.9%, p = 0.26), an excess of ICH occurred among those administered enoxaparin during the ASSENT-3 PLUS trial (6.7% v. 0.8%, p = 0.013), especially among women over 75 years of age. INTERPRETATION: These data demonstrated the benefit of enoxaparin used in conjunction with tenecteplase, but raised caution about its prehospital use to treat STEMI in elderly women.
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| 5. |
- Augustine, Robin, 1982-, et al.
(författare)
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Polymeric ferrite sheats for SAR reduction of Wearable ANtennas
- 2010
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Ingår i: Electronics Letters. - UK : Institution of Engineering and Technology (IET). - 0013-5194 .- 1350-911X. ; 46:3, s. 197-198
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Tidskriftsartikel (refereegranskat)abstract
- Reduction of specific absorption rate (SAR) has now become a buzz word because of the growing health concerns over microwave exposure. Ferrites are found to be effective in diminishing electromagnetic influence. In this reported work, flexible polymeric ferrite sheets are characterised on the basis of their shielding efficiencies. SAR measurements are carried out with a planar wearable antenna and polymeric ferrite shielding to confirm its competence.
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| 6. |
- Barro, Lassina, et al.
(författare)
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A double-virally-inactivated (Intercept-solvent/detergent) human platelet lysate for in vitro expansion of human mesenchymal stromal cells
- 2019
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Ingår i: Transfusion. - : John Wiley & Sons. - 0041-1132 .- 1537-2995. ; 59:6, s. 2061-2073
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND Pooled human platelet lysate (HPL) can replace fetal bovine serum (FBS) as xeno-free supplement for ex vivo expansion of mesenchymal stromal cells (MSCs). We evaluate here whether a double-virally-inactivated HPL (DVI-HPL) prepared from expired Intercept-treated platelet concentrates (PCs) and treated by solvent/detergent (S/D) can be used for MSC expansion. STUDY DESIGN AND METHODS Expired Intercept-treated PCs in 65% platelet (PLT) additive solution were pooled and subjected to a 1% tri-n-butyl phosphate/1% Triton X-45 treatment followed by soybean oil, hydrophobic interaction chromatography purification, and sterile filtration. Bone marrow-derived MSCs (BM-MSCs) were expanded for four passages in growth medium containing 10% DVI-HPL, I-HPL (from Intercept-PC only), untreated HPL, and FBS. MSC morphology, doubling time, immunophenotype, immunosuppressive activity, and differentiation capacity were compared. RESULTS Expanded cells had typical spindle morphology and showed higher viability in all HPL conditions than in FBS. The DVI-HPL and FBS-expanded cells were morphologically larger than in I-HPL and HPL supplements. The cumulative population doubling was lower using DVI-HPL than with HPL and I-HPL, but significantly higher than using FBS. Immunophenotype was not affected by the supplements used. Immunosuppressive activity was maintained with all supplements. Differentiation capacity into chondrocytes and osteocytes was more effective in DVI-HPL but less toward adipocytes compared to other supplements. CONCLUSIONS Human PLT lysate made from Intercept-PCs subjected to S/D treatment may be an alternative to untreated HPL and to I-HPL for BM-MSC expansion. This finding reinforces the potential of HPL as a virally safe alternative to FBS for clinical grade MSC expansion protocols.
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| 7. |
- Barro, Lassina, et al.
(författare)
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Nanofiltration of growth media supplemented with human platelet lysates for pathogen-safe xeno-free expansion of mesenchymal stromal cells
- 2020
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Ingår i: Cytotherapy. - : Elsevier BV. - 1465-3249 .- 1477-2566. ; 22:8, s. 458-472
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Tidskriftsartikel (refereegranskat)abstract
- Background aims: Human platelet lysate can replace fetal bovine serum (FBS) for xeno-free ex vivo expansion of mesenchymal stromal cells (MSCs), but pooling of platelet concentrates (PCs) increases risks of pathogen transmission. We evaluated the feasibility of performing nanofiltration of platelet lysates and determined the impact on expansion of bone marrow-derived MSCs. Methods: Platelet lysates were prepared by freeze-thawing of pathogen-reduced (Intercept) PCs suspended in 65% storage solution (SPP+) and 35% plasma, and by serum-conversion of PCs suspended in 100% plasma. Lysates were added to the MSC growth media at 10% (v/v), filtered and subjected to cascade nanofiltration on 35- and 19-nm Planova filters. Media supplemented with 10% starting platelet lysates or FBS were used as the controls. Impacts of nanofiltration on the growth media composition, removal of platelet extracellular vesicles (PEVs) and MSC expansion were evaluated. Results: Nanofiltration did not detrimentally affect contents of total protein and growth factors or the biochemical composition. The clearance factor of PEVs was >3 log values. Expansion, proliferation, membranemarkers, differentiation potential and immunosuppressive properties of cells in nanofiltered media were consistently better than those expanded in FBS-supplemented media. Compared with FBS, chondrogenesis and osteogenesis genes were expressed more in nanofiltered media, and there were fewer senescent cells over six passages. Conclusions: Nanofiltration of growth media supplemented with two types of platelet lysates, including one prepared from pathogen-reduced PCs, is technically feasible. These data support the possibility of developing pathogen-reduced xeno-free growth media for clinical-grade propagation of human cells.
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| 8. |
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| 9. |
- Heap, Michael J., et al.
(författare)
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The tensile strength of volcanic rocks : Experiments and models
- 2021
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Ingår i: Journal of Volcanology and Geothermal Research. - : Elsevier. - 0377-0273 .- 1872-6097. ; 418
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Tidskriftsartikel (refereegranskat)abstract
- The tensile strength of volcanic rock exerts control over several key volcanic processes, including fragmentation and magma chamber rupture. Despite its importance, there is a paucity of laboratory data for the tensile strength of volcanic rocks, leading to an incomplete understanding of the influence of microstructural parameters, such as pore size and shape (factors that vary widely for volcanic rocks), on their tensile strength. To circumvent problems associated with the variability of natural samples, we provide here a systematic study in which we use elastic damage mechanics code "Rock Failure Process Analysis" to perform numerical experiments to better understand the influence of porosity, pore diameter, pore aspect ratio, and pore orientation on the tensile strength of volcanic rocks. We find that porosity and pore diameter exert a first-order control on the tensile strength of volcanic rocks, and that pore aspect ratio and orientation also influence tensile strength. Tensile strength is reduced by up to a factor of two as porosity is increased from 0.05 to 0.35 or as pore diameter is increased from 1 to 2 mm. Small, but systematic, reductions in tensile strength are observed as the angle between the loading direction and the major axis of an elliptical pore is increased from 0 to 90 degrees. The influence of pore aspect ratio (the ratio of the minor to major axis of an ellipse) depends on the pore angle: when the pore angle is 0 degrees, a decrease in pore aspect ratio, from 1 (a circle) to 0.2, increases the tensile strength, whereas the same decrease in pore aspect ratio does not substantially change the tensile strength when the pore angle is 90 degrees. These latter numerical experiments show that the tensile strength of volcanic rocks can be anisotropic. Our numerical data are in broad agreement with new and compiled experimental data for the tensile strength of volcanic rocks. One of the goals of this contribution is to provide better constrained constitutive models for the tensile strength of volcanic rocks for use in volcano modelling. To this end, we present a series of theoretical and semi-empirical constitutive models that can be used to determine the tensile strength of volcanic rocks, and highlight how tensile strength estimations can influence predictions of magma overpressures and assessments of the volume and radius of a magma chamber. (c) 2021 Elsevier B.V. All rights reserved.
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| 10. |
- Henz Ryen, Astrid, 1986-
(författare)
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Exploring evolutionary and chemical space using chemoinformatic tools and traditional methods in pharmacognosy
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The number of new drugs coming to the market is declining while interest in lead discovery from natural resources is seeing a revival. Although methods for isolation and identification of natural products have advanced tremendously, methods for selection of potential leads have fallen behind. As part of the Marie Curie ITN “MedPlant: Phylogenetic exploration of medicinal plant diversity” this thesis contributed to the exploration of chemical diversity in angiosperms and the development of new tools to analyze and define the chemical potential of a plant.In Paper I, it was demonstrated that physicochemical properties of selected specialized metabolites change in different plant groups. Changes in properties were assessed using ChemGPS-NP and diversity was quantified by calculating the volume occupied by the compounds in chemical space. By discussing the results against the background of possible underlying evolutionary mechanisms, it was concluded that evolutionary processes are reflected in chemical property space. These results hold great value for further studies on the evolution of chemical diversity and biochemical traits in plants. The methods developed can be used e.g. to define and predict the chemical diversity of related taxa, providing a strategy for a guided plant selection in search for new drug leads.In Paper II, the scaffold and molecular diversity of over 5,200 sesquiterpene lactones (STLs) was investigated, using different chemoinformatic tools. Quantity and distribution of skeleton classes was determined and it was shown that different plant families possess specific sets of molecular frameworks, with considerable variation in their frequency. Clustering analysis enabled qualitative division of STLs into smaller groups with similar structural features, pointing out the differentiation of various plant groups. Including the study results, the dataset offers a compelling resource for chemosystematics, natural product research and drug lead discovery focused on STLs. It provides the basis for phylogenetic implementations due to the detailed taxonomic annotation. Since STLs display a source for new drugs, it is of high value for a guided search for plant derived drug leads.In Paper III, Lindera benzoin was subjected to phytochemical and pharmacological investigations. Phytochemical investigations led to the isolation of three new sesquiterpenes. As Native American tribes used this shrub for various medicinal purposes, e.g. cold remedy or diaphoretic, the isolated compounds were evaluated in vitro for their anti-inflammatory activity. In cellular assays, they reduced pro-inflammatory prostaglandin E2 production in A549 cells in a dose-dependent manner, which may rationalize the traditional use of this plant.
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