| 11. |
- Atla, Goutham, et al.
(författare)
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Genetic regulation of RNA splicing in human pancreatic islets
- 2022
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Ingår i: Genome Biology. - : Springer Science and Business Media LLC. - 1474-760X. ; 23, s. 1-28
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundNon-coding genetic variants that influence gene transcription in pancreatic islets play a major role in the susceptibility to type 2 diabetes (T2D), and likely also contribute to type 1 diabetes (T1D) risk. For many loci, however, the mechanisms through which non-coding variants influence diabetes susceptibility are unknown.ResultsWe examine splicing QTLs (sQTLs) in pancreatic islets from 399 human donors and observe that common genetic variation has a widespread influence on the splicing of genes with established roles in islet biology and diabetes. In parallel, we profile expression QTLs (eQTLs) and use transcriptome-wide association as well as genetic co-localization studies to assign islet sQTLs or eQTLs to T2D and T1D susceptibility signals, many of which lack candidate effector genes. This analysis reveals biologically plausible mechanisms, including the association of T2D with an sQTL that creates a nonsense isoform in ERO1B, a regulator of ER-stress and proinsulin biosynthesis. The expanded list of T2D risk effector genes reveals overrepresented pathways, including regulators of G-protein-mediated cAMP production. The analysis of sQTLs also reveals candidate effector genes for T1D susceptibility such as DCLRE1B, a senescence regulator, and lncRNA MEG3.ConclusionsThese data expose widespread effects of common genetic variants on RNA splicing in pancreatic islets. The results support a role for splicing variation in diabetes susceptibility, and offer a new set of genetic targets with potential therapeutic benefit.
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| 12. |
- 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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| 13. |
- Becker, Johan, et al.
(författare)
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Atmospheric corrosion of silver, copper and nickel exposed to hydrogen sulphide : a multi-analytical investigation approach
- 2022
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Ingår i: Corrosion Science. - : Elsevier Ltd. - 0010-938X .- 1879-0496. ; 209
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Tidskriftsartikel (refereegranskat)abstract
- The effect of two concentrations of H2S (0.5 and 2.5 ppm), in controlled laboratory conditions (20 °C, 75%RH), on the atmospheric corrosion of pure Ag, Cu and Ni was investigated in this study. The corrosion product morphology and composition were analysed through a multi-technique approach including SEM/EDX, Raman spectroscopy, XPS and XRD. Different corrosion products were identified depending on the type of characterisations providing a better overview of the effect of H2S on the atmospheric corrosion of pure Ag, Cu and Ni. Possible mechanisms involved in the formation of these corrosion products are also discussed in this work. © 2022 The Authors
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| 14. |
- Bin Mohamad Sultan, B, et al.
(författare)
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On the dissolution kinetics during acid pickling and Zr-based conversion coating of aluminum alloys using element-resolved electrochemistry
- 2024
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Ingår i: Electrochimica Acta. - : Elsevier Ltd. - 0013-4686 .- 1873-3859. ; 503
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Tidskriftsartikel (refereegranskat)abstract
- The acid pickling of Al-3at.%Mg, Al-3at.%Cu, and aluminum alloy (AA) 7449-T651 in nitro-sulfuro-ferric acid was investigated using element-resolved electrochemistry (AESEC) in terms of their elemental dissolution kinetics. The influence of this acid pickling on the subsequent Zr-based conversion coating process was also demonstrated on these alloys by monitoring the dissolution rates of the alloying elements during conversion and the final elemental depth profiles from calibrated glow discharge-optical emission spectroscopy (GD-OES). The separate influence of fluoride (F−) and nitrate (NO3−) as additives on the dissolution kinetics was also investigated when added to the conversion coating bath solution. F− increased the dissolution rate of Al but no significant effect was seen on Cu, while NO3− enhanced the dissolution rates of both elements. Fourier-transform infrared reflection absorption spectroscopy (FT-IRRAS) data suggested a greater Zr-fluoride presence if the conversion coating was performed on a non-acid-pickled surface.
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| 15. |
- Coomans, Marijke, et al.
(författare)
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Factors associated with health-related quality of life (HRQoL) deterioration in glioma patients during the progression-free survival period
- 2022
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Ingår i: Neuro-Oncology. - : Oxford University Press. - 1522-8517 .- 1523-5866. ; 24:12, s. 2159-2169
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Tidskriftsartikel (refereegranskat)abstract
- Background Maintenance of functioning and well-being during the progression-free survival (PFS) period is important for glioma patients. This study aimed to determine whether health-related quality of life (HRQoL) can be maintained during progression-free time, and factors associated with HRQoL deterioration in this period. Methods We included longitudinal HRQoL data from previously published clinical trials in glioma. The percentage of patients with stable HRQoL until progression was determined per scale and at the individual patient level (i.e. considering all scales simultaneously). We assessed time to a clinically relevant deterioration in HRQoL, expressed in deterioration-free survival and time-to-deterioration (the first including progression as an event). We also determined the association between sociodemographic and clinical factors and HRQoL deterioration in the progression-free period. Results Five thousand five hundred and thirty-nine patients with at least baseline HRQoL scores had a median time from randomization to progression of 7.6 months. Between 9-29% of the patients deteriorated before disease progression on the evaluated HRQoL scales. When considering all scales simultaneously, 47% of patients deteriorated on >= 1 scale. Median deterioration-free survival period ranged between 3.8-5.4 months, and median time-to-deterioration between 8.2-11.9 months. For most scales, only poor performance status was independently associated with clinically relevant HRQoL deterioration in the progression-free period. Conclusions HRQoL was maintained in only 53% of patients in their progression-free period, and treatment was not independently associated with this deterioration in HRQoL. Routine monitoring of the patients functioning and well-being during the entire disease course is therefore important, so that interventions can be initiated when problems are signaled.
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| 16. |
- El Masri, I., et al.
(författare)
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Development of a RFID sensitive tag dedicated to the monitoring of the environmental corrosiveness for indoor applications
- 2020
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Ingår i: Sensors and actuators. B, Chemical. - : Elsevier B.V.. - 0925-4005 .- 1873-3077. ; 322
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Tidskriftsartikel (refereegranskat)abstract
- The environmental corrosiveness is governed for indoor applications by the presence of gaseous pollutants in air and levels of temperature and relative humidity. Its determination is a challenging task and requires the monitoring of thickness reduction of selected metals in the range of few tens of nanometers. The present work aims at developing an UHF RFID (Ultra High Frequency Radio Frequency Identification) sensor dedicated to such measurements. The sensor is based on the coupling between the antenna of a commercial RFID tag and a thin layer of copper exposed to the environment. The ability of the proposed sensor to be sensitive to a variation of the metal thickness in the range of tens of nanometers is demonstrated experimentally through exposure tests in a climatic chamber. The results are supported by electromagnetic simulations performed in the case of a coupling between a dipolar antenna and a thin metallic layer.
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| 17. |
- 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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| 18. |
- Hegi, Monika E., et al.
(författare)
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No benefit from TMZ treatment in glioblastoma with truly unmethylated MGMT promoter : reanalysis of the CE.6 and the pooled Nordic/NOA-08 trials in elderly glioblastoma patients
- 2024
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Ingår i: Neuro-Oncology. - : Oxford University Press. - 1522-8517 .- 1523-5866.
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Tidskriftsartikel (refereegranskat)abstract
- Background: The treatment of elderly/ frail patients with glioblastoma is a balance between avoiding undue toxicity, while not withholding effective treatment. It remains debated, whether these patients should receive combined chemo-radiotherapy with temozolomide (RT/TMZ -> TMZ) regardless of the O6-methylguanine DNA methyltransferase gene promoter (MGMTp) methylation status. MGMT is a well-known resistance factor blunting the treatment effect of TMZ, by repairing the most genotoxic lesion. Epigenetic silencing of the MGMTp sensitizes glioblastoma to TMZ. For risk-adapted treatment, it is of utmost importance to accurately identify patients, who will not benefit from TMZ treatment.Methods: Here, we present a reanalysis of the clinical trials CE.6 and the pooled NOA-08 and Nordic trials in elderly glioblastoma patients that compared RT to RT/TMZ -> TMZ, or RT to TMZ, respectively. For 687 patients with available MGMTp methylation data, we applied a cutoff discerning truly unmethylated glioblastoma, established in a pooled analysis of 4 clinical trials for glioblastoma, with RT/TMZ -> TMZ treatment, using the same quantitative methylation-specific MGMTp PCR assay.Results: When applying this restricted cutoff to the elderly patient population, we confirmed that glioblastoma with truly unmethylated MGMTp derived no benefit from TMZ treatment. In the Nordic/NOA-08 trials, RT was better than TMZ, suggesting little or no benefit from TMZ.Conclusions: For evidence-based treatment of glioblastoma patients validated MGMTp methylation assays should be used that accurately identify truly unmethylated patients. Respective stratified management of patients will reduce toxicity without compromising outcomes and allow testing of more promising treatment options.
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| 19. |
- 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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| 20. |
- Joseph, A, et al.
(författare)
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Metabolic and psychiatric effects of acyl coenzyme A binding protein (ACBP)/diazepam binding inhibitor (DBI)
- 2020
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Ingår i: Cell death & disease. - : Springer Science and Business Media LLC. - 2041-4889. ; 11:7, s. 502-
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Tidskriftsartikel (refereegranskat)abstract
- Acyl coenzyme A binding protein (ACBP), also known as diazepam binding inhibitor (DBI) is a multifunctional protein with an intracellular action (as ACBP), as well as with an extracellular role (as DBI). The plasma levels of soluble ACBP/DBI are elevated in human obesity and reduced in anorexia nervosa. Accumulating evidence indicates that genetic or antibody-mediated neutralization of ACBP/DBI has anorexigenic effects, thus inhibiting food intake and inducing lipo-catabolic reactions in mice. A number of anorexiants have been withdrawn from clinical development because of their side effects including an increase in depression and suicide. For this reason, we investigated the psychiatric impact of ACBP/DBI in mouse models and patient cohorts. Intravenously (i.v.) injected ACBP/DBI protein conserved its orexigenic function when the protein was mutated to abolish acyl coenzyme A binding, but lost its appetite-stimulatory effect in mice bearing a mutation in the γ2 subunit of the γ-aminobutyric acid (GABA) A receptor (GABAAR). ACBP/DBI neutralization by intraperitoneal (i.p.) injection of a specific mAb blunted excessive food intake in starved and leptin-deficient mice, but not in ghrelin-treated animals. Neither i.v. nor i.p. injected anti-ACBP/DBI antibody affected the behavior of mice in the dark–light box and open-field test. In contrast, ACBP/DBI increased immobility in the forced swim test, while anti-ACBP/DBI antibody counteracted this sign of depression. In patients diagnosed with therapy-resistant bipolar disorder or schizophrenia, ACBP/DBI similarly correlated with body mass index (BMI), not with the psychiatric diagnosis. Patients with high levels of ACBP/DBI were at risk of dyslipidemia and this effect was independent from BMI, as indicated by multivariate analysis. In summary, it appears that ACBP/DBI neutralization has no negative impact on mood and that human depression is not associated with alterations in ACBP/DBI concentrations.
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