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2.
  • Bankell, Elisabeth, et al. (author)
  • LL-37-induced caspase-independent apoptosis is associated with plasma membrane permeabilization in human osteoblast-like cells
  • 2021
  • In: Peptides. - : Elsevier BV. - 0196-9781 .- 1873-5169. ; 135
  • Journal article (peer-reviewed)abstract
    • The host defense peptide LL-37 is active against both gram-positive and gram-negative bacteria, but it has also been shown to reduce human host cell viability. However, the mechanisms behind LL-37-induced human host cell cytotoxicity are not yet fully understood. Here, we assess if LL-37-evoked attenuation of human osteoblast-like MG63 cell viability is associated with apoptosis, and if the underlying mechanism may involve LL-37-induced plasma membrane permeabilization. MG63 cell viability and plasma membrane permeabilization were investigated by using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method and by measuring lactate dehydrogenase (LDH) release, respectively. Apoptosis was assessed by the terminal deoxynucleotidyl dUTP nick end labeling (TUNEL) assay and Annexin V flow cytometry, and caspase-3 and poly (ADP-ribose) polymerase (PARP) cleavage were determined by Western blot. LL-37 (4 and 10 μM) reduced both cell number and cell viability, and these effects were associated with a pro-apoptotic effect demonstrated by positive TUNEL staining and Annexin V flow cytometry. LL-37-induced apoptosis was not coupled to either caspase-3 or PARP cleavage, suggesting that LL-37 causes caspase-independent apoptosis in MG63 cells. Both LL-37 and the well-known plasma membrane permeabilizer Triton X-100 reduced cell viability and stimulated LDH release. Triton X-100-treated cells showed positive TUNEL staining, and the detergent accumulated cells in late apoptosis/necrosis. Similar to LL-37, Triton X-100 caused no PARP cleavage. We conclude that LL-37 promotes caspase-independent apoptosis, and that this effect seems coupled to plasma membrane permeabilization in human MG63 cells.
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3.
  • Dahl, Sara, et al. (author)
  • The host defense peptide LL-37 triggers release of nucleic acids from human mast cells
  • 2018
  • In: Peptides. - : Elsevier BV. - 0196-9781 .- 1873-5169. ; 109, s. 39-45
  • Journal article (peer-reviewed)abstract
    • The human host defense peptide LL-37 possesses antimicrobial activity but also affects host cell function and viability. Mast cells are involved in innate immunity but no data have been presented on effects of LL-37 on human mast cell viability and export of nucleic acids. Here, we demonstrated by immunofluorescence microscopy that synthesized LL-37 was internalized by human LAD2 mast cells and detected both in cytoplasm and nucleus. Treatment with high (4 and 10 μM) but not low (1 μM) concentrations of LL-37 for 4 h reduced cell viability assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Stimulation with 10 μM LL-37 for 4 h enhanced export of nucleic acids, total protein and lactate dehydrogenase (LDH), suggesting that both nuclear and plasma membranes are permeabilized by LL-37. Although LL-37 triggered release of nucleic acids, no extracellular trap-like structures were observed by laser scanning confocal microscopy of cells incubated with the plasma membrane impermeable nucleic acid fluorophore SYTOX-Green, indicating that LL-37 promotes export of nucleic acids but not formation of extracellular traps. On the other hand, phorbol-12-myristate-13-acetate (PMA), which is a well-known inducer of extracellular traps, stimulated export of nucleic acids and also formation of extracellular trap-like structures. However, PMA had no effect on export of either total protein or LDH. Hence, LL-37 and PMA seem to stimulate export of nucleic acids from LAD2 mast cells through different pathways. In conclusion, we demonstrate that LL-37 triggers release of nucleic acids from human mast cells but not the formation of extracellular trap-like structures.
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4.
  • Looi Chee Leong, Jeffrey, et al. (author)
  • Caudate nucleus volumes in frontotemporal lobar degeneration : differential atrophy in subtypes
  • 2008
  • In: American Journal of Neuroradiology. - 0195-6108 .- 1936-959X. ; 29:8, s. 1537-1543
  • Journal article (peer-reviewed)abstract
    • BACKGROUND AND PURPOSE: Frontostriatal circuits involving the caudate nucleus have been implicated in frontotemporal lobar degeneration (FTLD). We assessed caudate nucleus volumetrics in FTLD and subtypes: frontotemporal dementia (FTD, n = 12), semantic dementia (SD, n = 13), and progressive nonfluent aphasia (PNFA, n = 9) in comparison with healthy controls (n = 27) and subjects with Alzheimer disease (AD, n = 19). MATERIALS AND METHODS: Diagnoses were based on accepted clinical criteria. Manual volume measurement of the head and body of the caudate, excluding the tail, was conducted on T1-weighted brain MR imaging scans, using a published protocol, by a single analyst blinded to the diagnosis. RESULTS: Paired t tests (P < .05) showed that the right caudate nucleus volume was significantly larger than the left in controls and PNFA. No hemispheric asymmetry was found in AD, ETD, and SD. Across the groups, there was a positive partial correlation between the left caudate nucleus volume and Mini-Mental State Examination (MMSE) scores (r = 0.393, n = 76, P = .001) with higher left caudate volumes associated with higher MMSE scores. Multivariate analysis of covariance was used to assess the statistical significance between the subject groups (AD, ETD, SD, PNFA, and controls) as independent variables and raw right/left caudate volumes at the within-subject level (covariates: age and intracranial volume; P < .05). Control volume was largest, followed by AD (93% of control volume), SD (92%), PNFA (79%), and ETD (75%). CONCLUSIONS: Volume of the head and body of the caudate nucleus differs in subtypes of FTLD, due to differential frontostriatal dysfunction in subtypes being reflected in structural change in the caudate, and is correlated with cognition
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5.
  • Looi, Jefferey Chee Leong, et al. (author)
  • Shape analysis of the neostriatum in frontotemporal lobar degeneration, Alzheimer's disease, and controls
  • 2010
  • In: NeuroImage. - : Elsevier BV. - 1053-8119 .- 1095-9572. ; 51:3, s. 970-986
  • Journal article (peer-reviewed)abstract
    • Background and purpose: Frontostriatal circuit mediated cognitive dysfunction has been implicated in frontotemporal lobar degeneration (FTLD), but not Alzheimer's disease, or healthy aging. We measured the neostriatum (caudate nucleus and putamen) volume in FTLD (n=34), in comparison with controls (n=27) and Alzheimer's disease (AD, n=19) subjects. Methods: Diagnoses were based on international consensus criteria. Manual bilateral segmentation of the caudate nucleus and putamen was conducted blind to diagnosis by a single analyst, on MRI scans using a standardized protocol. Intra-cranial volume was calculated via a stereological point counting technique and was used for scaling the shape analysis. The manual segmentation binaries were analyzed using UNC Shape Analysis tools (University of North Carolina) to perform comparisons among FTLD, AD, and controls for global shape, local p-value significance maps, and mean magnitude of shape displacement. Results: Shape analysis revealed that there was significant shape difference between FTLD, AD, and controls, consistent with the predicted frontostriatal dysfunction and of significant magnitude, as measured by displacement maps. There was a lateralized difference in shape for the left caudate for FTLD compared to AD; non-specific global atrophy in AD compared to controls; while FTLD showed a more specific pattern in regions relaying fronto- and corticostriatal circuits. Conclusions: Shape analysis shows regional specificity of atrophy, manifest as shape deflation, with implications for frontostriatal and corticostriatal motoric circuits, in FTLD, AD, and controls.
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6.
  • Looi, Jeffrey Chee Leong, et al. (author)
  • Shape analysis of the neostriatum in subtypes of frontotemporal lobar degeneration : neuroanatomically significant regional morphologic change
  • 2011
  • In: Psychiatry Research. - : Elsevier BV. - 0925-4927 .- 1872-7506 .- 0165-1781. ; 191:2, s. 98-111
  • Journal article (peer-reviewed)abstract
    • Frontostriatal circuit mediated cognitive dysfunction has been implicated in frontotemporal lobar degeneration (FTLD) and may differ across subtypes of FTLD. We manually segmented the neostriatum (caudate nucleus and putamen) in FTLD subtypes: behavioral variant frontotemporal dementia, FTD, n=12; semantic dementia, SD, n=13; and progressive non-fluent aphasia, PNFA, n=9); in comparison with controls (n=27). Diagnoses were based on international consensus criteria. Manual bilateral segmentation of the caudate nucleus and putamen was conducted blind to diagnosis by a single analyst, on MRI scans using a standardized protocol. Intracranial volume was calculated via a stereological point counting technique and was used for normalizing the shape analysis. Segmented binaries were analyzed using the Spherical Harmonic (SPHARM) Shape Analysis tools (University of North Carolina) to perform comparisons between FTLD subtypes and controls for global shape difference, local significance maps and mean magnitude maps of shape displacement. Shape analysis revealed that there was significant shape difference between FTLD subtypes and controls, consistent with the predicted frontostriatal dysfunction and of significant magnitude, as measured by displacement maps. These differences were not significant for SD compared to controls; lesser for PNFA compared to controls; whilst FTD showed a more specific pattern in regions relaying fronto- and corticostriatal circuits. Shape analysis shows regional specificity of atrophy, manifest as shape deflation, with a differential between FTLD subtypes, compared to controls.
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7.
  • Regnell, Olof, et al. (author)
  • Linking Cellulose Fiber Sediment Methyl Mercury Levels to Organic Matter Decay and Major Element Composition.
  • 2014
  • In: Ambio: a Journal of Human Environment. - : Springer Science and Business Media LLC. - 0044-7447. ; 43:7, s. 878-890
  • Journal article (peer-reviewed)abstract
    • Methylation of mercury (Hg) to highly toxic methyl Hg (MeHg), a process known to occur when organic matter (OM) decomposition leads to anoxia, is considered a worldwide threat to aquatic ecosystems and human health. We measured temporal and spatial variations in sediment MeHg, total Hg (THg), and major elements in a freshwater lagoon in Sweden polluted with Hg-laden cellulose fibers. Fiber decomposition, confined to a narrow surface layer, resulted in loss of carbon (C), uptake of nitrogen (N), phosphorus (P), and sulfur (S), and increased MeHg levels. Notably, fiber decomposition and subsequent erosion of fiber residues will cause buried contaminants to gradually come closer to the sediment-water interface. At an adjacent site where decomposed fiber accumulated, there was a gain in C and a loss of S when MeHg increased. As evidenced by correlation patterns and vertical chemical profiles, reduced S may have fueled C-fixation and Hg methylation at this site.
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8.
  • Svensson, Daniel, et al. (author)
  • Inhibition of MicroRNA-125a Promotes Human Endothelial Cell Proliferation and Viability through an Antiapoptotic Mechanism.
  • 2014
  • In: Journal of Vascular Research. - : S. Karger AG. - 1423-0135 .- 1018-1172. ; 51:3, s. 239-245
  • Journal article (peer-reviewed)abstract
    • The microRNA-125a (miR-125a) is highly expressed in endothelial cells, but its role in vascular biology is not known. Endothelial cell proliferation and viability play an important role in endothelial healing, and we hypothesize that miR-125a regulates this process. The aim of the present study was to investigate if miR-125a controls human endothelial cell proliferation, viability and endothelial healing, and to assess the mechanisms involved. We showed that overexpression of miR-125a by transfection with miR-125a mimic reduced human umbilical vein endothelial cell (HUVEC) proliferation and viability, and stimulated apoptosis as demonstrated by a miR-125a-induced increase of the proportion of annexin V-positive cells monitored by flow cytometry. Moreover, we showed that the miR-125a mimic downregulated the antiapoptotic Bcl2 protein and upregulated caspase 3, suggesting that these two proteins represent molecular targets for miR-125a. Accordingly, transfection with miR-125a inhibitor, downregulating miR-125a expression, promoted HUVEC proliferation and viability, and reduced apoptosis. Importantly, transfection with miR-125a inhibitor promoted HUVEC tube formation in Matrigel, suggesting that reduction of miR-125a has a proangiogenic effect. In conclusion, downregulation of miR-125a through local transfection with miR-125a inhibitor might be a new way to enhance endothelial cell proliferation and viability, thereby promoting the reendothelialization observed in response to intimal injury. © 2014 S. Karger AG, Basel.
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9.
  • Svensson, Marie, et al. (author)
  • Osmotic stability of the cell membrane of Escherichia coli from a temperature-limited fed-batch process
  • 2005
  • In: Applied Microbiology and Biotechnology. - : Springer Science and Business Media LLC. - 0175-7598 .- 1432-0614. ; 67:3, s. 345-350
  • Journal article (peer-reviewed)abstract
    • The temperature-limited fed-batch (TLFB) process is a technique where the oxygen consumption rate is controlled by a gradually declining temperature profile rather than a growth-limiting glucose-feeding profile. In Escherichia coli cultures, it has been proven to prevent an extensive release of endotoxins, i.e. lipopolysaccharides, that occurs in the glucose-limited fed-batch (GLFB) processes at specific growth rates below 0.1 h(-1). The TLFB and the GLFB process were compared to each other when applied to produce the periplasmic, constitutively expressed, enzyme beta-lactamase. The extraction of the enzyme was performed by osmotic shock. A higher production of beta-lactamase was achieved with the TLFB technique while no difference in the endotoxin release was found during the extraction procedure. Furthermore, it was found that growth at declining temperature, generated by the TLFB technique, gradually stabilizes the cytoplasmic membrane, resulting in a significantly increased product quality in the extract from the TLFB cultures in the osmotic shock treatment.
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10.
  • Säll, Johanna, et al. (author)
  • The antimicrobial peptide LL-37 alters human osteoblast Ca2+ handling and induces Ca2+-independent apoptosis
  • 2013
  • In: Journal of Innate Immunity. - : S. Karger. - 1662-811X .- 1662-8128. ; 3:5, s. 290-300
  • Journal article (peer-reviewed)abstract
    • The human antimicrobial peptide cathelicidin LL-37 has, besides its antimicrobial properties, also been shown to regulate apoptosis in a cell type-specific manner. Mechanisms involved in LL-37-regulated apoptotic signaling are not identified. Here, we show that LL-37 reduces the human osteoblast-like MG63 cell number and cell viability in the micromolar concentration range with an IC50 value of about 5 µM. Treatment with 4 µM LL-37 increased the number of annexin V-positive cells and stimulated activation of caspase 3 showing that LL-37 promotes apoptosis. Treatment with 4 µM LL-37 caused an acute and sustained rise in intracellular Ca(2+) concentration assessed by laser-scanning confocal microscopy of Fluo-4-AM-loaded MG63 cells. LL-37 increased Ca(2+) also in the presence of the respective L- and T-type voltage-sensitive Ca(2+) channel blockers nifedipine and NiCl2. LL-37 had no effect on Ca(2+) in cells incubated with Ca(2+)-free solution. LL-37 (4 and 8 µM) reduced the MG63 cell number both in the presence and absence of Ca(2+) in the medium. In conclusion, LL-37 reduces the osteoblast cell number by promoting apoptosis, and furthermore, LL-37 stimulates Ca(2+) inflow via a mechanism independent of voltage-sensitive Ca(2+) channels. Interestingly, LL-37-induced lowering of the cell number seems to be mediated via a mechanism independent of Ca(2+).
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11.
  • Welin, Karl-Olof, et al. (author)
  • Epilepsy in tuberous sclerosis patients in Sweden – Healthcare utilization, treatment, morbidity, and mortality using national register data
  • 2017
  • In: Seizure. - : Elsevier BV. - 1059-1311. ; 53, s. 4-9
  • Journal article (peer-reviewed)abstract
    • Purpose This study is designed to estimate the prevalence of epilepsy associated with TSC in Sweden and to describe treatment, morbidity, and mortality of TSC patients with epilepsy. Methods Register data for 2004–2014 was obtained from the National Board of Health and Welfare in Sweden. Patients with TSC were identified using ICD-10 codes. Epilepsy was identified using ICD-10 codes, interventions aimed to treat epilepsy, or prescriptions for antiepileptic drugs. Results The prevalence of TSC was 5.38 per 100 000 individuals. We identified 551 unique patients with TSC, of which 386 (70.1%) had epilepsy. The mean study period was 8.82 years. Antiepileptic drugs were dispensed to 97.9% of patients with epilepsy. The most prescribed antiepileptic drug was sodium valproate. Ketogenic diet was used in 6 (1.6%) patients, vagus nerve stimulation in 23 (6.0%) patients, and epilepsy surgery was performed in 25 (6.5%) patients. The mean number of outpatient visits per year was 4.70 (SD 4.17) and the mean number of inpatient days per year was 3.25 (SD 5.61). The mean number of outpatient visits per year with an ICD-10 code for epilepsy was 1.65 (SD 1.95) and the corresponding number of inpatient days was 2.06 (SD 4.50). A total of 30 patients with TSC and epilepsy died during the study period. Conclusions The prevalence of epilepsy in this study was in the lower range of previously reported numbers, suggesting that epilepsy may be overestimated in non-population based studies. A substantial part of the healthcare utilization was directly related to epilepsy.
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12.
  • Zamora, Juan Carlos, et al. (author)
  • Considerations and consequences of allowing DNA sequence data as types of fungal taxa
  • 2018
  • In: IMA Fungus. - : INT MYCOLOGICAL ASSOC. - 2210-6340 .- 2210-6359. ; 9:1, s. 167-185
  • Journal article (peer-reviewed)abstract
    • Nomenclatural type definitions are one of the most important concepts in biological nomenclature. Being physical objects that can be re-studied by other researchers, types permanently link taxonomy (an artificial agreement to classify biological diversity) with nomenclature (an artificial agreement to name biological diversity). Two proposals to amend the International Code of Nomenclature for algae, fungi, and plants (ICN), allowing DNA sequences alone (of any region and extent) to serve as types of taxon names for voucherless fungi (mainly putative taxa from environmental DNA sequences), have been submitted to be voted on at the 11th International Mycological Congress (Puerto Rico, July 2018). We consider various genetic processes affecting the distribution of alleles among taxa and find that alleles may not consistently and uniquely represent the species within which they are contained. Should the proposals be accepted, the meaning of nomenclatural types would change in a fundamental way from physical objects as sources of data to the data themselves. Such changes are conducive to irreproducible science, the potential typification on artefactual data, and massive creation of names with low information content, ultimately causing nomenclatural instability and unnecessary work for future researchers that would stall future explorations of fungal diversity. We conclude that the acceptance of DNA sequences alone as types of names of taxa, under the terms used in the current proposals, is unnecessary and would not solve the problem of naming putative taxa known only from DNA sequences in a scientifically defensible way. As an alternative, we highlight the use of formulas for naming putative taxa (candidate taxa) that do not require any modification of the ICN.
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13.
  • Åsberg, Dennis, 1988-, et al. (author)
  • A quality control method enhancement concept : Continual improvement of regulatory approved QC methods
  • 2016
  • In: Journal of Pharmaceutical and Biomedical Analysis. - : Elsevier. - 0731-7085 .- 1873-264X. ; 129, s. 273-281
  • Journal article (peer-reviewed)abstract
    • Quality Control methods (QC-methods) play an important role in the overall control strategy for drug manufacturing. However, efficient life-cycle management and continual improvement are hindered due to a variety of post-approval variation legislations across territories and a lack of harmonization of the requirements. As a result, many QC-methods fall behind the technical development. Developing the QC-method in accordance with the Quality by Design guidelines gives the possibility to do continual improvements inside the original Method Operable Design Region (MODR). However, often it is necessary to do changes outside the MODR, e.g. to incorporate new technology that was not available at the time the original method was development. Here, we present a method enhancement concept which allows minor adjustments, within the same measuring principle, outside the original MODR without interaction with regulatory agencies. The feasibility of the concept is illustrated by a case study of a QC-method based on HPLC, assumed to be developed before the introduction of UHPLC, where the switch from HPLC to UHPLC is necessary as a continual improvement strategy. The concept relies on the assumption that the System Suitability Test (SST) and failure modes are relevant for other conditions outside the MODR as well when the same measuring principle is used. It follows that it should be possible to move outside the MODR as long as the SST has passed. All minor modifications of the original, approved QC-method must be re-validated according to a template given in the original submission and a statistical equivalence should be shown between the original and modified QC-methods. To summarize, revalidation is handled within the pharmaceutical quality control system according to internal change control procedures, but without interaction with regulating agencies.
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14.
  • Aidoukovitch, Alexandra, et al. (author)
  • Antimicrobial peptide LL-37 and its pro-form, hCAP18, in desquamated epithelial cells of human whole saliva
  • 2020
  • In: European Journal of Oral Sciences. - : Wiley. - 0909-8836 .- 1600-0722. ; 128:1, s. 1-6
  • Journal article (peer-reviewed)abstract
    • The antimicrobial peptide LL-37 is active against oral bacteria and has been demonstrated to be present in human saliva, but its distribution in different fractions of saliva is not known. LL-37 is formed from its intracellular pro-form, hCAP18, in an extracellular enzymatic reaction catalyzed by proteinase 3 and kallikrein 5. Here, we prepared cell-containing and cell-free fractions of unstimulated human whole saliva by centrifugation after depolymerization of mucins with dithiothreitol, and measured the levels of hCAP18/LL-37 in these fractions using ELISA. Cellular expression of hCAP18/LL-37 was determined by western blotting and immunocytochemistry. The ELISA analyses demonstrated that both cells and cell-free saliva contained hCAP18/LL-37. Western blot analysis of cell-pellet homogenates showed a strong band corresponding to hCAP18 at the correct molecular weight and a weak band corresponding to LL-37. Phase-contrast and light microscopy revealed that the cells consisted of desquamated epithelial cells. These cells expressed cytoplasmic immunoreactivity for hCAP18/LL-37. The peripheral part of the cytoplasm, corresponding to the plasma membrane, was particularly rich in hCAP18/LL-37 immunoreactivity. No immunoreactivity was observed after omission of the primary antibody. We conclude that desquamated epithelial cells of human whole saliva contain antimicrobial hCAP18/LL-37, suggesting that these cells may take part in the innate immune system by harboring and releasing these peptides.
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15.
  • Aidoukovitch, Alexandra, et al. (author)
  • Strontium chloride promotes cell proliferation in a human osteoblast cell line
  • 2014
  • Reports (other academic/artistic)abstract
    • Strontium ranelate (SrRan) is the active component of drugs currently used for reducing the risk of fractures in patients suffering from osteoporosis. Despite extensive use, the underlying mechanisms of action of Sr2+ are not fully understood. In the present study, we assess the impact of SrCl2 on human osteoblast activity and proliferation. Cultures of the human osteoblast-like cell line MG63 were treated for 72 h in presence of 0.1 mM, 1 mM, 5 mM and 10 mM SrCl2 or vehicle, used in control groups. Cells were counted manually using a Bürker chamber. Total protein content was determined by colorimetric analysis performed by a microplate reader using Bio-Rad protein assay. Alkaline phosphatase (ALP) activity was determined enzymatically and normalized to total protein content in each sample. Cell viability was assessed using the MTT assay. Treatment with 5 mM SrCl2 for 72 h enhanced total MG63 cell protein content by 37% compared to controls (p<0.01). A lower concentration (0.1 mM) of SrCl2 had no effect on total protein. Incubation with 5 mM SrCl2 for 72 h increased MG63 cell number by 38% compared to controls (p<0.001). The SrCl2-induced increase in cell number was associated with enhanced (+14% compared to controls, p<0.05) cell viability. Treatment with a higher concentration (10 mM) of SrCl2 enhanced cell number similar to 5 mM SrCl2 (+54% compared to controls, p<0.05). Treatment with 0.1 or 5 mM SrCl2 for 72 h had no effect (p>0.05) on MG63 cell ALP activity, while 1 mM SrCl2 reduced ALP activity as well as total protein content by about 25% compared to controls (p<0.05). The current results demonstrate that treatment with SrCl2 for 72 h, at concentrations higher than 1 mM promotes cell proliferation in human osteoblast-like cells, suggesting that Sr2+ may enhance bone formation through this mechanism.
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16.
  • Aidoukovitch, Alexandra, et al. (author)
  • The host defense peptide LL-37 is internalized by human periodontal ligament cells and prevents LPS-induced MCP-1 production
  • 2019
  • In: Journal of Periodontal Research. - : Wiley. - 0022-3484 .- 1600-0765. ; 54:6, s. 662-670
  • Journal article (peer-reviewed)abstract
    • Objective: The human host defense peptide LL-37 both shows antimicrobial effects and modulates host cell properties. Here, we assess the effects of synthesized LL-37 on lipopolysaccharide (LPS)-induced inflammation in human periodontal ligament (PDL) cells and investigates underlying mechanisms. Background: LL-37 has been detected in the periodontal tissues, but its functional importance for PDL cell innate immune responses is not known. Methods: Human PDL cells were obtained from premolars extracted on orthodontic indications. Cellular pro-inflammatory monocyte chemoattractant protein-1 (MCP-1) mRNA expression was determined using quantitative real-time RT-PCR. MCP-1 protein production was assessed by western blot and ELISA. Internalization of LL-37 by PDL cells was visualized by immunocytochemistry. Nuclear factor kappa-light-chain-enhancer of activated B-cell (NF-κB) activity was assessed by western blot of phosphorylated p65, phosphorylated p105, and IκBα proteins. Binding of LL-37 to PDL cell DNA was determined by isolation and purification of DNA and dot blot for LL-37 immunoreactivity. Results: Treatment with LL-37 (1 µmol/L) for 24 hours prevented LPS-induced stimulation of MCP-1 expression analyzed both on transcript and on protein levels. Stimulation with LL-37 (1 µmol/L) for 24 hours had no effect on toll-like receptor (TLR)2 and TLR4 transcript expression, suggesting that LL-37 acts downstream of the TLRs. Preincubation with LL-37 for 60 minutes followed by stimulation with LPS for 24 hours in the absence of LL-37 completely prevented LPS-evoked MCP-1 transcript expression, implying that LL-37 acts intracellularly and not via binding and neutralization of LPS. In PDL cells stimulated with LL-37 for 60 minutes, the peptide was internalized as demonstrated by immunocytochemistry, suggesting an intracellular mechanism of action. LL-37 immunoreactivity was observed both in the cytosol and in the nucleus. Downregulation of LPS-induced MCP-1 by LL-37 was not mediated by reduction in NF-κB activity as shown by unaltered expression of phosphorylated p65, phosphorylated p105, and IκBα NF-κB proteins in the presence of LL-37. Immunoreactivity for LL-37 was observed in PDL cell DNA treated with but not without 0.1 and 1 µmol/L LL-37 for 60 minutes in vitro. Conclusion: LL-37 abolishes LPS-induced MCP-1 production in human PDL cells through an intracellular, NF-κB-independent mechanism which probably involves direct interaction between LL-37 and DNA.
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17.
  • Aidoukovitch, Alexandra, et al. (author)
  • Vitamin D triggers hCAP18/LL-37 production : Implications for LL-37-induced human osteoblast cytotoxicity
  • 2024
  • In: Biochemical and Biophysical Research Communications. - 0006-291X. ; 712-713
  • Journal article (peer-reviewed)abstract
    • The human cathelicidin LL-37 shows activity against microorganisms, but it is also cytotoxic to host cells. The CAMP gene codes for the LL-37 precursor hCAP18 which is processed extracellularly to active LL-37. It has previously been shown that vitamin D stimulates CAMP gene activity, but less information is available demonstrating that vitamin D also can increase hCAP18/LL-37 protein production. Here, we show with RT-qPCR that a physiological concentration of vitamin D (50 nM) enhances CAMP mRNA levels by about 170 times in human THP-1 monocyte cells. Stimulation with 50 nM vitamin D increases hCAP18/LL-37 protein contents 3–4 times in THP-1 cell lysates demonstrated by both dot blot analysis and ELISA applying two different hCAP18/LL-37 antibodies. Treatment with the proteasome inhibitor MG132 enhances hCAP18/LL-37 levels, suggesting that turnover of hCAP18/LL-37 protein is regulated by the proteasome. The hCAP18/LL-37 concentration in vitamin D-stimulated THP-1 cells corresponds to 1.04 μM LL-37. Interestingly, synthetic LL-37, at this concentration, reduces viability of human osteoblast-like MG63 cells, whereas the THP-1 cells are less sensitive as demonstrated by the MTT assay. In summary, we show that vitamin D enhances hCAP18/LL-37 production, and that this effect can be of physiological/pathophysiological relevance for LL-37-induced human osteoblast toxicity.
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19.
  • Albin, Björn, et al. (author)
  • Situation for carers of the elderly in Sweden
  • 2008
  • In: Studies of Community Welfare: Chiiki Fukushi Kenkyu. - : Nihon Seimei Saiseikai Osaka. ; :38, s. 72-83
  • Journal article (peer-reviewed)abstract
    • In most societies informal care of the elderly (often given by a relative) plays an important role, this article describes the situation and support for carers that exist in Sweden. The description is partly based on the results from the evaluation of a project (“Anhörig 300”) aimed to develop support for carers in the County of Kronoberg as well as from information and documents. Four different typical situations for carers are identified and is an indication of how different situations for carers can be. In the future the support for carers must be paid attention to and further developed. The National Development Plan for the Nursing and Care for elderly in Sweden suggest increased support for carers as a supplement to the public sector elderly care. It is important to involve voluntary organizations to break isolation and loneliness among carers.
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20.
  • Allwood, Jens, 1947, et al. (author)
  • Språk och tanke
  • 1977
  • In: Språk och socialisation symposiet, Graninge.
  • Journal article (peer-reviewed)
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22.
  • Anders, Emma, et al. (author)
  • Globular C1q receptor (p33) binds and stabilizes pro-inflammatory MCP-1 : a novel mechanism for regulation of MCP-1 production and function
  • 2018
  • In: Biochemical Journal. - 0264-6021. ; 475:4, s. 775-786
  • Journal article (peer-reviewed)abstract
    • The protein gC1qR (globular C1q receptor), also named p33, was originally identified as a binding partner of the globular heads of C1q in the complement system. gC1qR/p33 is abundantly expressed in many cell types, but the functional importance of this protein is not completely understood. Here, we investigate the impact of gC1qR/p33 on the production and function of the pathophysiologically important chemokine monocyte chemoattractant protein-1 (MCP-1) and the underlying molecular mechanisms. Knockdown of gC1qR/p33 negatively regulated the production of MCP-1, but had no effect on the expression of transcript for MCP-1 in human periodontal ligament cells, suggesting a translational/post-translational mechanism of action. Laser scanning confocal microscopy showed considerable cytosolic co-localization of gC1qR/p33 and MCP-1, and co-immunoprecipitation disclosed direct physical interaction between gC1qR/p33 and MCP-1. Surface plasmon resonance analysis revealed a high-affinity binding (KD = 10.9 nM) between gC1qR/p33 and MCP-1. Using a transwell migration assay, we found that recombinant gC1qR/p33 enhances MCP-1-induced migration of human THP-1 monocytes, pointing to a functional importance of the interaction between gC1qR/p33 and MCP-1. An in vitro assay revealed a rapid turnover of the MCP-1 protein and that gC1qR/ p33 stabilizes MCP-1, hence preventing its degradation. We propose that endogenous gC1qR/p33 physically interacts with MCP-1 causing stabilization of the MCP-1 protein and stimulation of its activity in human periodontal ligament cells, suggesting a novel gC1qR/p33-mediated pro-inflammatory mechanism of action.
  •  
23.
  • Anders, Emma, et al. (author)
  • LL-37-induced human osteoblast cytotoxicity and permeability occurs independently of cellular LL-37 uptake through clathrin-mediated endocytosis
  • 2018
  • In: Biochemical and Biophysical Research Communications. - : Elsevier BV. - 0006-291X. ; 501:1, s. 280-285
  • Journal article (peer-reviewed)abstract
    • The host defense peptide LL-37 is cytotoxic for bacteria but it has also been reported to reduce host cell viability through an intracellular mechanism. LL-37-evoked cytotoxicity may be involved in the loss of bone tissue in periodontitis which is an inflammatory disease characterized by high concentrations of LL-37 observed locally in the periodontal tissue at the inflammation process. Here, we showed that LL-37 reduced human osteoblast-like MG63 cell viability assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and increased plasma membrane permeability determined by measuring intracellular Ca2+ levels and lactate dehydrogenase (LDH) release. Treatment with chlorpromazine, a well-recognized inhibitor of clathrin-mediated endocytosis, reduced cellular uptake of synthesized LL-37 b y about 30% assessed by Western blotting and ELISA, while filipin, an inhibitor of caveolin-mediated endocytosis, had no effect. The chlorpromazine-induced attenuation of LL-37 uptake was not associated with modulation of LL-37-induced cytotoxicity and LL-37-evoked plasma membrane permeability. Clathrin heavy chain 2 is a major protein of the polyhedral coat of coated pits and vesicles encoded by clathrin heavy chain like 1 gene. Down-regulation of clathrin heavy chain like 1 gene activity by siRNA reduced uptake of LL-37 but did not affect LL-37-induced cytotoxicity and permeability. Thus, we show, using both a pharmacological approach and knockdown of clathrin heavy chain like 1 expression, that LL-37-induced MG63 cell cytotoxicity and permeability occurs independently of LL-37 uptake via clathrin-mediated endocytosis.
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24.
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25.
  • Andersson, Jan, et al. (author)
  • Utslagen fiskrekrytering och sviktande fiskbestånd i Kalmar läns kustvatten
  • 2000
  • Reports (other academic/artistic)abstract
    • Undersökningar gjorda 1994-1997 i ett antal områden i Kalmarsund visade minskande bestånd av främst gädda och abborre samt en låg årsyngelproduktion vid jämförelse med tidigare studier. Observationerna stöddes av rapporter från fiskare och allmänhet och uppfattades så allvarliga, att ett tvåårigt forskningsprojekt beslutades genomföras för att dels dokumentera skadornas karaktär och geografiska utbredning, dels analyserade bakomliggande orsakerna. Projektet, som pågick under 1998-1999, omfattade ett flertal områden efter Kalmarsunds fastlandskust, ett område öster om Öland, samt några referensområden norr om sundet och ett söder därom. Inventerande provfisken och årsyngelundersökningar gjordes för att kartlägga fisksamhällets sammansättning och rekryteringen till de vuxna bestånden. Trålningar genomfördes under abborrens kläckningsperiod för att mäta tätheten av fisklarver samt undersöka deras överlevnad och tillväxt. I samband med detta gjordes insamlingar av djurplankton för att kartlägga larvernas födounderlag. Fält- och laboratorieexperiment genomfördes för att studera romutveckling, kläckning och larvöverlevnad hos gädda och abborre. Som stöd vid tolkningarna av resultaten inhämtades vattenkemiska data från den samordnade kustvattenkontrollen i Kalmar län.Tätheten av främst vuxen abborre men även gädda var mycket låg i områ­det mellan Emån och Revsudden i sundets mitt och andelen gamla fiskar var stor. Även längre ner mot länsgränsen fanns tecken på att bestånden var negativt påverkade. På lokalen vid östra Öland var tätheterna likaså mycket låga. Inventeringen av årsyngel gav en ännu mer negativ bild. Bara ett fåtal yngel av abborre och gädda fångades i hela Kalmarsundsområdet. Även yngel av karpfiskar,strömming och stubbar förekom i lågatätheter. Något påverkade alltså fiskrekryteringen så negativt, att även de vuxna bestånden av flertalet arter reducerats. Det strandnära yngel- och småfisksamhället dominerades av spiggar, vilka förekom i högre tätheter än i referensområdena. Resultaten från de lokaler som besökts vid upprepade tillfällen visade att skadorna förvärrats med tiden.Vattenkemiska data visade, att högsalt- eller ammoniumhalt knappast kunde vara en tänkbar förklaring till den uteblivna rekryteringen. Ammoniumhalterna når inte skadliga nivåer i rekryteringsområdena, och salthalten har minskat i stället för ökat i kustområdet under de senaste 10 åren. Såväl fält- som laboratorieexperimenten gav resultat som talar emot en toxisk påverkan på föräldrafiskar eller ägg och larver. Befruktningsgrad, kläckning och larvöverlevnad vartill synes normala. Undersökning av snäckor från de områden där kläckningsförsök och rekryteringsstudier genomfördes, visade att det åtminstone detta år inte förekom larver eller cerkarier ögonsugmasken Diplostomum sp. under den känsliga period då fisklarver kan dödas av parasitangrepp. Eutrofiering har förts fram som en tänkbar orsak till den sviktande fiskrekryteringen. Närsaltsdata visar att området är övergött, och en förändrad kvä­ve/fosforkvot antyder att primärproduktionen blivit alltmer kvävebegränsad under produktionsperioden senare år.Eutrofieringen yttrar sig som en ökning av primärproduktionen. Halterna klorofyll-a har tenderat att öka i de kustnära vattnen och bedöms som höga enligt Naturvårdsverkets bedömningsgrunder för miljökvalitet, Kust och Hav (1999). Under de senaste 4-5 åren har halterna emellertid sjunkit, vilket kan kopplas till ökat siktdjup. Utvecklingen indikerar att en större del av primärproduktionen under senare år sker i det bentiska växtsamhället. Denna utveckling ses inte i referensområdena. Även om en rik bottenvegetation normalt är positivt för fisk, kan alltför kraftig algpåväxt ha flera negativa effekter, t ex att leksubstraten försämras. En förskjutning av produktionen från pelagiska mikroalger till det bentiska systemet kan också innebära att fiskens födotillgång påverkas. Analyserna av zooplanktonproven visade tydliga avvikelser jämfört med referensmaterialen, såväl vad avser artsammansättning som täthet, och indikerar att födounderlaget försämrats för pelagiska fisklarver, t ex abborre, strömming och stubbar.Utsläppen från Mönsterås Bruk har också ansetts utgöra en möjlig förklaring. Om skadorna på fisk beror på eutrofiering, kan effekterna av brukets utsläpp ses som ett bidrag bland andra till den antropogena belastningen i området. Risken för att toxiska eller hormonellt stö­rande ämnen i avloppsvattnet påverkat fisken måste enligt resultaten från fält och laboratorieexperimenten bedömas vara liten.Kalmarsund hyser landets tätaste skarvkolonier. Teoretiska beräkningar, baserat på uppskattningar av skarvbeståndets storlek, visar att dess konsumtion skulle kunna uppgå till den totala produktionen av stationär fisk i området vilket kan vara en viktig förklaring till de minskande tätheterna. Det finns dock observationer som talar mot skarven som den enda bakomliggande faktorn. Årsyngel utnyttjas normalt inte som föda av skarvarna, och rekryteringen försämrades inte bara för de stationära arterna abborre och gädda, utan även för stubbar och sillar vars vuxna bestånd inte påverkas lika starkt av skarv. Modellsimuleringar visar dock, att i dagens situation kan skarvpredationen effektivt motverka att bestånden återhämtar sig när, förhoppningsvis, rekryteringen åter börjar bli normal.
  •  
26.
  • Andersson, Peter, et al. (author)
  • Active Matrix Displays Based on All-Organic Electrochemical Smart Pixels Printed on Paper
  • 2002
  • In: Advanced Materials. - Weinheim, Germany : Wiley-VCH Verlagsgesellschaft. - 0935-9648 .- 1521-4095. ; 14:20, s. 1460-1464
  • Journal article (peer-reviewed)abstract
    • An organic electronic paper display technology (see Figure and also inside front cover) is presented. The electrochromic display cell together with the addressing electrochemical transistor form simple smart pixels that are included in matrix displays, which are achieved on coated cellulose-based paper using printing techniques. The ion-electronic technology presented offers an opportunity to extend existing use of ordinary paper. 
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27.
  •  
28.
  •  
29.
  • Aronson, Åke, et al. (author)
  • Ulv i Skandinavia : Statusrapport for vinteren 2009-2010
  • 2010
  • Reports (other academic/artistic)abstract
    • The wolves in Sweden and Norway are members of a joint Scandinavian wolf population. In a combined Swedish-Norwegian monitoring project, wolves on the Scandinavian Peninsula were located and counted during the winter of 2009-2010. In Sweden, County administrative boards perform the fieldwork and collection of field data (snow-tracking, DNA-samples), whereas the Wildlife Damage Center (VSC) at Grimsö Research Station was responsible for evaluating and summarizing the results of the wolf monitoring. In Norway, wolf biologists at Hedmark University College and a genetist at Rovdata (Trondheim) in cooperation with the Norwegian Nature Inspectorate (SNO) were responsible for the monitoring of resident and non-resident wolves, respectively. Furthermore, cooperative wolf pack monitoring has been carried out in Fennoscandia in collaboration with Finland. A large number of volunteers and organizations such as hunting associations in both countries and the Swedish Carnivore Association also report observations and participate in wolf monitoring activities. The estimated number of wolves in Scandinavia is mainly based on long distances of ground tracking on snow, but also by radio-telemetry and DNA-analysis. The estimate was restricted to the period of October 1, 2009 – February 28, 2010. To guarantee the quality of the reports used, the majority have been checked in the field by the project, or by other personnel with experience of ground tracking wolves on snow. Wolves were classified as 1) family groups (packs), 2) scent-marking pairs, 3) other resident wolves, or 4) other wolves. The results were presented as minimum-maximum numbers where the minimum was exclusively based on confirmed field-checked reports, while the maximum also included other reports. A total of 252-291 wolves were estimated on the Scandinavian Peninsula during the 2009-2010 winter. Among these, 28 packs included 165-175 wolves, and 44-49 wolves belonged to 21-24 scent-marking pairs. The majority of the wolves (186-215) were located in Sweden. Of the 33-39 wolves restricted to Norway, 21-23 were members of 3 packs, 6 were scent-marking pair members, none were classified as “other resident wolves”, and 6-10 were classified as “other wolves”. Areas were utilized on both sides of the national border between Sweden and Norway by 33-37 resident wolves. Successful reproduction in the spring of 2009 was confirmed in 26 of the Scandinavian wolf territories. Among these, 19 litters were born in Sweden, 4 litters was born in a transboundary packs, and 3 litters grew up in Norway. In 2009, two Finnish-Russian male wolves reproduced for the second time, one litter in Sweden (the Galven territory) and one in Norway (the Kynna territory). In Finland, during the winter 2009-10, a total of 76-78 wolves in 15 packs were estimated to have exclusively Finnish territories. In addition 72-74 wolves were pack members within 13 territories across the Finnish-Russian border
  •  
30.
  • Aronson, Åke, et al. (author)
  • Ulv i Skandinavia : statusrapport for vinteren 2010-2011
  • 2011
  • Reports (other academic/artistic)abstract
    • The wolves in Sweden and Norway are members of a joint Scandinavian wolf population. In a combined Swedish-Norwegian monitoring project, wolves on the Scandinavian Peninsula were located and counted during the winter of 2010-2011. In Sweden, County administrative boards perform the fieldwork and collection of field data (snow-tracking, DNA-samples), whereas the Wildlife Damage Center (VSC) at Grimsö Research Station was responsible for evaluating and summarizing the results of the wolf monitoring. In Norway, wolf biologists at Hedmark University College and a genetist at Rovdata (Trondheim) in cooperation with the Norwegian Nature Inspectorate (SNO) were responsible for the monitoring of resident and non-resident wolves, respectively. Furthermore, cooperative wolf pack monitoring has been carried out in Fennoscandia in collaboration with Finland. A large number of volunteers and organizations such as hunting associations in both countries and the Swedish Carnivore Association also report observations and participate in wolf monitoring activities. The estimated number of wolves in Scandinavia is mainly based on long distances of ground tracking on snow, but also by DNA-analysis and radio-telemetry. The estimate was restricted to the period of October 1, 2010 – February 28, 2011. To guarantee the quality of the reports used, the majority have been checked in the field by the project, or by other personnel with experience of ground tracking wolves on snow. Wolves were classified as 1) family groups (packs), 2) scent-marking pairs, 3) other resident wolves, or 4) other wolves. The results were presented as minimum-maximum numbers where the minimum was exclusively based on confirmed field-checked reports, while the maximum also included other reports. A total of 289-325 wolves were estimated on the Scandinavian Peninsula during the 2010-2011 winter. Among these, 31 packs included 183-189 wolves, and 57-61 wolves belonged to 27-30 scent-marking pairs. The majority of the wolves (235-266) were located in Sweden, of which 149-154 were members of 25 packs, 43-44 lived in 20-22 scent-marking pairs, 4 were classified as “other resident wolves”, and 39-64 were classified as “other wolves”. Of the 32-34 wolves restricted to Norway, 18-19 were members of 3 packs, 8 were scent-marking pair members, one was classified as “other resident wolves”, and 5-6 were classified as “other wolves”. Another 22-25 resident wolves lived in 6-7 packs or scent-marking pairs in territories covering areas on both sides of the Swedish-Norwegian border. Successful reproduction in spring 2010 was confirmed in 31 of the Scandinavian wolf territories. Among these, 25 litters were born in Sweden, 3 litters were born in transboundary packs, and 3 litters grew up in Norway. In 2010, two Finnish-Russian male wolves reproduced for the third time, one litter in Sweden (the Galven territory) and one in Norway (the Kynna territory). In Finland, during the winter 2010-11, a total of 48 wolves in 8 packs were estimated to have exclusively Finnish territories. In addition 59-64 wolves were pack members within 11 territories across the Finnish-Russian border
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31.
  • Axelsson, Karl, 1976- (author)
  • The Sublime : Precursors and British Eighteenth-Century Conceptions
  • 2007
  • Doctoral thesis (other academic/artistic)abstract
    • This dissertation studies the attraction of the sublime in British criticism during the eighteenth century, with particular emphasis on the arguments that served as precursors to the interest in the experience of the sublime. The first part explores Samuel H. Monk’s standard work on the British eighteenth-century sublime, along with more recent studies. In order to expand the contextual features of Monk’s established account, and to be able to connect the sublime with the impact of the criticism of intellectual literature during the second half of the seventeenth century, this study needs to begin by considering the arguments put forth by Longinus in his treatise Peri Hupsous, a work that exerted considerable influence on eighteenth-century critics. Thus, the second part addresses the relevance of the arguments made by Longinus, who reflected on the significance of the concentrated exercise of the imagination and drew attention to the inner carriage required to bring about the experience of the sublime. The third part, then, demonstrates the importance assigned by critics of the sublime to the intense exercise of the imagination. However, to fully understand the attraction of the Longinian sublime, this demonstration also needs to take into account the attention given to the exercise of the imagination in criticism of intellectual literature during the second half of the seventeenth century. Finally, I illustrate the relevance of including such criticism in the interpretation of the attraction of the sublime during the eighteenth century by considering Thomas Hobbes’ claims on the subject of the imagination.
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32.
  • Axelsson, Robert, et al. (author)
  • Evaluation of Multi-level Social Learning for Sustainable Landscapes : Perspective of a Development Initiative in Bergslagen, Sweden
  • 2013
  • In: Ambio. - : Springer Netherlands. - 0044-7447 .- 1654-7209. ; 42:2, s. 241-253
  • Journal article (peer-reviewed)abstract
    • To implement policies about sustainable landscapes and rural development necessitates social learning about states and trends of sustainability indicators, norms that define sustainability, and adaptive multi-level governance. We evaluate the extent to which social learning at multiple governance levels for sustainable landscapes occur in 18 local development initiatives in the network of Sustainable Bergslagen in Sweden. We mapped activities over time, and interviewed key actors in the network about social learning. While activities resulted in exchange of experiences and some local solutions, a major challenge was to secure systematic social learning and make new knowledge explicit at multiple levels. None of the development initiatives used a systematic approach to secure social learning, and sustainability assessments were not made systematically. We discuss how social learning can be improved, and how a learning network of development initiatives could be realized.
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33.
  • Bankell, Elisabeth, et al. (author)
  • The antimicrobial peptide LL-37 triggers release of apoptosis-inducing factor and shows direct effects on mitochondria
  • 2022
  • In: Biochemistry and Biophysics Reports. - : Elsevier BV. - 2405-5808. ; 29
  • Journal article (peer-reviewed)abstract
    • The human antimicrobial peptide LL-37 permeabilizes the plasma membrane of host cells, but LL-37-induced direct effects on mitochondrial membrane permeability and function has not been reported. Here, we demonstrate that LL-37 is rapidly (within 20 min) internalized by human osteoblast-like MG63 cells, and that the peptide co-localizes with MitoTracker arguing for accumulation in mitochondria. Subcellular fractionation and Western blot disclose that stimulation with LL-37 (8 μM) for 2 h triggers release of the mitochondrial protein apoptosis-inducing factor (AIF) to the cytosol, whereas LL-37 causes no release of cytochrome C oxidase subunit IV of the inner mitochondrial membrane, suggesting that LL-37 affects mitochondrial membrane permeability in a specific manner. Next, we investigated release of AIF and cytochrome C from isolated mitochondria by measuring immunoreactivity by dot blot. The media of mitochondria treated with LL-37 (8 μM) for 2 h contained 50% more AIF and three times more cytochrome C than that of control mitochondria, showing that LL-37 promotes release of both AIF and cytochrome C. Moreover, in vesicles reflecting mitochondrial membrane lipid composition, LL-37 stimulates membrane permeabilization and release of tracer molecules. We conclude that LL-37 is rapidly internalized by MG63 cells and accumulates in mitochondria, and that the peptide triggers release of pro-apoptotic AIF and directly affects mitochondrial membrane structural properties.
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34.
  • Baravdish, George, 1964-, et al. (author)
  • Brain Tumour Evolution Backwards in Time via Reaction-Diffusion Models and Sobolev Regularisation
  • 2024
  • In: Modelling and Computational Approaches for Multi-scale Phenomena in Cancer Research. - London : World Scientific. - 9781800614376
  • Book chapter (peer-reviewed)abstract
    • Evolution of brain tumours backwards in time is studied using well-established brain tumour growth models being semilinear parabolic equations of reaction-diffusion type. To run the models backwards, the tumour cell density data at a fixed (final) time is used, rendering an inverse ill-posed problem. This problem is recast as the minimisation of a cost functional matching the data against the solution at a final time of a forward parabolic model having the initial cell density as a control function. Regularisation is incorporated via penalising terms involving Sobolev norms. Mathematical properties of the semilinear parabolic equations are shown in Sobolev-Bochner spaces including uniqueness of a solution to the inverse problem. Differentiability of the control-to-state map is established rendering a sensitivity problem. The derivative of the cost functional is calculated and the adjoint state is derived via the Lagrange formalism. A non-linear conjugate gradient method (NCG) is presented for the minimisation. Numerical realisation of the minimisation on the BraTS'20 dataset is included using a standard finite difference discretisation of the space and time derivatives, showing that tumour evolution backwards in time can be accomplished and that the initial tumour cell density can be reconstructed. Comparison is done with a non-linear Landweber method.
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35.
  • Baravdish, George, et al. (author)
  • Damped second order flow applied to image denoising
  • 2019
  • In: IMA Journal of Applied Mathematics. - : Oxford University Press. - 0272-4960 .- 1464-3634. ; 84:6, s. 1082-1111
  • Journal article (peer-reviewed)abstract
    • In this paper, we introduce a new image denoising model: the damped flow (DF), which is a second order nonlinear evolution equation associated with a class of energy functionals of an image. The existence, uniqueness and regularization property of DF are proven. For the numerical implementation, based on the Störmer–Verlet method, a discrete DF, SV-DDF, is developed. The convergence of SV-DDF is studied as well. Several numerical experiments, as well as a comparison with other methods, are provided to demonstrate the efficiency of SV-DDF.
  •  
36.
  • Baravdish, George, et al. (author)
  • Extension of p-Laplace Operator for Image Denoising
  • 2016
  • In: 27th IFIP TC 7 Conference, CSMO 2015, Sophia Antipolis, France, June 29 - July 3, 2015, Revised Selected Papers. - Cham : Springer. - 9783319557946 - 9783319557953 ; , s. 107-116, s. 107-116
  • Book chapter (peer-reviewed)abstract
    • In this work we introduce a novel operator $$\displaystyle \varDelta _(p,q)$$ as an extended family of operators that generalize the p-Laplace operator. The operator is derived with an emphasis on image processing applications, and particularly, with a focus on image denoising applications. We propose a non-linear transition function, coupling p and q, which yields a non-linear filtering scheme analogous to adaptive spatially dependent total variation and linear filtering. Well-posedness of the final parabolic PDE is established via pertubation theory and connection to classical results in functional analysis. Numerical results demonstrates the applicability of the novel operator $$\displaystyle \varDelta _(p,q)$$ .
  •  
37.
  • Baravdish, George, 1964-, et al. (author)
  • Generalizations of p-Laplace operator for image enhancement : Part 2
  • 2020
  • In: Communications on Pure and Applied Analysis. - Springfield, MO, United States : American Institute of Mathematical Sciences. - 1534-0392 .- 1553-5258. ; 19:7, s. 3477-3500
  • Journal article (peer-reviewed)abstract
    • We have in a previous study introduced a novel elliptic operator Delta((p,q))u = vertical bar del u vertical bar(q) Delta(1)u + (p - 1) vertical bar del u vertical bar(p-2)Delta(infinity) u, p >= 1, q >= 0, as a generalization of the p-Laplace operator. In this paper, we establish the well-posedness of the parabolic equation u(t) =vertical bar del u vertical bar(1-q) Delta((1+q,q)), where q = q(vertical bar del u vertical bar) is continuous and has range in [0, 1], in the framework of viscosity solutions. We prove the consistency and convergence of the numerical scheme of finite differences of this parabolic equation. Numerical simulations shows the advantage of this operator applied to image enhancement.
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38.
  • Baravdish, George, et al. (author)
  • Identifying a response parameter in a model of brain tumour evolution under therapy
  • 2023
  • In: IMA Journal of Applied Mathematics. - : Oxford University Press. - 0272-4960 .- 1464-3634. ; 88:2, s. 378-404
  • Journal article (peer-reviewed)abstract
    • A nonlinear conjugate gradient method is derived for the inverse problem of identifying a treatment parameter in a nonlinear model of reaction-diffusion type corresponding to the evolution of brain tumours under therapy. The treatment parameter is reconstructed from additional information about the tumour taken at a fixed instance of time. Well-posedness of the direct problems used in the iterative method is outlined as well as uniqueness of a solution to the inverse problem. Moreover, the parameter identification is recasted as the minimization of a Tikhonov type functional and the existence of a minimizer to this functional is shown. Finite-difference discretization of the space and time derivatives are employed for the numerical implementation. Numerical simulations on full 3D brain data are included showing that information about a spacewise-dependent treatment parameter can be recovered in a stable way.
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39.
  • Baravdish, George, 1964-, et al. (author)
  • On a new singular and degenerate extension of the p-Laplace operator
  • 2024
  • In: Nonlinear Analysis. - : PERGAMON-ELSEVIER SCIENCE LTD. - 0362-546X .- 1873-5215. ; 244
  • Journal article (peer-reviewed)abstract
    • We study a novel degenerate and singular elliptic operator Δ˜(τ,χ) defined by Δ˜(τ,χ)u=τ(x,Du)(|Du|Δ1u+χ(x,Du)Δ∞u), where the singular weights τ(x,s)>0 and χ(x,s)≥0 are continuous functions on Ω×Rn∖{0}. The operator Δ˜(τ,χ) is an extension of Δ(p,q)u=|Du|qΔ1u+(p−1)|Du|p−2Δ∞u,p≥1,q≥0, introduced by the authors in Baravdishet al. (2020), which in turn is an extension of the p-Laplace operator Δp. We establish the well-posedness of the Neumann boundary value problem for the parabolic equation ut=Δ˜(τ,χ)u in the framework of viscosity solutions. For the solution u, the weight χ controls the evolution along the tangential and the normal directions, respectively, on the level surface of u. The weight τ controls the total speed of the evolution of u. We also prove the consistency and the convergence of the numerical scheme for the finite differences method of the parabolic equation above. Numerical simulations show that our novel nonlinear operator Δ˜(τ,χ) gives better results than both the Perona–Malik (Perona and Malik, 1990) and total variation (TV) methods (Chan and Shen, 2005) when applied to image enhancement.
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40.
  • Baravdish, George, et al. (author)
  • On Backward p(x)-Parabolic Equations for Image Enhancement
  • 2015
  • In: Numerical Functional Analysis and Optimization. - : Taylor & Francis. - 0163-0563 .- 1532-2467. ; 36:2, s. 147-168
  • Journal article (peer-reviewed)abstract
    • In this study, we investigate the backward p(x)-parabolic equation as a new methodology to enhance images. We propose a novel iterative regularization procedure for the backward p(x)-parabolic equation based on the nonlinear Landweber method for inverse problems. The proposed scheme can also be extended to the family of iterative regularization methods involving the nonlinear Landweber method. We also investigate the connection between the variable exponent p(x) in the proposed energy functional and the diffusivity function in the corresponding Euler-Lagrange equation. It is well known that the forward problems converges to a constant solution destroying the image. The purpose of the approach of the backward problems is twofold. First, solving the backward problem by a sequence of forward problems we obtain a smooth image which is denoised. Second, by choosing the initial data properly we try to reduce the blurriness of the image. The numerical results for denoising appear to give improvement over standard methods as shown by preliminary results.
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41.
  • Baravdish, George, et al. (author)
  • PDE-SVD Based Audio Denoising
  • 2012
  • In: Proceedings of the 5th International Symposium on Communications Control and Signal Processing (ISCCSP), 2012. - Piscataway, NJ, USA : IEEE. - 9781467302746 ; , s. 1-6
  • Conference paper (peer-reviewed)abstract
    • In this paper we present a new method for denoising audio signals. The method is based on the Singular Value Decomposition (SVD) of the frame matrix representing the signal inthe Overlap Add decomposition. Denoising is performed by modifying both the singular values, using a tapering model, and the singular vectors of the representation, using a nonlinear PDE method. The performance of the method is evaluated and compared with denoising obtained by filtering.
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42.
  • Berggren, Magnus, et al. (author)
  • PEDOT : PSS-Based Electrochemical Transistors for Ion-to-Electron Transduction and Sensor Signal Amplification
  • 2008. - 1
  • In: Organic Semiconductors in Sensor Applications. - Berlin, Heidelberg : Springer. - 9783540763147 - 9783540763130 - 9783642095177 ; , s. 263-280
  • Book chapter (other academic/artistic)abstract
    • The chapter reports the use of organic electrochemical transistors in sensor applications. These transistors are excellent ion-to-electron transducers and can serve as very sensitive transducers in amperometric sensor applications. To further improve their sensitivity, we outline various amplification circuits all realized in organic electrochemical transistors.
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43.
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44.
  • Berntsson Svensson, Richard, 1978-, et al. (author)
  • BAM : backlog assessment method
  • 2019
  • In: Lecture Notes in Business Information Processing. - Cham : Springer Verlag. - 1865-1348. - 9783030190330 ; , s. 53-68
  • Conference paper (peer-reviewed)abstract
    • The necessity of software as stand-alone products, and as central parts of non-traditional software products have changed how software products are developed. It started with the introduction of the agile manifesto and has resulted in a change of how software process improvements (SPI) are conducted. Although there are agile SPI methods and several agile practices for evaluating and improving current processes and ways-of-working, no method or practices for evaluating the backlog exists. To address this gap, the Backlog Assessment Method (BAM) was developed and applied in collaboration with Telenor Sweden. BAM enables agile organizations to assess backlogs, and assure that the backlog items are good-enough for their needs and well aligned with the decision process. The results from the validation show that BAM is feasible and relevant in an industrial environment, and it indicates that BAM is useful as a tool to perform analysis of items in a specific backlog. © The Author(s) 2019.
  •  
45.
  • Bjärstig, Therese, 1978-, et al. (author)
  • Between protocol and reality : Swedish municipal comprehensive planning
  • 2018
  • In: European Planning Studies. - : Informa UK Limited. - 0965-4313 .- 1469-5944. ; 26:1, s. 35-54
  • Journal article (peer-reviewed)abstract
    • Spatial planning using a landscape approach has been recognized as being essential for reconciling ecological, cultural and socioeconomic dimensions in sustainable development (SuD). Although embraced as a concept, there is a lack of planning tools capable of incorporating multi-level, multifunctional and multi-sectoral perspectives, especially in a rural context. The departure point in this paper is the legal requirements for municipal comprehensive planning (MCP) in Sweden and an e-mail survey about incentives, stakeholder involvement, policy integration and implementation in MCP in all 15 Swedish mountain municipalities. The purpose of this explorative study is to examine whether MCP could be a tool in planning for SuD. Results indicate a general lack of resources and a low status of MCP that affect, and even limit, stakeholder involvement, policy integration and implementation. However, legal requirements for MCP are targeted at SuD, and municipal personnel responsible for planning appreciate the potential of MCP. Therefore, there is potential to develop the MCP into an effective landscape planning tool. To accomplish this, the status of an active planning process has to be raised, the mandate of the local planning agency has to be secured, and residents and land users have to be involved throughout the planning process.
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46.
  •  
47.
  • Boström, Pontus, 1982, et al. (author)
  • Hypoxia converts human macrophages into triglyceride-loaded foam cells.
  • 2006
  • In: Arteriosclerosis, thrombosis, and vascular biology. - 1524-4636. ; 26:8, s. 1871-6
  • Journal article (peer-reviewed)abstract
    • OBJECTIVE: Atherosclerotic lesions have regions that are hypoxic. Because the lesion contains macrophages that are loaded with lipid, we investigated whether hypoxia can influence the accumulation of lipids in these cells. METHODS AND RESULTS: Exposure of human macrophages to hypoxia for 24 hours resulted in an increased formation of cytosolic lipid droplets and an increased accumulation of triglycerides. Exposure of the macrophages to oxidized low-density lipoprotein (oxLDL) increased the accumulation of cytosolic lipid droplets because of an increase in cellular cholesterol esters. The accumulation of lipid droplets in oxLDL-treated cells was further increased after hypoxia, caused by an increased level of triglycerides. Expression analyses combined with immunoblot or RT-PCR demonstrated that hypoxia increased the expression of several genes that could promote the accumulation of lipid droplets. Hypoxia increased the mRNA and protein levels of adipocyte differentiation-related protein (ADRP). It is well known that an increased expression of ADRP increases the formation of lipid droplets. Hypoxia decreased the expression of enzymes involved in beta-oxidation (acyl-coenzyme A synthetase and acyl-coenzyme A dehydrogenase) and increased the expression of stearoyl-coenzyme A desaturase, an important enzyme in the fatty acid biosynthesis. Moreover, exposure to hypoxia decreased the rate of beta-oxidation, whereas the accumulation of triglycerides increased. CONCLUSIONS: The results demonstrate that exposure of human macrophages to hypoxia causes an accumulation of triglyceride-containing cytosolic lipid droplets. This indicates that the hypoxia present in atherosclerotic lesions can contribute to the formation of the lipid-loaded macrophages that characterize the lesion and to the accumulation of triglycerides in such lesions.
  •  
48.
  • Boström, Pontus, 1982, et al. (author)
  • The SNARE protein SNAP23 and the SNARE-interacting protein Munc18c in human skeletal muscle are implicated in insulin resistance/type 2 diabetes.
  • 2010
  • In: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 59:8, s. 1870-8
  • Journal article (peer-reviewed)abstract
    • OBJECTIVE: Our previous studies suggest that the SNARE protein synaptosomal-associated protein of 23 kDa (SNAP23) is involved in the link between increased lipid levels and insulin resistance in cardiomyocytes. The objective was to determine whether SNAP23 may also be involved in the known association between lipid accumulation in skeletal muscle and insulin resistance/type 2 diabetes in humans, as well as to identify a potential regulator of SNAP23. RESEARCH DESIGN AND METHODS: We analyzed skeletal muscle biopsies from patients with type 2 diabetes and healthy, insulin-sensitive control subjects for expression (mRNA and protein) and intracellular localization (subcellular fractionation and immunohistochemistry) of SNAP23, and for expression of proteins known to interact with SNARE proteins. Insulin resistance was determined by a euglycemic hyperinsulinemic clamp. Potential mechanisms for regulation of SNAP23 were also investigated in the skeletal muscle cell line L6. RESULTS: We showed increased SNAP23 levels in skeletal muscle from patients with type 2 diabetes compared with that from lean control subjects. Moreover, SNAP23 was redistributed from the plasma membrane to the microsomal/cytosolic compartment in the patients with the type 2 diabetes. Expression of the SNARE-interacting protein Munc18c was higher in skeletal muscle from patients with type 2 diabetes. Studies in L6 cells showed that Munc18c promoted the expression of SNAP23. CONCLUSIONS: We have translated our previous in vitro results into humans by showing that there is a change in the distribution of SNAP23 to the interior of the cell in skeletal muscle from patients with type 2 diabetes. We also showed that Munc18c is a potential regulator of SNAP23.
  •  
49.
  • Bowler, Matthew W., et al. (author)
  • Automation and Experience of Controlled Crystal Dehydration: Results from the European Synchrotron HC1 Collaboration
  • 2015
  • In: Crystal Growth & Design. - : American Chemical Society (ACS). - 1528-7483 .- 1528-7505. ; 15:3, s. 1043-1054
  • Journal article (peer-reviewed)abstract
    • Controlled dehydration of macromolecular crystals can lead to significant improvements in crystalline order, which often manifests itself in higher diffraction quality. Devices that can accurately control the humidity surrounding crystals on a beamline have led to this technique being increasingly adopted as experiments become easier and more reproducible. However, these experiments are often carried out by trial and error, and in order to facilitate and streamline them four European synchrotrons have established a collaboration around the HC1b dehydration device. The MAX IV Laboratory, Diamond Light Source, BESSY II, and the EMBL Grenoble Outstation/ESRF have pooled information gathered from user experiments, and on the use of the device, to propose a set of guidelines for these experiments. Here, we present the status and automation of the installations, advice on how best to perform experiments using the device, and an analysis of successful experiments that begins to show some trends in the type of protocols required by some systems. The dehydration methods shown are applicable to any device that allows control of the relative humidity of the air surrounding a macromolecular crystal.
  •  
50.
  • Bredewold, Obbo W, et al. (author)
  • Cardiovascular Risk Following Conversion to Belatacept From a Calcineurin Inhibitor in Kidney Transplant Recipients : A Randomized Clinical Trial
  • 2023
  • In: Kidney Medicine. - : Elsevier. - 2590-0595. ; 5:1
  • Journal article (peer-reviewed)abstract
    • RATIONALE & OBJECTIVE: In kidney transplant recipients (KTRs), a belatacept-based immunosuppressive regimen is associated with beneficial effects on cardiovascular (CV) risk factors compared with calcineurin inhibitor (CNI)-based regimens. Our objective was to compare the calculated CV risk between belatacept and CNI (predominantly tacrolimus) treatments using a validated model developed for KTRs.STUDY DESIGN: Prospective, randomized, open-label, parallel-group, investigator-initiated, international multicenter trial.SETTING & PARTICIPANTS: KTRs aged 18-80 years with a stable graft function (estimated glomerular filtration rate > 20 mL/min/1.73 m2), 3-60 months after transplantation, treated with tacrolimus or cyclosporine A, were eligible for inclusion.INTERVENTION: Continuation with a CNI-based regimen or switch to belatacept for 12 months.OUTCOMES: Comparison of the change in the estimated 7-year risk of major adverse CV events and all-cause mortality, changes in traditional markers of CV health, as well as measures of arterial stiffness.RESULTS: Among the 105 KTRs randomized, we found no differences between the treatment groups in the predicted risk for major adverse CV events or mortality. Diastolic blood pressure, measured both centrally by using a SphygmoCor device and peripherally, was lower after the belatacept treatment than after the CNI treatment. The mean changes in traditional cardiovascular (CV) risk factors, including kidney transplant function, were otherwise similar in both the treatment groups. The belatacept group had 4 acute rejection episodes; 2 were severe rejections, of which 1 led to graft loss.LIMITATIONS: The heterogeneous baseline estimated glomerular filtration rate and time from transplantation to trial enrollment in the participants. A limited study duration of 1 year.CONCLUSIONS: We found no effects on the calculated CV risk by switching to the belatacept treatment. Participants in the belatacept group had not only lower central and peripheral diastolic blood pressure but also a higher rejection rate.FUNDING: The trial has received a financial grant from Bristol-Myers Squibb.TRIAL REGISTRATION: EudraCT no. 2013-001178-20.
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