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| 5. |
- Galluzzi, L, et al.
(författare)
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Guidelines for the use and interpretation of assays for monitoring cell death in higher eukaryotes.
- 2009
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Ingår i: Cell death and differentiation. - : Springer Science and Business Media LLC. - 1476-5403 .- 1350-9047. ; 16:8, s. 1093-107
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Forskningsöversikt (refereegranskat)abstract
- Cell death is essential for a plethora of physiological processes, and its deregulation characterizes numerous human diseases. Thus, the in-depth investigation of cell death and its mechanisms constitutes a formidable challenge for fundamental and applied biomedical research, and has tremendous implications for the development of novel therapeutic strategies. It is, therefore, of utmost importance to standardize the experimental procedures that identify dying and dead cells in cell cultures and/or in tissues, from model organisms and/or humans, in healthy and/or pathological scenarios. Thus far, dozens of methods have been proposed to quantify cell death-related parameters. However, no guidelines exist regarding their use and interpretation, and nobody has thoroughly annotated the experimental settings for which each of these techniques is most appropriate. Here, we provide a nonexhaustive comparison of methods to detect cell death with apoptotic or nonapoptotic morphologies, their advantages and pitfalls. These guidelines are intended for investigators who study cell death, as well as for reviewers who need to constructively critique scientific reports that deal with cellular demise. Given the difficulties in determining the exact number of cells that have passed the point-of-no-return of the signaling cascades leading to cell death, we emphasize the importance of performing multiple, methodologically unrelated assays to quantify dying and dead cells.
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| 6. |
- Saliba-Gustafsson, P., et al.
(författare)
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Subclinical atherosclerosis and its progression are modulated by PLIN2 through a feed-forward loop between LXR and autophagy
- 2019
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Ingår i: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 286:6, s. 660-675
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Tidskriftsartikel (refereegranskat)abstract
- Background Hyperlipidaemia is a major risk factor for cardiovascular disease, and atherosclerosis is the underlying cause of both myocardial infarction and stroke. We have previously shown that the Pro251 variant of perilipin-2 reduces plasma triglycerides and may therefore be beneficial to reduce atherosclerosis development. Objective We sought to delineate putative beneficial effects of the Pro251 variant of perlipin-2 on subclinical atherosclerosis and the mechanism by which it acts. Methods A pan-European cohort of high-risk individuals where carotid intima-media thickness has been assessed was adopted. Human primary monocyte-derived macrophages were prepared from whole blood from individuals recruited by perilipin-2 genotype or from buffy coats from the Karolinska University hospital blood central. Results The Pro251 variant of perilipin-2 is associated with decreased intima-media thickness at baseline and over 30 months of follow-up. Using human primary monocyte-derived macrophages from carriers of the beneficial Pro251 variant, we show that this variant increases autophagy activity, cholesterol efflux and a controlled inflammatory response. Through extensive mechanistic studies, we demonstrate that increase in autophagy activity is accompanied with an increase in liver-X-receptor (LXR) activity and that LXR and autophagy reciprocally activate each other in a feed-forward loop, regulated by CYP27A1 and 27OH-cholesterol. Conclusions For the first time, we show that perilipin-2 affects susceptibility to human atherosclerosis through activation of autophagy and stimulation of cholesterol efflux. We demonstrate that perilipin-2 modulates levels of the LXR ligand 27OH-cholesterol and initiates a feed-forward loop where LXR and autophagy reciprocally activate each other; the mechanism by which perilipin-2 exerts its beneficial effects on subclinical atherosclerosis.
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| 9. |
- Hangen, E, et al.
(författare)
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A brain-specific isoform of mitochondrial apoptosis-inducing factor: AIF2.
- 2010
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Ingår i: Cell death and differentiation. - : Springer Science and Business Media LLC. - 1476-5403 .- 1350-9047. ; 17:7, s. 1155-66
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Tidskriftsartikel (refereegranskat)abstract
- Apoptosis-inducing factor (AIF) has important supportive as well as potentially lethal roles in neurons. Under normal physiological conditions, AIF is a vital redox-active mitochondrial enzyme, whereas in pathological situations, it translocates from mitochondria to the nuclei of injured neurons and mediates apoptotic chromatin condensation and cell death. In this study, we reveal the existence of a brain-specific isoform of AIF, AIF2, whose expression increases as neuronal precursor cells differentiate. AIF2 arises from the utilization of the alternative exon 2b, yet uses the same remaining 15 exons as the ubiquitous AIF1 isoform. AIF1 and AIF2 are similarly imported to mitochondria in which they anchor to the inner membrane facing the intermembrane space. However, the mitochondrial inner membrane sorting signal encoded in the exon 2b of AIF2 is more hydrophobic than that of AIF1, indicating a stronger membrane anchorage of AIF2 than AIF1. AIF2 is more difficult to be desorbed from mitochondria than AIF1 on exposure to non-ionic detergents or basic pH. Furthermore, AIF2 dimerizes with AIF1, thereby preventing its release from mitochondria. Conversely, it is conceivable that a neuron-specific AIF isoform, AIF2, may have been 'designed' to be retained in mitochondria and to minimize its potential neurotoxic activity.Cell Death and Differentiation advance online publication, 29 January 2010; doi:10.1038/cdd.2009.211.
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- Blideanu, V., et al.
(författare)
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Nucleon-induced reactions at intermediate energies : New data at 96 MeV and theoretical status
- 2004
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Ingår i: Physical Review C. Nuclear Physics. - 0556-2813 .- 1089-490X. ; 70:1, s. 014607-
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Tidskriftsartikel (refereegranskat)abstract
- Double-differential cross sections for light charged particle production (up to A=4) were measured in 96 MeV neutron-induced reactions, at the TSL Laboratory Cyclotron in Uppsala (Sweden). Measurements for three targets, Fe, Pb, and U, were performed using two independent devices, SCANDAL and MEDLEY. The data were recorded with low-energy thresholds and for a wide angular range (20°–160°). The normalization procedure used to extract the cross sections is based on the np elastic scattering reaction that we measured and for which we present experimental results. A good control of the systematic uncertainties affecting the results is achieved. Calculations using the exciton model are reported. Two different theoretical approaches proposed to improve its predictive power regarding the complex particle emission are tested. The capabilities of each approach is illustrated by comparison with the 96 MeV data that we measured, and with other experimental results available in the literature.
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| 15. |
- Brinson, Robert G., et al.
(författare)
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Enabling adoption of 2D-NMR for the higher order structure assessment of monoclonal antibody therapeutics
- 2019
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Ingår i: mAbs. - : Informa UK Limited. - 1942-0862 .- 1942-0870. ; 11:1, s. 94-105
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Tidskriftsartikel (refereegranskat)abstract
- The increased interest in using monoclonal antibodies (mAbs) as a platform for biopharmaceuticals has led to the need for new analytical techniques that can precisely assess physicochemical properties of these large and very complex drugs for the purpose of correctly identifying quality attributes (QA). One QA, higher order structure (HOS), is unique to biopharmaceuticals and essential for establishing consistency in biopharmaceutical manufacturing, detecting process-related variations from manufacturing changes and establishing comparability between biologic products. To address this measurement challenge, two-dimensional nuclear magnetic resonance spectroscopy (2D-NMR) methods were introduced that allow for the precise atomic-level comparison of the HOS between two proteins, including mAbs. Here, an inter-laboratory comparison involving 26 industrial, government and academic laboratories worldwide was performed as a benchmark using the NISTmAb, from the National Institute of Standards and Technology (NIST), to facilitate the translation of the 2D-NMR method into routine use for biopharmaceutical product development. Two-dimensional H-1,N-15 and H-1,C-13 NMR spectra were acquired with harmonized experimental protocols on the unlabeled Fab domain and a uniformly enriched-N-15, 20%-C-13-enriched system suitability sample derived from the NISTmAb. Chemometric analyses from over 400 spectral maps acquired on 39 different NMR spectrometers ranging from 500 MHz to 900 MHz demonstrate spectral fingerprints that are fit-for-purpose for the assessment of HOS. The 2D-NMR method is shown to provide the measurement reliability needed to move the technique from an emerging technology to a harmonized, routine measurement that can be generally applied with great confidence to high precision assessments of the HOS of mAb-based biotherapeutics.
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| 17. |
- Falconer, C, et al.
(författare)
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Paraurethral connective tissue in stress-incontinent women after menopause
- 1998
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Ingår i: Acta Obstetricia et Gynecologica Scandinavica. - 0001-6349. ; 77:1, s. 95-100
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To study whether stress urinary incontinence after menopause is correlated to changes in the paraurethral connective tissue ultrastructure and metabolism.METHODS: Transvaginal biopsies were obtained from the paraurethral connective tissue in stress urinary incontinent women after menopause with and without estrogen replacement therapy, and from comparable controls. All the stress-incontinent women underwent urodynamic investigation. In the specimens, collagen concentration, measured as hydroxyproline, and the degree of extractability by pepsin digestion, were quantified. Proteoglycan composition and concentration were analyzed using Alcian Blue precipitation, followed by electro-phoretic separation and quantification. Using Northern blots, mRNA levels for the collagens I and III, the small proteoglycans decorin and biglycan, and the large proteoglycan versican, were quantified. Collagen structure was examined with transmission electron microscopy, and the diameters of collagen fibrils were analyzed with an interactive image analysis system (IBAS, Zeiss/Kontron).RESULTS: No significant difference in paraurethral connective tissue biochemistry or ultrastructure was registered between women with stress incontinence and controls. Estrogen replacement therapy resulted in a lower collagen concentration both between the controls (p = 0.02) and between the incontinent women (0.02). In the women with stress incontinence also the extractability by pepsin digestion was higher in the group with estrogen treatment (p = 0.004), indicating a decrease in cross-linking. The proteoglycan/collagen ratio was higher in the control group with estrogen treatment compared to untreated (p = 0.02), but no difference was found between estrogen treated and untreated incontinent women. The median collagen fibril diameter was 15% larger in the incontinent group of women without estrogen therapy compared to the control group and 5% larger when comparing the incontinent group on estrogen replacement therapy to the corresponding control group.CONCLUSION: The extracellular matrix of paraurethral connective tissue in stress urinary incontinent women after menopause reacted differently to estrogen replacement therapy compared to continent controls. In contrast to incontinent women of fertile age no major changes in collagen metabolism were found in stress urinary incontinent women after menopause.
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| 20. |
- Ledoux, X, et al.
(författare)
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A neutron beam facility at SPIRAL-2
- 2007
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Ingår i: International Conference on Nuclear Data for Science and Technology, Nice, France, April 22-27, 2007, (accepted).
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Konferensbidrag (refereegranskat)
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| 24. |
- Ryzhov, I.V., et al.
(författare)
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Fragment-mass distributions in neutron-induced fission of 232Th and 238U at 33, 45, and 60 MeV
- 2011
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Ingår i: Physical Review C. Nuclear Physics. - 0556-2813 .- 1089-490X. ; 83:5, s. 054603-
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Tidskriftsartikel (refereegranskat)abstract
- We have measured fission fragment-mass yields for neutron-induced fission of Th-232 and U-238 at energies 32.8, 45.3, and 59.9 MeV. The experiments were done at quasimonoenergetic neutron beams of the Cyclotron Research Center at Louvain-la-Neuve. To detect the fission fragments, a multisection Frisch-gridded ionization chamber was used. The measurement and data analysis techniques are discussed in detail. The obtained mass yields are compared to model calculations with the intermediate-energy nuclear reaction code MCFX. The MCFX code is used to calculate the fraction of fissioning nuclei after cascade, preequilibrium, and statistical reaction stages. The formation of mass distributions is considered as a result of oscillations of the mass-asymmetry degree of freedom in the potential well calculated with the temperature-dependent shell correction method. The experimental results as well as the results of the model calculations demonstrate that the probability of symmetric fission increases with incident neutron energy for both nuclei. The comparison also shows that the symmetric fission is more enhanced for thorium than for uranium with increasing neutron energy. We also compare U-238 results with available experimental data; the Th-232 data were measured for the first time.
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| 27. |
- Sagrado Garcia, I. C., et al.
(författare)
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Neutron production in neutron-induced reactions at 96 MeV on (56)Fe and (208)Pb
- 2011
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Ingår i: Physical Review C. Nuclear Physics. - 0556-2813 .- 1089-490X. ; 84:4, s. 044619-
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Tidskriftsartikel (refereegranskat)abstract
- Double-differential cross sections for neutron production were measured in 96-MeV neutron-induced reactions at The Svedberg Laboratory in Uppsala, Sweden. Measurements for Fe and Pb targets were performed using two independent setups: DECOI-DEMON, time-of-flight telescope dedicated to the detection of emitted neutrons with energies between a few and 50 MeV and CLODIA-SCANDAL device devoted to measuring emitted neutrons with energies above 40 MeV. Double-differential cross sections were measured for an angular range between 15 and 98 deg and with low-energy thresholds (approximate to 2 MeV). Angular and energy distributions and total neutron emission cross sections have been obtained from those measurements. Results have been compared with predictions given by different models included in several transport codes (MCNPX, GEANT, TALYS, PHITS, and DYWAN) and with other experimental data (the EXFOR database).
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| 28. |
- Simutkin, Vasily D., et al.
(författare)
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Experimental Neutron-induced Fission Fragment Mass Yields of Th-232 and U-238 at Energies from 10 to 33 MeV
- 2014
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Ingår i: Nuclear Data Sheets. - : Elsevier BV. - 0090-3752 .- 1095-9904. ; 119, s. 331-333
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Tidskriftsartikel (refereegranskat)abstract
- Development of nuclear energy applications requires data for neutron-induced reactions for actinides in a wide neutron energy range. Here we describe measurements of pre-neutron emission fission fragment mass yields of Th-232 and U-238 at incident neutron energies from 10 to 33 MeV. The measurements were done at the quasi-monoenergetic neutron beam of the Louvain-la-Neuve cyclotron facility CYCLONE; a multi-section twin Frisch-gridded ionization chamber was used to detect fission fragments. For the peak neutron energies at 33, 45 and 60 MeV, the details of the data analysis and the experimental results were published in Ref. [1]. In this work we present data analysis in the low-energy tail of the neutron energy spectra. The preliminary measurement results are compared with available experimental data and theoretical predictions.
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| 32. |
- Zanni, G., et al.
(författare)
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Lithium treatment reverses irradiation-induced changes in rodent neural progenitors and rescues cognition
- 2019
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Ingår i: Molecular Psychiatry. - : Springer Nature. - 1359-4184 .- 1476-5578. ; 26:1, s. 322-340
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Tidskriftsartikel (refereegranskat)abstract
- Cranial radiotherapy in children has detrimental effects on cognition, mood, and social competence in young cancer survivors. Treatments harnessing hippocampal neurogenesis are currently of great relevance in this context. Lithium, a well-known mood stabilizer, has both neuroprotective, pro-neurogenic as well as antitumor effects, and in the current study we introduced lithium treatment 4 weeks after irradiation. Female mice received a single 4 Gy whole-brain radiation dose on postnatal day (PND) 21 and were randomized to 0.24% Li2CO3 chow or normal chow from PND 49 to 77. Hippocampal neurogenesis was assessed on PND 77, 91, and 105. We found that lithium treatment had a pro-proliferative effect on neural progenitors, but neuronal integration occurred only after it was discontinued. Also, the treatment ameliorated deficits in spatial learning and memory retention observed in irradiated mice. Gene expression profiling and DNA methylation analysis identified two novel factors related to the observed effects, Tppp, associated with microtubule stabilization, and GAD2/65, associated with neuronal signaling. Our results show that lithium treatment reverses irradiation-induced loss of hippocampal neurogenesis and cognitive impairment even when introduced long after the injury. We propose that lithium treatment should be intermittent in order to first make neural progenitors proliferate and then, upon discontinuation, allow them to differentiate. Our findings suggest that pharmacological treatment of cognitive so-called late effects in childhood cancer survivors is possible.
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| 37. |
- Badiola, N, et al.
(författare)
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Induction of ER stress in response to oxygen-glucose deprivation of cortical cultures involves the activation of the PERK and IRE-1 pathways and of caspase-12.
- 2011
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Ingår i: Cell death & disease. - : Springer Science and Business Media LLC. - 2041-4889. ; 2
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Tidskriftsartikel (refereegranskat)abstract
- Disturbance of calcium homeostasis and accumulation of misfolded proteins in the endoplasmic reticulum (ER) are considered contributory components of cell death after ischemia. However, the signal-transducing events that are activated by ER stress after cerebral ischemia are incompletely understood. In this study, we show that caspase-12 and the PERK and IRE pathways are activated following oxygen-glucose deprivation (OGD) of mixed cortical cultures or neonatal hypoxia-ischemia (HI). Activation of PERK led to a transient phosphorylation of eIF2α, an increase in ATF4 levels and the induction of gadd34 (a subunit of an eIF2α-directed phosphatase). Interestingly, the upregulation of ATF4 did not lead to an increase in the levels of CHOP. Additionally, IRE1 activation was mediated by the increase in the processed form of xbp1, which would be responsible for the observed expression of edem2 and the increased levels of the chaperones GRP78 and GRP94. We were also able to detect caspase-12 proteolysis after HI or OGD. Processing of procaspase-12 was mediated by NMDA receptor and calpain activation. Moreover, our data suggest that caspase-12 activation is independent of the unfolded protein response activated by ER stress.
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| 44. |
- Bilski, P., et al.
(författare)
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The problems associated with the monitoring of complex workplace radiation fields at European high-energy accelerators and thermonuclear fusion facilities
- 2007
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Ingår i: Radiation Protection Dosimetry. - : Oxford University Press (OUP). - 0144-8420 .- 1742-3406. ; 126:1-4, s. 491-496
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Tidskriftsartikel (refereegranskat)abstract
- The European Commission is funding within its Sixth Framework Programme a three-year project (2005-2007) called CONRAD, COordinated Network for RAdiation Dosimetry. The organisational framework for this project is provided by the European Radiation Dosimetry Group EURADOS. One task within the CONRAD project, Work Package 6 (WP6), was to provide a report outlining research needs and research activities within Europe to develop new and improved methods and techniques for the characterisation of complex radiation fields at workplaces around high-energy accelerators, but also at the next generation of thermonuclear fusion facilities. The paper provides an overview of the report, which will be available as CERN Yellow Report.
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| 48. |
- Blomgren, Lena, 1957-, et al.
(författare)
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Coagulation and fibrinolysis in chronic venous insufficiency
- 2001
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Ingår i: VASA. - : Hogrefe & Huber Publishers. - 0301-1526 .- 1664-2872. ; 30:3, s. 184-187
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Varicose veins (VV) are common, but only some patients will develop chronic venous insufficiency (CVI) with skin changes or venous ulcer. The pathophysiology of venous ulcer development is complex, and may involve abnormalities in coagulation, fibrinolysis and proinflammatory cytokines. The purpose of this study was to correlate plasma markers within these systems and skin pathology.METHOD: A group of twenty consecutive patients with active or recent venous ulcer were matched for sex and age with further three groups of individuals i.e. controls and patients with VV with and without skin changes respectively. Blood samples were analysed for hemoglobin (HB), total platelet count (TPC), C-reactive protein (CRP), activated partial thromboplastin time (APTT), prothrombin complex (PT), fibrinogen, interleukin-1 beta (IL-1 beta), tumor necrosis factor alpha (TNF alpha), D-dimer, tissue plasminogen activator (t-PA), plasminogen activator inhibitor 1 (PAI-1), prothrombin fragments 1 and 2 (F1 + 2), and thrombin antithrombin III complex (TAT).RESULTS AND CONCLUSION: There was an increase of systemic levels of PAI-1 activity and tPA with progressive skin pathology in patients with CVI, and in the group with active ulcer there was an elevation of F1 + 2. Those findings could reflect a defect fibrinolysis, a thrombotic potential or a damaged endothelium.
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| 50. |
- Blomgren, Lena, et al.
(författare)
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Cost consequences or preoperative duplex examination before varicose vein surgery : a randomozed clnical trial
- 2006
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Ingår i: Phlebology. - : SAGE Publications. - 0268-3555 .- 1758-1125. ; 21:2, s. 90-95
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: To investigate the cost consequences of the addition of a duplex scan to the routine clinical examination prior to surgery for varicose veins (VV). Methods: Cost data are based on a prospective study, which randomized 293 VV patients for surgery either with or without a preoperative duplex scan. Costs are collected during a two-year follow-up time and include direct costs for primary surgery and reoperation. Results: The mean cost for the primary operation was SEK 12,827 (E1410) in the duplex group and SEK 9856 (E1083) in the control group (P < 0.001). A significant part of this increase was due to more extensive primary surgery. Costs for redo surgery decreased by SEK 1131 (E124) (P = 0.011). The mean net cost increase because of duplex is estimated to be SEK 1840 (E202) (P < 0.003). Conclusion: The savings in costs for redo surgery did not offset the costs for preoperative duplex examination before VV surgery during a two-year follow-up period.
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