| 1. |
- Bach, Anders, et al.
(författare)
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A high-affinity, dimeric inhibitor of PSD-95 bivalently interacts with PDZ1-2 and protects against ischemic brain damage
- 2012
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 109:9, s. 3317-3322
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Tidskriftsartikel (refereegranskat)abstract
- Inhibition of the ternary protein complex of the synaptic scaffolding protein postsynaptic density protein-95 (PSD-95), neuronal nitric oxide synthase (nNOS), and the N-methyl-D-aspartate (NMDA) receptor is a potential strategy for treating ischemic brain damage, but high-affinity inhibitors are lacking. Here we report the design and synthesis of a novel dimeric inhibitor, Tat-NPEG4(IETDV)(2) (Tat-N-dimer), which binds the tandem PDZ1-2 domain of PSD-95 with an unprecedented high affinity of 4.6 nM, and displays extensive protease-resistance as evaluated in vitro by stability-measurements in human blood plasma. X-ray crystallography, NMR, and small-angle X-ray scattering (SAXS) deduced a true bivalent interaction between dimeric inhibitor and PDZ1-2, and also provided a dynamic model of the conformational changes of PDZ1-2 induced by the dimeric inhibitor. A single intravenous injection of Tat-N-dimer (3 nmol/g) to mice subjected to focal cerebral ischemia reduces infarct volume with 40% and restores motor functions. Thus, Tat-N-dimer is a highly efficacious neuroprotective agent with therapeutic potential in stroke.
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| 2. |
- Chi, Celestine N., et al.
(författare)
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Deciphering the kinetic binding mechanism of dimeric ligands, using a potent plasma-stable dimeric inhibitor of postsynaptic density protein-95 as an example
- 2010
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Ingår i: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 285:36, s. 28252-28260
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Tidskriftsartikel (refereegranskat)abstract
- Dimeric ligands can be potent inhibitors of protein-protein or enzyme-substrate interactions. They have increased affinity and specificity towards their targets due to their ability to bind simultaneously to two binding sites and are therefore very attractive in drug design. However, few studies have addressed the kinetic mechanism of interaction of such bivalent ligands. We have investigated the binding interaction of a recently identified potent plasma-stable dimeric pentapeptide of PDZ1-2 of PSD-95 using protein engineering in combination with fluorescence polarisation, isothermal titration calorimetry and stopped-flow fluorimetry. Our experiments demonstrate that binding occurs via a two-step process, where an initial binding to either one of the two PDZ domains is followed by an intramolecular step, which produces the bidentate complex. We have determined all rate constants involved in the binding reaction and we also find evidence for a conformational transition of the complex. Our data demonstrate the importance of a slow dissociation for a successful dimeric ligand, but also highlight the possibility of optimizing the intramolecular association rate. The results may therefore aid the design of dimeric inhibitors in general.
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| 3. |
- Aidas, Kestutis, et al.
(författare)
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The Dalton quantum chemistry program system
- 2014
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Ingår i: WIREs Computational Molecular Science. - : Wiley. - 1759-0876 .- 1759-0884. ; 4:3, s. 269-284
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Tidskriftsartikel (refereegranskat)abstract
- Dalton is a powerful general-purpose program system for the study of molecular electronic structure at the Hartree-Fock, Kohn-Sham, multiconfigurational self-consistent-field, MOller-Plesset, configuration-interaction, and coupled-cluster levels of theory. Apart from the total energy, a wide variety of molecular properties may be calculated using these electronic-structure models. Molecular gradients and Hessians are available for geometry optimizations, molecular dynamics, and vibrational studies, whereas magnetic resonance and optical activity can be studied in a gauge-origin-invariant manner. Frequency-dependent molecular properties can be calculated using linear, quadratic, and cubic response theory. A large number of singlet and triplet perturbation operators are available for the study of one-, two-, and three-photon processes. Environmental effects may be included using various dielectric-medium and quantum-mechanics/molecular-mechanics models. Large molecules may be studied using linear-scaling and massively parallel algorithms. Dalton is distributed at no cost from for a number of UNIX platforms.
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| 4. |
- Björck, Inger, et al.
(författare)
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Cereal grains for nutrition and health benefits: Overview of results from in vitro, animal and human studies in the HEALTHGRAIN project
- 2012
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Ingår i: Trends in Food Science & Technology. - : Elsevier BV. - 1879-3053 .- 0924-2244. ; 25:2, s. 87-100
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Tidskriftsartikel (refereegranskat)abstract
- Epidemiological studies have linked whole grain intake to the prevention of the metabolic syndrome, obesity and associated chronic diseases such as CVD and T2D. The Nutrition module within the HEALTHGRAIN project, included 10 partners and undertook in vitro, animal and humanin vivo studies with the overall aims of elucidating the components and mechanisms underlying the health benefits of cereal grains. This review summarises the major outcomes of these studies, including yet unpublished findings.
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| 5. |
- Campos, Paula F., et al.
(författare)
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Ancient DNA sequences point to a large loss of mitochondrial genetic diversity in the saiga antelope (Saiga tatarica) since the Pleistocene
- 2010
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Ingår i: Molecular Ecology. - 0962-1083 .- 1365-294X. ; 19:22, s. 4863-4875
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Tidskriftsartikel (refereegranskat)abstract
- Prior to the Holocene, the range of the saiga antelope (Saiga tatarica) spanned from France to the Northwest Territories of Canada. Although its distribution subsequently contracted to the steppes of Central Asia, historical records indicate that it remained extremely abundant until the end of the Soviet Union, after which its populations were reduced by over 95%. We have analysed the mitochondrial control region sequence variation of 27 ancient and 38 modern specimens, to assay how the species' genetic diversity has changed since the Pleistocene. Phylogenetic analyses reveal the existence of two well-supported, and clearly distinct, clades of saiga. The first, spanning a time range from >49 500 C-14 ybp to the present, comprises all the modern specimens and ancient samples from the Northern Urals, Middle Urals and Northeast Yakutia. The second clade is exclusive to the Northern Urals and includes samples dating from between 40 400 to 10 250 C-14 ybp. Current genetic diversity is much lower than that present during the Pleistocene, an observation that data modelling using serial coalescent indicates cannot be explained by genetic drift in a population of constant size. Approximate Bayesian Computation analyses show the observed data is more compatible with a drastic population size reduction (c. 66-77%) following either a demographic bottleneck in the course of the Holocene or late Pleistocene, or a geographic fragmentation (followed by local extinction of one subpopulation) at the Holocene/Pleistocene transition.
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| 6. |
- Dengjel, Joern, et al.
(författare)
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Identification of Autophagosome-associated Proteins and Regulators by Quantitative Proteomic Analysis and Genetic Screens
- 2012
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Ingår i: Molecular & Cellular Proteomics. - 1535-9476 .- 1535-9484. ; 11:3
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Tidskriftsartikel (refereegranskat)abstract
- Autophagy is one of the major intracellular catabolic pathways, but little is known about the composition of autophagosomes. To study the associated proteins, we isolated autophagosomes from human breast cancer cells using two different biochemical methods and three stimulus types: amino acid deprivation or rapamycin or concanamycin A treatment. The autophagosome- associated proteins were dependent on stimulus, but a core set of proteins was stimulus- independent. Remarkably, proteasomal proteins were abundant among the stimulus- independent common autophagosome- associated proteins, and the activation of autophagy significantly decreased the cellular proteasome level and activity supporting interplay between the two degradation pathways. A screen of yeast strains defective in the orthologs of the human genes encoding for a common set of autophagosome- associated proteins revealed several regulators of autophagy, including subunits of the retromer complex. The combined spatiotemporal proteomic and genetic data sets presented here provide a basis for further characterization of autophagosome biogenesis and cargo selection.
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| 7. |
- Gülfe, Anders, et al.
(författare)
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Efficacy and drug survival of anti-tumour necrosis factor-alpha therapies in patients with non-radiographic axial spondyloarthritis: an observational cohort study from Southern Sweden.
- 2014
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Ingår i: Scandinavian Journal of Rheumatology. - : Informa UK Limited. - 1502-7732 .- 0300-9742. ; 43:6, s. 493-497
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: To evaluate the efficacy and drug survival of anti-tumour necrosis factor (anti-TNF) therapy in non-radiographic axial spondyloarthritis (nr-axSpA) patients treated in clinical practice in Southern Sweden. Method: In this cohort study we prospectively included 112 patients with nr-axSpA and high disease activity as well as inadequate response or intolerance to non-steroidal anti-inflammatory drugs (NSAIDs) receiving their first course of anti-TNF therapy. Patients fulfilling modified New York criteria for ankylosing spondylitis (AS) were excluded. The Assessment of SpondyloArthritis International Society (ASAS) criteria for axial SpA were fulfilled by 77% (n = 86) of the included patients. Results: At baseline, the median age of the cohort was 38 years, 59% were males, 79% of the patients had imaging suggestive of sacroiliitis (primarily inflammation on magnetic resonance imaging, MRI), 71% were HLA-B27 positive, and the median disease duration was 6 years and 10 months. At 6 months of follow-up, the median Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) decreased from 5.6 to 3.2 (p = 0.002), the Bath Ankylosing Spondylitis Functional Index (BASFI) decreased from 3.9 to 1.8 (p = 0.005), and C-reactive protein (CRP) level decreased from 4.4 to 1.7 mg/L (p = 0.001). After 1 year of treatment the Kaplan-Meier estimated drug survival was 76%, and at 2 years of follow-up this value decreased to 65%. Patients with inflammatory MRI findings at baseline had significantly better drug survival [hazard ratio (HR) 0.24, 95% confidence interval (CI) 0.10-0.55, p = 0.001]. Male sex was also associated with higher drug survival (HR 0.45, 95% CI 0.24-0.85, p = 0.011). CRP level at baseline was not associated with drug survival. Conclusions: Anti-TNF treatment of patients with nr-axSpA in clinical practice resulted in reduced BASDAI and BASFI scores and good drug survival. The results from this study suggest that male gender and positive imaging at baseline are associated with a favourable treatment course.
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| 8. |
- Gülfe, Anders, et al.
(författare)
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Rapid and sustained health utility gain in anti-TNF treated inflammatory arthritis. Observational data during seven years in southern Sweden.
- 2010
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 69:2, s. 352-357
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Rheumatoid arthritis (RA), psoriatic arthritis (PsA), and other spondylarthritides (SpA) impose great impact on the individual in addition to the costs on society, which may be reduced by effective pharmacological treatment. Industry independent health economic studies should complement studies sponsored by industry. OBJECTIVE: To study secular trends in baseline health utilities in patients commencing TNF blockade for arthritis in clinical practice over 7 years; to address utility changes during treatment; to investigate the influence of previous treatment courses; to study the feasibility of health utility measures, and to compare them across diagnostic entities. METHODS: /B> EuroQoL 5 Dimensions (EQ-5D) utility data were collected from a structured clinical follow-up program of anti-TNF treated patients with RA (N=2554), PsA (N=574) or SpA (N=586). Time trends were calculated. Completer analysis was used. RESULTS: /B> There were weak or non-significant secular trends for increasing baseline utilities over time for RA, PsA and SpA. Maximum gain in utilities occurred already after 2 weeks for all diagnoses and remained stable for patients remaining on therapy. First and second anti-TNF courses performed similarly. CONCLUSIONS: Utilities at inclusion remained largely unchanged for RA, PsA and SpA over 7 years. Improvement occurred early during treatment and not beyond 6 weeks at the group level. Improvement during the first course was not consistently greater than the second. There were no major differences between RA, PsA and SpA. EQ-5D proved feasible and applicable across these diagnoses. These "real world" data may be useful for health economic modelling.
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| 9. |
- Gülfe, Anders, et al.
(författare)
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Utility-based outcomes made easy: The number needed per QALY gained (NNQ). Observational cohort study from Southern Sweden of TNF blockade in inflammatory arthritis.
- 2010
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Ingår i: Arthritis Care and Research. - : Wiley. - 2151-4658 .- 2151-464X. ; 62:10, s. 1399-1406
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE.: To introduce a novel, simple, utility based outcome measure, the Number Needed per Quality adjusted life year (QALY) gained (NNQ), and to apply it in clinical practice in anti-TNF treated patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), and spondylarthritis (SpA). METHODS.: The NNQ is the number of patients one has to treat in order to gain 1 QALY. It is calculated as the inverted value of the utility gain (area under curve) over 1 year in a cohort subjected to an intervention. EuroQoL-5-dimensions (EQ-5D) utility data from the South Swedish Arthritis Treatment Register was used. RESULTS.: 1001 RA, 241 PsA, and 255 SpA patients were eligible for the study. First, 2(nd) and 3(rd) treatment courses were studied. For RA, NNQ was 4.5, 6.4 and 5.2 for 1(st), 2(nd) and 3(rd) courses, respectively. For PsA and SpA, NNQ was 4.2-4.5 irrespective of treatment order. Treatment groups with N<50 were not analysed. During the study period 2002-2007, there were no secular trends of utility gains. CONCLUSION.: The NNQ is an easily derived and understandable, utility based outcome measure that may be useful for stakeholders, decision makers as well as for clinicians. It was readily applied in this study of TNF blockade across 3 arthritis diagnoses. NNQ varied little over diagnoses and treatment course order, with a possible exception in 2(nd) treatment course in RA.
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| 10. |
- Karlsson, Johan, et al.
(författare)
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National EQ-5D tariffs and quality-adjusted life-year estimation: comparison of UK, US and Danish utilities in south Swedish rheumatoid arthritis patients.
- 2011
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 70, s. 2163-2166
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To study how the choice of national EQ-5D tariff may affect utility and incremental quality-adjusted life-year (QALY) estimates. METHODS: South Swedish rheumatoid arthritis patients in an observational study, starting and continuing anti-tumour necrosis factor (TNF) monotherapy (n=54) or anti-TNF plus methotrexate (n=215) for 1 year during May 2002 to April 2009, were included. EQ-5D questionnaires were completed at baseline, 3, 6 and 12 months. Utilities and accumulated QALY were compared using the UK, US and Danish EQ-5D tariffs. Utilities for all 243 possible EQ-5D health states were also compared. RESULTS: US utilities were generally higher than UK, with Danish falling in between. A substantial 1-year mean utility improvement was seen in both study groups using all tariffs (UK 0.28 vs 0.29; US 0.18 vs 0.19; Danish 0.20 vs 0.22). Adjusting for baseline differences between groups, the incremental QALY gain of combined treatment was 0.09 using the UK tariff, while 0.06 according to both US and Danish tariffs. Inter-tariff disagreement in utility and accumulated QALY varied irregularly across the range of utilities. CONCLUSIONS: Applying different national EQ-5D tariffs to the same data may result in substantially different incremental QALY estimates, crucial knowledge when interpreting cost-utility analyses. Studies using different tariffs cannot be directly compared.
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| 11. |
- Kjaergaard, Benedict, et al.
(författare)
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Low plasma potassium in deep hypothermic cardiac arrest indicates that cardiac arrest is secondary to hypothermia : a porcine study
- 2010
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Ingår i: European journal of emergency medicine. - 0969-9546 .- 1473-5695. ; 17:3, s. 131-135
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: In accidental hypothermia, normal signs of death are unreliable. It is generally accepted that a lifeless person is beyond the limits of rescue if plasma potassium (P-potassium) is higher than10 mmol/l. However, the rate of increase in potassium or in other markers after cardiac arrest has not been carefully studied in hypothermic individuals. The aim of this animal study was to assess biochemical changes after anoxic circulatory arrest at hypothermia and at normothermia followed by external cooling. METHODS: Five pigs were treated with heparin and extracorporeal circulation and cooled to 20 degrees C (primary hypothermia group). The animals were weaned from extracorporeal circulation, suffered cardiac arrest, and were cooled externally with ice to mimic victims found in a cold environment. With the use of intermittent external cardiac compressions mixing the blood, arterial P-potassium was followed after cardiac arrest until the level exceeded 10 mmol/l. Another group of five pigs (anoxic cardiac arrest group) were treated with heparin and killed by anoxia at normothermia and were thereafter treated and followed similarly to the primary hypothermia group. RESULTS: In primary hypothermia P-potassium exceeded 10 mmol/l after median 3.5 h, whereas in anoxic cardiac arrest P-potassium exceeded 10 mmol/l after median 1 h. CONCLUSION: This study shows that if cardiac arrest occurs before hypothermia is established, P-potassium increases quickly in contrast to the situation when hypothermia induces cardiac arrest. Thus, a low P-potassium in a hypothermic individual with cardiac arrest indicates that cardiac arrest occurred recently or was secondary to the hypothermic event.
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| 12. |
- Kristensen, Lars Erik, et al.
(författare)
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Is Swollen to Tender Joint Count Ratio a New and Useful Clinical Marker for Biologic Drug Response in Rheumatoid Arthritis? Results From a Swedish Cohort
- 2014
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Ingår i: Arthritis Care and Research. - : Wiley. - 2151-4658 .- 2151-464X. ; 66:2, s. 173-179
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Tidskriftsartikel (refereegranskat)abstract
- ObjectiveTo study the impact of swollen to tender joint count ratio (STR) and other baseline characteristics on treatment response to a first course of anti-tumor necrosis factor (anti-TNF) therapy in rheumatoid arthritis (RA) patients. MethodsPatients with RA initiating their first course of anti-TNF treatment were included in a structured clinical followup protocol. Based on pragmatic thresholds and plausibility, patients were categorized as having low (STR <0.5), moderate (0.5 STR 1.0), or high (STR >1.0) joint count ratios. The data were collected and followed during the period of March 1999 through December 2010. ResultsA total of 2,507 patients were included in the study (median age 56 years, 78% women). Of these patients, 344 (14%) had a low STR, 1,180 (47%) had a moderate STR, and 983 (39%) had a high STR. According to these STR thresholds, 23% of patients (95% confidence interval [95% CI] 18-29%) with low, 39% (95% CI 35-43%) with moderate, and 40% (95% CI 36-44%) with high STR achieved the American College of Rheumatology criteria for 50% improvement (ACR50) response at 6 months after initiation. Correlation tests showed that STR was associated with ACR50 response independent of both swollen and tender joint counts. Logistic regression analysis consistently showed that moderate STR, high STR, not using prednisolone, high baseline Disease Activity Score in 28 joints, and low baseline Health Assessment Questionnaire scores were significantly associated with favorable ACR50 response with odds ratios of 1.93 (P < 0.01), 2.82 (P < 0.01), 0.65 (P < 0.01), 1.49 (P < 0.01), and 0.47 (P < 0.01), respectively. ConclusionSTR is a new and feasible predictor of treatment response in RA. RA patients with a moderate to high STR have a 2- to 3-fold increased likelihood of responding according to ACR50 criteria.
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| 13. |
- Ladenson, Paul W, et al.
(författare)
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Use of the Thyroid Hormone Analogue Eprotirome in Statin-Treated Dyslipidemia
- 2010
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Ingår i: NEW ENGLAND JOURNAL OF MEDICINE. - 0028-4793 .- 1533-4406. ; 362:10, s. 906-916
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND Dyslipidemia increases the risk of atherosclerotic cardiovascular disease and is incompletely reversed by statin therapy alone in many patients. Thyroid hormone lowers levels of serum low-density lipoprotein (LDL) cholesterol and has other potentially favorable actions on lipoprotein metabolism. Consequently, thyromimetic drugs hold promise as lipid-lowering agents if adverse effects can be avoided. METHODS We performed a randomized, placebo-controlled, double-blind, multicenter trial to assess the safety and efficacy of the thyromimetic compound eprotirome (KB2115) in lowering the level of serum LDL cholesterol in patients with hypercholesterolemia who were already receiving simvastatin or atorvastatin. In addition to statin treatment, patients received either eprotirome (at a dose of 25, 50, or 100 mu g per day) or placebo. Secondary outcomes were changes in levels of serum apolipoprotein B, triglycerides, and Lp(a) lipoprotein. Patients were monitored for potential adverse thyromimetic effects on the heart, bone, and pituitary. RESULTS The addition of placebo or eprotirome at a dose of 25, 50, or 100 mu g daily to statin treatment for 12 weeks reduced the mean level of serum LDL cholesterol from 141 mg per deciliter (3.6 mmol per liter) to 127, 113, 99, and 94 mg per deciliter (3.3, 2.9, 2.6, and 2.4 mmol per liter), respectively, (mean reduction from baseline, 7%, 22%, 28%, and 32%). Similar reductions were seen in levels of serum apolipoprotein B, triglycerides, and Lp(a) lipoprotein. Eprotirome therapy was not associated with adverse effects on the heart or bone. No change in levels of serum thyrotropin or triiodothyronine was detected, although the thyroxine level decreased in patients receiving eprotirome. CONCLUSIONS In this 12-week trial, the thyroid hormone analogue eprotirome was associated with decreases in levels of atherogenic lipoproteins in patients receiving treatment with statins.
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| 14. |
- Ladenson, Paul W, et al.
(författare)
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Use of the Thyroid Hormone Analogue Eprotirome in Statin-Treated Dyslipidemia
- 2010
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Ingår i: Obstetrical and Gynecological Survey. - : Lippincott Williams & Wilkins. - 0029-7828 .- 1533-9866. ; 65:8, s. 512-513
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Statins effectively reduce levels of serum cholesterol and lower the risk of cardiovascular disease, but have limited effectiveness if stringent goals for serum low-density lipoprotein (LDL) cholesterol levels are not met or adverse effects develop, requiring a dose reduction or drug discontinuation. Previous studies have shown that thyroid hormone and some of its metabolites reduce levels of serum LDL cholesterol and have potentially favorable actions on other lipoproteins. The studies were discontinued because of reports of adverse effects on heart and bone, and possible deaths. In a recent report, eprotirome, a thyromimetic compound with minimal uptake in nonhepatic-tissues, was shown to reduce levels of serum total and LDL cholesterol and apolipoprotein B without apparent side effects in patients not receiving statin therapy. This randomized, placebo-controlled, double-blind, multicenter trial investigated the safety and efficacy of eprotirome in lowering the level of serum LDL cholesterol in patients with hypercholesterolemia who already were receiving simvastatin or atorvastatin. The aim of the study was to determine whether adding eprotirome to statin therapy would provide additional lipid-lowering actions without producing adverse extrahepatic thyromimetic effects. Patients were randomly assigned to receive daily oral doses of 25, 50, or 100 mcg of eprotirome or a placebo for 12 weeks. The primary study outcome was changes in serum LDL cholesterol. The potential adverse thyromimetic effects on the heart, bone, and pituitary were examined. Treatment of patients for 12 weeks already receiving statins with either placebo or eprotirome at a dose of 25, 50, or 100 mu g reduced the mean level of serum LDL cholesterol from 141 mg per deciliter (3.6 mmol per liter) at baseline to 127, 113, 99, and 94 mg per deciliter (3.3, 2.9, 2.6, and 2.4 mmol per liter), respectively; this represented a mean reduction from baseline of 7%, 22%, 28%, and 32%, respectively. Similar reductions were found in the secondary study outcomes, which included serum levels of apolipoprotein B, triglycerides, and Lp(a) lipoprotein. No evidence of adverse effects of eprotirome on the heart, bone, or pituitary was noted. Although reductions in serum levels of thyroxine occurred in some patients who received eprotirome, there were no changes in levels of thyrotropin or triiodothyronine. These findings demonstrate that the addition of eprotirome to statin therapy produces substantial further reductions in serum LDL cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein B. The drug appears to have an excellent safety profile.
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| 15. |
- Liljefors, Max, et al.
(författare)
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Atrocity Media: Negotiating the Abject in Images of Torture and Death
- 2013
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Ingår i: Transvisuality: the Cultural Dimension of Visuality. Volume 1: Boundaries and Creative Openings. - 9781846318917 ; , s. 185-206
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Bokkapitel (refereegranskat)abstract
- This essay discusses the dissemination of atrocity images in contemporary mass media, from the photographs of mass-graves in the Nazi concentration camps to the pictures of torture of Iraqi prisoners in Abu Ghraib. The central question is one of distances: the distance between the image and the event, between the picture and the beholder, and between the destroyed human body and the cultural forms through which it is represented. These distances, their upholding and overcoming, are analyzed through the works of three visual artists that have dealt with atrocity imagery in their art: in 1945, an Italian artist encountering the Nazi camps in 1945; a Holocaust survivor merging mass-grave photographs with pornography in the 1960s; and in 2002, a Taiwanese video artist re-enacting a century-old photograph of Chinese torture. The article interprets these artworks as reflecting processes of abjection at work in the mediatization of atrocities throughout late modern society. Julia Kristeva's theory of the abject underpins the argument, that the media, while bringing atrocities to the public’s attention, also establish a reassuring distance to the scenes of atrocity, and enthrall the viewer in a fascination with the images themselves. In the end, this tension between distance and proximity may open for critical reflection and political action.
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| 16. |
- Malm, Jan, et al.
(författare)
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Implementation of a new CSF dynamic device: a multicenter feasibility study in 562 patients
- 2012
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Ingår i: Acta Neurologica Scandinavica. - : John Wiley and Sons. - 0001-6314 .- 1600-0404. ; 125:3, s. 199-205
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Tidskriftsartikel (refereegranskat)abstract
- Objectives - The cerebrospinal fluid (CSF) infusion test is frequently used when selecting hydrocephalus patients for shunt surgery. Very little has been reported regarding adverse events. We present a prospective feasibility study. Methods -Standardized devices for measuring CSF dynamics were built and 562 patients investigated: Needles were placed by lumbar puncture (LP). An automatic CSF infusion protocol was performed. Course of events during the investigation as well as adverse events were registered. Results Preoperative evaluation of normal-pressure hydrocephalus was the most common indication (63%), followed by evaluation of shunt function (23%) and intracranial pressure recordings (14%). The LP was successfully performed in all but nine cases with 24 patients (4.3%) reporting major discomfort. Ringer infusion was performed in 474 investigations, and a valid measurement of the outflow resistance was received in 439 (93%). During the infusion phase, 17 (4%) patients reported severe headache. Infusion volume was significantly higher in patients having subjective symptoms during the infusion phase compared with those without adverse events. During 269 preoperative CSF tap tests, six (2%) patients had severe headache. Postinvestigational headache was reported by 83 (15%) patients at the 24-h follow-up. No serious adverse events were observed. Conclusion Infusion testing was safe and without serious adverse events with a high rate of successful procedures. The investigation was associated with expected mild to moderate discomfort.
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| 17. |
- Muggerud, Aslaug Aa, et al.
(författare)
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Frequent aberrant DNA methylation of ABCB1, FOXC1, PPP2R2B and PTEN in ductal carcinoma in situ and early invasive breast cancer
- 2010
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Ingår i: Breast Cancer Research. - : Springer Science and Business Media LLC. - 1465-5411 .- 1465-542X. ; 12:1, s. R3-
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Ductal carcinoma in situ (DCIS) is a non-invasive lesion of the breast that is frequently detected by mammography and subsequently removed by surgery. However, it is estimated that about half of the detected lesions would never have progressed into invasive cancer. Identifying DCIS and invasive cancer specific epigenetic lesions and understanding how these epigenetic changes are involved in triggering tumour progression is important for a better understanding of which lesions are at risk of becoming invasive. METHODS: Quantitative DNA methylation analysis of ABCB1, CDKN2A/p16INK4a, ESR1, FOXC1, GSTP1, IGF2, MGMT, MLH1, PPP2R2B, PTEN and RASSF1A was performed by pyrosequencing in a series of 27 pure DCIS, 28 small invasive ductal carcinomas (IDCs), 34 IDCs with a DCIS component and 5 normal breast tissue samples. FOXC1, ABCB1, PPP2R2B and PTEN were analyzed in 23 additional normal breast tissue samples. Real-Time PCR expression analysis was performed for FOXC1. RESULTS: Aberrant DNA methylation was observed in all three diagnosis groups for the following genes: ABCB1, FOXC1, GSTP1, MGMT, MLH1, PPP2R2B, PTEN and RASSF1A. For most of these genes, methylation was already present at the DCIS level with the same frequency as within IDCs. For FOXC1 significant differences in methylation levels were observed between normal breast tissue and invasive tumours (P < 0.001). The average DNA methylation levels were significantly higher in the pure IDCs and IDCs with DCIS compared to pure DCIS (P = 0.007 and P = 0.001, respectively). Real-time PCR analysis of FOXC1 expression from 25 DCIS, 23 IDCs and 28 normal tissue samples showed lower gene expression levels of FOXC1 in both methylated and unmethylated tumours compared to normal tissue (P < 0.001). DNA methylation levels of FOXC1, GSTP1, ABCB1 and RASSF1A were higher in oestrogen receptor (ER) positive vs. ER negative tumours; whereas methylation levels of FOXC1, ABCB1, PPP2R2B and PTEN were lower in tumours with a TP53 mutation. CONCLUSIONS: Quantitative methylation analysis identified ABCB1, FOXC1, PPP2R2B and PTEN as novel genes to be methylated in DCIS. In particular, FOXC1 showed a significant increase in the methylation frequency in invasive tumours. Low FOXC1 gene expression in both methylated and unmethylated DCIS and IDCs indicates that the loss of its expression is an early event during breast cancer progression.
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| 18. |
- Pedersen, Soren W., et al.
(författare)
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Probing backbone hydrogen bonding in PDZ/ligand interactions by protein amide-to-ester mutations
- 2014
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 5, s. 3215-
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Tidskriftsartikel (refereegranskat)abstract
- PDZ domains are scaffolding modules in protein-protein interactions that mediate numerous physiological functions by interacting canonically with the C-terminus or non-canonically with an internal motif of protein ligands. A conserved carboxylate-binding site in the PDZ domain facilitates binding via backbone hydrogen bonds; however, little is known about the role of these hydrogen bonds due to experimental challenges with backbone mutations. Here we address this interaction by generating semisynthetic PDZ domains containing backbone amide-to-ester mutations and evaluating the importance of individual hydrogen bonds for ligand binding. We observe substantial and differential effects upon amide-to-ester mutation in PDZ2 of postsynaptic density protein 95 and other PDZ domains, suggesting that hydrogen bonding at the carboxylate-binding site contributes to both affinity and selectivity. In particular, the hydrogen-bonding pattern is surprisingly different between the non-canonical and canonical interaction. Our data provide a detailed understanding of the role of hydrogen bonds in protein-protein interactions.
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| 19. |
- Persson, Fredrik, 1979, et al.
(författare)
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Local conformation of confined DNA studied using emission polarization anisotropy
- 2010
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Ingår i: Biophysical Society 54th Annual Meeting.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- When confined in nanochannels with dimensions smaller than the DNA radius of gyration, DNA will extend along the channel. We investigate long DNA confined in nanochannels, using fluorescence microscopy and intercalated dyes. Studies of the dynamics and statics of DNA in such nanoscale confinements as a function of e.g. degree of confinement and ionic strength have yielded new insights into the physical properties of DNA with relevance for applications in genomics as well as fundamental understanding of DNA packaging in vivo. Our work extends the field by not only studying the location of the emitting dyes along a confined DNA molecule but also monitoring the polarization of the emitted light. By measuring the emission polarized parallel and perpendicular to the extension axis of the stretched DNA, information on the local spatial distribution of the DNA backbone can be obtained. Comparing polarizations in two directions for DNA confined in channels of effective diameters of 85 nm and 170 nm reveals a striking difference. Whereas the DNA in the larger channels shows an isotropic polarization of the emitted light, the light is to a large extent polarized perpendicular to the elongation of the DNA in the smaller channels. We expect this technique to have a large impact on the studies of changes in DNA conformation induced by protein binding or during DNA compactation as well as in fundamental polymer physics studies of DNA in confined environments, for example in bacterial spores and viruses.
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| 20. |
- Persson, Fredrik, 1979, et al.
(författare)
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Local conformation of confined DNA studied using emission polarization anisotropy
- 2010
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Ingår i: NanoBioTech-Montreux 2009.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- In nanochannels with dimensions smaller than the DNA radius of gyration, DNA will extend along the channel. We investigate long DNA confined in nanochannels using fluorescence microscopy and intercalated dyes. Studies of the dynamics and statics of the DNA extension or position in such nanoscale confinements as a function of e.g. DNA contour length, degree and shape of confinement as well as ionic strength have yielded new insights in the physical properties of DNA with relevance for applications in genomics as well as fundamental understanding of DNA packaging in vivo. Our work extends the field by not only studying the location of the emitting dyes along a confined DNA molecule but also monitoring the polarization of the emitted light. We use intercalating dyes (YOYO-1) whose emission is polarized perpendicular to the DNA extension axis, and by measuring the emission polarized parallel and perpendicular to the extension axis of the stretched DNA, information on the local spatial distribution of the DNA backbone can be obtained. The results obtained are analogous to linear dichroism (LD) but on a single-molecule level, and obtained in a highly parallel fashion. We will discuss results in shallow (60 nm) and deep (180 nm) channels and describe an example of how the technique can be used to investigate non-uniform stretching of DNA on the single molecule level. Comparing polarizations in two directions for DNA confined in channels of effective diameters of 85 nm and 170 nm reveals a striking difference. Whereas the DNA in the larger channels shows an isotropic polarization of the emitted light, the light is to a large extent polarized perpendicular to the elongation of the DNA in the smaller channels. The ratio of the polarization parallel and perpendicular to the elongation direction, I|| / I⊥, is a measure of the relative local orientation of the DNA backbone. We believe that this technique will have a large impact on the studies of changes in DNA conformation induced by protein binding or during DNA compactation as well as in fundamental polymer physics studies of DNA in confined environments, for example in bacterial spores and viruses.
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| 21. |
- Reisner, Walter, et al.
(författare)
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Single-molecule denaturation mapping of DNA in nanofluidic channels
- 2010
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Ingår i: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 107:30, s. 13294-13299
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Tidskriftsartikel (refereegranskat)abstract
- Here we explore the potential power of denaturation mapping as a single-molecule technique. By partially denaturing YOYO (R)-1-labeled DNA in nanofluidic channels with a combination of formamide and local heating, we obtain a sequence-dependent "barcode" corresponding to a series of local dips and peaks in the intensity trace along the extended molecule. We demonstrate that this structure arises from the physics of local denaturation: statistical mechanical calculations of sequence-dependent melting probability can predict the barcode to be observed experimentally for a given sequence. Consequently, the technique is sensitive to sequence variation without requiring enzymatic labeling or a restriction step. This technique may serve as the basis for a new mapping technology ideally suited for investigating the long-range structure of entire genomes extracted from single cells.
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| 22. |
- Thorup, Kasper, et al.
(författare)
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Timing of songbird migration: individual consistency within and between seasons
- 2013
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Ingår i: Journal of Avian Biology. - 0908-8857. ; 44:5, s. 486-494
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Tidskriftsartikel (refereegranskat)abstract
- The timing of migration is generally considered of utmost importance for reproduction and survival, and timing is furthermore considered to be under strong genetic control. The individual timing of migration is presumably a result of a combination of genetic, phenotypic and environmental factors as well as some degree of randomness. However, potential differences in consistency of timing between spring and autumn and between migration strategies are not well studied. Using long-term Danish ringing data, we study such differences by correlating date of ringing with date of recaptures for a suite of common migrating passerines in Denmark. We found that individuals marked early in one year tended to be recaptured early in the same season in a following year indicating that individuals time their migration in spring or autumn similarly between years. The relationship between spring and autumn migration was overall slightly negative, suggesting that birds arriving early in spring tended to depart late in autumn and vice versa. There were only weak effects of geographical location on timing, suggesting that the patterns found are not primarily caused by different populations being involved. Knowledge of individual consistency in migration timing is needed for understanding changes in migration timing. The consistent patterns of repeatabilities within and between seasons found here highlight the importance of timing of migration in songbirds.
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| 23. |
- Tottrup, Anders P., et al.
(författare)
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The annual cycle of a trans-equatorial Eurasian-African passerine migrant: different spatio-temporal strategies for autumn and spring migration
- 2012
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Ingår i: Royal Society of London. Proceedings B. Biological Sciences. - : The Royal Society. - 1471-2954. ; 279:1730, s. 1008-1016
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Tidskriftsartikel (refereegranskat)abstract
- The small size of the billions of migrating songbirds commuting between temperate breeding sites and the tropics has long prevented the study of the largest part of their annual cycle outside the breeding grounds. Using light-level loggers (geolocators), we recorded the entire annual migratory cycle of the red-backed shrike Lanius collurio, a trans-equatorial Eurasian-African passerine migrant. We tested differences between autumn and spring migration for nine individuals. Duration of migration between breeding and winter sites was significantly longer in autumn (average 96 days) when compared with spring (63 days). This difference was explained by much longer staging periods during autumn (71 days) than spring (9 days). Between staging periods, the birds travelled faster during autumn (356 km d(-1)) than during spring (233 km d(-1)). All birds made a protracted stop (53 days) in Sahelian sub-Sahara on southbound migration. The birds performed a distinct loop migration (22 000 km) where spring distance, including a detour across the Arabian Peninsula, exceeded the autumn distance by 22 per cent. Geographical scatter between routes was particularly narrow in spring, with navigational convergence towards the crossing point from Africa to the Arabian Peninsula. Temporal variation between individuals was relatively constant, while different individuals tended to be consistently early or late at different departure/arrival occasions during the annual cycle. These results demonstrate the existence of fundamentally different spatio-temporal migration strategies used by the birds during autumn and spring migration, and that songbirds may rely on distinct staging areas for completion of their annual cycle, suggesting more sophisticated endogenous control mechanisms than merely clockand-compass guidance among terrestrial solitary migrants. After a century with metal-ringing, year-round tracking of long-distance migratory songbirds promises further insights into bird migration.
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| 24. |
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| 25. |
- Westerlund, Fredrik, 1978, et al.
(författare)
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Fluorescence Enhancement From Single DNA Molecules Confined In Si/SiO2 Nanochannels
- 2010
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Ingår i: Biophysical Society, 54th Annual Meeting.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- A large challenge in biophysics when studying single molecules using fluorescence microscopy is to obtain a signal that is clearly detectable above the background noise. Ways to improve or optimize the fluorescence signal is therefore of great interest. We here study DNA extended in 320 nm deep funnel-shaped SiO2 nanochannels with a width ranging from 40nm to 600nm. The DNA is stained with a fluorescent dye (YOYO-1) and we show that the total emission from the DNA varies significantly with the dimensions of the channels (Figure) and has a peak intensity at half the wavelength of the emitted light. Measurements at varying salt concentrations, where the same confinement leads to different extension of the DNA, confirm that it is solely the geometry of the channel that governs the enhancement effect, ruling out alternative explanations, such as self-quenching. By using polarizers on the emission side we can investigate the light polarized parallel and perpendicular to the channel separately and we see that they show vastly different behavior with the peak in emission only detected in the light polarized parallel to the channels. We will discuss how our data may be explained by cavity-resonance effects when the lateral dimensions of the channels coincide with half the wavelength of the emitted light. Our results suggest that it is possible to fine-tune the size and shape of the nanochannels to maximize the number of photons collected from the molecule under study, for example when studying DNA interacting with single DNA-binding proteins where maximizing the photon budget is paramount.
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| 26. |
- Westerlund, Fredrik, 1978, et al.
(författare)
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Fluorescence Enhancement of Single DNA Molecules Confined in Si/SiO2 Nanochannels
- 2010
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Ingår i: Lab on a Chip. - : Royal Society of Chemistry (RSC). - 1473-0197 .- 1473-0189. ; 10:16, s. 2049-2051
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Tidskriftsartikel (refereegranskat)abstract
- We demonstrate that the detected emission intensity from YOYO- labeled DNA molecules confined in 180 nm deep Si/SiO2 nano- funnels changes significantly and not monotonically with the width of the funnel. This effect may be of importance for quantitative fluorescence microscopy and for experiments with a tight photon budget.
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