| 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: Wiley Interdisciplinary Reviews. Computational Molecular Science. - : Wiley. - 1759-0876. ; 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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