| 1. |
- Romanelli, F, et al.
(author)
-
Overview of the JET results
- 2011
-
In: Nuclear Fusion. - : IOP Publishing. - 1741-4326 .- 0029-5515. ; 51:9
-
Journal article (peer-reviewed)abstract
- Since the last IAEA Conference JET has been in operation for one year with a programmatic focus on the qualification of ITER operating scenarios, the consolidation of ITER design choices and preparation for plasma operation with the ITER-like wall presently being installed in JET. Good progress has been achieved, including stationary ELMy H-mode operation at 4.5 MA. The high confinement hybrid scenario has been extended to high triangularity, lower ρ*and to pulse lengths comparable to the resistive time. The steady-state scenario has also been extended to lower ρ*and ν*and optimized to simultaneously achieve, under stationary conditions, ITER-like values of all other relevant normalized parameters. A dedicated helium campaign has allowed key aspects of plasma control and H-mode operation for the ITER non-activated phase to be evaluated. Effective sawtooth control by fast ions has been demonstrated with3He minority ICRH, a scenario with negligible minority current drive. Edge localized mode (ELM) control studies using external n = 1 and n = 2 perturbation fields have found a resonance effect in ELM frequency for specific q95values. Complete ELM suppression has, however, not been observed, even with an edge Chirikov parameter larger than 1. Pellet ELM pacing has been demonstrated and the minimum pellet size needed to trigger an ELM has been estimated. For both natural and mitigated ELMs a broadening of the divertor ELM-wetted area with increasing ELM size has been found. In disruption studies with massive gas injection up to 50% of the thermal energy could be radiated before, and 20% during, the thermal quench. Halo currents could be reduced by 60% and, using argon/deuterium and neon/deuterium gas mixtures, runaway electron generation could be avoided. Most objectives of the ITER-like ICRH antenna have been demonstrated; matching with closely packed straps, ELM resilience, scattering matrix arc detection and operation at high power density (6.2 MW m-2) and antenna strap voltages (42 kV). Coupling measurements are in very good agreement with TOPICA modelling. © 2011 IAEA, Vienna.
|
|
| 2. |
- Abel, I, et al.
(author)
-
Overview of the JET results with the ITER-like wall
- 2013
-
In: Nuclear Fusion. - : IOP Publishing. - 1741-4326 .- 0029-5515. ; 53:10, s. 104002-
-
Journal article (peer-reviewed)abstract
- Following the completion in May 2011 of the shutdown for the installation of the beryllium wall and the tungsten divertor, the first set of JET campaigns have addressed the investigation of the retention properties and the development of operational scenarios with the new plasma-facing materials. The large reduction in the carbon content (more than a factor ten) led to a much lower Z(eff) (1.2-1.4) during L- and H-mode plasmas, and radiation during the burn-through phase of the plasma initiation with the consequence that breakdown failures are almost absent. Gas balance experiments have shown that the fuel retention rate with the new wall is substantially reduced with respect to the C wall. The re-establishment of the baseline H-mode and hybrid scenarios compatible with the new wall has required an optimization of the control of metallic impurity sources and heat loads. Stable type-I ELMy H-mode regimes with H-98,H-y2 close to 1 and beta(N) similar to 1.6 have been achieved using gas injection. ELM frequency is a key factor for the control of the metallic impurity accumulation. Pedestal temperatures tend to be lower with the new wall, leading to reduced confinement, but nitrogen seeding restores high pedestal temperatures and confinement. Compared with the carbon wall, major disruptions with the new wall show a lower radiated power and a slower current quench. The higher heat loads on Be wall plasma-facing components due to lower radiation made the routine use of massive gas injection for disruption mitigation essential.
|
|
| 3. |
- Ederle, Joerg, et al.
(author)
-
Carotid artery stenting compared with endarterectomy in patients with symptomatic carotid stenosis (International Carotid Stenting Study): an interim analysis of a randomised controlled trial
- 2010
-
In: The Lancet. - 1474-547X. ; 375:9719, s. 985-997
-
Journal article (peer-reviewed)abstract
- Background Stents are an alternative treatment to carotid endarterectomy for symptomatic carotid stenosis, but previous trials have not established equivalent safety and efficacy. We compared the safety of carotid artery stenting with that of carotid endarterectomy. Methods The International Carotid Stenting Study (ICSS) is a multicentre, international, randomised controlled trial with blinded adjudication of outcomes. Patients with recently symptomatic carotid artery stenosis were randomly assigned in a 1:1 ratio to receive carotid artery stenting or carotid endarterectomy. Randomisation was by telephone call or fax to a central computerised service and was stratified by centre with minimisation for sex, age, contralateral occlusion, and side of the randomised artery. Patients and investigators were not masked to treatment assignment. Patients were followed up by independent clinicians not directly involved in delivering the randomised treatment. The primary outcome measure of the trial is the 3-year rate of fatal or disabling stroke in any territory, which has not been analysed yet. The main outcome measure for the interim safety analysis was the 120-day rate of stroke, death, or procedural myocardial infarction. Analysis was by intention to treat (ITT). This study is registered, number ISRCTN25337470. Findings The trial enrolled 1713 patients (stenting group, n=855; endarterectomy group, n=858). Two patients in the stenting group and one in the endarterectomy group withdrew immediately after randomisation, and were not included in the ITT analysis. Between randomisation and 120 days, there were 34 (Kaplan-Meier estimate 4.0%) events of disabling stroke or death in the stenting group compared with 27 (3.2%) events in the endarterectomy group (hazard ratio [HR] 1.28, 95% CI 0.77-2.11). The incidence of stroke, death, or procedural myocardial infarction was 8.5% in the stenting group compared with 5.2% in the endarterectomy group (72 vs 44 events; HR 1.69, 1.16-2.45, p=0.006), Risks of any stroke (65 vs 35 events; HR 1.92, 1.27-2.89) and all-cause death (19 vs seven events; HR 2.76, 1.16-6.56) were higher in the stenting group than in the endarterectomy group. Three procedural myocardial infarctions were recorded in the stenting group, all of which were fatal, compared with four, all non-fatal, in the endarterectomy group. There was one event of cranial nerve palsy in the stenting group compared with 45 in the endarterectomy group. There were also fewer haematomas of any severity in the stenting group than in the endarterectomy group (31 vs 50 events; p=0.0197). Interpretation Completion of long-term follow-up is needed to establish the efficacy of carotid artery stenting compared with endarterectomy. In the meantime, carotid endarterectomy should remain the treatment of choice for patients suitable for surgery.
|
|
| 4. |
- Bergman, Åke, et al.
(author)
-
Science and policy on endocrine disrupters must not be mixed : a reply to a "common sense" intervention by toxicology journal editors
- 2013
-
In: Environmental Health. - : BioMed Central (BMC). - 1476-069X. ; 12
-
Journal article (peer-reviewed)abstract
- The "common sense" intervention by toxicology journal editors regarding proposed European Union endocrine disrupter regulations ignores scientific evidence and well-established principles of chemical risk assessment. In this commentary, endocrine disrupter experts express their concerns about a recently published, and is in our considered opinion inaccurate and factually incorrect, editorial that has appeared in several journals in toxicology. Some of the shortcomings of the editorial are discussed in detail. We call for a better founded scientific debate which may help to overcome a polarisation of views detrimental to reaching a consensus about scientific foundations for endocrine disrupter regulation in the EU.
|
|
| 5. |
- Andersson, Lisa, et al.
(author)
-
Mutations in DMRT3 affect locomotion in horses and spinal circuit function in mice
- 2012
-
In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 488:7413, s. 642-646
-
Journal article (peer-reviewed)abstract
- Locomotion in mammals relies on a central pattern-generating circuitry of spinal interneurons established during development that coordinates limb movement(1). These networks produce left-right alternation of limbs as well as coordinated activation of flexor and extensor muscles(2). Here we show that a premature stop codon in the DMRT3 gene has a major effect on the pattern of locomotion in horses. The mutation is permissive for the ability to perform alternate gaits and has a favourable effect on harness racing performance. Examination of wild-type and Dmrt3-null mice demonstrates that Dmrt3 is expressed in the dI6 subdivision of spinal cord neurons, takes part in neuronal specification within this subdivision, and is critical for the normal development of a coordinated locomotor network controlling limb movements. Our discovery positions Dmrt3 in a pivotal role for configuring the spinal circuits controlling stride in vertebrates. The DMRT3 mutation has had a major effect on the diversification of the domestic horse, as the altered gait characteristics of a number of breeds apparently require this mutation.
|
|
| 6. |
- Chapman, Henry N, et al.
(author)
-
Femtosecond X-ray protein nanocrystallography.
- 2011
-
In: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 470:7332, s. 73-7
-
Journal article (peer-reviewed)abstract
- X-ray crystallography provides the vast majority of macromolecular structures, but the success of the method relies on growing crystals of sufficient size. In conventional measurements, the necessary increase in X-ray dose to record data from crystals that are too small leads to extensive damage before a diffraction signal can be recorded. It is particularly challenging to obtain large, well-diffracting crystals of membrane proteins, for which fewer than 300 unique structures have been determined despite their importance in all living cells. Here we present a method for structure determination where single-crystal X-ray diffraction 'snapshots' are collected from a fully hydrated stream of nanocrystals using femtosecond pulses from a hard-X-ray free-electron laser, the Linac Coherent Light Source. We prove this concept with nanocrystals of photosystem I, one of the largest membrane protein complexes. More than 3,000,000 diffraction patterns were collected in this study, and a three-dimensional data set was assembled from individual photosystem I nanocrystals (∼200nm to 2μm in size). We mitigate the problem of radiation damage in crystallography by using pulses briefer than the timescale of most damage processes. This offers a new approach to structure determination of macromolecules that do not yield crystals of sufficient size for studies using conventional radiation sources or are particularly sensitive to radiation damage.
|
|
| 7. |
- Crosby, Jacy, et al.
(author)
-
Loss-of-Function Mutations in APOC3, Triglycerides, and Coronary Disease
- 2014
-
In: New England Journal of Medicine. - 0028-4793 .- 1533-4406. ; 371:1, s. 22-31
-
Journal article (peer-reviewed)abstract
- Background Plasma triglyceride levels are heritable and are correlated with the risk of coronary heart disease. Sequencing of the protein-coding regions of the human genome (the exome) has the potential to identify rare mutations that have a large effect on phenotype. Methods We sequenced the protein-coding regions of 18,666 genes in each of 3734 participants of European or African ancestry in the Exome Sequencing Project. We conducted tests to determine whether rare mutations in coding sequence, individually or in aggregate within a gene, were associated with plasma triglyceride levels. For mutations associated with triglyceride levels, we subsequently evaluated their association with the risk of coronary heart disease in 110,970 persons. Results An aggregate of rare mutations in the gene encoding apolipoprotein C3 (APOC3) was associated with lower plasma triglyceride levels. Among the four mutations that drove this result, three were loss-of-function mutations: a nonsense mutation (R19X) and two splice-site mutations (IVS2+1G -> A and IVS3+1G -> T). The fourth was a missense mutation (A43T). Approximately 1 in 150 persons in the study was a heterozygous carrier of at least one of these four mutations. Triglyceride levels in the carriers were 39% lower than levels in noncarriers (P<1x10(-20)), and circulating levels of APOC3 in carriers were 46% lower than levels in noncarriers (P = 8x10(-10)). The risk of coronary heart disease among 498 carriers of any rare APOC3 mutation was 40% lower than the risk among 110,472 noncarriers (odds ratio, 0.60; 95% confidence interval, 0.47 to 0.75; P = 4x10(-6)). Conclusions Rare mutations that disrupt APOC3 function were associated with lower levels of plasma triglycerides and APOC3. Carriers of these mutations were found to have a reduced risk of coronary heart disease. (Funded by the National Heart, Lung, and Blood Institute and others.)
|
|
| 8. |
|
|
| 9. |
- Alvarsson, Jonathan, et al.
(author)
-
Benchmarking Study of Parameter Variation When Using Signature Fingerprints Together with Support Vector Machines
- 2014
-
In: Journal of Chemical Information and Modeling. - : American Chemical Society (ACS). - 1549-9596 .- 1549-960X. ; 54:11, s. 3211-3217
-
Journal article (peer-reviewed)abstract
- QSAR modeling using molecular signatures and support vector machines with a radial basis function is increasingly used for virtual screening in the drug discovery field. This method has three free parameters: C, ?, and signature height. C is a penalty parameter that limits overfitting, ? controls the width of the radial basis function kernel, and the signature height determines how much of the molecule is described by each atom signature. Determination of optimal values for these parameters is time-consuming. Good default values could therefore save considerable computational cost. The goal of this project was to investigate whether such default values could be found by using seven public QSAR data sets spanning a wide range of end points and using both a bit version and a count version of the molecular signatures. On the basis of the experiments performed, we recommend a parameter set of heights 0 to 2 for the count version of the signature fingerprints and heights 0 to 3 for the bit version. These are in combination with a support vector machine using C in the range of 1 to 100 and gamma in the range of 0.001 to 0.1. When data sets are small or longer run times are not a problem, then there is reason to consider the addition of height 3 to the count fingerprint and a wider grid search. However, marked improvements should not be expected.
|
|
| 10. |
- Berglund, Eva C., et al.
(author)
-
Genome dynamics of Bartonella grahamii in micro-populations of woodland rodents
- 2010
-
In: BMC Genomics. - : Springer Science and Business Media LLC. - 1471-2164. ; 11, s. 152-
-
Journal article (peer-reviewed)abstract
- Background: Rodents represent a high-risk reservoir for the emergence of new human pathogens. The recent completion of the 2.3 Mb genome of Bartonella grahamii, one of the most prevalent blood-borne bacteria in wild rodents, revealed a higher abundance of genes for host-cell interaction systems than in the genomes of closely related human pathogens. The sequence variability within the global B. grahamii population was recently investigated by multi locus sequence typing, but no study on the variability of putative host-cell interaction systems has been performed. Results: To study the population dynamics of B. grahamii, we analyzed the genomic diversity on a whole-genome scale of 27 B. grahamii strains isolated from four different species of wild rodents in three geographic locations separated by less than 30 km. Even using highly variable spacer regions, only 3 sequence types were identified. This low sequence diversity contrasted with a high variability in genome content. Microarray comparative genome hybridizations identified genes for outer surface proteins, including a repeated region containing the fha gene for filamentous hemaggluttinin and a plasmid that encodes a type IV secretion system, as the most variable. The estimated generation times in liquid culture medium for a subset of strains ranged from 5 to 22 hours, but did not correlate with sequence type or presence/absence patterns of the fha gene or the plasmid. Conclusion: Our study has revealed a geographic microstructure of B. grahamii in wild rodents. Despite near-identity in nucleotide sequence, major differences were observed in gene presence/absence patterns that did not segregate with host species. This suggests that genetically similar strains can infect a range of different hosts.
|
|
| 11. |
- Caron, L., et al.
(author)
-
Magnetocrystalline anisotropy and the magnetocaloric effect in Fe2P
- 2013
-
In: Physical Review B. Condensed Matter and Materials Physics. - 1098-0121 .- 1550-235X. ; 88:9, s. 094440-
-
Journal article (peer-reviewed)abstract
- Magnetic and magnetocaloric properties of high-purity, giant magnetocaloric polycrystalline and single-crystalline Fe2P are investigated. Fe2P displays a moderate magnetic entropy change, which spans over 70 K and the presence of strong magnetization anisotropy proves this system is not fully itinerant but displays a mix of itinerant and localized magnetism. The properties of pure Fe2P are compared to those of giant magnetocaloric (Fe,Mn)2(P,A) (where A = As, Ge, Si) compounds helping understand the exceptional characteristics shown by the latter, which are so promising for heat pump and energy conversion applications.
|
|
| 12. |
- Dupont, Chris L., et al.
(author)
-
Functional Tradeoffs Underpin Salinity-Driven Divergence in Microbial Community Composition
- 2014
-
In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:2, s. e89549-
-
Journal article (peer-reviewed)abstract
- Bacterial community composition and functional potential change subtly across gradients in the surface ocean. In contrast, while there are significant phylogenetic divergences between communities from freshwater and marine habitats, the underlying mechanisms to this phylogenetic structuring yet remain unknown. We hypothesized that the functional potential of natural bacterial communities is linked to this striking divide between microbiomes. To test this hypothesis, metagenomic sequencing of microbial communities along a 1,800 km transect in the Baltic Sea area, encompassing a continuous natural salinity gradient from limnic to fully marine conditions, was explored. Multivariate statistical analyses showed that salinity is the main determinant of dramatic changes in microbial community composition, but also of large scale changes in core metabolic functions of bacteria. Strikingly, genetically and metabolically different pathways for key metabolic processes, such as respiration, biosynthesis of quinones and isoprenoids, glycolysis and osmolyte transport, were differentially abundant at high and low salinities. These shifts in functional capacities were observed at multiple taxonomic levels and within dominant bacterial phyla, while bacteria, such as SAR11, were able to adapt to the entire salinity gradient. We propose that the large differences in central metabolism required at high and low salinities dictate the striking divide between freshwater and marine microbiomes, and that the ability to inhabit different salinity regimes evolved early during bacterial phylogenetic differentiation. These findings significantly advance our understanding of microbial distributions and stress the need to incorporate salinity in future climate change models that predict increased levels of precipitation and a reduction in salinity.
|
|
| 13. |
- Fagerqvist, Therese, et al.
(author)
-
Monoclonal antibodies selective for α-synuclein oligomers/protofibrils recognize brain pathology in Lewy body disorders and α-synuclein transgenic mice with the disease-causing A30P mutation
- 2013
-
In: Journal of Neurochemistry. - : Wiley-Blackwell. - 0022-3042 .- 1471-4159. ; 126:1, s. 131-144
-
Journal article (peer-reviewed)abstract
- Inclusions of intraneuronal alpha-synuclein (-synuclein) can be detected in brains of patients with Parkinson's disease and dementia with Lewy bodies. The aggregation of -synuclein is a central feature of the disease pathogenesis. Among the different -synuclein species, large oligomers/protofibrils have particular neurotoxic properties and should therefore be suitable as both therapeutic and diagnostic targets. Two monoclonal antibodies, mAb38F and mAb38E2, with high affinity and strong selectivity for large -synuclein oligomers were generated. These antibodies, which do not bind amyloid-beta or tau, recognize Lewy body pathology in brains from patients with Parkinson's disease and dementia with Lewy bodies and detect pathology earlier in -synuclein transgenic mice than linear epitope antibodies. An oligomer-selective sandwich ELISA, based on mAb38F, was set up to analyze brain extracts of the transgenic mice. The overall levels of -synuclein oligomers/protofibrils were found to increase with age in these mice, although the levels displayed a large interindividual variation. Upon subcellular fractionation, higher levels of -synuclein oligomers/protofibrils could be detected in the endoplasmic reticulum around the age when behavioral disturbances develop. In summary, our novel oligomer-selective -synuclein antibodies recognize relevant pathology and should be important tools to further explore the pathogenic mechanisms in Lewy body disorders. Moreover, they could be potential candidates both for immunotherapy and as reagents in an assay to assess a potential disease biomarker.
|
|
| 14. |
- He, Wenxiao, 1985, et al.
(author)
-
Osteogenesis-inducing calcium phosphate nanoparticle precursors applied to titanium surfaces
- 2013
-
In: Biomedical Materials (Bristol). - : IOP Publishing. - 1748-605X .- 1748-6041. ; 8:3
-
Journal article (peer-reviewed)abstract
- This study investigated the effects of the morphology and physicochemical properties of calcium phosphate (CaP) nanoparticles on osteogenesis. Two types of CaP nanoparticles were compared, namely amorphous calcium phosphate (ACP) nano-spheres (diameter: 9-13 nm) and poorly crystalline apatite (PCA) nano-needles (30-50 nm x 2-4 nm) that closely resemble bone apatite. CaP particles were spin-coated onto titanium discs and implants; they were evaluated in cultured mouse calvarial osteoblasts, as well as after implantation in rabbit femurs. A significant dependence of CaP coatings was observed in osteoblast-related gene expression (Runx2, Colla1 and Spp1). Specifically, the PCA group presented an up-regulation of the osteospecific genes, while the ACP group suppressed the Runx2 and Colla1 expression when compared to blank titanium substrates. Both the ACP and PCA groups presented a more than three-fold increase of calcium deposition, as suggested by Alizarin red staining. The removal torque results implied a slight tendency in favour of the PCA group. Different forms of CaP nanostructures presented different biologic differences; the obtained information can be used to optimize surface coatings on biomaterials.
|
|
| 15. |
- Khan, Omar M., 1980, et al.
(author)
-
Geranylgeranyltransferase type I (GGTase-I) deficiency hyperactivates macrophages and induces erosive arthritis in mice.
- 2011
-
In: The Journal of clinical investigation. - 1558-8238. ; 121:2, s. 628-39
-
Journal article (peer-reviewed)abstract
- RHO family proteins are important for the function of inflammatory cells. They are modified with a 20-carbon geranylgeranyl lipid in a process catalyzed by protein geranylgeranyltransferase type I (GGTase-I). Geranylgeranylation is viewed as essential for the membrane targeting and activity of RHO proteins. Consequently, inhibiting GGTase-I to interfere with RHO protein activity has been proposed as a strategy to treat inflammatory disorders. However, here we show that mice lacking GGTase-I in macrophages develop severe joint inflammation resembling erosive rheumatoid arthritis. The disease was initiated by the GGTase-I-deficient macrophages and was transplantable and reversible in bone marrow transplantation experiments. The cells accumulated high levels of active GTP-bound RAC1, CDC42, and RHOA, and RAC1 remained associated with the plasma membrane. Moreover, GGTase-I deficiency activated p38 and NF-κB and increased the production of proinflammatory cytokines. The results challenge the view that geranylgeranylation is essential for the activity and localization of RHO family proteins and suggest that reduced geranylgeranylation in macrophages can initiate erosive arthritis.
|
|
| 16. |
- Kilsgård, Ola, et al.
(author)
-
Peptidylarginine deiminases present in the airways during tobacco smoking and inflammation can citrullinate the host defense peptide LL-37, resulting in altered activities.
- 2012
-
In: American journal of respiratory cell and molecular biology. - 1535-4989 .- 1044-1549. ; 46:2, s. 240-8
-
Journal article (peer-reviewed)abstract
- Bacterial colonization of the lower respiratory tract is frequently seen in chronic obstructive pulmonary disease (COPD), and may cause exacerbations leading to disease progression. Antimicrobial peptides comprise an important part of innate lung immunity, and not least the cathelicidin human cationic antimicrobial protein-18/LL-37. Peptidylarginine deiminases (PADIs) post-translationally modify proteins by converting cationic peptidylarginine residues to neutral peptidylcitrulline. An increased presence of PADI2 and citrullinated proteins was demonstrated in the lungs of smokers. In this study, preformed PADI4, stored in granulocytes and extracellularly in the lumina of bronchi, was found in lung tissue of individuals suffering from COPD. In vitro, recombinant human PADI2 and PADI4 both caused a time- and dose-dependent citrullination of LL-37. The citrullination resulted in impaired antibacterial activity against Staphylococcus aureus, Streptococcus pneumoniae, and nontypable Haemophilus influenzae, but less so against Pseudomonas aeruginosa. Using artificial lipid bilayers, we observed discrete differences when comparing the disrupting activity of native and citrullinated LL-37, suggesting that differences in cell wall composition are important during interactions with whole bacteria. Furthermore, citrullinated LL-37 showed higher chemotactic activity against mononuclear leukocytes than did native LL-37, but was less efficient at neutralizing lipolysaccharide, and also in converting apoptotic neutrophils into a state of secondary necrosis. In addition, citrullinated LL-37 was more prone to degradation by proteases, whereas the V8 endopetidase of S. aureus cleaved the modified peptide at additional sites, compared with native LL-37. Together, these findings demonstrate novel mechanisms whereby the inflammation-dependent deiminases PADI2 and PADI4 can alter the activites of antibacterial polypeptides, affecting the course of inflammatory disorders such as COPD.
|
|
| 17. |
- Shafaat, Hannah S., et al.
(author)
-
Electronic Structural Flexibility of Heterobimetallic Mn/Fe Cofactors : R2lox and R2c Proteins
- 2014
-
In: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 136:38, s. 13399-13409
-
Journal article (peer-reviewed)abstract
- The electronic structure of the Mn/Fe cofactor identified in a new class of oxidases (R2lox) described by Andersson and Hogbom [Proc. Natl. Acad. Sci. U.S.A. 2009, 106, 5633] is reported. The R2lox protein is homologous to the small subunit of class Ic ribonucleotide reductase (R2c) but has a completely different in vivo function. Using multifrequency EPR and related pulse techniques, it is shown that the cofactor of R2lox represents an antiferromagnetically coupled Mn-III/Fe-III dimer linked by a mu-hydroxo/bis-mu-carboxylato bridging network. The Mn-III ion is coordinated by a single water ligand. The R2lox cofactor is photoactive, converting into a second form (R2lox(photo)) upon visible illumination at cryogenic temperatures (77 K) that completely decays upon warming. This second, unstable form of the cofactor more closely resembles the Mn-III/Fe-III cofactor seen in R2c. It is shown that the two forms of the R2lox cofactor differ primarily in terms of the local site geometry and electronic state of the Mn-III ion, as best evidenced by a reorientation of its unique Mn-55 hyperfine axis. Analysis of the metal hyperfine tensors in combination with density functional theory (DFT) calculations suggests that this change is triggered by deprotonation of the mu-hydroxo bridge. These results have important consequences for the mixed-metal R2c cofactor and the divergent chemistry R2lox and R2c perform.
|
|
| 18. |
- Snygg-Martin, Ulrika, 1965, et al.
(author)
-
Warfarin therapy and incidence of cerebrovascular complications in left-sided native valve endocarditis.
- 2011
-
In: European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology. - : Springer Science and Business Media LLC. - 1435-4373. ; 30:2, s. 151-157
-
Journal article (peer-reviewed)abstract
- Anticoagulant therapy has been anticipated to increase the risk of cerebrovascular complications (CVC) in native valve endocarditis (NVE). This study investigates the relationship between ongoing oral anticoagulant therapy and the incidence of symptomatic CVC in left-sided NVE. In a prospective cohort study, the CVC incidence was compared between NVE patients with and without ongoing warfarin. Among 587 NVE episodes, 48 (8%) occurred in patients on warfarin. A symptomatic CVC was seen in 144 (25%) patients, with only three on warfarin. CVC were significantly less frequent in patients on warfarin (6% vs. 26%, odds ratio [OR] 0.20, 95% confidence interval [CI] 0.06-0.6, p=0.006). No increase in haemorrhagic lesions was detected in patients on warfarin. Staphylococcus aureus aetiology (adjusted OR [aOR] 6.3, 95% CI 3.8-10.4) and vegetation length (aOR 1.04, 96% CI 1.01-1.07) were risk factors for CVC, while warfarin on admission (aOR 0.26, 95% CI 0.07-0.94), history of congestive heart failure (adjusted OR 0.22, 95% CI 0.1-0.52) and previous endocarditis (aOR 0.1, 95% CI 0.01-0.79) correlated with lower CVC frequency.
|
|
| 19. |
- Tschirren, Barbara, et al.
(author)
-
Polymorphisms at the innate immune receptor TLR2 are associated with Borrelia infection in a wild rodent population
- 2013
-
In: Royal Society of London. Proceedings B. Biological Sciences. - : The Royal Society. - 1471-2954. ; 280:1759
-
Journal article (peer-reviewed)abstract
- The discovery of the key role of Toll-like receptors (TLRs) in initiating innate immune responses and modulating adaptive immunity has revolutionized our understanding of vertebrate defence against pathogens. Yet, despite their central role in pathogen recognition and defence initiation, there is little information on how variation in TLRs influences disease susceptibility in natural populations. Here, we assessed the extent of naturally occurring polymorphisms at TLR2 in wild bank voles (Myodes glareolus) and tested for associations between TLR2 variants and infection with Borrelia afzelii, a common tick-transmitted pathogen in rodents and one of the causative agents of human Lyme disease. Bank voles in our population had 15 different TLR2 haplotypes (10 different haplotypes at the amino acid level), which grouped in three well-separated clusters. In a large-scale capture-mark-recapture study, we show that voles carrying TLR2 haplotypes of one particular cluster (TLR2(c2)) were almost three times less likely to be Borrelia infected than animals carrying other haplotypes. Moreover, neutrality tests suggested that TLR2 has been under positive selection. This is, to our knowledge, the first demonstration of an association between TLR polymorphism and parasitism in wildlife, and a striking example that genetic variation at innate immune receptors can have a large impact on host resistance.
|
|
| 20. |
- Westas, Emma, 1982, et al.
(author)
-
Biofilm formation on nanostructured hydroxyapatite-coated titanium
- 2014
-
In: Journal of Biomedical Materials Research - Part A. - : Wiley. - 1552-4965 .- 1549-3296. ; 102:4, s. 1063-1070
-
Journal article (peer-reviewed)abstract
- Biofilm formation on medical devices is a common cause of implant failure, especially regarding implants that breach the epithelial tissue, so-called transcutaneous implants. Nanotechnology and the development of new nanomaterials have given the opportunity to design nanotextured implant surfaces. Such surfaces have been studied using various in vitro methods showing that nanosized features strongly benefit bone cell growth. However, little is known on how nanostructured features affect biofilm formation. The aim of this study was therefore to examine the shape- and chemical-dependent effect of a nanostructured hydroxyapatite (HA) coating on the degree of Staphylococcus epidermidis biofilm formation. Three different types of nanosized HA particles having different shapes and calcium to phosphate ratios were compared to uncoated turned titanium using safranin stain in a biofilm assay and confocal laser scanning microscopy (CLSM) for assessment of biofilm biomass and bacterial volume, respectively. No difference in biofilm biomass was detected for the various surfaces after 6 h incubation with S. epidermidis. Additionally, image analysis of CLSM Z-stacks confirmed the biofilm assay and showed similar results. In conclusion, the difference in nanomorphology and chemical composition of the surface coatings did not influence the adhesion and biofilm formation of S. epidermidis.
|
|
