| 1. |
- Uhlén, Mathias, et al.
(författare)
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A human protein atlas for normal and cancer tissues based on antibody proteomics
- 2005
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Ingår i: Molecular & Cellular Proteomics. - 1535-9476 .- 1535-9484. ; 4:12, s. 1920-1932
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Tidskriftsartikel (refereegranskat)abstract
- Antibody-based proteomics provides a powerful approach for the functional study of the human proteome involving the systematic generation of protein-specific affinity reagents. We used this strategy to construct a comprehensive, antibody-based protein atlas for expression and localization profiles in 48 normal human tissues and 20 different cancers. Here we report a new publicly available database containing, in the first version, similar to 400,000 high resolution images corresponding to more than 700 antibodies toward human proteins. Each image has been annotated by a certified pathologist to provide a knowledge base for functional studies and to allow queries about protein profiles in normal and disease tissues. Our results suggest it should be possible to extend this analysis to the majority of all human proteins thus providing a valuable tool for medical and biological research.
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| 2. |
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| 3. |
- Ahlberg, Jörgen, 1971-, et al.
(författare)
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Three-dimensional hyperspectral imaging technique
- 2017
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Ingår i: ALGORITHMS AND TECHNOLOGIES FOR MULTISPECTRAL, HYPERSPECTRAL, AND ULTRASPECTRAL IMAGERY XXIII. - : SPIE - International Society for Optical Engineering. - 9781510608979 - 9781510608986
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Konferensbidrag (refereegranskat)abstract
- Hyperspectral remote sensing based on unmanned airborne vehicles is a field increasing in importance. The combined functionality of simultaneous hyperspectral and geometric modeling is less developed. A configuration has been developed that enables the reconstruction of the hyperspectral three-dimensional (3D) environment. The hyperspectral camera is based on a linear variable filter and a high frame rate, high resolution camera enabling point-to-point matching and 3D reconstruction. This allows the information to be combined into a single and complete 3D hyperspectral model. In this paper, we describe the camera and illustrate capabilities and difficulties through real-world experiments.
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| 4. |
- Akrami, Yashar, et al.
(författare)
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A Profile Likelihood Analysis of the Constrained MSSM with Genetic Algorithms
- 2010
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Ingår i: Journal of High Energy Physics (JHEP). - 1126-6708 .- 1029-8479. ; :4, s. 057-
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Tidskriftsartikel (refereegranskat)abstract
- The Constrained Minimal Supersymmetric Standard Model (CMSSM) is one of the simplest and most widely-studied supersymmetric extensions to the standard model of particle physics. Nevertheless, current data do not sufficiently constrain the model parameters in a way completely independent of priors, statistical measures and scanning techniques. We present a new technique for scanning supersymmetric parameter spaces, optimised for frequentist profile likelihood analyses and based on Genetic Algorithms. We apply this technique to the CMSSM, taking into account existing collider and cosmological data in our global fit. We compare our method to the MultiNest algorithm, an efficient Bayesian technique, paying particular attention to the best-fit points and implications for particle masses at the LHC and dark matter searches. Our global best-fit point lies in the focus point region. We find many high-likelihood points in both the stau co-annihilation and focus point regions, including a previously neglected section of the co-annihilation region at large m 0. We show that there are many high-likelihood points in the CMSSM parameter space commonly missed by existing scanning techniques, especially at high masses. This has a significant influence on the derived confidence regions for parameters and observables, and can dramatically change the entire statistical inference of such scans.
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| 5. |
- Akrami, Yashar, 1980-
(författare)
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Supersymmetry vis-à-vis Observation : Dark Matter Constraints, Global Fits and Statistical Issues
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Weak-scale supersymmetry is one of the most favoured theories beyond the Standard Model of particle physics that elegantly solves various theoretical and observational problems in both particle physics and cosmology. In this thesis, I describe the theoretical foundations of supersymmetry, issues that it can address and concrete supersymmetric models that are widely used in phenomenological studies. I discuss how the predictions of supersymmetric models may be compared with observational data from both colliders and cosmology. I show why constraints on supersymmetric parameters by direct and indirect searches of particle dark matter are of particular interest in this respect. Gamma-ray observations of astrophysical sources, in particular dwarf spheroidal galaxies, by the Fermi satellite, and recording nuclear recoil events and energies by future ton-scale direct detection experiments are shown to provide powerful tools in searches for supersymmetric dark matter and estimating supersymmetric parameters. I discuss some major statistical issues in supersymmetric global fits to experimental data. In particular, I further demonstrate that existing advanced scanning techniques may fail in correctly mapping the statistical properties of the parameter spaces even for the simplest supersymmetric models. Complementary scanning methods based on Genetic Algorithms are proposed.
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| 6. |
- Almandoz Gil, Leire, 1988-
(författare)
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Characterization of Physiological and Pathological Alpha-Synuclein : Implications for Parkinson’s Disease and Related Disorders
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Aggregated alpha-synuclein is the main component of Lewy bodies and Lewy neurites, intraneuronal inclusions found in the brains of Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) patients (synucleinopathies). Alpha-synuclein is a presynaptic protein, which is most commonly an unfolded monomer in its physiological state. However, under pathological conditions it can start to misfold and enter an aggregation pathway that will lead to the formation of oligomers of increasing size and finally insoluble fibrils. The oligomers have been hypothesized to be the most neurotoxic species, but studies of their properties have been hindered by their heterogeneity and kinetic instability. The overall aim of this thesis was to characterize and compare physiological and pathological forms of alpha-synuclein from different sources: recombinant monomers, oligomers formed in vitro through exposure to oxidative stress related reactive aldehydes, aggregates from a synucleinopathy mouse model and from synucleinopathy patients.In paper I we studied the effect of low molar excess of two lipid peroxidation products, 4-oxo-2-nonenal (ONE) and 4-hydroxy-2-nonenal (HNE), on the oligomerization of alpha-synuclein. Through biophysical methods we observed that, although both aldehydes bound to alpha-synuclein directly, ONE produced SDS-stable oligomers more rapidly than HNE. Moreover, ONE induced oligomerization at both acidic and neutral pH, while HNE only formed oligomers at neutral pH.In paper II we mapped the surface exposed epitopes of in vitro and in vivo generated alpha-synuclein species by using immunoglobulin Y antibodies raised against short linear peptides covering most of the alpha-synuclein sequence. Monomers were found to react with most antibodies, while the latter part of the N-terminus and mid-region of HNE oligomers and fibrils was found to be occluded in oligomers and fibrils. Through immunohistochemistry we compared alpha-synuclein aggregates in brain tissue from patients with synucleinopathies as well as from a mouse model expressing A30P human alpha-synuclein. Although the exposed epitopes were found to be similar overall, subtle differences were detected in the C-terminus.An additional aim of this thesis was to characterize synaptic aggregates of alpha-synuclein. In paper III we obtained synaptosomal preparations of the A30P mouse model and found that a subset of the alpha-synuclein present in the synaptosomes was proteinase K resistant and therefore aggregated. Further biochemical analyses showed that the aggregated alpha-synuclein mainly was of human, i.e. transgenic, origin and that Ser 129 was not phosphorylated, which otherwise is a common post translational modification of alpha-synuclein in Lewy bodies.It has been suggested that alpha-synuclein plays a role in neurotransmitter release by binding to the SNARE protein VAMP-2 and thereby chaperoning the SNARE complex assembly. In paper IV we used proximity ligation assay to visualize the co-localization of alpha-synuclein and the SNARE proteins in primary neurons from non-transgenic and A30P transgenic mice.In conclusion, in this thesis we have characterized a variety of alpha-synuclein species and shed light on the diversity of alpha-synuclein aggregates. Additionally, we have characterized synaptic species of alpha-synuclein and analyzed the co-localization between alpha-synuclein and SNARE proteins in neurons.
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| 7. |
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| 8. |
- Almandoz-Gil, Leire, et al.
(författare)
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In situ proximity ligation assay reveals co-localization of alpha-synuclein and SNARE proteins in murine primary neurons
- 2018
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Ingår i: Frontiers in Neurology. - : Frontiers Media S.A.. - 1664-2295. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- The aggregation of alpha-synuclein (alpha Syn) is the pathological hallmark of Parkinson's disease, dementia with Lewy bodies and related neurological disorders. However, the physiological function of the protein and how this function relates to its pathological effects remain poorly understood. One of the proposed roles of aSyn is to promote the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex assembly by binding to VAMP-2. The objective of this study was to visualize the co-localization between aSyn and the SNARE proteins (VAMP-2, SNAP-25, and syntaxin-1) for the first time using in situ proximity ligation assay (PLA). Cortical primary neurons were cultured from either non-transgenic or transgenic mice expressing human aSyn with the A30P mutation under the Thy-1 promoter. With an antibody recognizing both mouse and human aSyn, a PLA signal indicating close proximity between aSyn and the three SNARE proteins was observed both in the soma and throughout the processes. No differences in the extent of PLA signals were seen between non-transgenic and transgenic neurons. With an antibody specific against human aSyn, the PLA signal was mostly located to the soma and was only present in a few cells. Taken together, in situ PLA is a method that can be used to investigate the co-localization of aSyn and the SNARE proteins in primary neuronal cultures
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| 9. |
- Almandoz-Gil, Leire, et al.
(författare)
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Low molar excess of 4-oxo-2-nonenal and 4-hydroxy-2-nonenal promote oligomerization of alpha-synuclein through different pathways
- 2017
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Ingår i: Free Radical Biology & Medicine. - : Elsevier BV. - 0891-5849 .- 1873-4596. ; 110, s. 421-431
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Tidskriftsartikel (refereegranskat)abstract
- Aggregated alpha-synuclein is the main component of Lewy bodies, intraneuronal inclusions found in brains with Parkinson's disease and dementia with Lewy bodies. A body of evidence implicates oxidative stress in the pathogenesis of these diseases. For example, a large excess (30:1, aldehyde:protein) of the lipid peroxidation end products 4-oxo-2-nonenal (ONE) or 4-hydroxy-2-nonenal (HNE) can induce alpha-synuclein oligomer formation. The objective of the study was to investigate the effect of these reactive aldehydes on alpha-synuclein at a lower molar excess (3:1) at both physiological (7.4) and acidic (5.4) pH. As observed by size-exclusion chromatography, ONE rapidly induced the formation of alpha-synuclein oligomers at both pH values, but the effect was less pronounced under the acidic condition. In contrast, only a small proportion of alpha-synuclein oligomers were formed with low excess HNE-treatment at physiological pH and no oligomers at all under the acidic condition. With prolonged incubation times (up to 96 h), more alpha-synuclein was oligomerized at physiological pH for both ONE and HNE. As determined by Western blot, ONE-oligomers were more SDS-stable and to a higher-degree cross-linked as compared to the HNE-induced oligomers. However, as shown by their greater sensitivity to proteinase K treatment, ONE-oligomers, exhibited a less compact structure than HNE-oligomers. As indicated by mass spectrometry, ONE modified most Lys residues, whereas HNE primarily modified the His50 residue and fewer Lys residues, albeit to a higher degree than ONE. Taken together, our data show that the aldehydes ONE and HNE can modify alpha-synuclein and induce oligomerization, even at low molar excess, but to a higher degree at physiological pH and seemingly through different pathways.
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| 10. |
- Almandoz-Gil, Leire, et al.
(författare)
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Mapping of Surface-Exposed Epitopes of In Vitro and In Vivo Aggregated Species of Alpha-Synuclein
- 2017
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Ingår i: Cellular and molecular neurobiology. - : Springer Science and Business Media LLC. - 0272-4340 .- 1573-6830. ; 37:7, s. 1217-1226
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Tidskriftsartikel (refereegranskat)abstract
- Aggregated alpha-synuclein is the main component of Lewy bodies, intraneuronal deposits observed in Parkinson's disease and dementia with Lewy bodies. The objective of the study was to identify surface-exposed epitopes of alpha-synuclein in vitro and in vivo formed aggregates. Polyclonal immunoglobulin Y antibodies were raised against short linear peptides of the alpha-synuclein molecule. An epitope in the N-terminal region (1-10) and all C-terminal epitopes (90-140) were found to be exposed in an indirect enzyme-linked immunosorbent assay (ELISA) using recombinant monomeric, oligomeric, and fibrillar alpha-synuclein. In a phospholipid ELISA, the N-terminus and mid-region of alpha-synuclein (i.e., 1-90) were associated with phosphatidylserine and thus occluded from antibody binding. The antibodies that reacted most strongly with epitopes in the in vitro aggregates (i.e., 1-10 and epitopes between positions 90-140) also labeled alpha-synuclein inclusions in brains from transgenic (Thy-1)-h[A30P] alpha-synuclein mice and Lewy bodies and Lewy neurites in brains of patients with alpha-synucleinopathies. However, differences in reactivity were observed with the C-terminal antibodies when brain tissue from human and transgenic mice was compared. Taken together, the study shows that although similar epitopes are exposed in both in vitro and in vivo formed alpha-synuclein inclusions, structural heterogeneity can be observed between different molecular species.
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| 11. |
- Andersson, Camilla, 1979-, et al.
(författare)
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Interannual variation and trends in air pollution over Europe due to climate variability during 1958–2001 simulated with a regional CTM coupled to the ERA40 reanalysis
- 2007
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Ingår i: Tellus. Series B, Chemical and physical meteorology. - Stockholm : Tellus. - 0280-6509 .- 1600-0889. ; 59, s. 77-98
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Tidskriftsartikel (refereegranskat)abstract
- A three-dimensional Chemistry Transport Model was used to study the meteorologically induced interannual variability and trends in deposition of sulphur and nitrogen as well as concentrations of surface ozone (O3), nitrogen dioxide (NO2) and particulate matter (PM) and its constituents over Europe during 1958–2001. The model was coupled to the meteorological reanalysis ERA40, produced at the European Centre for Medium-range Weather Forecasts. Emissions and boundary conditions of chemical compounds and PM were kept constant at present levels. The average European interannual variation, due to meteorological variability, ranges from 3% for O3, 5%for NO2, 9% for PM, 6–9% for dry deposition, to about 20% for wet deposition of sulphur and nitrogen. For the period 1979–2001 the trend in ozone, due to climate variability is increasing in central and southwestern Europe and decreasing in northeastern Europe, the trend in NO2 is approximately opposite. The trend in PM is positive in eastern Europe. There are negative trends in wet deposition in southwestern and central Europe and positive trends in dry deposition overall. A bias in ERA40 precipitation could be partly responsible for the trends. The variation and trends need to be considered when interpreting measurements and designing measurement campaigns.
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| 12. |
- Andersson, Vincent, et al.
(författare)
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Macrocyclic Prodrugs of a Selective Nonpeptidic Direct Thrombin Inhibitor Display High Permeability, Efficient Bioconversion but Low Bioavailability
- 2016
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 59:14, s. 6658-6670
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Tidskriftsartikel (refereegranskat)abstract
- The only oral direct thrombin inhibitors that have reached the market, ximelagatran and dabigatran etexilat, are double prodrugs with low bioavailability in humans. We have evaluated an alternative strategy: the preparation of a nonpeptidic, polar direct thrombin inhibitor as a single, macrocyclic esterase-cleavable (acyloxy)alkoxy prodrug. Two homologous prodrugs were synthesized and displayed high solubilities and Caco-2 cell permeabilities, suggesting high absorption from the intestine. In addition, they were rapidly and completely converted to the active zwitterionic thrombin inhibitor in human hepatocytes. Unexpectedly, the most promising prodrug displayed only moderately higher oral bioavailability in rat than the polar direct thrombin inhibitor, most likely due to rapid metabolism in the intestine or the intestinal wall. To the best of our knowledge, this is the first in vivo ADME study of macrocyclic (acyloxy)alkoxy prodrugs, and it remains to be established if the modest increase in bioavailability is a general feature of this category of prodrugs or not.
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| 13. |
- Aniszewska, Agata, et al.
(författare)
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Modeling Parkinson's disease-related symptoms in alpha-synuclein overexpressing mice
- 2022
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Ingår i: Brain and Behavior. - : John Wiley & Sons. - 2162-3279 .- 2162-3279. ; 12:7
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Forskningsöversikt (refereegranskat)abstract
- Background: Intracellular deposition of alpha-synuclein (alpha-syn) as Lewy bodies and Lewy neurites is a central event in the pathogenesis of Parkinson's disease (PD) and other alpha-synucleinopathies. Transgenic mouse models overexpressing human alpha-syn, are useful research tools in preclinical studies of pathogenetic mechanisms. Such mice develop alpha-syn inclusions as well as neurodegeneration with a topographical distribution that varies depending on the choice of promoter and which form of alpha-syn that is overexpressed. Moreover, they display motor symptoms and cognitive disturbances that to some extent resemble the human conditions.Purpose: One of the main motives for assessing behavior in these mouse models is to evaluate the potential of new treatment strategies, including their impact on motor and cognitive symptoms. However, due to a high within-group variability with respect to such features, the behavioral studies need to be applied with caution. In this review, we discuss how to make appropriate choices in the experimental design and which tests that are most suitable for the evaluation of PD-related symptoms in such studies.Methods: We have evaluated published results on two selected transgenic mouse models overexpressing wild type (L61) and mutated (A30P) alpha-syn in the context of their validity and utility for different types of behavioral studies.Conclusions: By applying appropriate behavioral tests, alpha-syn transgenic mouse models provide an appropriate experimental platform for studies of symptoms related to PD and other alpha-synucleinopathies.
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| 14. |
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| 15. |
- Austin, Åsa N., et al.
(författare)
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Synergistic Effects of Rooted Aquatic Vegetation and Drift Wrack on Ecosystem Multifunctionality
- 2021
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Ingår i: Ecosystems (New York. Print). - : Springer Science and Business Media LLC. - 1432-9840 .- 1435-0629. ; 24:7, s. 1670-1686
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Tidskriftsartikel (refereegranskat)abstract
- Ecosystem multifunctionality is an increasingly popular concept used to approximate multifaceted ecosystem functioning, which in turn may help advance ecosystem-based management. However, while experimental studies have shown a positive effect of diversity on multifunctionality, observational studies from natural systems-particularly aquatic-are scarce. Here, we tested the relative importance of species richness and cover of rooted aquatic vegetation, as well as cover of the loose-lying form of the macroalgae bladderwrack (Fucus vesiculosus), for ecosystem multifunctionality in shallow bays along the western Baltic Sea coast. We estimated multifunctionality based on four indicators of functions that support ecosystem services: recruitment of large predatory fish, grazer biomass, inverted 'nuisance' algal biomass, and water clarity. Piecewise path analysis showed that multifunctionality was driven by high cover of rooted aquatic vegetation and bladderwrack, particularly when the two co-occurred. This synergistic effect was nearly three times as strong as a negative effect of land-derived nitrogen loading. Species richness of aquatic vegetation indirectly benefitted multifunctionality by increasing vegetation cover. Meanwhile, high bladderwrack cover tended to decrease vegetation species richness, indicating that bladderwrack has both positive and negative effects on multifunctionality. We conclude that managing for dense and diverse vegetation assemblages may mitigate effects of anthropogenic pressures (for example, eutrophication) and support healthy coastal ecosystems that provide a range of benefits. To balance the exploitation of coastal ecosystems and maintain their multiple processes and services, management therefore needs to go beyond estimation of vegetation cover and consider the diversity and functional types of aquatic vegetation.
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| 16. |
- Axen, Iben, et al.
(författare)
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Misinformation, chiropractic, and the COVID-19 pandemic
- 2020
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Ingår i: Chiropractic and Manual Therapies. - : BioMed Central (BMC). - 2045-709X. ; 28:1
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background: In March 2020, the World Health Organization elevated the coronavirus disease (COVID-19) epidemic to a pandemic and called for urgent and aggressive action worldwide. Public health experts have communicated clear and emphatic strategies to prevent the spread of COVID-19. Hygiene rules and social distancing practices have been implemented by entire populations, including 'stay-at-home' orders in many countries. The long-term health and economic consequences of the COVID-19 pandemic are not yet known.Main text: During this time of crisis, some chiropractors made claims on social media that chiropractic treatment can prevent or impact COVID-19. The rationale for these claims is that spinal manipulation can impact the nervous system and thus improve immunity. These beliefs often stem from nineteenth-century chiropractic concepts. We are aware of no clinically relevant scientific evidence to support such statements. We explored the internet and social media to collect examples of misinformation from Europe, North America, Australia and New Zealand regarding the impact of chiropractic treatment on immune function. We discuss the potential harm resulting from these claims and explore the role of chiropractors, teaching institutions, accrediting agencies, and legislative bodies.Conclusions: Members of the chiropractic profession share a collective responsibility to act in the best interests of patients and public health. We hope that all chiropractic stakeholders will view the COVID-19 pandemic as a call to action to eliminate the unethical and potentially dangerous claims made by chiropractors who practise outside the boundaries of scientific evidence.
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| 17. |
- Baltz, Edward A., et al.
(författare)
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Pre-launch estimates for GLAST sensitivity to Dark Matter annihilation signals
- 2008
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Ingår i: Journal of Cosmology and Astroparticle Physics. - : IOP Publishing. - 1475-7516. ; 0807:013
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Tidskriftsartikel (refereegranskat)abstract
- We investigate the sensitivity of the Gamma-ray Large Area Space Telescope (GLAST) for indirectly detecting weakly interacting massive particles (WIMPs) through the γ-ray signal that their pair annihilation produces. WIMPs are among the favorite candidates for explaining the compelling evidence that about 80% of the mass in the Universe is non-baryonic dark matter (DM). They are serendipitously motivated by various extensions of the standard model of particle physics such as supersymmetry and universal extra dimensions (UED). With its unprecedented sensitivity and its very large energy range (20 MeV to more than 300 GeV) the main instrument on board the GLAST satellite, the Large Area Telescope (LAT), will open a new window of discovery. As our estimates show, the LAT will be able to detect an indirect DM signature for a large class of WIMP models given a cuspy profile for the DM distribution. Using the current state of the art Monte Carlo and event reconstruction software developed within the LAT collaboration, we present preliminary sensitivity studies for several possible sources inside and outside the Galaxy. We also discuss the potential of the LAT to detect UED via the electron/positron channel. Diffuse background modeling and other background issues that will be important in setting limits or seeing a signal are presented
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| 18. |
- Bandaru, Sashidar, et al.
(författare)
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Targeting filamin A reduces macrophage activity and atherosclerosis. : Filamin A in atherogenesis
- 2019
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Ingår i: Circulation. - 1524-4539. ; 140:1, s. 67-79
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Tidskriftsartikel (refereegranskat)abstract
- The actin-binding protein FLNA (filamin A) regulates signal transduction important for cell locomotion, but the role of macrophage-specific FLNA during atherogenesis has not been explored.We analyzed FLNA expression in human carotid atherosclerotic plaques by immunofluorescence. We also produced mice with Flna-deficient macrophages by breeding conditional Flna-knockout mice ( Flna o/fl) with mice expressing Cre from the macrophage-specific lysosome M promoter ( LC). Atherosclerosis in vivo was studied by transplanting bone marrow from male Flna o/fl/ LC mice to atherogenic low-density lipoprotein receptor-deficient ( Ldlr-/-) mice; and by infecting Flna o/fl and Flna o/fl/ LC mice with AdPCSK9 (adenoviral vector overexpressing proprotein convertase subtilisin/kexin type 9). Furthermore, C57BL/6 mice were infected with AdPCSK9 and then treated with the calpain inhibitor calpeptin to inhibit FLNA cleavage.We found that macrophage FLNA expression was higher in advanced than in intermediate human atherosclerotic plaques. Flna o/fl/ LC macrophages proliferated and migrated less than controls; expressed lower levels of phosphorylated AKT and ERK1/2; exhibited reduced foam cell formation and lipid uptake; and excreted more lipids. The deficiency of Flna in macrophages markedly reduced the size of aortic atherosclerotic plaques in both Ldlr-/-BMT: Flnao/fl/LC and AdPCSK9-infected Flna o/fl/ LC mice. Intima/media ratios and numbers of CD68-positive macrophages in atherosclerotic plaques were lower in Flna-deficient mice than in control mice. Moreover, we found that STAT3 interacts with a calpain-cleaved carboxyl-terminal fragment of FLNA. Inhibiting calpain-mediated FLNA cleavage with calpeptin in macrophages reduced nuclear levels of phosphorylated STAT3, interleukin 6 secretion, foam cell formation, and lipid uptake. Finally, calpeptin treatment reduced the size of atherosclerotic plaques in C57BL/6 mice infected with AdPCSK9.Genetic inactivation of Flna and chemical inhibition of calpain-dependent cleavage of FLNA impaired macrophage signaling and function, and reduced atherosclerosis in mice, suggesting that drugs targeting FLNA may be useful in the treatment of atherosclerosis.
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| 19. |
- Behere, Anish, et al.
(författare)
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A proximity ligation assay recognizing phosphorylated α-syn reveals previously undetected α-syn pathology in the brains of synucleinopathy patients and mouse model.
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Aim: To enhance detection sensitivity of phosphorylated α-synuclein (pSynS129) on post mortem synucleinopathy brains using the newly developed PLA and characterize possible ‘strain’-specific differences in the synucleinopathy brains.Experimental plan: Four different antibodies detecting different epitopes from N- to C- terminal of α-syn were paired systematically with an antibody detecting pSynS129 to reveal patho-morphological features of α-syn aggregates on post mortem brain tissue. In addition, we tested the application of our novel PLA technique in the A30P-tg mouse model that shows different types of pSynS129 aggregates in different stages of PD.Results: The PLA experiments revealed a wide distribution of pSynS129 aggregates in post mortem synucleinopathy-patient brains. We observed unique staining patterns on the brain tissue sections using only certain antibody combinations in a PLA setup, which could not be visualized using regular immunohistochemistry. In A30P-tg mice, the morphological pattern of PLA signal indicated an age-progressive, intracellular shift of pSynS129 aggregation species from periphery towards soma in the prefrontal cortex.Significance: Here we demonstrate that employing PLA with certain α-syn antibodies pair combinations can enhance detection sensitivity and specificity of α-syn pathology in the respective synucleinopathies. Additionally, it could be a useful tool to monitor the ‘strain’-specific aggregation and intracellular morphology of α-syn on post mortem brain tissue.
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| 20. |
- Behere, Anish, et al.
(författare)
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Alpha synuclein pre-formed fibrils trigger astrocytic activation prior to intra-neuronal deposition in a seeding mouse model of Parkinson’s disease
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Aim: To monitor temporal evolution of glial and peripheral events occurring, prior to pSynS129 inclusion formation, after a single intra-cranial injection of pre-formed fibrils (PFFs) in the wild-type (wt) mice.Experimental plan: Here we perform intracerebral inoculations with mouse PFFs in wt mice (n=30) to study early pathological and inflammatory events from 1 to 30 days post-injections (dpi) at regular time intervals. The paraffin-fixed brain sections were stained against pSynS129 species with the in house developed proximity ligation assay. Furthermore, studies using different glial and inflammatory markers revealed more information regarding the early cellular interactions involving formation and propagation pSynS129 species.Results: Already after 1 dpi, we observe strong pSynS129 immunoreactivity close the striatal injection site. Intriguingly, this type of staining disappeared with the concurrent formation of peri-nuclear pSynS129 inclusions in motor and piriform cortex, amygdala and periventricular hypothalamus after 14 dpi. Concomitantly, we observed astrocytic activation as early event happening prior to intracellular formation and propagation pSynS129 inclusions in the brain and peripheral organs.Significance: Our study elucidates the temporal relationship regarding inflammation and formation of pSynS129 inclusions. Our results indicate that a single PFF injection is enough to induce astrocytic activation and neuro-inflammatory response that occur prior to intra-neuronal accumulation of misfolded α-syn.
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| 21. |
- Behere, Anish, 1993-
(författare)
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Ex‘PLA’ining the progression of pathological proteins in Alzheimer’s and Parkinson’s diseases : see(d)ing is believing
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the two most common forms of neurodegenerative disorders affecting approximately 50 million people worldwide. The underlying neuropathological processes leading to AD and PD share many similarities, i.e. aberrant protein aggregation of tau and alpha-synuclein (αSyn) in the brain. Monitoring tau and αSyn aggregation is challenging, due to morphological heterogeneity of the aggregating species and problems in preserving the antigen conformation ex vivo.In paper-I, we validated the usefulness of proximity ligation assay (PLA), a technique that enabled us to visualize previously undetected early αSyn pathology in the A30P-tg mouse model of PD. We observed an age-progressive increase in the levels of phosphorylated αSyn (pSynS129) and the compactness of aggregates in the brain. Although loss of dopaminergic neurons was not found, a subtle dysregulation of other catecholamines was recorded in the older mice.In paper-II, we revealed a wide distribution of pSynS129 aggregates in alpha-synucleinopathy-patient brains. By using a PLA setup with certain antibody pair combinations on brain sections, we observed unique staining patterns, which could not be visualized using regular immunohistochemistry (IHC). In A30P-tg mice, the morphological pattern of the PLA signals indicated an intracellular shift of pSynS129 from the periphery towards the neuronal soma.In Paper-III, we demonstrated that multiplex pTauS202,T205-pTauT231, singleplex pTauT231 and singleplex pSynS129 PLAs can recognize an extensive tau and αSyn pathology compared to regular IHC. We found that using our PLA approach we could differentiate between pTauS202,T205 and pTauT231 pathology in AD brains, whereas IHC could not. Similarly, in the PD brain, singleplex pSynS129 PLA detected novel structures, i.e. apparent thick intercellular tunnelling nanotubes and early aggregates; whereas pSynS129 IHC was limited to the detection of mature pathology. Lastly, we demonstrated that our multiplex PLA approach detected co-aggregates of pSynS129-pTau.In Paper-IV, in an αSyn seeding mouse model we observed pSynS129 immunoreactivity close to the striatal injection site one day post-injection (dpi). Intriguingly, this type of staining disappeared with the concurrent formation of peri-nuclear pSynS129 inclusions in specific brain regions after 14 dpi. In parallel, astrocytic activation prior to pSynS129 inclusion formation was observed.In conclusion, we have developed several novel PLAs that detect both tau and αSyn pathology with a higher ex vivo sensitivity and specificity than currently used immunostaining methods. This thesis work provides valuable insights that potentially could be used for the development of future biomarkers for tauopathies and synucleinopathies.
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| 22. |
- Behere, Anish, et al.
(författare)
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Novel visualization of phosphorylated tau and alpha-synuclein aggregates in the Alzheimer’s disease and Parkinson’s disease brain
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Several neurodegenerative diseases, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), display deposits of phosphorylated tau (pTau) and/or alpha-synuclein (pSyn) in affected parts of the brain. However, the pathological and morphological properties of these protein aggregates remain poorly characterized, due to lack of specificity and sensitivity of in situ detection techniques. The aim of this study was to investigate the patho-morphological properties of phosphorylated tau and α-syn aggregates on AD and PD brain tissues with a novel sensitive in situ proximity ligation assay (PLA) technique. We took advantage of the sensitivity and <40 nm resolution of PLA, along with the selectivity of different antibodies directed against pTau and pSyn epitopes. Most notably, multiplex pTauS202, T205-pTauT231, singleplex pTauT231 and pSynS129 PLA recognized more extensive phosphorylated tau and αSyn pathology, compared to conventional immunohistochemistry (IHC) using the same antibodies on adjacent brain sections. Furthermore, singleplex pTauT231 PLA captured additional pathological aggregates compared to the singleplex pTauS202, T205 PLA in late Braak stage AD brains, where traditional IHC failed to distinguish between pTauS202, T205 and pTauT231 pathology. Similarly, in PD brains, singleplex pSynS129 PLA detected novel pathological structures, such as intercellular thick tunneling nanotubes and pre-Lewy body intracytoplasmic aggregates, whereas pSynS129 IHC was limited to the detection of mature Lewy body/neurite pathology. Lastly, we could demonstrate that our dual PLA approach also can be applied to detect co-aggregates of pSyn-pTau.
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| 23. |
- Behere, Anish, 1993-, et al.
(författare)
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Visualization of early oligomeric α‐synuclein pathology and its impact on the dopaminergic system in the (Thy‐1)‐h[A30P]α‐syn transgenic mouse model
- 2021
-
Ingår i: Journal of Neuroscience Research. - : John Wiley & Sons. - 0360-4012 .- 1097-4547. ; 99:10, s. 2525-2539
-
Tidskriftsartikel (refereegranskat)abstract
- Aggregation of alpha-synuclein (alpha-syn) into Lewy bodies and Lewy neurites is a pathological hallmark in the Parkinson ' s disease (PD) brain. The formation of alpha-syn oligomers is believed to be an early pathogenic event and the A30P mutation in the gene encoding alpha-syn, causing familial PD, has been shown to cause an accelerated oligomerization. Due to the problem of preserving antigen conformation on tissue surfaces, alpha-syn oligomers are difficult to detect ex vivo using conventional immunohistochemistry with oligomer-selective antibodies. Herein, we have instead employed the previously reported alpha-syn oligomer proximity ligation assay (ASO-PLA), along with a wide variety of biochemical assays, to discern the pathological progression of alpha-syn oligomers and their impact on the dopaminergic system in male and female (Thy-1)-h[A30P]alpha-syn transgenic (A30P-tg) mice. Our results reveal a previously undetected abundance of alpha-syn oligomers in midbrain of young mice, whereas phosphorylated (pS129) and proteinase k-resistant alpha-syn species were observed to a larger extent in aged mice. Although we did not detect loss of dopaminergic neurons in A30P-tg mice, a dysregulation in the monoaminergic system was recorded in older mice. Taken together, ASO-PLA should be a useful method for the detection of early changes in alpha-syn aggregation on brain tissue, from experimental mouse models in addition to post mortem PD cases.
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| 24. |
- Belgrano, Andrea, et al.
(författare)
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Överfiske - en miljöfarlig aktivitet : orsaker till fiskbeståndens utarmning och dess konsekvenser i svenska hav
- 2011
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Bestånden av marina fiskarter har minskat dramatiskt i både Västerhavet och i Östersjön under de senaste 100 åren. Flera olika faktorer påverkar fiskbeståndens storlek, men ett ökande antal studier tyder på att överfiske är en huvudorsak i de flesta fall. Fisket med trål anses också skada många bottenlevande organismer, men det är idag oklart hur omfattande denna miljöpåverkan är. Vidare tyder nya studier på att förlusten av stora rovfiskar kan ge negativa effekter på hela ekosystem genom trofiska kedjereaktioner. Sammantaget anser många forskare idag att fisket utgör ett av de allvarligaste miljöhoten mot svenska hav. Denna rapport sammanställer det vetenskapliga kunskapsläget över orsakerna till nedgången av svenska marina fiskbestånd, samt fiskets roll för minskning av biodiversitet och förändringar i svenska kust- och utsjöekosystem.
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| 25. |
- Bergh, Johan, 1983-
(författare)
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Structural investigation of SOD1 aggregates in ALS : identification of prion strains using anti-peptide antibodies
- 2018
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative syndrome characterized by progressive degeneration of motor neurons that result in muscle wasting. The symptoms advance gradually to paralysis and eventually death. Most patients suffer from sporadic ALS (sALS) but 10% report a familial predisposition. Mutations in the gene encoding superoxide dismutase-1 (SOD1) were the first identified cause of ALS. The disease mechanism is debated but there is a consensus that mutations in this protein confer a cytotoxic gain of function. SOD1 aggregates in motor neurons are hallmarks of ALS both in patients and in transgenic mouse models expressing a mutated form of human SOD1 (hSOD1). Recently, our group showed that SOD1 aggregates are present also in sALS patients, thus indicating a broader involvement of this protein in ALS. Misfolding and aggregation of SOD1 are difficult to study in vivo since aggregate concentration in the central nervous system (CNS) is exceedingly low. The aim of this thesis was to find a method circumventing this problem to investigate the hSOD1 aggregate structure, distribution and spread in ALS disease.Many studies provide circumstantial evidence that the wild-type hSOD1 protein can be neurotoxic. We developed the first homozygous mouse model that highly overexpresses the wild-type enzyme. These mice developed an ALS-like syndrome and become terminally ill after around 370 days. Motor neuron loss and SOD1 aggregate accumulation in the CNS were observed. This lends further support to the hypothesis of a more general involvement of SOD1 in human disease.A panel of polyclonal antibodies covering 90% of the SOD1 protein was developed by our laboratory. These antibodies were shown to be highly specific for misfolded SOD1. Aggregated hSOD1 was purified from the CNS of terminally ill hSOD1 mice. Disordered segments in aggregated hSOD1 could be identified with these antibodies. Two aggregate strains with different structural architectures, molecular properties, and growth kinetics, were found using this novel method. The strains, denoted A and B, were also associated with different disease progression. Aggregates formed in vitro were structurally different from these strains. The results gave rise to questions about aggregate development and possible prion-like spread. To investigate this, inoculations of purified strain A and B hSOD1 seeds was performed in lumbar spinal cords of 100-day old mice carrying a hSOD1G85R mutation. Mice seeded with A or B aggregates developed premature signs of ALS and became terminally ill 200 days earlier than mice inoculated with control preparation. Interestingly, a templated spread of aggregates along the neuraxis was concomitantly observed, with strain A and B provoking the buildup of their respective hSOD1 aggregate structure. The phenotypes initiated by the A and B strains differed regarding progression rates, distribution, end-stage aggregate levels, and histopathology. To further establish the importance of hSOD1 aggregates in human disease, purification and inoculation of aggregate seeds from spinal cords of ALS patients and mice carrying the hSOD1G127X mutation were performed. Inoculation of both human and mouse seeds as described above, induced strain A aggregation and premature fatal ALS-like disease.In conclusion, the data presented in this thesis provide a new, straightforward method for characterization of aggregate strains in ALS, and plausibly also in other neurodegenerative diseases. Two different prion strains of hSOD1 aggregates were identified in mice that resulted in ALS-like disease. Emerging data suggest that prion-like growth and spread of hSOD1 aggregation could be the primary pathogenic mechanism not only in hSOD1 transgenic models, but also in human ALS.
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| 26. |
- Bergström, Erik, 1976-, et al.
(författare)
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Erfarenheter, lärdomar och effekter med gränsöverskridande arbete för utbytesstudier
- 2018
-
Ingår i: NU2018 - Det akademiska lärarskapet.
-
Konferensbidrag (refereegranskat)abstract
- I Högskolan i Skövdes (HS) nuvarande utvecklingsplan beskrivs att samtliga utbildningsprogram som ges vid lärosätet skall erbjuda möjligheter till studier utomlands. Som en konsekvens har en strategisk satsning för att stimulera en ökad mobilitet vid HS initierats genom att Institutionen för informationsteknologi (IIT) tillsammans med verksamhetsstödet har deltagit i ett UHR-projekt med fokus på vägledningsprocessen i samband med mobilitet.Projektet har pågått under 18 månader och ett 10-tal deltagare som representerar de flesta roller som är involverade i internationaliseringsarbetet på IIT och verksamhetsstödet har ingått. Projektet har bedrivits främst som en serie av workshoppar där parallell datainsamling har skett med hjälp av intervjuer och enkätstudier.I detta bidrag vill vi visa några av de mål som projektet fokuserat på samt syftet med dessa. Projektet har haft följande mål:Identifiera minst tre partnerlärosäten som passar varje utbildningsprogram - Målet syftar till att kartlägga både existerande och nya partnerlärosäte för att på så sätt sänka tröskeln för studenter som är intresserade av utbyte, men som har svårt att hitta lämpliga alternativ.Tydliggöra roll- och ansvarsfördelning i mobilitetsprocessen - Detta mål syftar till att utforma processbeskrivningar för att tydliggöra roll- och ansvarsfördelning kring utresandeprocessen för programansvarig, ämnesföreträdare, internationell koordinator, studie- och karriärvägledaren, studenten och partnerlärosätet. Även kommunikationsaspekter och studentperspektiv beaktas i detta mål.Skapa adekvat vägledning och informationsinsatser gentemot studenterna - Syftet med målet är att utveckla, strukturera och systematisera informationsvägar och kommunikation mellan vägledning, programansvarig, partnerlärosäte och studenter.Identifiera och utvärdera nyckelfaktorerna för att förbättra stödet till studenterna, undanröja hinder i mobilitetsprocessen samt underlätta programansvarigas och studie- och karriärvägledarnas arbete med utresande studenter - Målet är att identifiera och utvärdera nyckelfaktorer som hindrar mobilitet som kan spridas internt på HS samt externt för att i förlängningen öka mobiliteten bland Sveriges studenter.Se till att samtliga kandidatprogram på IIT har en termin avsatt för utlandsstudier och undanröja de hinder som finns i befintliga programstrukturer - Syftet är att göra det enklare för studenter att under sin ordinarie studietid genomföra utbytesstudier utan att deras studier vid HS blir drabbade av förkunskapsstrukturer som hindrar fortsatta studier vid hemkomst.I studien inkludera de studenter som har varit intresserade eller sökt utbytesstudier men som inte kommit iväg på utbyte - Syftet är att skapa en god översikt över vilka skäl denna studentkategori har haft för att avstå utbytesstudier för att på så vis kunna förbättra existerande processer för utbytesstudier och därmed minimera risken att intresserade studenter väljer att avstå från utbytesstudier.Vid projektets avslut analyserades projektets direkta och indirekta interorganisatoriska effekter tillsammans med aktuell statistik för de studenter som under 2017 nominerats för utbytesstudier. En uppenbar effekt av projektets arbete är att antalet studenter som 2017 vid IIT nominerats för utbytesstudier ökat kraftigt. Likaså observeras ökade kunskaper om processen kring utbytesstudier och ett förbättrat studentperspektiv och bättre kunskaper om studenternas upplevelse av nomineringsprocessen.Under presentation vill vi visa upp fler detaljer från vår analys samt hur vi planerar att arbeta vidare med de resultat vi fått fram i projektet.
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| 27. |
- Bergström, Göran, 1964, et al.
(författare)
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Prevalence of Subclinical Coronary Artery Atherosclerosis in the General Population
- 2021
-
Ingår i: Circulation. - Philadelphia : American Heart Association. - 0009-7322 .- 1524-4539. ; 144:12, s. 916-929
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Early detection of coronary atherosclerosis using coronary computed tomography angiography (CCTA), in addition to coronary artery calcification (CAC) scoring, may help inform prevention strategies. We used CCTA to determine the prevalence, severity, and characteristics of coronary atherosclerosis and its association with CAC scores in a general population.Methods: We recruited 30 154 randomly invited individuals age 50 to 64 years to SCAPIS (the Swedish Cardiopulmonary Bioimage Study). The study includes individuals without known coronary heart disease (ie, no previous myocardial infarctions or cardiac procedures) and with high-quality results from CCTA and CAC imaging performed using dedicated dual-source CT scanners. Noncontrast images were scored for CAC. CCTA images were visually read and scored for coronary atherosclerosis per segment (defined as no atherosclerosis, 1% to 49% stenosis, or ≥50% stenosis). External validity of prevalence estimates was evaluated using inverse probability for participation weighting and Swedish register data.Results: In total, 25 182 individuals without known coronary heart disease were included (50.6% women). Any CCTA-detected atherosclerosis was found in 42.1%; any significant stenosis (≥50%) in 5.2%; left main, proximal left anterior descending artery, or 3-vessel disease in 1.9%; and any noncalcified plaques in 8.3% of this population. Onset of atherosclerosis was delayed on average by 10 years in women. Atherosclerosis was more prevalent in older individuals and predominantly found in the proximal left anterior descending artery. Prevalence of CCTA-detected atherosclerosis increased with increasing CAC scores. Among those with a CAC score >400, all had atherosclerosis and 45.7% had significant stenosis. In those with 0 CAC, 5.5% had atherosclerosis and 0.4% had significant stenosis. In participants with 0 CAC and intermediate 10-year risk of atherosclerotic cardiovascular disease according to the pooled cohort equation, 9.2% had CCTA-verified atherosclerosis. Prevalence estimates had excellent external validity and changed marginally when adjusted to the age-matched Swedish background population.Conclusions: Using CCTA in a large, random sample of the general population without established disease, we showed that silent coronary atherosclerosis is common in this population. High CAC scores convey a significant probability of substantial stenosis, and 0 CAC does not exclude atherosclerosis, particularly in those at higher baseline risk.
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| 28. |
- Bergström, Göran, et al.
(författare)
-
Prevalence of Subclinical Coronary Artery Atherosclerosis in the General Population
- 2021
-
Ingår i: Circulation. - : Wolters Kluwer. - 0009-7322 .- 1524-4539. ; 144:12, s. 916-929
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Early detection of coronary atherosclerosis using coronary computed tomography angiography (CCTA), in addition to coronary artery calcification (CAC) scoring, may help inform prevention strategies. We used CCTA to determine the prevalence, severity, and characteristics of coronary atherosclerosis and its association with CAC scores in a general population.Methods: We recruited 30 154 randomly invited individuals age 50 to 64 years to SCAPIS (the Swedish Cardiopulmonary Bioimage Study). The study includes individuals without known coronary heart disease (ie, no previous myocardial infarctions or cardiac procedures) and with high-quality results from CCTA and CAC imaging performed using dedicated dual-source CT scanners. Noncontrast images were scored for CAC. CCTA images were visually read and scored for coronary atherosclerosis per segment (defined as no atherosclerosis, 1% to 49% stenosis, or ≥50% stenosis). External validity of prevalence estimates was evaluated using inverse probability for participation weighting and Swedish register data.Results: In total, 25 182 individuals without known coronary heart disease were included (50.6% women). Any CCTA-detected atherosclerosis was found in 42.1%; any significant stenosis (≥50%) in 5.2%; left main, proximal left anterior descending artery, or 3-vessel disease in 1.9%; and any noncalcified plaques in 8.3% of this population. Onset of atherosclerosis was delayed on average by 10 years in women. Atherosclerosis was more prevalent in older individuals and predominantly found in the proximal left anterior descending artery. Prevalence of CCTA-detected atherosclerosis increased with increasing CAC scores. Among those with a CAC score >400, all had atherosclerosis and 45.7% had significant stenosis. In those with 0 CAC, 5.5% had atherosclerosis and 0.4% had significant stenosis. In participants with 0 CAC and intermediate 10-year risk of atherosclerotic cardiovascular disease according to the pooled cohort equation, 9.2% had CCTA-verified atherosclerosis. Prevalence estimates had excellent external validity and changed marginally when adjusted to the age-matched Swedish background population.Conclusions: Using CCTA in a large, random sample of the general population without established disease, we showed that silent coronary atherosclerosis is common in this population. High CAC scores convey a significant probability of substantial stenosis, and 0 CAC does not exclude atherosclerosis, particularly in those at higher baseline risk.
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| 29. |
- Bergström, Joakim, 1987-
(författare)
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A Search for the Masked Mechanism Behind IgG-Mediated Suppression of Antibody Responses
- 2017
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Antibodies passively administered together with their specific antigen can enhance or suppress the specific antibody response. This phenomenon is known as antibody feedback regulation. Whether this modulation causes up- or downregulation of the antibody response depends both on the antibody isotype and the antigen used. IgG antibodies passively administered together with particulate antigens, e.g. erythrocytes, can completely prevent the induction of an antibody response to the antigen. The suppressive capacity of IgG has been routinely used in the clinic since the 1960’s in RhD-prophylaxis to prevent hemolytic disease of the fetus and newborn. Although studied for decades, the underlying mechanism of IgG-suppression has remained elusive. The main focus of this thesis has been to elucidate the mechanism behind IgG-suppression of antibody responses in vivo in mouse models using intravenous immunization with specific IgG together with native or haptenated sheep red blood cells, SRBC. We show that IgG-suppression of IgM and long-term serum IgG-responses operates independently of activating FcγRI, III, IV, or the inhibitory FcγRIIB, thus confirming and extending previous findings. Moreover, we demonstrate for the first time that C1q, C3 and CR1/2 are dispensable for IgG-suppression of antibody responses. These findings strongly argue against the involvement of Fc-dependent mechanisms as the explanation for IgG-suppression. Interestingly, GC formation occurs in IgG-suppressed mice although the antibody response to surface SRBC epitopes are completely suppressed. The data suggests that these GCs develop in response to intracellular SRBC epitopes as well as to the passively administered suppressive IgG. Moreover, we demonstrate that passively administered IgG suppresses several parameters of an antibody/B cell response including antigen specific GC and non-GC B cells, extra-follicular antibody secreting cells, long-lived plasma cells and induction of immunological memory. Before the onset of the present study, two mechanisms appeared compatible with the majority of experimental findings: IgG-mediated antigen clearance and epitope masking. Herein we show that the contribution of IgG-mediated antigen clearance is negligible and that suppression of IgG-responses is strictly epitope specific. This provides compelling evidence that a very important mechanism underlying IgG-suppression is epitope masking.
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| 30. |
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| 31. |
- Bergström, Joakim, et al.
(författare)
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An Overview of Mechanical Properties and Material Modeling of Polylactide (PLA) for Medical Applications
- 2016
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Ingår i: Annals of Biomedical Engineering. - : Springer Science and Business Media LLC. - 0090-6964 .- 1573-9686. ; 44:2, s. 330-340
-
Tidskriftsartikel (refereegranskat)abstract
- This article provides an overview of the connection between the microstructural state and the mechanical response of various bioresorbable polylactide (PLA) devices for medical applications. PLLA is currently the most commonly used material for bioresorbable stents and sutures, and its use is increasing in many other medical applications. The non-linear mechanical response of PLLA, due in part to its low glass transition temperature (T g ≈ 60 °C), is highly sensitive to the molecular weight and molecular orientation field, the degree of crystallinity, and the physical aging time. These microstructural parameters can be tailored for specific applications using different resin formulations and processing conditions. The stress-strain, deformation, and degradation response of a bioresorbable medical device is also strongly dependent on the time history of applied loads and boundary conditions. All of these factors can be incorporated into a suitable constitutive model that captures the multiple physics that are involved in the device response. Currently developed constitutive models already provide powerful computations simulation tools, and more progress in this area is expected to occur in the coming years.
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| 32. |
- Bergström, Joakim, 1972-
(författare)
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Apolipoprotein A-IV and Transthyretin in Swedish Forms of Systemic Amyloidosis
- 2004
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Over 20 different plasma proteins have been shown to have the capacity to undergo conformational changes and self-assemble into highly stable and insoluble amyloid fibrils. One, transthyretin (TTR), consists of 127 amino acid residues arranged in eight β-strands (named A to H) and is involved in two different clinical forms of amyloidosis. In familial amyloidotic polyneuropathy (FAP), mutated TTR is found in the amyloid deposits while in senile systemic amyloidosis (SSA) only wild type TTR is present in the amyloid deposits.In this study, we have identified a novel form of amyloidosis that is caused by the deposition of an N-terminal fragment of apolipoprotein A-IV (apoA-IV). Interestingly, apoA-IV amyloid was found deposited in a patient that also suffered from SSA. Thus, this patient had two biochemically distinct and concurrent forms of amyloidosis that were derived from apoA-IV and TTR. We have also discovered that two different morphological deposition patterns (identified as patterns A and B) exist in TTR-derived amyloidosis. Pattern A, observed in all SSA patients studied and in half of the FAP patients examined contained large homogenous deposits that were composed of short randomly oriented fibrils. In contrast, pattern B was observed in the remaining FAP patients and was represented by smaller-sized deposits that consisted of longer fibrils that were arranged in parallel bundles. The predominant TTR component deposited also differed between the two amyloid patterns. Amyloid pattern A contained mainly C-terminal TTR fragments while pattern B amyloid consisted of full-length TTR. Our findings suggest that two different mechanisms of fibril formation may exist in TTR-derived amyloidosis. We have found two epitopes, corresponding to strand C and H that are surface-exposed in TTR-derived amyloid fibrils but hidden and part of the hydrophobic core in the native molecular structure. This indicates that TTR undergoes partial unfolding during fibril formation.
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| 33. |
- Bergström, Joakim, et al.
(författare)
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Codeposition of apolipoprotein A-IV and transthyretin in senile systemic (ATTR) amyloidosis
- 2001
-
Ingår i: Biochemical and Biophysical Research Communications - BBRC. - : Elsevier BV. - 0006-291X .- 1090-2104. ; 285:4, s. 903-908
-
Tidskriftsartikel (refereegranskat)abstract
- Protein material was extracted from amyloid-rich sections of formalin-fixed and paraffin-embedded heart tissue from an individual with senile systemic amyloidosis, known to contain wild-type transthyretin as major amyloid fibril protein. Amino acid sequence analysis of tryptic peptides of this material revealed in addition to transthyretin sequences, also amino acid sequence corresponding to an N-terminal fragment of apolipoprotein A-IV. In immunohistochemistry, an antiserum to a synthetic apolipoprotein A-IV peptide labeled amyloid specifically. This peptide formed spontaneously amyloid-like fibrils in vitro and enhanced fibril formation from wild-type transthyretin. We conclude that several apolipoproteins, including apolipoprotein A-IV, may be important minor amyloid constituents, promoting fibril formation.
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| 34. |
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| 35. |
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| 36. |
- Bergström, Joakim, et al.
(författare)
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Epitope-Specific Suppression of IgG Responses by Passively Administered Specific IgG : Evidence of Epitope Masking
- 2017
-
Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 8
-
Tidskriftsartikel (refereegranskat)abstract
- Specific IgG, passively administered together with particulate antigen, can completely prevent induction of antibody responses to this antigen. The ability of IgG to suppress antibody responses to sheep red blood cells (SRBCs) is intact in mice lacking Fc gamma Rs, complement factor 1q, C3, or complement receptors 1 and 2, suggesting that Fc-dependent effector functions are not involved. Two of the most widely discussed explanations for the suppressive effect are increased clearance of IgG-antigen complexes and/or that IgG "hides" the antigen from recognition by specific B cells, so-called epitope masking. The majority of data on how IgG induces suppression was obtained through studies of the effects on IgM-secreting single spleen cells during the first week after immunization. Here, we show that IgG also suppresses antigen-specific extrafollicular antibody-secreting cells, germinal center B-cells, longlived plasma cells, long-term IgG responses, and induction of memory antibody responses. IgG anti-SRBC reduced the amount of SRBC in the spleens of wild-type, but not of Fc gamma R-deficient mice. However, no correlation between suppression and the amount of SRBC in the spleen was observed, suggesting that increased clearance does not explain IgG-mediated suppression. Instead, we found compelling evidence for epitope masking because IgG anti-NP administered with NP-SRBC suppressed the IgG anti-NP, but not the IgG anti-SRBC response. Vice versa, IgG anti-SRBC administered with NP-SRBC, suppressed only the IgG anti-SRBC response. In conclusion, passively transferred IgG suppressed all measured parameters of an antigen-specific antibody/B cell response and an important mechanism of action is likely to be epitope masking.
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| 37. |
- Bergström, Joakim H., 1977, et al.
(författare)
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AGR2, an endoplasmic reticulum protein, is secreted into the gastrointestinal mucus.
- 2014
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Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 9:8
-
Tidskriftsartikel (refereegranskat)abstract
- The MUC2 mucin is the major constituent of the two mucus layers in colon. Mice lacking the disulfide isomerase-like protein Agr2 have been shown to be more susceptible to colon inflammation. The Agr2(-/-) mice have less filled goblet cells and were now shown to have a poorly developed inner colon mucus layer. We could not show AGR2 covalently bound to recombinant MUC2 N- and C-termini as have previously been suggested. We found relatively high concentrations of Agr2 in secreted mucus throughout the murine gastrointestinal tract, suggesting that Agr2 may play extracellular roles. In tissue culture (CHO-K1) cells, AGR2 is normally not secreted. Replacement of the single Cys in AGR2 with Ser (C81S) allowed secretion, suggesting that modification of this Cys might provide a mechanism for circumventing the KTEL endoplasmic reticulum retention signal. In conclusion, these results suggest that AGR2 has both intracellular and extracellular effects in the intestine.
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| 38. |
- Bergström, Joakim H., 1977, et al.
(författare)
-
Gram-positive bacteria are held at a distance in the colon mucus by the lectin-like protein ZG16
- 2016
-
Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 113:48, s. 13833-13838
-
Tidskriftsartikel (refereegranskat)abstract
- The small lectin-like protein ZG16 (zymogen granulae protein 16) aggregates bacteria and by that works together with the inner colon mucus layer to maintain bacteria at a safe distance from the epithelial cell surface. In the absence of Zg16, more bacteria penetrate the epithelium, enter the regional lymph nodes and spleen, trigger the immune system, and cause abdominal fat pad mass increase. ZG16 is important for a safe normal host-bacteria symbiosis as it does not kill commensal bacteria, but limit bacterial translocation into the host.
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| 39. |
- Bergström, Joakim H., 1977
(författare)
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Mucus associated proteins and their functional role in the distal intestine
- 2014
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The mammalian intestine, especially the large intestine, harbors complex societies of beneficial bacteria coexisting with the host. This is a mutualistic relationship, where the host provides nutrients and a favorable environment while the bacteria in return ferment indigestible polysaccharides to short chain fatty acids. The host needs to keep the bacteria at a safe distance from the intestinal cells to prevent disease. The first line of defense hindering these microorganisms from invading the underlying epithelium is a mucus layer built by the highly polymeric and heavily O-glycosylated MUC2 mucin, the main structural component. In the colon this mucus barrier is made up of two layers with similar composition. The outer layer is loose and easy removable while the inner is more dense and firmly adherent to the underlying epithelium. The inner layer is impermeable to bacteria and therefore separates the bacteria that reside in the lumen from the epithelial cells. In order to obtain a better understanding of the function and structure of this dynamic barrier we analyzed the mucus using proteomics based approaches to identify novel mucus components The focus of this thesis has been trying to understand the specific protective role of the MUC2 assosiated proteins in the mucus layer. Three proteins were chosen for further studies based on their abundance and production by the mucus secreting goblet cell. AGR2 belongs to the protein disulfide isomerase family, and has been proven important for proper MUC2 production. Using molecular biology tools and cell culture experiment it was shown that AGR2 does not covalently bind the MUC2 terminal recombinant proteins and that secretion of the molecule is dependent on an internal cysteine residue. The mucin-like protein FCGBP is a highly repetitive molecule that contains 13 von Willebrand D domains. Eleven of these contain an autocatalytic cleavage site that forms a new reactive C-terminus after cleavage, which occurs early during biosynthesis. ZG16 is a lectin-like molecule that has now been shown to bind peptidoglycan, the major bacterial cell wall component, via its carbohydrate recognition domain. It was shown that ZG16 is not bactericidal, but that it binds and aggregates Gram-positive bacteria and translocate them further out in the mucus. ZG16 is also able to bind to enterocytes via a protein receptor implying a novel sensory function. In summary, the results from this thesis demonstrate that these MUC2 associated proteins are important to form a functional protective mucus layer that prevents bacteria to reach the epithelium and by this cause disease.
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| 40. |
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| 41. |
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| 42. |
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| 43. |
- Bergström, Joakim J E, et al.
(författare)
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IgG Suppresses Antibody Responses in Mice Lacking C1q, C3, Complement Receptors 1 and 2, or IgG Fc-Receptors.
- 2015
-
Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:11
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Tidskriftsartikel (refereegranskat)abstract
- Antigen-specific IgG antibodies, passively administered to mice or humans together with large particulate antigens like erythrocytes, can completely suppress the antibody response against the antigen. This is used clinically in Rhesus prophylaxis, where administration of IgG anti-RhD prevents RhD-negative women from becoming immunized against RhD-positive fetal erythrocytes aquired transplacentally. The mechanisms by which IgG suppresses antibody responses are poorly understood. We have here addressed whether complement or Fc-receptors for IgG (FcγRs) are required for IgG-mediated suppression. IgG, specific for sheep red blood cells (SRBC), was administered to mice together with SRBC and the antibody responses analyzed. IgG was able to suppress early IgM- as well as longterm IgG-responses in wildtype mice equally well as in mice lacking FcγRIIB (FcγRIIB knockout mice) or FcγRI, III, and IV (FcRγ knockout mice). Moreover, IgG was able to suppress early IgM responses equally well in mice lacking C1q (C1qA knockout mice), C3 (C3 knockout mice), or complement receptors 1 and 2 (Cr2 knockout mice) as in wildtype mice. Owing to the previously described severely impaired IgG responses in the complement deficient mice, it was difficult to assess whether passively administered IgG further decreased their IgG response. In conclusion, Fc-receptor binding or complement-activation by IgG does not seem to be required for its ability to suppress antibody responses to xenogeneic erythrocytes.
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| 44. |
- Bergström, Joakim J. E., et al.
(författare)
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Mice Immunized With IgG Anti-Sheep Red Blood Cells (SRBC) Together With SRBC Have a Suppressed Anti-SRBC Antibody Response but Generate Germinal Centers and Anti-IgG Antibodies in Response to the Passively Administered IgG
- 2017
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Ingår i: Frontiers in Immunology. - : Frontiers Media S.A.. - 1664-3224. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Antigen-specific IgG antibodies, passively administered together with large particulate antigens such as erythrocytes, can completely suppress the antigen-specific antibody response. The mechanism behind has been elusive. Herein, we made the surprising observation that mice immunized with IgG anti-sheep red blood cells (SRBC) and SRBC, in spite of a severely suppressed anti-SRBC response, have a strong germinal center (GC) response. This occurred regardless of whether the passively administered IgG was of the same allotype as that of the recipient or not. Six days after immunization, the GC size and the number of GC B cells were higher in mice immunized with SRBC alone than in mice immunized with IgG and SRBC, but at the other time points these parameters were similar. GCs in the IgG-groups had a slight shift toward dark zone B cells 6 days after immunization and toward light zone B cells 10 days after immunization. The proportions of T follicular helper cells (TFH) and T follicular regulatory cells (TFR) were similar in the two groups. Interestingly, mice immunized with allogeneic IgG anti-SRBC together with SRBC mounted a vigorous antibody response against the passively administered suppressive IgG. Thus, although their anti-SRBC response was almost completely suppressed, an antibody response against allogeneic, and probably also syngeneic, IgG developed. This most likely explains the development of GCs in the absence of an anti-SRBC antibody response.
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| 45. |
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| 46. |
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| 47. |
- Bergström, Joakim, et al.
(författare)
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Surface exposed epitopes and structural heterogeneity of in vivo formed transthyretin amyloid fibrils
- 2006
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Ingår i: Biochemical and Biophysical Research Communications - BBRC. - : Elsevier BV. - 0006-291X .- 1090-2104. ; 348:2, s. 532-539
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Tidskriftsartikel (refereegranskat)abstract
- We have investigated the structure of in vivo formed transthyretin (TTR) amyloid deposits by using antisera raised against short linear sequences of the TTR molecule. In immunohistochemistry, antisera anti-TTR41-50 and anti-TTR115-124-a reacted specifically with both wildtype ATTR and ATTR V30M material, whereas only anti-TTR41-50 recognized ATTR Y114C material. Similar results were obtained by ELISA analysis of ATTR V30M and ATTR Y114C vitreous amyloid, where the anti-TTR115-124-a antiserum failed to react with ATTR Y114C material. Moreover, neither of the antisera recognized natively structured TTR present in pancreatic alpha cells. Our results strongly indicate that the TTR molecule undergoes structural changes during fibrillogenesis in vivo. The finding of a structural difference between wildtype ATTR and ATTR V30M material on one hand and ATTR Y114C material on the other suggests that the fibril formation pathway of these ATTR variants may differ in vivo.
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| 48. |
- Bergström, Joakim, et al.
(författare)
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Two different types of amyloid deposits - apolipoprotein A-IV and transthyretin - in a patient with systemic amyloidosis
- 2004
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Ingår i: Lab. Invest.. ; 84, s. 981-988
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Tidskriftsartikel (refereegranskat)abstract
- Certain forms of systemic amyloidosis have been associated with the pathologic deposition as fibrils of three different apolipoprotein-related proteins--apolipoprotein A-I, apolipoprotein A-II, and serum amyloid A. We have previously reported (Bergstrom et al, Biochem Biophys Res Commun 2001;285:903-908) that amyloid fibrils extracted from the heart of an elderly male with senile systemic amyloidosis contained, in addition to wild-type transthyretin-related molecules, an N-terminal fragment of yet a fourth apolipoprotein--apolipoprotein A-IV (apoA-IV). We now provide the results of our studies that have established the complete amino-acid sequence of this approximately 70-residue component and, additionally, have shown this protein to be the product of an unmutated apoA-IV gene. Notably, the apoA-IV and transthyretin fibrils were not codeposited but, rather, had anatomically distinct patterns of distribution within the heart and other organs, as evidenced immunohistochemically, by variation in the ultra structural morphology and by differences in the intensity of Congo red birefringence. These findings provide the first conclusive evidence that two separate forms of amyloid, each derived from a wild-type amyloidogenic precursor protein, were present in a patient with systemic amyloidosis.
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| 49. |
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| 50. |
- Bergström, Lars, et al.
(författare)
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Complementarity of direct dark matter detection and indirect detection through gamma rays
- 2011
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Ingår i: Physical Review D. - 1550-7998 .- 1550-2368. ; 83:4, s. 045024-
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Tidskriftsartikel (refereegranskat)abstract
- We show, by using an extensive sample of viable supersymmetric models as templates, that indirect detection of dark matter through gamma rays may have a large potential for identifying the nature of dark matter. This is, in particular, true also for models that give too weak dark matter-nucleon scattering cross sections to be probed by present and planned direct detection experiments. Also models with a mass scale too high to be accessible at CERN's LHC accelerator may show up in next-generation imaging Cherenkov telescope arrays. Based on our findings, we therefore suggest to view indirect searches as genuine particle physics experiments, complementing other strategies to probe so far unknown regions in the parameter space of e.g. supersymmetric models, and propose a new approach that would make use of telescopes dedicated for dark matter searches. As a concrete example for the potential of such an approach, we consider an array of imaging air Cherenkov telescopes, the Dark Matter Array (DMA), and show that such an experiment could extend present-day limits by several orders of magnitude, reaching a large class of models that would remain undetected in both direct detection experiments and searches at the LHC. In addition, in a sizable part of the parameter space, signals from more than one type of dark matter detection experiment would be possible, something that may eventually be necessary in order to identify the dark matter candidate.
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