SwePub
Sök i SwePub databas

  Utökad sökning

Träfflista för sökning "WFRF:(Hammarström Per) "

Sökning: WFRF:(Hammarström Per)

  • Resultat 1-50 av 299
Sortera/gruppera träfflistan
   
NumreringReferensOmslagsbildHitta
1.
  •  
2.
  • Forsberg, Göte, et al. (författare)
  • Presence of bacteria and innate immunity of intestinal epithelium in childhood celiac disease
  • 2004
  • Ingår i: American Journal of Gastroenterology. - : Ovid Technologies (Wolters Kluwer Health). - 0002-9270 .- 1572-0241. ; 99:5, s. 894-904
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVES: Exposure to gliadin and related prolamins and appropriate HLA-DQ haplotype are necessary but not sufficient for contracting celiac disease (CD). Aberrant innate immune reactions could be contributing risk factors. Therefore, jejunal biopsies were screened for bacteria and the innate immune status of the epithelium investigated.METHODS: Children with untreated, treated, challenged CD, and controls were analyzed. Bacteria were identified by scanning electron microscopy. Glycocalyx composition and mucin and antimicrobial peptide production were studied by quantitative RT-PCR, antibody and lectin immunohistochemistry.RESULTS: Rod-shaped bacteria were frequently associated with the mucosa of CD patients, with both active and inactive disease, but not with controls. The lectin Ulex europaeus agglutinin I (UEAI) stained goblet cells in the mucosa of all CD patients but not of controls. The lectin peanut agglutinin (PNA) stained glycocalyx of controls but not of CD patients. mRNA levels of mucin-2 (MUC2), alpha-defensins HD-5 and HD-6, and lysozyme were significantly increased in active CD and returned to normal in treated CD. Their expression levels correlated to the interferon-gamma mRNA levels in intraepithelial lymphocytes. MUC2, HD-5, and lysozyme proteins were seen in absorptive epithelial cells. beta-defensins hBD-1 and hBD-2, carcinoembryonic antigen (CEA), CEA cell adhesion molecule-1a (CEACAM1a), and MUC3 were not affected.CONCLUSIONS: Unique carbohydrate structures of the glycocalyx/mucous layer are likely discriminating features of CD patients. These glycosylation differences could facilitate bacterial adhesion. Ectopic production of MUC2, HD-5, and lysozyme in active CD is compatible with goblet and Paneth cell metaplasia induced by high interferon-gamma production by intraepithelial lymphocytes.
  •  
3.
  •  
4.
  • Hedberg, Maria E, 1959-, et al. (författare)
  • Lachnoanaerobaculum a new genus in Lachnospiraceae; characterization of Lachnoanaerobaculum umeaense gen. nov., sp. nov., isolated from human small intestine, Lachnoanaerobaculum orale gen. nov., sp. nov., isolated from saliva and reclassification of Eubacterium saburreum (Prevot) Holdeman and Moore 1970 as Lachnoanaerobaculum saburreum comb. nov.
  • 2012
  • Ingår i: International Journal of Systematic and Evolutionary Microbiology. - : Microbiology Society. - 1466-5026 .- 1466-5034. ; 62:11, s. 2685-2690
  • Tidskriftsartikel (refereegranskat)abstract
    • Two new obligately anaerobic Gram-positive, saccharolytic and non-proteolytic spore-forming bacilli (strain CD3:22 and N1) are described. Strain CD3:22 was isolated from a biopsy of the small intestine of a child with celiac disease and strain N1 from the saliva of a healthy young man. The cells of both strains were observed to be filamentous with lengths of approximately 5 to >20 µm, some of them curving and with swellings. The novel organisms produced H2S, NH3, butyric acid and acetic acid as major metabolic end products. Phylogenetic analyses, based on comparative 16S rRNA gene sequencing, revealed close relationships (98 % sequence similarity) between the two isolates, as well as the type strain of Eubacterium saburreum CCUG 28089T and four other Lachnospiraceae bacterium/E. saburreum-like organisms. This group of bacteria were clearly different from any of the 19 known genera in the family Lachnospiraceae. While Eubacterium spp. are reported to be non-spore-forming, reanalysis of E. saburreum CCUG 28089T confirmed that the bacterium, indeed, is able to form spores. Based on 16S rRNA gene sequencing, phenotypic and biochemical properties, CD3:22 (CCUG 58757T) and N1 (CCUG 60305T) represent new species of a new and distinct genus, named Lachnoanaerobaculum, in the family Lachnospiraceae [within the order Clostridiales, class Clostridia, phylum Firmicutes]. Strain CD3:22 is the type strain of the type species, Lachnoanaerobaculum umeaense gen. nov., sp. nov., of the proposed new genus. Strain N1 is the type strain of the species, Lachnoanaerobaculum orale gen. nov., sp. nov. Moreover, E. saburreum CCUG 28089T is reclassified as Lachnoanaerobaculum saburreum comb. nov.
  •  
5.
  • Hedberg, Maria E, et al. (författare)
  • Lachnoanaerobaculum gen. nov., a new genus in the Lachnospiraceae: characterization of Lachnoanaerobaculum umeaense gen. nov., sp. nov., isolated from the human small intestine, and Lachnoanaerobaculum orale sp. nov., isolated from saliva, and reclassification of Eubacterium saburreum (Prevot 1966) Holdeman and Moore 1970 as Lachnoanaerobaculum saburreum comb. nov.
  • 2012
  • Ingår i: International journal of systematic and evolutionary microbiology. - : Microbiology Society. - 1466-5034 .- 1466-5026. ; 62:Pt 11, s. 2685-90
  • Tidskriftsartikel (refereegranskat)abstract
    • Two novel obligately anaerobic, Gram-stain-positive, saccharolytic and non-proteolytic spore-forming bacilli (strains CD3:22(T) and N1(T)) are described. Strain CD3:22(T) was isolated from a biopsy of the small intestine of a child with coeliac disease, and strain N1(T) from the saliva of a healthy young man. The cells of both strains were observed to be filamentous, approximately 5 to >20 µm long, some of them curving and with swellings. The novel organisms produced H(2)S, NH(3), butyric acid and acetic acid as major metabolic end products. Phylogenetic analyses, based on comparative 16S rRNA gene sequencing, revealed close relationships (98% sequence similarity) between the two isolates, as well as the type strain of Eubacterium saburreum and four other Lachnospiraceae bacterium-/E. saburreum-like organisms. This group of bacteria were clearly different from any of the 19 known genera in the family Lachnospiraceae. While Eubacterium species are reported to be non-spore-forming, reanalysis of E. saburreum CCUG 28089(T) confirmed that the bacterium is indeed able to form spores. Based on 16S rRNA gene sequencing, phenotypic and biochemical properties, strains CD3:22(T) and N1(T) represent novel species of a new and distinct genus, named Lachnoanaerobaculum gen. nov., in the family Lachnospiraceae [within the order Clostridiales, class Clostridia, phylum Firmicutes]. Strain CD3:22(T) (=CCUG 58757(T) =DSM 23576(T)) is the type strain of the type species, Lachnoanaerobaculum umeaense gen. nov., sp. nov., of the proposed new genus. Strain N1(T) (=CCUG 60305(T)=DSM 24553(T)) is the type strain of Lachnoanaerobaculum orale sp. nov. Moreover, Eubacterium saburreum is reclassified as Lachnoanaerobaculum saburreum comb. nov. (type strain CCUG 28089(T) =ATCC 33271(T) =CIP 105341(T) =DSM 3986(T) =JCM 11021(T) =VPI 11763(T)).
  •  
6.
  •  
7.
  • Hueting, David A., et al. (författare)
  • Design, structure and plasma binding of ancestral β-CoV scaffold antigens
  • 2023
  • Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1
  • Tidskriftsartikel (refereegranskat)abstract
    • We report the application of ancestral sequence reconstruction on coronavirus spike protein, resulting in stable and highly soluble ancestral scaffold antigens (AnSAs). The AnSAs interact with plasma of patients recovered from COVID-19 but do not bind to the human angiotensin-converting enzyme 2 (ACE2) receptor. Cryo-EM analysis of the AnSAs yield high resolution structures (2.6–2.8 Å) indicating a closed pre-fusion conformation in which all three receptor-binding domains (RBDs) are facing downwards. The structures reveal an intricate hydrogen-bonding network mediated by well-resolved loops, both within and across monomers, tethering the N-terminal domain and RBD together. We show that AnSA-5 can induce and boost a broad-spectrum immune response against the wild-type RBD as well as circulating variants of concern in an immune organoid model derived from tonsils. Finally, we highlight how AnSAs are potent scaffolds by replacing the ancestral RBD with the wild-type sequence, which restores ACE2 binding and increases the interaction with convalescent plasma.
  •  
8.
  • Ihse, Elisabet, 1977- (författare)
  • Two Types of Fibrils in ATTR Amyloidosis : Implications for Clinical Phenotype and Treatment Outcome
  • 2011
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Systemic amyloidoses are a group of lethal diseases where proteins aggregate into fibrillar structures, called amyloid fibrils, that deposits throughout the body. Transthyretin (TTR) causes one type of amyloidosis, in which the aggregates mainly infiltrate nervous and cardiac tissue. Almost a hundred different mutations in the TTR gene are known to trigger the disease, but wild-type (wt) TTR is also incorporated into the fibrils, and may alone form amyloid. Patients with the TTRV30M mutation show, for unknown reasons, two clinical phenotypes. Some have an early onset of disease without cardiomyopathy while others have a late onset and cardiomyopathy. It has previously been described that amyloid fibrils formed from TTRV30M can have two different compositions; either with truncated molecules beside full-length TTR (type A) or only-full-length molecules (type B).  In this thesis, the clinical importance of the two types of amyloid fibrils was investigated. We found that the fibril composition types are correlated to the two clinical phenotypes seen among TTRV30M patients, with type A fibrils present in late onset patients and type B fibrils in early onset patients. The only treatment for hereditary TTR amyloidosis has been liver transplantation, whereby the liver producing the mutant TTR is replaced by an organ only producing wt protein. However, in some patients, cardiac symptoms progress post-transplantationally. We demonstrated that the propensity to incorporate wtTTR differs between fibril types and tissue types in TTRV30M patients, with cardiac amyloid of type A having the highest tendency. This offers an explanation to why particularly cardiac amyloidosis develops after transplantation, and suggests which patients that are at risk for such development. By examining patients with other mutations than TTRV30M, we showed that, in contrast to the general belief, a fibril composition with truncated TTR is very common and might even be the general rule. This may explain why TTRV30M patients often have a better outcome after liver transplantation than patients with other mutations. In conclusion, this thesis has contributed with one piece to the puzzle of understanding the differences in clinical phenotype and treatment response between TTR amyloidosis patients, by demonstrating corresponding differences at a molecular level.
  •  
9.
  • Laursen, Louise, 1988- (författare)
  • Exploring the Role of the PDZ Domain in a Supramodule
  • 2021
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • The postsynaptic density (PSD) is a large, dense and membraneless compartment of proteins associated below the postsynaptic membrane bilayer, and which constantly undergoes morphological alteration in response to synaptic activity. Formation of PSD is associated with liquid-liquid phase separation of scaffold proteins in complex with other PSD proteins. PSD-95, one of the most abundant scaffold proteins, contains five domains: PDZ1, PDZ2, PDZ3, Src homology 3 (SH3), and guanylate kinase-like (GK) domain. The domains are functionally divided in two supramodules: PDZ1-PDZ2 and PDZ3-SH3-GK (PSG). Multi-domain proteins are characterized through their isolated domains in most studies and represented by “beads on a string” model, which means that the function of a single domain is independent of the context. In this thesis, the properties of PDZ3 and PSG are compared to elucidate how and when PSD-95 can been characterized by the simple “beads on a string” model. Kinetic characterization of CRIPT binding to PDZ3 showed a two-state mechanism, but a more complex mechanism involving two conformational states upon binding to PSG. The results were consistent with recent structural findings of conformational changes in PSD-95, altogether showing that conformational transitions in supertertiary structures can shape the ligand-binding energy landscape and modulate protein-protein interactions. Next the allosteric networks in a PDZ:ligand complex were experimentally mapped, both in isolation and in the context of a supramodular structure. Data showed that allosteric networks in a PDZ3 domain has high dependency on the supertertiary structure. Furthermore, equilibrium and kinetic folding experiments were applied to demonstrate that the PDZ3 domain folds faster and independently from the SH3-GK tandem, which folds as one cooperative unit. However, concurrent folding of the PDZ3 domain slows down folding of SH3-GK by non-native interactions, resulting in an off-pathway folding intermediate. Finally, the interactome of PSG in PSD was mapped. PDZ3 and PSG show high specificity for peptides with type I PBM. Interestingly, two proteins called SynGap and AGRB1 only bind with high affinity to PSG and forms concentration dependent liquid droplets. The results show how context in terms of supertertiary structure alter affinity and function, and suggest a model for how PSD anchor to the postsynaptic membrane. Altogether, the findings in the thesis show that binding energy landscape, interactome, allosteric network, folding mechanism and phase separation are dependent on the context, which suggest that we need to be careful in interpretation of data obtained from isolated domains in multi-domain proteins.
  •  
10.
  •  
11.
  • Lundqvist, Carina (författare)
  • Human intraepithelial lymphocytes : a comparative study of phenotype, morphology, and functional properties of intraepithelial lymphocytes in gut and oral mucosa
  • 1995
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Human intraepithelial lymphocytes (IEL) constitute a unique cell population situated in the first line of defense of the alimentary tract. Here they are continuously exposed to a massive antigenic load of high complexity. However, different conditions prevail along the alimentary tract. In small intestine food antigens dominate whereas bacterial antigens are abundant in large intestine. The oral cavity is exposed to an enormous variety of antigens from the microflora as well as food constituents. The abundance and selective localization of lymphocytes in the surface epithelium of these challenged tissues implicate important roles for IEL in immune protection.IEL in normal human jejunum, ileum and colon as well as in normal and chronically inflamed gingiva were studied in situ and after isolation, with regard to phenotype, ultrastructure, cytokine mRNA expression and response to T-cell mitogens. Furthermore, an isolation technique was developed which yielded highly purified, functionally active IEL and enterocytes from the same sample.Intestinal IEL were situated in the basal part of the epithelium, often in small clusters and in close contact with adjacent lymphocytes and epithelial cells. They had an irregular shape with long processes and some had pseudopodium-like extensions penetrating the basement membrane. This indicates cell co-operation within the epithelium, as well as transmigration of IEL to underlying tissues. Freshly isolated IEL expressed several cytokines (IL-1β, IL-8, IL-2, TNF-α and IFN-γ) and in vitro activation induced expression of IL-2, IL-10, IFN-γ, TNF-α, TNF-β and TGF-β1, suggesting that IEL are involved in cell mediated cytotoxicity and suppressor cell activities.γδ T cells showed preferential homing to the epithelium both in gingiva and in intestine. They constituted the major lymphocyte population in normal gingiva and on average 30% of IEL at all levels of the intestine. Gingival as well as intestinal γδ IEL showed preferential usage of Vδ1Vγ8, suggesting common reactivity patterns along the alimentary tract. Intestinal γδ IEL and γδ IEL in normal gingiva were CD4-CD8-. In contrast, γδ IEL in chronically inflamed gingiva were predominantly CD8+ and showed induced expression of CD45RO. This indicates that γδ IEL participate in anti-bacterial immune responses in mucosa. Intestinal and gingival γδ IEL displayed ultrastructural features of cytolytic effector cells, e.g. electron-dense cytoplasmic granules and multivesicular bodies. They also expressed cytokines indicative of cell mediated-cytolytic effector functions. γδ IEL from inflamed gingiva expressed IFN-γ, TNF-α, TGF-β1 and IL-6 mRNA while intestinal γδ IEL expressed IL-2, IFN-γ and TNF-α.Intraepithelial αβ T cells were rare in gingiva while they constituted the major population of intestinal IEL. The phenotype of αβ IEL varied at different levels of the intestine. Thus, CD8+αβ IEL dominated in jejunum while cells with the unusual T-cell phenotype, CD4-CD8- TCR αβ+, constituted a major population of colonic IEL. CD4+ αβ IEL were equally represented, as a minor population, at all three levels of the gut. Intestinal αβ IEL had the same cytokine profile as γδ IEL. Taken together, these data suggest that αβ IEL are involved in immunoregulatory responses to luminal antigens.IEL with thymocyte-like phenotyped (CD2+TCR/CD3-, CD1+TCR/CD3-, CD1+TCRαβ+ and CD1+TCRγδ+) were present in jejunal epithelium. Furthermore, recombination activating gene-1 (RAG-1) mRNA was expressed in CD2+TCR/CD3- and CD3+/TCR- jejunal IEL. RAG-1 was not expressed in colonic IEL. Thus, the epithelium of small intestine is a site for extrathymic T cell maturation in humans.
  •  
12.
  • Mezheyeuski, Artur, et al. (författare)
  • An immune score reflecting pro- and anti-tumoural balance of tumour microenvironment has major prognostic impact and predicts immunotherapy response in solid cancers
  • 2023
  • Ingår i: EBioMedicine. - : Elsevier. - 2352-3964. ; 88
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Cancer immunity is based on the interaction of a multitude of cells in the spatial context of the tumour tissue. Clinically relevant immune signatures are therefore anticipated to fundamentally improve the accuracy in predicting disease progression.Methods: Through a multiplex in situ analysis we evaluated 15 immune cell classes in 1481 tumour samples. Single-cell and bulk RNAseq data sets were used for functional analysis and validation of prognostic and predictive associations.Findings: By combining the prognostic information of anti-tumoural CD8+ lymphocytes and tumour supportive CD68+CD163+ macrophages in colorectal cancer we generated a signature of immune activation (SIA). The prognostic impact of SIA was independent of conventional parameters and comparable with the state-of-art immune score. The SIA was also associated with patient survival in oesophageal adenocarcinoma, bladder cancer, lung adenocarcinoma and melanoma, but not in endometrial, ovarian and squamous cell lung carcinoma. We identified CD68+CD163+ macrophages as the major producers of complement C1q, which could serve as a surrogate marker of this macrophage subset. Consequently, the RNA-based version of SIA (ratio of CD8A to C1QA) was predictive for survival in independent RNAseq data sets from these six cancer types. Finally, the CD8A/C1QA mRNA ratio was also predictive for the response to checkpoint inhibitor therapy.Interpretation: Our findings extend current concepts to procure prognostic information from the tumour immune microenvironment and provide an immune activation signature with high clinical potential in common human cancer types.
  •  
13.
  • Mezheyeuski, Artur, et al. (författare)
  • The ratio of CD8+ lymphocytes to CD68+CD163+ macrophages is prognostic in immunogenic tumors and predicts immunotherapy response
  • Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
    • Immune cells in the microenvironment shape tumor development and progression. Through in situ analyses we assessed 15 immune cell classes in 352 colorectal cancers and identified a simpleprognostic signature based on the ratio of anti-tumoral CD8+ lymphocytes to tumor-supportiveCD68+CD163+ macrophages in the tumor microenvironment. The prognostic ability of this signature was superior to the state-of-art immune score and was also demonstrated in four other tumor types. Single-cell analyses identified these CD68+CD163+ macrophages as the source of complement C1q, and the ratio of CD8A to C1QA gene expression levels in bulk RNA predicted survival in five tumor types. In single cell analyses, RNA-based versions of the signature also predicted response to checkpoint inhibitor therapy. This supports broad clinical applicability of immune scores considering CD68+CD163+ macrophages as prognostic and predictive biomarkers in common cancers.
  •  
14.
  • Mincheva-Nilsson, Lucia, et al. (författare)
  • Human milk contains proteins that stimulate and suppress T lymphocyte proliferation
  • 1990
  • Ingår i: Clinical and Experimental Immunology. - : Oxford University Press. - 0009-9104 .- 1365-2249. ; 79:3, s. 463-469
  • Tidskriftsartikel (refereegranskat)abstract
    • The modulatory effect of human milk proteins from colostrum and late milk on the proliferative response of human T lymphocytes activated by mitogens (OKT3 and leucoagglutinin from Phaseolus vulgaris) and alloantigens was studied. High concentrations (10-100 micrograms/ml) of crude colostral milk proteins had an inhibitory effect on T cell growth while low concentrations (0.1-1 microgram/ml) enhanced T cells growth. In contrast, proteins from late milk did not inhibit T lymphocyte proliferation while the enhancing effect was retained. Colostrum was fractionated by ammonium sulphate precipitation and gel filtration on sepharose 6B. The inhibitory activity was recovered in a protein fraction containing lactoferrin as its major component. Lactoferrin was, however, not responsible for the observed inhibition. On the contrary, lactoferrin in most cases augmented the proliferative response induced by polyclonal activators. The inhibitory activity was found to bind concanavalin A-sepharose suggesting an association with glycoprotein. Inhibitory fractions contained glycoproteins of the following molecular sizes 26, 74/76 (doublet), 84, 145 and 160 kD under reducing conditions. The inhibitory effect appeared to be lymphocyte specific since the active fraction did not inhibit the growth of tissue culture cells (HeLa cells and human fibroblasts) or bacteria. Furthermore, the fraction was not toxic for lymphocytes. The inhibitory colostrum factor may prevent the newborn from overreacting immunologically against the environmental antigens encountered at birth.
  •  
15.
  •  
16.
  • Nordeman, Patrik, et al. (författare)
  • C-11 and F-18 Radiolabeling of Tetra- and Pentathiophenes as PET-Ligands for Amyloid Protein Aggregates
  • 2016
  • Ingår i: ACS Medicinal Chemistry Letters. - : American Chemical Society (ACS). - 1948-5875. ; 7:4, s. 368-373
  • Tidskriftsartikel (refereegranskat)abstract
    • Three oligothiophenes were evaluated as PET ligands for the study of local and systemic amyloidosis ex vivo using tissue from patients with amyloid deposits and in vivo using healthy animals and PET-CT. The ex vivo binding studies revealed that all three labeled compounds bound specifically to human amyloid deposits. Specific binding was found in the heart, kidney, liver, and spleen. To verify the specificity of the oligothiophenes toward amyloid deposits, tissue sections with amyloid pathology were stained using the fluorescence exhibited by the compounds and evaluated with multiphoton microscopy. Furthermore, a in vivo monkey PET-CT study showed very low uptake in the brain, pancreas, and heart of the healthy animal indicating low nonspecific binding to healthy tissue. The biological evaluations indicated that this is a promising group of compounds for the visualization of systemic and localized amyloidosis.
  •  
17.
  •  
18.
  • Ou, Gangwei, et al. (författare)
  • Proximal small intestinal microbiota and identification of rod-shaped bacteria associated with childhood celiac disease
  • 2009
  • Ingår i: American Journal of Gastroenterology. - : Ovid Technologies (Wolters Kluwer Health). - 0002-9270 .- 1572-0241. ; 104:12, s. 3058-3067
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVES: Alterations in the composition of the microbiota in the intestine may promote development of celiac disease (CD). Using scanning electron microscopy (SEM) we previously demonstrated that rod-shaped bacteria were present on the epithelium of proximal small intestine in children with CD but not in controls. In this study we characterize the microbiota of proximal small intestine in children with CD and controls and identify CD-associated rod-shaped bacteria. METHODS: Proximal small intestine biopsies from 45 children with CD and 18 clinical controls were studied. Bacteria were identified by 16S rDNA sequencing in DNA extracted from biopsies washed with buffer containing dithiothreitol to enrich bacteria adhering to the epithelial lining, by culture-based methods and by SEM and transmission electron microscopy. RESULTS: The normal, mucosa-associated microbiota of proximal small intestine was limited. It was dominated by the genera Streptococcus and Neisseria, and also contained Veillonella, Gemella, Actinomyces, Rothia, and Haemophilus. The proximal small intestine microbiota in biopsies from CD patients collected during 2004-2007 differed only marginally from that of controls, and only one biopsy (4%) had rod-shaped bacteria by SEM (SEM+). In nine frozen SEM+ CD biopsies from the previous study, microbiotas were significantly enriched in Clostridium, Prevotella, and Actinomyces compared with SEM- biopsies. Bacteria of all three genera were isolated from children born during the Swedish CD epidemic. New Clostridium and Prevotella species and Actinomyces graevenitzii were tentatively identified. CONCLUSIONS: Rod-shaped bacteria, probably of the indicated species, constituted a significant fraction of the proximal small intestine microbiota in children born during the Swedish CD epidemic and may have been an important risk factor for CD contributing to the fourfold increase in disease incidence in children below 2 years of age during that time.
  •  
19.
  • Parvin, Farjana, et al. (författare)
  • Divergent Age-Dependent Conformational Rearrangement within Aβ Amyloid Deposits in APP23, APPPS1, and AppNL-F Mice
  • 2024
  • Ingår i: ACS Chemical Neuroscience. - : AMER CHEMICAL SOC. - 1948-7193. ; 15:10, s. 2058-2069
  • Tidskriftsartikel (refereegranskat)abstract
    • Amyloid plaques composed of fibrils of misfolded A beta peptides are pathological hallmarks of Alzheimer's disease (AD). A beta fibrils are polymorphic in their tertiary and quaternary molecular structures. This structural polymorphism may carry different pathologic potencies and can putatively contribute to clinical phenotypes of AD. Therefore, mapping of structural polymorphism of A beta fibrils and structural evolution over time is valuable to understanding disease mechanisms. Here, we investigated how A beta fibril structures in situ differ in A beta plaque of different mouse models expressing familial mutations in the A beta PP gene. We imaged frozen brains with a combination of conformation-sensitive luminescent conjugated oligothiophene (LCO) ligands and A beta-specific antibodies. LCO fluorescence mapping revealed that mouse models APP23, APPPS1, and App(NL-F) have different fibril structures within A beta-amyloid plaques depending on the A beta PP-processing genotype. Co-staining with A beta-specific antibodies showed that individual plaques from APP23 mice expressing A beta PP Swedish mutation have two distinct fibril polymorph regions of core and corona. The plaque core is predominantly composed of compact A beta 40 fibrils, and the corona region is dominated by diffusely packed A beta 40 fibrils. Conversely, the A beta PP knock-in mouse App(NL-F), expressing the A beta PP Iberian mutation along with Swedish mutation has tiny, cored plaques consisting mainly of compact A beta 42 fibrils, vastly different from APP23 even at elevated age up to 21 months. Age-dependent polymorph rearrangement of plaque cores observed for APP23 and APPPS1 mice >12 months, appears strongly promoted by A beta 40 and was hence minuscule in App(NL-F). These structural studies of amyloid plaques in situ can map disease-relevant fibril polymorph distributions to guide the design of diagnostic and therapeutic molecules.
  •  
20.
  • Sjölander, Daniel, et al. (författare)
  • Establishing the fluorescent amyloid ligand h-FTAA for studying human tissues with systemic and localized amyloid
  • 2016
  • Ingår i: Amyloid. - : Informa UK Limited. - 1350-6129 .- 1744-2818. ; 23:2, s. 98-108
  • Tidskriftsartikel (refereegranskat)abstract
    • Rapid and accurate detection of amyloid deposits in routine surgical pathology settings are of great importance. The use of fluorescence microscopy in combination with appropriate amyloid specific dyes is very promising in this regard. Here we report that a luminescent conjugated oligothiophene, h-FTAA, rapidly and with high sensitivity and selectivity detects amyloid deposits in verified clinical samples from systemic amyloidosis patients with AA, AL and ATTR types; as well as in tissues laden with localized amyloidosis of AANF, AIAPP and ASem1 type. The probe h-FTAA emitted yellow red fluorescence on binding to amyloid deposits, whereas no apparent staining was observed in surrounding tissue. The only functional structure stained with h-FTAA showing the amyloidotypic fluorescence spectrum was Paneth cell granules in intestine. Screening of 114 amyloid containing tissues derived from 107 verified (Congo red birefringence and/or immunohistochemistry) amyloidosis patients revealed complete correlation between h-FTAA and Congo red fluorescence (107/107, 100% sensitivity). The majority of Congo red negative control cases (27 of 32, 85% specificity) were negative with h-FTAA. Small Congo red negative aggregates in kidney, liver, pancreas and duodenum were found by h-FTAA fluorescence in five control patients aged 72-83 years suffering from diverse diseases. The clinical significance of these false-positive lesions is currently not known. Because h-FTAA fluorescence is one magnitude brighter than Congo red and as the staining is performed four magnitudes lower than the concentration of dye, we believe that these inclusions are beyond detection by Congo red. We conclude that h-FTAA is a fluorescent hypersensitive, rapid and powerful tool for identifying amyloid deposits in tissue sections. Use of h-FTAA can be exploited as a rapid complementary technique for accurate detection of amyloid in routine surgical pathology settings. Our results also implicate the potential of the technique for detection of prodromal amyloidosis as well as for discovery of new amyloid-like protein aggregates in humans.
  •  
21.
  • Sjölander, Daniel, et al. (författare)
  • Evaluation of the fluorescent amyloid ligand h-FTAA in human tissues with systemic and localized amyloid
  • 2014
  • Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
    • Rapid and accurate detection of amyloid deposits in routine surgical pathology settings are of great importance. The use of fluorescence microscopy in combination with appropriate amyloid specific dyes is very promising in this regard. Most systemic amyloidosis are progressive and lethal. Disease specific therapy depends on the identification of the offending proteins. Here we report that a luminescent conjugated oligothiophene, h-FTAA, rapidly and with high sensitivity and selectivity detects amyloid deposits in verified clinical samples from systemic amyloidosis patients with AA, AL, and ATTR types; as well as in tissues laden with localized amyloidosis of AANF, AIAPP and ASem1 type. The probe h-FTAA emitted yellow red fluorescence on binding to amyloid deposits, whereas no apparent staining was observed in surrounding tissue. Screening of 114 amyloid containing tissues derived from §07 verified (Congo red birefringence and immunohistochemistry) amyloidosis patients revealed complete correlation between h-FTAA and Congo red fluorescence. We conclude that h-FTAA is a fluorescent hypersensitive, rapid and powerful tool for identifying amyloid deposits in tissue sections. H-FTAA staining can be utilized as a rapid complementary technique for accurate detection of amyloid in routine surgical pathology settings. It was also revealed that within 5 of 15 age matched Congo red negative control samples h-FTAA detects microdeposits of amyloid-like protein aggregates in liver and kidney. The results emphasize the potential of the dye for detection of prodromal amyloidosis as well as for discovery of novel amyloid-like protein aggregates in humans.
  •  
22.
  • Solé-Domènech, Santiago, et al. (författare)
  • Localization of cholesterol, amyloid and glia in Alzheimer's disease transgenic mouse brain tissue using time-of-flight secondary ion mass spectrometry (ToF-SIMS) and immunofluorescence imaging
  • 2013
  • Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 125:1, s. 145-157
  • Tidskriftsartikel (refereegranskat)abstract
    • The spatial distributions of lipids, amyloid-beta deposits, markers of neurons and glial cells were imaged, at submicrometer lateral resolution, in brain structures of a mouse model of Alzheimer's disease using a new methodology that combines time-of-flight secondary ion mass spectrometry (ToF-SIMS) and confocal fluorescence microscopy. The technology, which enabled us to simultaneously image the lipid and glial cell distributions in Tg2576 mouse brain structures, revealed micrometer-sized cholesterol accumulations in hippocampal regions undergoing amyloid-beta deposition. Such cholesterol granules were either associated with individual amyloid deposits or spread over entire regions undergoing amyloidogenesis. Subsequent immunohistochemical analysis of the same brain regions showed increased microglial and astrocytic immunoreactivity associated with the amyloid deposits, as expected from previous studies, but did not reveal any particular astrocytic or microglial feature correlated with cholesterol granulation. However, dystrophic neurites as well as presynaptic vesicles presented a distribution similar to that of cholesterol granules in regions undergoing amyloid-beta accumulation, thus indicating that these neuronal endpoints may retain cholesterol in areas with lesions. In conclusion, the present study provides evidence for an altered cholesterol distribution near amyloid deposits that would have been missed by several other lipid analysis methods, and opens for the possibility to study in detail the putative liaison between lipid environment and protein structure and function in Alzheimer's disease.
  •  
23.
  • Syrén, Per-Olof, et al. (författare)
  • Design, structure and plasma binding of ancestral β-CoV scaffold antigens
  • 2024
  • Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
    • The pandemic caused by Severe acute respiratory syndrome coronavirus 2 has had devastating consequences on global health and economy. Despite the success of vaccination campaigns emerging variants are of concern and novel viruses with the potential to drive future pandemics are circulating in nature. Development of vaccines can be challenging, as key viral protein antigens can be unstable or aggregate. In this study, we present the application of ancestral sequence reconstruction on coronavirus spike protein, resulting in stable and highly soluble ancestral scaffold antigens (AnSAs). The AnSAs interacted with plasma of patients recovered from COVID-19 but did not bind to the human angiotensin-converting enzyme 2 (ACE2) receptor. Cryo-EM analysis of the AnSAs yielded high resolution structures (2.6-2.8 Å) indicating a closed pre-fusion conformation in which all three receptor-binding domains (RBDs) are facing downwards. This captured closed state is stabilised by an intricate hydrogen‑bonding network mediated by well-resolved loops, both within and across monomers, tethering the N‑terminal domain and RBD together, which determines their relative spatial orientation. Finally, we show how AnSAs are potent scaffolds by replacing the ancestral RBD with the Wuhan wild-type sequence, which restored ACE2 binding and increased the interaction with convalescent plasma. In contrast to rational antigen design depending on prior structural knowledge, our work highlights how stable and potentially interesting antigens can be generated using exclusively available sequence information.
  •  
24.
  • Abrahamsson, Maria, et al. (författare)
  • Steric influence on the excited-state lifetimes of ruthenium complexes with bipyridyl-alkanylene-pyridyl ligands.
  • 2008
  • Ingår i: Inorganic Chemistry. - : ACS. - 0020-1669 .- 1520-510X. ; 47:9, s. 3540-3548
  • Tidskriftsartikel (refereegranskat)abstract
    • The structural effect on the metal-to-ligand charge transfer (MLCT) excited-state lifetime has been investigated in bis-tridentate Ru(II)-polypyridyl complexes based on the terpyridine-like ligands [6-(2,2'-bipyridyl)](2-pyridyl)methane (1) and 2-[6-(2,2'-bipyridyl)]-2-(2-pyridyl)propane (2). A homoleptic ([Ru(2)(2)](2+)) and a heteroleptic complex ([Ru(ttpy)(2)](2+)) based on the new ligand 2 have been prepared and their photophysical and structural properties studied experimentally and theoretically and compared to the results for the previously reported [Ru(1)(2)](2+). The excited-state lifetime of the homoleptic Ru-II complex with the isopropylene-bridged ligand 2 was found to be 50 times shorter than that of the corresponding homoleptic Ru-II complex of ligand 1, containing a methylene bridge. A comparison of the ground-state geometries of the two homoleptic complexes shows that steric interactions involving the isopropylene bridges make the coordination to the central Ru-II ion less octahedral in [Ru(2)(2)](2+) than in [Ru(1)(2))(2+). Calculations indicate that the structural differences in these complexes influence their ligand field splittings as well as the relative stabilities of the triplet metal-to-ligand charge transfer ((MLCT)-M-3) and metal-centered ((MC)-M-3) excited states. The large difference in measured excited-state lifetimes for the two homoleptic Ru-II complexes is attributed to a strong influence of steric interactions on the ligand field strength, which in turn affects the activation barriers for thermal conversion from (MLCT)-M-3 states to short-lived (MC)-M-3 states.
  •  
25.
  • Aguilar-Calvo, Patricia, et al. (författare)
  • Generation of novel neuroinvasive prions following intravenous challenge
  • 2018
  • Ingår i: Brain Pathology. - : WILEY. - 1015-6305 .- 1750-3639. ; 28:6, s. 999-1011
  • Tidskriftsartikel (refereegranskat)abstract
    • Prions typically spread into the central nervous system (CNS), likely via peripheral nerves. Yet prion conformers differ in their capacity to penetrate the CNS; certain fibrillar prions replicate persistently in lymphoid tissues with no CNS entry, leading to chronic silent carriers. Subclinical carriers of variant Creutzfeldt-Jakob (vCJD) prions in the United Kingdom have been estimated at 1:2000, and vCJD prions have been transmitted through blood transfusion, however, the circulating prion conformers that neuroinvade remain unclear. Here we investigate how prion conformation impacts brain entry of transfused prions by challenging mice intravenously to subfibrillar and fibrillar strains. We show that most strains infiltrated the brain and caused terminal disease, however, the fibrillar prions showed reduced CNS entry in a strain-dependent manner. Strikingly, the highly fibrillar mCWD prion strain replicated in the spleen and emerged in the brain as a novel strain, indicating that a new neuroinvasive prion had been generated from a previously non-neuroinvasive strain. The new strain showed altered plaque morphology, brain regions targeted and biochemical properties and these properties were maintained upon intracerebral passage. Intracerebral passage of prion-infected spleen re-created the new strain. Splenic prions resembled the new strain biochemically and intracerebral passage of prion-infected spleen re-created the new strain, collectively suggesting splenic prion replication as a potential source. Taken together, these results indicate that intravenous exposure to prion-contaminated blood or blood products may generate novel neuroinvasive prion conformers and disease phenotypes, potentially arising from prion replication in non-neural tissues or from conformer selection.
  •  
26.
  • Almstedt, Karin, 1980-, et al. (författare)
  • Amyloid fibrils of human prion protein are spun and woven from morphologically disordered aggregates
  • 2009
  • Ingår i: Prion. - Austin : Landes Bioscience Journals. - 1933-6896 .- 1933-690X. ; 3:4, s. 224-235
  • Tidskriftsartikel (refereegranskat)abstract
    • Propagation and infectivity of prions in human prionopathies are likely associated with conversion of the mainly α-helical human prion protein, HuPrP, into an aggregated form with amyloid-like properties. Previous reports on efficient conversion of recombinant HuPrP have used mild to harsh denaturing conditions to generate amyloid fibrils in vitro. Herein we report on the in vitro conversion of four forms of truncated HuPrP (sequences 90-231 and 121-231 with and without an N-terminal hexa histidine tag) into amyloid-like fibrils within a few hours by using a protocol (phosphate buffered saline solutions at neutral pH with intense agitation) close to physiological conditions. The conversion process monitored by thioflavin T, ThT, revealed a three stage process with lag, growth and equilibrium phases. Seeding with preformed fibrils shortened the lag phase demonstrating the classic nucleated polymerization mechanism for the reaction. Interestingly, comparing thioflavin T kinetics with solubility and turbidity kinetics it was found that the protein initially formed non-thioflavionophilic, morphologically disordered aggregates that over time matured into amyloid fibrils. By transmission electron microscopy and by fluorescence microscopy of aggregates stained with luminescent conjugated polythiophenes (LCPs); we demonstrated that HuPrP undergoes a conformational conversion where spun and woven fibrils protruded from morphologically disordered aggregates. The initial aggregation functioned as a kinetic trap that decelerated nucleation into a fibrillation competent nucleus, but at the same time without aggregation there was no onset of amyloid fibril formation. The agitation, which was necessary for fibril formation to be induced, transiently exposes the protein to the air-water interface suggests a hitherto largely unexplored denaturing environment for prion conversion.
  •  
27.
  • Almstedt, Karin, 1980- (författare)
  • Protein Misfolding in Human Diseases
  • 2009
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • There are several diseases well known that are due to aberrant protein folding. These types of diseases can be divided into three main categories:Loss-of-function diseasesGain-of-toxic-function diseasesInfectious misfolding diseases Most loss-of-function diseases are caused by aberrant folding of important proteins. These proteins often misfold due to inherited mutations. The rare disease marble brain disease (MBD) also known as carbonic anhydrase II deficiency syndrome (CADS) can manifest in carriers of point mutations in the human carbonic anhydrase II (HCA II) gene. We have over the past 10-15 years studied the folding, misfolding and aggregation of the enzyme human carbonic anhydrase II. In summary our HCA II folding studies have shown that the protein folds via an intermediate of molten-globule type, which lacks enzyme activity and the molten globule state of HCA II is prone to aggregation. One mutation associated with MBD entails the His107Tyr (H107Y) substitution. We have demonstrated that the H107Y mutation is a remarkably destabilizing mutation influencing the folding behavior of HCA II. A mutational survey of position H107 and a neighboring conserved position E117 has been performed entailing the mutants H107A, H107F, H107N, E117A and the double mutants H107A/E117A and H107N/E117A. All mutants were severely destabilized versus GuHCl and heat denaturation. Thermal denaturation and GuHCl phase diagram and ANS analyses showed that the mutants shifted HCA II towards populating ensembles of intermediates of molten globule type under physiological conditions. The enormously destabilizing effects of the H107Y mutation is not due to loss of specific interactions of H107 with residue E117, instead it is caused by long range sterical destabilizing effects of the bulky tyrosine residue. We also showed that the folding equilibrium can be shifted towards the native state by binding of the small-molecule drug acetazolamide, and we present a small molecule inhibitor assessment with select sulfonamide inhibitors of varying potency to investigate the effectiveness of these molecules to inhibit the misfolding of HCA II H107Y. We also demonstrate that high concentration of the activator compound L-His increases the enzyme activity of the mutant but without stabilizing the folded protein. The infectious misfolding diseases is the smallest group of misfolding diseases. The only protein known to have the ability to be infectious is the prion protein. The human prion diseases Kuru, Gerstmann-Sträussler-Scheinker disease (GSS) and variant Creutzfeldt-Jakob are characterized by depositions of amyloid plaque from misfolded prion protein (HuPrP) in various regions of the brain depending on disease. Amyloidogenesis of HuPrP is hence strongly correlated with prion disease.Our results show that amyloid formation of recHuPrP90-231 can be achieved starting from the native protein under gentle conditions without addition of denaturant or altered pH. The process is efficiently catalyzed by addition of preformed recHuPrP90-231 amyloid seeds. It is plausible that amyloid seeding reflect the mechanism of transmissibility of prion diseases. Elucidating the mechanism of PrP amyloidogenesis is therefore of interest for strategic prevention of prion infection.
  •  
28.
  • Almstedt, Karin, et al. (författare)
  • Small-Molecule Suppression of Misfolding of Mutated Human Carbonic Anhydrase II Linked to Marble Brain Disease
  • 2009
  • Ingår i: Biochemistry. - : American Chemical Society (ACS). - 0006-2960 .- 1520-4995. ; 48:23, s. 5358-5364
  • Tidskriftsartikel (refereegranskat)abstract
    • Carbonic anhydrase II deficiency syndrome or Marble brain disease (MBD) is caused by autosomal recessive mutations in the human carbonic anhydrase II (HCA II) gene. Here we report a small-molecule stabilization study of the exceptionally destabilized HCA II mutant H107Y employing inhibitors based on p-aminobenzoyisulfonamide compounds and 1,3,4-thiadiazolylsulfonamides as well as amino acid activators. Protein stability assays showed a significant stabilization by the aromatic sulfonamide inhibitors when present at 10 mu M concentration, providing shifts of the midpoint of thermal denaturation between 10 degrees C and 16 degrees C and increasing the free energies of denaturation 0.5-3.0 kcal/mol as deduced from GuHCl denaturation. This study could be used as a starting point for the design of small-molecule folding modulators and possibly autoactivatable molecules for suppression of misfolding of destabilized HCA II mutants.
  •  
29.
  • Almstedt, Karin, 1980-, et al. (författare)
  • Thermodynamic interrogation of a folding disease. Mutant mapping of position 107 in human carbonic anhydrase II linked to marble brain disease.
  • 2008
  • Ingår i: Biochemistry. - Washington : ACS. - 0006-2960 .- 1520-4995. ; 47:5, s. 1288-1298
  • Tidskriftsartikel (refereegranskat)abstract
    • Marble brain disease (MBD) also known as Guibaud−Vainsel syndrome is caused by autosomal recessive mutations in the human carbonic anhydrase II (HCA II) gene. HCA II is a 259 amino acid single domain enzyme and is dominated by a 10-stranded β-sheet. One mutation associated with MBD entails the H107Y substitution where H107 is a highly conserved residue in the carbonic anhydrase protein family. We have previously demonstrated that the H107Y mutation is a remarkably destabilizing folding mutation [Almstedt et al. (2004) J. Mol. Biol. 342, 619−633]. Here, the exceptional destabilization by the H107Y mutation has been further investigated. A mutational survey of position H107 and a neighboring conserved position E117 has been performed entailing the mutants H107A, H107F, H107N, E117A and the double mutants H107A/E117A and H107N/E117A. All mutants were severely destabilized versus GuHCl and heat denaturation. Thermal denaturation and GuHCl phase diagram and ANS analyses showed that the mutants shifted HCA II toward populating ensembles of intermediates of molten globule type under physiological conditions. The native state stability of the mutants was in the following order:  wt > H107N > E117A > H107A > H107F > H107Y > H107N/E117A > H107A/E117A. In conclusion:  (i) H107N is least destabilizing likely due to compensatory H-bonding ability of the introduced Asn residue. (ii) Double mutant cycles surprisingly reveal additive destabilization of H107N and E117A showing that H107 and E117 are independently stabilizing the folded protein. (iii) H107Y and H107F are exceptionally destabilizing due to bulkiness of the side chains whereas H107A is more accommodating, indicating long-range destabilizing effects of the natural pathogenic H107Y mutation.
  •  
30.
  • Almstedt, Karin, 1980-, et al. (författare)
  • Unfolding a folding disease: folding, misfolding and aggregation of the marble brain syndrome-associated mutant H107Y of human carbonic anhydrase II
  • 2004
  • Ingår i: Journal of Molecular Biology. - Oxford : Elsevier. - 0022-2836 .- 1089-8638. ; 342:2, s. 619-633
  • Tidskriftsartikel (refereegranskat)abstract
    • Most loss-of-function diseases are caused by aberrant folding of important proteins. These proteins often misfold due to mutations. The disease marble brain syndrome (MBS), known also as carbonic anhydrase II deficiency syndrome (CADS), can manifest in carriers of point mutations in the human carbonic anhydrase II (HCA II) gene. One mutation associated with MBS entails the His107Tyr substitution. Here, we demonstrate that this mutation is a remarkably destabilizing folding mutation. The loss-of-function is clearly a folding defect, since the mutant shows 64% of CO2 hydration activity compared to that of the wild-type at low temperature where the mutant is folded. On the contrary, its stability towards thermal and guanidine hydrochloride (GuHCl) denaturation is highly compromised. Using activity assays, CD, fluorescence, NMR, cross-linking, aggregation measurements and molecular modeling, we have mapped the properties of this remarkable mutant. Loss of enzymatic activity had a midpoint temperature of denaturation (Tm) of 16 °C for the mutant compared to 55 °C for the wild-type protein. GuHCl-denaturation (at 4 °C) showed that the native state of the mutant was destabilized by 9.2 kcal/mol. The mutant unfolds through at least two equilibrium intermediates; one novel intermediate that we have termed the molten globule light state and, after further denaturation, the classical molten globule state is populated. Under physiological conditions (neutral pH; 37 °C), the His107Tyr mutant will populate the molten globule light state, likely due to novel interactions between Tyr107 and the surroundings of the critical residue Ser29 that destabilize the native conformation. This intermediate binds the hydrophobic dye 8-anilino-1-naphthalene sulfonic acid (ANS) but not as strong as the molten globule state, and near-UV CD reveals the presence of significant tertiary structure. Notably, this intermediate is not as prone to aggregation as the classical molten globule. As a proof of concept for an intervention strategy with small molecules, we showed that binding of the CA inhibitor acetazolamide increases the stability of the native state of the mutant by 2.9 kcal/mol in accordance with its strong affinity. Acetazolamide shifts the Tm to 34 °C that protects from misfolding and will enable a substantial fraction of the enzyme pool to survive physiological conditions.
  •  
31.
  • Andersson, D., et al. (författare)
  • Cofactor-induced refolding : Refolding of molten globule carbonic anhydrase induced by Zn(II) and Co(II)
  • 2001
  • Ingår i: Biochemistry. - : American Chemical Society (ACS). - 0006-2960 .- 1520-4995. ; 40:9, s. 2653-2661
  • Tidskriftsartikel (refereegranskat)abstract
    • The stability versus unfolding to the molten globule intermediate of bovine carbonic anhydrase II (BCA II) in guanidine hydrochloride (GuHCl) was found to depend on the metal ion cofactor [Zn(II) or Co(II)], and the apoenzyme was observed to be least stable. Therefore, it was possible to find a denaturant concentration (1.2 M GuHCl) at which refolding from the molten globule to the native state could be initiated merely by adding the metal ion to the apo molten globule. Thus, refolding could be performed without changing the concentration of the denaturant. The molten globule intermediate of BCA II could still bind the metal cofactor. Cofactor-effected refolding from the molten globule to the native state can be summarized as follows: (1) initially, the metal ion binds to the molten globule, (2) compaction of the metal-binding site region is then induced by the metal ion binding, (3) a functioning active center is formed, and (4) finally, the native tertiary structure is generated in the outer parts of the protein.
  •  
32.
  • Andersson, Per Ola, et al. (författare)
  • Polymorph and size dependent uptake and toxicity of TiO2 nanoparticles in living lung epithelial cells
  • 2011
  • Ingår i: Small. - : Wiley. - 1613-6810 .- 1613-6829. ; 7:4, s. 514-523
  • Tidskriftsartikel (refereegranskat)abstract
    • The cellular uptake and distribution of five types of well-characterized anatase and rutile TiO(2) nanoparticles (NPs) in A549 lung epithelial cells is reported. Static light scattering (SLS), in-vitro Raman microspectroscopy (mu-Raman) and transmission electron spectroscopy (TEM) reveal an intimate correlation between the intrinsic physicochemical properties of the NPs, particle agglomeration, and cellular NP uptake. It is shown that mu-Raman facilitates chemical-, polymorph-, and size-specific discrimination of endosomal-particle cell uptake and the retention of particles in the vicinity of organelles, including the cell nucleus, which quantitatively correlates with TEM and SLS data. Depth-profiling mu-Raman coupled with hyperspectral data analysis confirms the location of the NPs in the cells and shows that the NPs induce modifications of the biological matrix. NP uptake is found to be kinetically activated and strongly dependent on the hard agglomeration size-not the primary particle size-which quantitatively agrees with the measured intracellular oxidative stress. Pro-inflammatory responses are also found to be sensitive to primary particle size.
  •  
33.
  • Arja, Katriann, et al. (författare)
  • Enhanced Fluorescent Assignment of Protein Aggregates by an Oligothiophene-Porphyrin-Based Amyloid Ligand
  • 2013
  • Ingår i: Macromolecular rapid communications. - : Wiley-VCH Verlag. - 1022-1336 .- 1521-3927. ; 34:9, s. 723-730
  • Tidskriftsartikel (refereegranskat)abstract
    • Fluorescent probes identifying protein aggregates are of great interest, as deposition of aggregated proteins is associated with many devastating diseases. Here, we report that a fluorescent amyloid ligand composed of two distinct molecular moieties, an amyloidophilic pentameric oligothiophene and a porphyrin, can be utilized for spectral and lifetime imaging assessment of recombinant A 1-42 amyloid fibrils and A deposits in brain tissue sections from a transgenic mouse model with Alzheimers disease pathology. The enhanced spectral range and distinct lifetime diversity of this novel oligothiopheneporphyrin-based ligand allow a more precise assessment of heterogeneous amyloid morphology compared with the corresponding oligothiophene dye.
  •  
34.
  • Babu Moparthi, Satish, et al. (författare)
  • Differential conformational modulations of MreB folding upon interactions with GroEL/ES and TRiC chaperonin components
  • 2016
  • Ingår i: Scientific Reports. - : NATURE PUBLISHING GROUP. - 2045-2322. ; 6:28386
  • Tidskriftsartikel (refereegranskat)abstract
    • Here, we study and compare the mechanisms of action of the GroEL/GroES and the TRiC chaperonin systems on MreB client protein variants extracted from E. coli. MreB is a homologue to actin in prokaryotes. Single-molecule fluorescence correlation spectroscopy (FCS) and time-resolved fluorescence polarization anisotropy report the binding interaction of folding MreB with GroEL, GroES and TRiC. Fluorescence resonance energy transfer (FRET) measurements on MreB variants quantified molecular distance changes occurring during conformational rearrangements within folding MreB bound to chaperonins. We observed that the MreB structure is rearranged by a binding-induced expansion mechanism in TRiC, GroEL and GroES. These results are quantitatively comparable to the structural rearrangements found during the interaction of beta-actin with GroEL and TRiC, indicating that the mechanism of chaperonins is conserved during evolution. The chaperonin-bound MreB is also significantly compacted after addition of AMP-PNP for both the GroEL/ES and TRiC systems. Most importantly, our results showed that GroES may act as an unfoldase by inducing a dramatic initial expansion of MreB (even more than for GroEL) implicating a role for MreB folding, allowing us to suggest a delivery mechanism for GroES to GroEL in prokaryotes.
  •  
35.
  • Babu Moparthi, Satish, et al. (författare)
  • Transient conformational remodeling of folding proteins by GroES - Individually and in concert with GroEL
  • 2014
  • Ingår i: Journal of chemical biology. - : Springer Berlin/Heidelberg. - 1864-6158 .- 1864-6166. ; 7:1, s. 1-15
  • Forskningsöversikt (refereegranskat)abstract
    • The commonly accepted dogma of the bacterial GroE chaperonin system entails protein folding mediated by cycles of several ATP-dependent sequential steps where GroEL interacts with the folding client protein. In contrast, we herein report GroES-mediated dynamic remodeling (expansion and compression) of two different protein substrates during folding: the endogenous substrate MreB and carbonic anhydrase (HCAII), a well-characterized protein folding model. GroES was also found to influence GroEL binding induced unfolding and compression of the client protein underlining the synergistic activity of both chaperonins, even in the absence of ATP. This previously unidentified activity by GroES should have important implications for understanding the chaperonin mechanism and cellular stress response. Our findings necessitate a revision of the GroEL/ES mechanism.
  •  
36.
  • Bagheri, Maryam, et al. (författare)
  • Amyloid Beta1-40-Induced Astrogliosis and the Effect of Genistein Treatment in Rat: A Three-Dimensional Confocal Morphometric and Proteomic Study
  • 2013
  • Ingår i: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 8:10
  • Tidskriftsartikel (refereegranskat)abstract
    • Astrocytes are highly involved in regulation and homeostasis of the extracellular environment in the healthy brain. In pathological conditions, these cells play a major role in the inflammatory response seen in CNS tissues, which is called reactive astrogliosis and includes hypertrophy and proliferation of astrocytes. Here, we performed 3D confocal microscopy to evaluate the morphological response of reactive astrocytes positive for glial fibrillary acidic protein (GFAP) in rats, to the presence of Aβ1–40 in the rat brain before and after treatment with genistein. In 50 astrocytes per animal, we measured the volume and surface area for the nucleus, cell body, the entire cell, the tissue covered by single astrocytes and quantified the number and length of branches, the density of the astrocytes and the intensity of GFAP immunoreactivity. Injecting Aβ1–40 into the brain of rats caused astrogliosis indicated by increased values for all measured parameters. Mass spectrometric analysis of hippocampal tissue in Aβ1–40-injected brain showed decreased amounts of tubulins, enolases and myelin basic protein, and increased amounts of dihydropyrimidinase-related protein 2. In Aβ1–40-injected rats pretreated with genistein, GFAP intensity was decreased to the sham-operated group level, and Aβ1–40-induced astrogliosis was significantly ameliorated.
  •  
37.
  • Bauer, Susanne (författare)
  • Cell type-specific translatome analysis of mouse models of three genetic neurodegenerative diseases
  • 2023
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • The burden neurodegenerative diseases place on patients, their loved ones, and the healthcare system is significant, and despite extensive research efforts, there is currently no cure. Since degenerative changes in the brain can begin years before symptoms appear, early intervention is critical. Additionally, neurodegenerative diseases target certain brain regions and neuron types early on. A more comprehensive understanding of the affected cells during the presymptomatic phase is therefore crucial for an effective and targeted intervention. Herein, we isolated, sequenced, and analyzed translatome samples from six neuronal cell types in knock-in mouse models of three monogenic neurodegenerative diseases at a presymptomatic stage: genetic Creutzfeldt-Jakob disease (gCJD), fatal familial insomnia (FFI), and Huntington’s disease (HD). To obtain the translatome samples, we used RiboTag to immunoprecipitate HA-tagged ribosomes with their translating mRNAs from targeted cell types. We analyzed six cell types across two brain regions: cerebral and cerebellar glutamatergic and GABAergic neurons, and cerebral parvalbumin (PV) and somatostatin (SST)-expressing neurons. In the first paper, we focused our analysis on the prion diseases, gCJD (E200K) and FFI (D178N). Here observed a similar response of SST+ neurons, a cell type not previously reported as affected, in both disease models. This was characterized by upregulation of ribosomeassociated genes, and downregulation of cytoskeleton and synapse-associated genes in FFI. Weighted gene co-expression network analysis of SST+ neurons pointed towards the downregulation of mTOR inhibition as a potential mechanism underlying the observed gene expression changes. In the second paper, we analyzed a 129S4-HdhQ200 knock-in mouse model of HD. Histological and behavioral assessment revealed pathological changes in the striatum and cerebellum at 9 months and a later, mild behavioral phenotype. Translatome analysis indicated a surprisingly strong response in reportedly resistant glutamatergic neurons of the cerebellum, marked by upregulation of cell cycle regulators Ccnd1 and chromobox protein genes. In the third paper, we aimed to compare disease-specific responses of PV+ neurons across the three disease models. This analysis revealed a milder response in HD compared to prion disease at comparable disease stages. Functional analysis further indicated PV+ neurons may respond differently in the investigated diseases, showing upregulation of immune response-associated pathways in gCJD, neurodegenerative-disease pathways in FFI, and autophagy in HD. Lastly, the generation of mouse models such as were used in papers I-III requires stable and predictable transgene expression without interfering with the expression of endogenous genes. In the fourth paper, we conducted a pilot study to compare three potential loci, Rpl6, Rpl7, and Eef1a1, as potential safe harbors for transgene integration. Preliminary results indicated that the Rpl6 locus may be best suited for our purposes. Furthermore, this work generated a novel dataset consisting of translatome profiles of six cell types in three neurodegenerative disease models. This provides gene expression data at a previously unavailable level of cellular resolution, especially in prion disease. We believe that this data will serve as a valuable resource for future research and help expand our understanding of the early molecular mechanisms in neurodegenerative disease beyond the scope of this thesis. 
  •  
38.
  • Bednarska, Natalia G., et al. (författare)
  • Protein aggregation as an antibiotic design strategy
  • 2016
  • Ingår i: Molecular Microbiology. - : WILEY-BLACKWELL. - 0950-382X .- 1365-2958. ; 99:5, s. 849-865
  • Tidskriftsartikel (refereegranskat)abstract
    • Taking advantage of the xenobiotic nature of bacterial infections, we tested whether the cytotoxicity of protein aggregation can be targeted to bacterial pathogens without affecting their mammalian hosts. In particular, we examined if peptides encoding aggregation-prone sequence segments of bacterial proteins can display antimicrobial activity by initiating toxic protein aggregation in bacteria, but not in mammalian cells. Unbiased in vitro screening of aggregating peptide sequences from bacterial genomes lead to the identification of several peptides that are strongly bactericidal against methicillin-resistant Staphylococcus aureus. Upon parenteral administration in vivo, the peptides cured mice from bacterial sepsis without apparent toxic side effects as judged from histological and hematological evaluation. We found that the peptides enter and accumulate in the bacterial cytosol where they cause aggregation of bacterial polypeptides. Although the precise chain of events that leads to cell death remains to be elucidated, the ability to tap into aggregation-prone sequences of bacterial proteomes to elicit antimicrobial activity represents a rich and unexplored chemical space to be mined in search of novel therapeutic strategies to fight infectious diseases.
  •  
39.
  • Begum, Afshan, et al. (författare)
  • Transthyretin Binding Mode Dichotomy of Fluorescent trans-Stilbene Ligands
  • 2023
  • Ingår i: ACS Chemical Neuroscience. - : American Chemical Society (ACS). - 1948-7193. ; 14:5, s. 820-828
  • Tidskriftsartikel (refereegranskat)abstract
    • The orientations of ligands bound to the transthyretin (TTR) thyroxine (T4) binding site are difficult to predict. Conflicting binding modes of resveratrol have been reported. We previously reported two resveratrol based trans-stilbene fluorescent ligands, (E)-4-(2-(naphthalen-1-yl)vinyl)benzene-1,2-diol (SB-11) and (E)-4-(2-(naphthalen-2-yl)vinyl)-benzene-1,2-diol (SB-14), that bind native and misfolded protofibrillar TTR. The binding orientations of these two analogous ligands to native tetrameric TTR were predicted to be opposite. Herein we report the crystal structures of these TTR:ligand complexes. Opposite binding modes were verified but were different than predicted. The reverse binding mode (SB14) placing the naphthalene moiety toward the opening of the binding pocket renders the fluorescent ligand pH sensitive due to changes in Lys15 amine protonation. Conversely, the forward binding mode (SB-11) placing the naphthalene inward mediates a stabilizing conformational change, allowing intersubunit H-bonding between Ser117 of different monomers across the dimer interface. Our structures of TTR complexes answer important questions in ligand design and interpretation of trans-stilbene binding modes to the TTR T4 binding site.
  •  
40.
  • Berg, Ina, 1982-, et al. (författare)
  • Curcumin alleviates Aβ indcuced neurotoxicity and vice versa without removing amyloid deposits in transgenic Drosophila
  • Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
    • Curcumin has been proposed to facilitate clearance of toxic amyloid formed by the Aβ peptide. To further address this notion, different concentrations of curcumin were tried for its effects in various Drosophila Alzheimer’s disease (AD) models. This study entailed five different Drosophila AD models (four Aβ expressing lines, and one tau expressing line), expressing the AD associated proteins using the Gal4/UAS system. These were assayed for several aspects of neurological impairment, including survival, climbing behavior, as well as locomotor activity. In addition, amyloid deposition was assessed by histological analysis. Curcumin treatment substantially prolonged the lifespan and improved climbing and locomotor activity for flies with severe disease geneotypes (Aβ1-42 E22G and double expressing Aβ1-42). In comparison, curcumin feeding of control flies resulted in a concentration-dependent shortened lifespan, whereas no such toxic side effects were found for AD genotypes with a mild phenotype (single expressors of Aβ1-40 and Aβ1-42). All flies expressing Aβ and tau displayed a higher total locomotor activity, and a continuation of the activity over a larger number of hours upon curcumin treatment. Unexpectedly, no change in tissue amyloid deposition upon curcumin treatment was observed. In vitro fibrillation of Aβ1-42, followed by Western blot and transmission electron microscopy in the presence and absence of curcumin, displayed enhanced fibrillation into large aggregates and decreased population of oligomers in curcumin samples. The decrease in oligomer formation by curcumin may explain why it increases the lifespan and activity without removing of the amyloid deposits seen in tissues. We also suggest that Aβ, at least in the context of Drosophila, functions as a chemical detoxifier sequestering curcumin and thereby mitigating its toxicity.
  •  
41.
  • Berg, Ina, 1982-, et al. (författare)
  • Efficient imaging of amyloid deposits in Drosophila models of human amyloidoses
  • 2010
  • Ingår i: Nature Protocols. - : Macmillan Publishers Ltd.. - 1754-2189 .- 1750-2799. ; 5:5, s. 935-944
  • Tidskriftsartikel (refereegranskat)abstract
    • Drosophila melanogaster is emerging as an important model system for neurodegenerative disease research. In this protocol, we describe an efficient method for imaging amyloid deposits in the Drosophila brain, by the use of a luminescent-conjugated oligothiophene (lco), p-Ftaa polymer probe. We also demonstrate the feasibility of co-staining with antibodies and compare the lco staining with standard amyloid-specific probes. the lco protocol enables high-resolution imaging of several different protein aggregates, such as aβ1-42, aβ1-42e22G, transthyretin V30M and human tau, in the Drosophila brain. aβ and tau aggregates could also be distinguished from each other because of distinct lco emission spectra. Furthermore, this protocol enables threedimensional brain mapping of amyloid distribution in whole-mount Drosophila brains. the use of p-Ftaa combined with other probes, antibodies and/or dyes will aid the rapid characterization of various amyloid deposits in the rapidly growing number of Drosophila models of neurodegenerative diseases.
  •  
42.
  • Berg, Ina, 1982- (författare)
  • Modeling Amyloid Disease in Drosophila melanogaster
  • 2010
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Amyloid diseases are caused by protein misfolding and aggregation. To date there are 27 known proteins causing amyloid disorders involving brain and peripheral protein deposition. The proteins involved in this mechanism do not share sequence homology, but the amyloid fibrils share biophysical properties and possibly a common pathogenic mechanism. Amyloid deposits are known to be involved in a broad range of neurodegenerative diseases, such as Alzheimer’s disease and Creutzfeldt-Jakob disease, as well as in non-neuropathic diseases, such as senile systemic amyloidosis and type II diabetes.During the last decade the fruit fly, Drosophila melanogaster (Drosophila), have increasingly been used as a model for neurodegenerative disease, such as Alzheimer’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and familial amyloidotic polyneuropathy. The advantages of using the Drosophila model are the well-defined genetic characteristics, the quantity, short life span, simplicity in genetic manipulation and the powerful binary UAS-Gal4 transgenic system. The UAS-Gal4 system allows for rapid generation of individual strains in which expression of a specific gene of interest can be directed to different tissues or cell types. The system allows the target gene to be activated in different cell- and tissue-types by altering the activator-expressing lines.This thesis has been focused on modeling amyloid diseases in Drosophila. This has been performed by:Creating new model systems of senile systemic amyloidosis and familial amyloidotic polyneuropathy in DrosophilaDeveloping a new staining protocol for detection of amyloid in DrosophilaInitiate a compound screen of Alzheimer’s disease modeled in Drosophila
  •  
43.
  • Berg, Ina, et al. (författare)
  • Modeling Familial Amyloidotic Polyneuropathy (Transthyretin V30M) in Drosophila melanogaster
  • 2009
  • Ingår i: NEURODEGENERATIVE DISEASES. - : S. Karger AG. - 1660-2854 .- 1660-2862. ; 6:3, s. 127-138
  • Tidskriftsartikel (refereegranskat)abstract
    • Background/Aims: Transthyretin (TTR) is a prevalent plasma and cerebrospinal fluid protein associated with sporadic and heritable amyloidosis. TTR amyloidosis is linked to a vast number of mutations with varying phenotype, tissue distribution and age of onset. The most prevalent mutation associated with familial amyloidotic polyneuropathy (FAP) is the V30M mutation. Studies of transgenic mouse models of TTR V30M FAP have been hampered by variable phenotype, low disease penetrance, and slow onset. Methods/Results: To model TTR-associated amyloid disease in the Drosophila model system, transgenic Drosophila were generated, expressing wild-type (wt) TTR or TTR V30M, associated with sporadic senile systemic amyloidosis (SSA) and inherited FAP, respectively. We found that expression of FAP-associated TTR V30M mutant in the nervous system resulted in reduced lifespan and in reduced climbing ability indicating neurological impairment, whereas expression of TTR wt showed a milder phenotype. Congo red staining of the Drosophila brain shows positive amyloid binding in the aged TTR V30M flies. Extensive brain vacuole formation was evident for the aged TTR V30M flies, whereas a milder phenotype was shown by the TTR wt flies. In addition, expression of TTR V30M in the eye leads to tissue damage, including rough eye, morphological changes and fibrous deposition. Conclusion: Our results suggest that Drosophila is a promising complementary system for studies of TTR-associated amyloid diseases.
  •  
44.
  • Björk, Linnea, et al. (författare)
  • Amino-Acid Side-Chain Nanoarchitectonics for Tuning the Chiroptical Properties and Supramolecular Structure of Pentameric Oligothiophenes
  • 2024
  • Ingår i: ChemPhotoChem. - : WILEY-V C H VERLAG GMBH. - 2367-0932.
  • Tidskriftsartikel (refereegranskat)abstract
    • Oligothiophenes with specific photophysical properties and molecular organization are of great interest, since this class of materials are used in organic electronics and bioelectronics, as well as biosensing. Herein, 8 different pentameric oligothiophenes, denoted proteophenes, with different amino acid substitution patterns at distinct positions along the thiophene backbone were investigated. Spectroscopic and microscopic studies of the ligands revealed the formation of optically active self-assembled materials under acidic or basic conditions. The distinct photophysical characteristics, including induced circular dichroism, as well as the supramolecular structures of the assemblies deduced from light scattering and transmission electron microscopy, were highly influenced by the positioning of distinct amino acid moieties along the thiophene backbone. Proteophenes functionalized with only glutamate residues or these functionalities in combination with hydrophobic valine moieties formed fibrillar structures with excellent chiroptical properties under acidic conditions. In addition, the amino acid functionality at the beta-position of distinct thiophene moieties influenced the induced circular dichroism pattern observed from the proteophenes. Overall, the obtained results demonstrate how changes in the position of various amino acid functionalities, as well as the chemical nature of the amino acid side chain functionality greatly affect the optical properties as well as the architecture of the self-assembled materials. Self-assembled Proteophenes. Oligothiophenes with distinct amino acid side-chain functionalities along the conjugated backbone displayed distinct chiroptical and structural properties in acidic or alkaline solutions. The distinct photophysical characteristics, as well as the supramolecular structures of the assemblies were highly influenced by the chemical nature of the amino acid, as well as the positioning of distinct amino acid moieties along the thiophene backbone.image
  •  
45.
  • Björkman, Andrea, et al. (författare)
  • Aberrant recombination and repair during immunoglobulin class switching in BRCA1-deficient human B cells.
  • 2015
  • Ingår i: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 112:7, s. 2157-2162
  • Tidskriftsartikel (refereegranskat)abstract
    • Breast cancer type 1 susceptibility protein (BRCA1) has a multitude of functions that contribute to genome integrity and tumor suppression. Its participation in the repair of DNA double-strand breaks (DSBs) during homologous recombination (HR) is well recognized, whereas its involvement in the second major DSB repair pathway, nonhomologous end-joining (NHEJ), remains controversial. Here we have studied the role of BRCA1 in the repair of DSBs in switch (S) regions during immunoglobulin class switch recombination, a physiological, deletion/recombination process that relies on the classical NHEJ machinery. A shift to the use of microhomology-based, alternative end-joining (A-EJ) and increased frequencies of intra-S region deletions as well as insertions of inverted S sequences were observed at the recombination junctions amplified from BRCA1-deficient human B cells. Furthermore, increased use of long microhomologies was found at recombination junctions derived from E3 ubiquitin-protein ligase RNF168-deficient, Fanconi anemia group J protein (FACJ, BRIP1)-deficient, or DNA endonuclease RBBP8 (CtIP)-compromised cells, whereas an increased frequency of S-region inversions was observed in breast cancer type 2 susceptibility protein (BRCA2)-deficient cells. Thus, BRCA1, together with its interaction partners, seems to play an important role in repairing DSBs generated during class switch recombination by promoting the classical NHEJ pathway. This may not only provide a general mechanism underlying BRCA1's function in maintaining genome stability and tumor suppression but may also point to a previously unrecognized role of BRCA1 in B-cell lymphomagenesis.
  •  
46.
  • Bohlin, Anna, et al. (författare)
  • Perceived gender inequality in the couple relationship and musculoskeletal pain in middle-aged women and men
  • 2013
  • Ingår i: Scandinavian Journal of Public Health. - : Sage Publications. - 1403-4948 .- 1651-1905. ; 41:8, s. 825-831
  • Tidskriftsartikel (refereegranskat)abstract
    • Aims: Musculoskeletal pain is a major health problem, especially in women, and is partially determined by psychosocial factors. The aim of the present study was to investigate whether gender inequality in the couple relationship was related to musculoskeletal pain. Methods: Participants (n=721; 364 women and 357 men) were all individuals living in a couple relationship in the Northern Swedish Cohort, a 26-year Swedish cohort study. Self-administered questionnaire data at age 42 years comprised perceived gender inequality in the couple relationship and musculoskeletal pain (in three locations, summarised into one score and median-split), concurrent demographic factors, psychological distress, and previous musculoskeletal pain at age 30 years. Associations were examined using logistic regression. Results: Gender inequality was positively associated with symptoms of musculoskeletal pain in the total sample, remaining significant after addition of possible confounders and of previous musculoskeletal pain. Separate adjustment for concurrent psychological distress attenuated the association but not below significance. The association was present and of comparable strength in both women and men. Conclusions: Gender inequality in the couple relationship might contribute to the experience of musculoskeletal pain in both women and men. The results highlight the potential adverse bodily consequences of living in unequal relationships.
  •  
47.
  • Brydsten, Anna, et al. (författare)
  • Does contextual unemployment matter for health status across the life course?
  • 2016
  • Ingår i: European Journal of Public Health. - : Oxford University Press. - 1101-1262 .- 1464-360X. ; 26:Suppl 1, s. 142-142
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Individual health is affected by one’s individual life conditionsand by the context in which individuals live, interact anddevelop. Research shows that living in a neighbourhood withhigh levels of unemployment might affect residents’ health, atleast partially independent of own labour market status.However, how such contextual-individual transactions playout across the life course is unknown. The present study aims:(i) to examine whether neighbourhood unemployment isrelated to health status across the life course independently ofthe individual employment from adolescence to middle age(age 16 to 42); and (ii) to analyse whether this relationship isobservable at four specific life course periods from adolescenceto middle age (age 16, 21, 30 and 42).Methods: A 26-year prospective Swedish cohort (n = 1010), linked toregister data on neighbourhood unemployment. Individualemployment and functional somatic symptoms were measuredby self-reported questionnaire data. Two models of hierarchallinear regressions were built: a longitudinal analysis, and a setof age-specific cross-sectional analyses at each age.Results: The longitudinal analysis showed an independent contributionof neighbourhood unemployment and individual employmenton FSS across the life course. The cross-sectional analysisshowed an association at age 30, when accounting forindividual employment, but no association was found at age21 and 42.Conclusions: Neighbourhood unemployment has a significant relationshipwith functional somatic symptoms across the life course. Thereseems to be an age-specific pattern where neighbourhoodunemployment may have stronger implications in earlyadulthood than in other phases of the life courseKey messages:High neighbourhood unemployment predicts higher levelsof individual FSS across the life course, independently ofown labour market position, socioeconomic status andeducationThese findings stress the importance of neighbourhoodunemployment for current health status as well as development of health status across the life course, particular duringearly adulthood
  •  
48.
  • Brydsten, Anna, et al. (författare)
  • Does contextual unemployment matter for health status across the life course? A longitudinal multilevel study exploring the link between neighbourhood unemployment and functional somatic symptoms
  • 2017
  • Ingår i: Health and Place. - : Elsevier BV. - 1353-8292 .- 1873-2054. ; 43, s. 113-120
  • Tidskriftsartikel (refereegranskat)abstract
    • This study examines whether neighbourhood unemployment is related to functional somatic symptoms, independently of the individual employment, across the life course and at four specific life course periods (age 16, 21, 30 and 42). Self-reported questioner data was used from a 26-year prospective Swedish cohort (n=1010) with complementary neighbourhood register data. A longitudinal and a set of age-specific cross-sectional hierarchal linear regressions was carried out. The results suggest that living in a neighbourhood with high unemployment has implications for residents' level of functional somatic symptoms, regardless of their own unemployment across time, particularly at age 30.
  •  
49.
  • Brydsten, Anna, 1984- (författare)
  • Yesterday once more? Unemployment and health inequalities across the life course in northern Sweden
  • 2017
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • AbstractBackground. It is relatively well established in previous research that unemployment has direct health consequences in terms of mental and physical ill health. Recently, knowledge has emerged indicating that unemployment can lead to economic consequences that remain long after re-establishment in the labour market. However, few empirical studies have been able to apply a life course perspective asking whether there are also long-term health consequences of unemployment, and, when and in which context unemployment may affect the individual health status across the life course. The aim of this thesis was to analyse the relationship between unemployment and illness across the life course, and how it relates to individual and structural factors in the geographical setting of northern Sweden. In particular, three main areas have been explored: youth unemployment and illness in adulthood (Paper I and Paper II), contextual unemployment of national unemployment rate and neighbourhood unemployment (Paper II and Paper III) and lastly, social determinants of health inequality between employment statuses (Paper IV).Methods. This thesis is positioned in Sweden between the early 1980s and the mid-2010s, following two comparable cohorts sampled from northern Sweden (26 and 19 years follow-up time respectively from youth to midlife) and a cross-sectional sample from 2014 of the four northernmost counties in Sweden. The two longitudinal cohorts comprised the Northern Swedish Cohort and the Younger Northern Swedish Cohort, consisting of all pupils in the 9th grade of compulsory school in Luleå municipality in 1981 and 1989. The participants responded to an extensive questionnaire on socioeconomic factors, work and health, in 5 and 2 waves respectively of data collections. Neighbourhood register data from Statistics Sweden was also collected for all participants in the Northern Sweden Cohort. At the latest data collection, 94.3% (n=1010) participated in the Northern Sweden Cohort and 85.6% (n=686) in the Younger Northern Sweden Cohort. The cross-sectional study Health on Equal Terms is a national study, administered by the Public Health Agency together with Statistics Sweden and county councils with the aim of mapping public health and living conditions in the country over time. In this thesis, material from 2014 has been used for northern Sweden with a response rate of around 50% (effective sample n=12769). The statistical analyses used were linear regression, multilevel analysis and difference-in-difference analysis to estimate the concurrent and long-term health consequences of unemployment, and a decomposition analysis to disentangle the inequality in health between different labour market positions. The health outcomes in focus were functional somatic symptoms (the occurrence of relatively common physical illnesses such as head, muscle and stomach ache, insomnia and palpitation) and psychological distress.Results. Among men only, as little as one month of youth unemployment was related to increased levels of functional somatic symptoms in midlife, regardless of previous ill health or unemployment later in life, although only during relatively low national unemployment (pre-recession) when comparing with youth unemployment during high national unemployment (recession). This was explained by the health promoting effect of more time spent in higher education during the recession period. Furthermore, the health impact of neighbourhood unemployment highlights the importance of the contextual setting for individuals’ health both across the life course and at specific periods of life. Lastly, employment-related mental health inequalities exist for both men and women in all life phases (youth, adulthood and midlife). Economic and social deprivation related to unemployment and illness varied across different phases in life and across genders.Conclusion. The key findings of this thesis paint a rather pessimistic vision of the future: one’s own and others’ unemployment may cause not only ill health today but also ill health later in life. Importantly, the responsibility of unemployment and the associated ill health should not be placed on the already marginalised individuals and communities. Instead, the responsibility should be directed towards the structural aspects of society and the political choices that shape these. In other words, health inequality manifested by the position in the labour market is socially produced, unfair and changeable through political decisions. The results of this study therefore cannot contribute to any simple or concrete solutions to the concurrent or long-term health consequences of individual or contextual unemployment, as the solution is beyond the areas of responsibility and abilities of research. However, if there are long-term health consequences of one’s own and other people’s unemployment, labour market and public health policies should be initiated from a young age and continue throughout the life course to reduce individual suffering and future costs of social insurance, sick-leave and unemployment benefits.
  •  
50.
  • Byhamre, Marja Lisa, et al. (författare)
  • Snus use during the life-course and risk of the metabolic syndrome and its components
  • 2017
  • Ingår i: Scandinavian Journal of Public Health. - : Sage Publications. - 1403-4948 .- 1651-1905. ; 45:8, s. 733-740
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective: We aimed to investigate the association between life-course exposure to snus and prevalence of the metabolic syndrome and its components in adulthood.Design and method: Tobacco habits at baseline (age 16) and three follow-ups (ages 21, 30 and 43) were assessed among 880 participants in a population-based cohort in Northern Sweden. Presence of the metabolic syndrome at age 43 was ascertained using the International Diabetes Federation criteria. Odds ratios and CIs for risk of the metabolic syndrome and its components by snus use at 16, 21, 30 and 43 years were calculated using logistic regression. Cumulative snus use was defined as number of life periods (1-4) with current snus use.Results: At age 43, 164 participants (18.6%) were current snus users. We found no association between exclusive snus use at the ages of 16, 21, 30 and 43 years and the metabolic syndrome at age 43 years. Snus use (among non-smokers) was associated with raised triglycerides and high blood pressure in crude analysis, but not in multivariable models. There was no association between cumulative snus use and risk of the metabolic syndrome. Cumulative snus use was associated with central obesity, raised triglycerides and impaired fasting glucose/diabetes mellitus type 2 in crude analyses, but not after adjustments.Conclusion: The health consequences of snus exposure from adolescence to mid-adulthood do not seem to include increased risk of the metabolic syndrome or its components. The cardio-metabolic risk of dual exposure to snus and cigarettes may warrant further attention.
  •  
Skapa referenser, mejla, bekava och länka
  • Resultat 1-50 av 299
Typ av publikation
tidskriftsartikel (210)
doktorsavhandling (26)
konferensbidrag (21)
annan publikation (18)
bokkapitel (8)
rapport (6)
visa fler...
forskningsöversikt (5)
recension (3)
licentiatavhandling (2)
visa färre...
Typ av innehåll
refereegranskat (207)
övrigt vetenskapligt/konstnärligt (80)
populärvet., debatt m.m. (12)
Författare/redaktör
Hammarström, Per (134)
Nilsson, Peter (61)
Hammarström, Anne (44)
Nyström, Sofie (37)
Gustafsson, Per E. (35)
Hammarström, Per, 19 ... (29)
visa fler...
Lindgren, Mikael (29)
Carlsson, Uno (20)
Konradsson, Peter (13)
Jonsson, Bengt-Haral ... (12)
Westerlund, Hugo (12)
Janlert, Urban (12)
Åslund, Andreas (11)
Virtanen, Pekka (11)
Theorell, Töres (10)
San Sebastian, Migue ... (10)
Hammarström, Per, Pr ... (10)
Carlsson, Uno, 1946- (10)
Sjölander, Daniel (10)
Klingstedt, Therése (9)
Lindgren, M. (8)
Thor, Stefan (8)
Nyström, Sofie, 1970 ... (7)
Inganäs, Olle (6)
Henriksson, Per (6)
Herland, Anna (6)
Villebeck, Laila (6)
Hammarström, Per, Pr ... (6)
Jonsson, Bengt-Haral ... (6)
Bäck, Marcus (6)
Hammarström, Ulf (6)
Hammarström, Marie-L ... (5)
Hammarström, Sten (5)
Borgquist, Signe (5)
Svensson, Samuel (5)
Kågedal, Katarina (5)
Czene, Kamila (5)
Hall, Per (5)
Wennberg, Patrik (5)
Zhang, Jun (5)
Mårtensson, Lars-Gör ... (5)
Mishra, Rajesh (5)
Westermark, Per (5)
Westermark, Gunilla ... (5)
Wennberg, Maria (5)
Nilsson, Peter, 1970 ... (5)
Nilsson, K. Peter R. (5)
Nilsson, Lars N G (5)
Gabrielson, Marike (5)
Hammarström, Mattias (5)
visa färre...
Lärosäte
Linköpings universitet (176)
Uppsala universitet (60)
Umeå universitet (56)
Karolinska Institutet (29)
Mittuniversitetet (24)
Stockholms universitet (20)
visa fler...
Göteborgs universitet (17)
Lunds universitet (16)
VTI - Statens väg- och transportforskningsinstitut (7)
Kungliga Tekniska Högskolan (6)
Malmö universitet (4)
Chalmers tekniska högskola (4)
RISE (3)
Karlstads universitet (2)
Högskolan i Gävle (1)
Jönköping University (1)
Södertörns högskola (1)
Högskolan i Skövde (1)
Linnéuniversitetet (1)
visa färre...
Språk
Engelska (266)
Svenska (32)
Odefinierat språk (1)
Forskningsämne (UKÄ/SCB)
Medicin och hälsovetenskap (111)
Naturvetenskap (69)
Humaniora (23)
Teknik (7)
Samhällsvetenskap (4)

År

Kungliga biblioteket hanterar dina personuppgifter i enlighet med EU:s dataskyddsförordning (2018), GDPR. Läs mer om hur det funkar här.
Så här hanterar KB dina uppgifter vid användning av denna tjänst.

 
pil uppåt Stäng

Kopiera och spara länken för att återkomma till aktuell vy