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Öhman, Anders
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Publications (10 of 33) Show all publications
Figueira, J., Adolfsson, R., Nordin Adolfsson, A., Nyberg, L. & Öhman, A. (2019). Serum Metabolite Markers of Dementia Through Quantitative NMR Analysis: The Importance of Threonine-Linked Metabolic Pathways. Journal of Alzheimer's Disease, 69(3), 763-774
Open this publication in new window or tab >>Serum Metabolite Markers of Dementia Through Quantitative NMR Analysis: The Importance of Threonine-Linked Metabolic Pathways
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2019 (English)In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 69, no 3, p. 763-774Article in journal (Refereed) Published
Abstract [en]

There is a great need for diagnostic biomarkers of impending dementia. Metabolite markers in blood have been investigated in several studies, but inconclusive findings encourage further investigation, particularly in the pre-diagnostic phase. In the present study, the serum metabolomes of 110 dementia or pre-diagnostic dementia individuals and 201 healthy individuals matched for age, gender, and education were analyzed by nuclear magnetic resonance spectroscopy in combination with multivariate data analysis. 58 metabolites were quantified in each of the 311 samples. Individuals with dementia were discriminated from controls using a panel of seven metabolites, while the pre-diagnostic dementia subjects were distinguished from controls using a separate set of seven metabolites, where threonine was a common significant metabolite in both panels. Metabolite and pathway alterations specific for dementia and pre-diagnostic dementia were identified, in particular a disturbed threonine catabolism at the pre-diagnostic stage that extends to several threonine-linked pathways at the dementia stage.

Place, publisher, year, edition, pages
IOS Press, 2019
Keywords
Alzheimer's disease, biomarker, dementia, metabolomics/metabonomics, NMR, serum, vascular dementia
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:umu:diva-161551 (URN)10.3233/JAD-181189 (DOI)000471781600013 ()31127768 (PubMedID)
Funder
Knut and Alice Wallenberg FoundationThe Kempe Foundations
Available from: 2019-07-10 Created: 2019-07-10 Last updated: 2019-07-10Bibliographically approved
Figueira, J., Gouveia-Figueira, S., Öhman, C., Lif Holgerson, P., Nording, M. L. & Öhman, A. (2017). Metabolite quantification by NMR and LC-MS/MS reveals differences between unstimulated, stimulated, and pure parotid saliva. Journal of Pharmaceutical and Biomedical Analysis, 140, 295-300, Article ID S0731-7085(16)31308-5.
Open this publication in new window or tab >>Metabolite quantification by NMR and LC-MS/MS reveals differences between unstimulated, stimulated, and pure parotid saliva
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2017 (English)In: Journal of Pharmaceutical and Biomedical Analysis, ISSN 0731-7085, E-ISSN 1873-264X, Vol. 140, p. 295-300, article id S0731-7085(16)31308-5Article in journal (Refereed) Published
Abstract [en]

Saliva is a readily available biofluid that is sensitive to metabolic changes and can be collected through rapid and non-invasive collection procedures, and it shows great promise for clinical metabolomic studies. This work studied the metabolite composition of, and the differences between, saliva samples collected by unstimulated spitting/drooling, paraffin chewing-stimulated spitting, and parotid gland suction using targeted nuclear magnetic resonance (NMR) spectroscopy and liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) for metabolite quantification. As applied here, these two analytical techniques provide complementary metabolite information and together extend the metabolome coverage with robust NMR quantification of soluble metabolites and sensitive targeted LC-MS/MS analysis of bioactive lipids in specific metabolic pathways. The NMR analysis was performed on ultrafiltrated (3kDa cutoff) saliva samples and resulted in a total of 45 quantified metabolites. The LC-MS/MS analysis was performed on both filtered and unfiltered samples and resulted in the quantification of two endocannabinoids (AEA and PEA) and 22 oxylipins, which at present is the most comprehensive targeted analysis of bioactive lipids in human saliva. Important differences in the metabolite composition were observed between the three saliva sample collection methods, which should be taken into consideration when designing metabolomic studies of saliva. Furthermore, the combined use of the two metabolomics platforms (NMR and LC-MS/MS) proved to be viable for research and clinical studies of the salivary metabolome.

Keywords
Eicosanoids, Endocannabinoids, LC-MS/MS, NMR, Oxylipins, Saliva
National Category
Medical and Health Sciences Natural Sciences
Identifiers
urn:nbn:se:umu:diva-134056 (URN)10.1016/j.jpba.2017.03.037 (DOI)000402850500036 ()28380387 (PubMedID)
Available from: 2017-04-26 Created: 2017-04-26 Last updated: 2018-06-09Bibliographically approved
Wu, J., Wuolikainen, A., Trupp, M., Jonsson, P., Marklund, S. L., Andersen, P. M., . . . Öhman, A. (2016). NMR analysis of the CSF and plasma metabolome of rigorously matched amyotrophic lateral sclerosis, Parkinson's disease and control subjects. Metabolomics, 12(6), Article ID 101.
Open this publication in new window or tab >>NMR analysis of the CSF and plasma metabolome of rigorously matched amyotrophic lateral sclerosis, Parkinson's disease and control subjects
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2016 (English)In: Metabolomics, ISSN 1573-3882, E-ISSN 1573-3890, Vol. 12, no 6, article id 101Article in journal (Refereed) Published
Abstract [en]

Introduction: Amyotrophic lateral sclerosis (ALS) and Parkinson’s disease (PD) are two severe neurodegenerative disorders for which the disease mechanisms are poorly understood and reliable biomarkers are absent.

Objectives: To identify metabolite biomarkers for ALS and PD, and to gain insights into which metabolic pathways are involved in disease.

Methods: Nuclear magnetic resonance (NMR) metabolomics was utilized to characterize the metabolite profiles of cerebrospinal fluid (CSF) and plasma from individuals in three age, gender, and sampling-date matched groups, comprising 22 ALS, 22 PD and 28 control subjects.

Results: Multivariate analysis of NMR data generated robust discriminatory models for separation of ALS from control subjects. ALS patients showed increased concentrations of several metabolites in both CSF and plasma, these are alanine (CSF fold change = 1.22, p = 0.005), creatine (CSF-fc = 1.17, p = 0.001), glucose (CSF-fc = 1.11, p = 0.036), isoleucine (CSF-fc = 1.24, p = 0.002), and valine (CSF-fc = 1.17, p = 0.014). Additional metabolites in CSF (creatinine, dimethylamine and lactic acid) and plasma (acetic acid, glutamic acid, histidine, leucine, pyruvate and tyrosine) were also important for this discrimination. Similarly, panels of CSF-metabolites that discriminate PD from ALS and control subjects were identified.

Conclusions: The results for the ALS patients suggest an affected creatine/creatinine pathway and an altered branched chain amino acid (BCAA) metabolism, and suggest links to glucose and energy metabolism. Putative metabolic markers specific for ALS (e.g. creatinine and lactic acid) and PD (e.g. 3-hydroxyisovaleric acid and mannose) were identified, while several (e.g. creatine and BCAAs) were shared between ALS and PD, suggesting some overlap in metabolic alterations in these disorders.

Keywords
Amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), NMR metabolomics, Biomarker, rebrospinal fluid (CSF), Plasma
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-124194 (URN)10.1007/s11306-016-1041-6 (DOI)000378752900006 ()
Available from: 2016-08-04 Created: 2016-07-28 Last updated: 2019-05-10Bibliographically approved
Figueira, J., Jonsson, P., Nordin Adolfsson, A., Adolfsson, R., Nyberg, L. & Öhman, A. (2016). NMR analysis of the human saliva metabolome distinguishes dementia patients from matched controls. Molecular Biosystems, 12(8), 2562-2571
Open this publication in new window or tab >>NMR analysis of the human saliva metabolome distinguishes dementia patients from matched controls
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2016 (English)In: Molecular Biosystems, ISSN 1742-206X, E-ISSN 1742-2051, Vol. 12, no 8, p. 2562-2571Article in journal (Refereed) Published
Abstract [en]

Saliva is a biofluid that is sensitive to metabolic changes and is straightforward to collect in a non-invasive manner, but it is seldom used for metabolite analysis when studying neurodegenerative disorders. We present a procedure for both an untargeted and targeted analysis of the saliva metabolome in which nuclear magnetic resonance (NMR) spectroscopy is used in combination with multivariate data analysis. The applicability of this approach is demonstrated on saliva samples selected from the 25 year prospective Betula study, including samples from dementia subjects with either Alzheimer's disease (AD) or vascular dementia at the time of sampling or who developed it by the next sampling/assessment occasion five years later, and age-, gender-, and education-matched control individuals without dementia. Statistically significant multivariate models were obtained that separated patients with dementia from controls and revealed seven discriminatory metabolites. Dementia patients showed significantly increased concentrations of acetic acid (fold change (fc) = 1.25, p = 2 x 10(-5)), histamine (fc = 1.26, p = 0.019), and propionate (fc = 1.35, p = 0.002), while significantly decreased levels were observed for dimethyl sulfone (fc = 0.81, p = 0.005), glycerol (fc = 0.79, p = 0.04), taurine (fc = 0.70, p = 0.007), and succinate (fc = 0.62, p = 0.008). Histamine, succinate, and taurine are known to be important in AD, and acetic acid and glycerol are involved in related pathways. Dimethyl sulfone and propionate originate from the diet and bacterial flora and might reflect poorer periodontal status in the dementia patients. For these seven metabolites, a weak but statistically significant pre-diagnostic value was observed. Taken together, we present a robust and general NMR analysis approach for studying the saliva metabolome that has potential use for screening and early detection of dementia.

National Category
Clinical Laboratory Medicine Neurology
Identifiers
urn:nbn:se:umu:diva-124525 (URN)10.1039/c6mb00233a (DOI)000379873100022 ()27265744 (PubMedID)
Available from: 2016-08-17 Created: 2016-08-15 Last updated: 2018-06-07Bibliographically approved
Wu, J., Domellöf, M., Zivkovic, A. M., Larsson, G., Öhman, A. & Nording, M. L. (2016). NMR-based metabolite profiling of human milk: A pilot study of methods for investigating compositional changes during lactation. Biochemical and Biophysical Research Communications - BBRC, 469(3), 626-632
Open this publication in new window or tab >>NMR-based metabolite profiling of human milk: A pilot study of methods for investigating compositional changes during lactation
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2016 (English)In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 469, no 3, p. 626-632Article in journal (Refereed) Published
Abstract [en]

Low-molecular-weight metabolites in human milk are gaining increasing interest in studies of infant nutrition. In the present study, the milk metabolome from a single mother was explored at different stages of lactation. Metabolites were extracted from sample aliquots using either methanol water (MeOH/H2O) extraction or ultrafiltration. Nuclear magnetic resonance (NMR) spectroscopy was used for metabolite identification and quantification, and multi- and univariate statistical data analyses were used to detect changes over time of lactation. Compared to MeOH/H2O extraction, ultrafiltration more efficiently reduced the interference from lipid and protein resonances, thereby enabling the identification and quantification of 36 metabolites. The human milk metabolomes at the early (9-24 days after delivery) and late (31-87 days after delivery) stages of lactation were distinctly different according to multi- and univariate statistics. The late lactation stage was characterized by significantly elevated concentrations of lactose, choline, alanine, glutamate, and glutamine, as well as by reduced levels of citrate, phosphocholine, glycerophosphocholine, and N-acetylglucosamine. Our results indicate that there are significant compositional changes of the human milk metabolome also in different phases of the matured lactation stage. These findings complement temporal studies on the colostrum and transitional metabolome in providing a better understanding of the nutritional variations received by an infant.

Keywords
Human milk, Lactation, NMR, Metabolomics, Metabonomics
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-117401 (URN)10.1016/j.bbrc.2015.11.114 (DOI)000369352800046 ()26655810 (PubMedID)
Available from: 2016-04-05 Created: 2016-02-29 Last updated: 2018-06-07Bibliographically approved
Öhman, A. & Forsgren, L. (2015). NMR metabonomics of cerebrospinal fluid distinguishes between Parkinson's disease and controls. Neuroscience Letters, 594, 36-39
Open this publication in new window or tab >>NMR metabonomics of cerebrospinal fluid distinguishes between Parkinson's disease and controls
2015 (English)In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 594, p. 36-39Article in journal (Refereed) Published
Abstract [en]

This study assesses if nuclear magnetic resonance (NMR) metabonomics can discriminate between Parkinson's disease (PD) patients and control subjects, and consequently identify metabolic markers for the disease. One-dimensional H-1 NMR spectroscopy was used for quantitative analysis of metabolites in the cerebrospinal fluid (CSF) from 10 PD patients and 10 control individuals, together with uni- and multivariate statistical analysis to discriminate between the groups and to identify significantly altered metabolite concentrations. In total 60 metabolites were identified and of those 38 were quantified in all CSF samples. An overall lowering of metabolite content was observed in PD patients compared to control subjects (fold change of 0.85 +/- 0.30). Multivariate statistics reveal significant changes (vertical bar w*vertical bar>0.2) among nine metabolites (alanine, creatinine, dimethylamine, glucose, lactate, mannose, phenylalanine, 3-hydroxyisobutyric acid and 3-hydroxyisovaleric acid). Three of these (alanine, creatinine and mannose) are identified as significantly changed also by univariate statistics (p < 0.00132, Bonferroni corrected). Panels with all or a selected set of these metabolites were successfully used for discriminating between the two groups. In conclusion, NMR metabonomics can readily determine metabolite concentrations in CSF, identify putative biomarkers that distinguish between the PD patients and control subjects, and thus potentially become a tool for diagnostic purposes.

Keywords
Parkinson's disease, Cerebrospinal fluid, NMR, Metabonomics, Biomarker
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:umu:diva-103719 (URN)10.1016/j.neulet.2015.03.051 (DOI)000353750200007 ()25817365 (PubMedID)
Available from: 2015-06-10 Created: 2015-05-28 Last updated: 2018-06-07Bibliographically approved
Edwin, A., Persson, C., Mayzel, M., Wai, S. N., Öhman, A., Karlsson, B. G. & Sauer-Eriksson, A. E. (2015). Structure of the N-terminal domain of the metalloprotease PrtV from Vibrio cholerae. Protein Science, 24(12), 2076-2080
Open this publication in new window or tab >>Structure of the N-terminal domain of the metalloprotease PrtV from Vibrio cholerae
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2015 (English)In: Protein Science, ISSN 0961-8368, E-ISSN 1469-896X, Vol. 24, no 12, p. 2076-2080Article in journal (Refereed) Published
Abstract [en]

The metalloprotease PrtV from Vibrio cholerae serves an important function for the ability of bacteria to invade the mammalian host cell. The protein belongs to the family of M6 proteases, with a characteristic zinc ion in the catalytic active site. PrtV constitutes a 918 amino acids (102 kDa) multidomain pre-pro-protein that undergoes several N- and C-terminal modifications to form a catalytically active protease. We report here the NMR structure of the PrtV N- terminal domain (residues 23-103) that contains two short alpha-helices in a coiled coil motif. The helices are held together by a cluster of hydrophobic residues. Approximately 30 residues at the C-terminal end, which were predicted to form a third helical structure, are disordered. These residues are highly conserved within the genus Vibrio, which suggests that they might be functionally important.

Keywords
Vibrio cholera, metalloproteases, PrtV, N-terminal domain, NMR, LAGLIO F, 1995, JOURNAL OF BIOMOLECULAR NMR, V6, P277 inoda Sumio, 2011, BIOCONTROL SCIENCE, V16, P1 lm L., 2008, BIOINFORMATICS, V24, P2780 itkevicius Karolis, 2008, FEBS JOURNAL, V275, P3167 itkevicius K, 2006, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-116102 (URN)10.1002/pro.2815 (DOI)000368292000017 ()26434928 (PubMedID)
Available from: 2016-02-08 Created: 2016-02-08 Last updated: 2018-06-07Bibliographically approved
Edwin, A., Grundström, C., Wai, S. N., Öhman, A., Stier, G. & Sauer-Eriksson, A. E. (2014). Domain isolation, expression, purification and proteolytic activity of the metalloprotease PrtV from Vibrio cholerae. Protein Expression and Purification, 96, 39-47
Open this publication in new window or tab >>Domain isolation, expression, purification and proteolytic activity of the metalloprotease PrtV from Vibrio cholerae
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2014 (English)In: Protein Expression and Purification, ISSN 1046-5928, E-ISSN 1096-0279, Vol. 96, p. 39-47Article in journal (Refereed) Published
Abstract [en]

The metalloprotease PrtV from Vibrio cholerae serves an important function for the bacteria's ability to invade the mammalian host cell. The protein belongs to the family of M6 proteases, with a characteristic zinc ion in the catalytic active site. PrtV constitutes a 918 amino acids (102kDa) multidomain pre-pro-protein that so far has only been expressed in V. cholerae. Structural studies require high amounts of soluble protein with high purity. Previous attempts for recombinant expression have been hampered by low expression and solubility of protein fragments. Here, we describe results from parallel cloning experiments in Escherichia coli where fusion tagged constructs of PrtV fragments were designed, and protein products tested for expression and solubility. Of more than 100 designed constructs, three produced protein products that expressed well. These include the N-terminal domain (residues 23-103), the PKD1 domain (residues 755-839), and a 25kDa fragment (residues 581-839). The soluble fusion proteins were captured with Ni(2+) affinity chromatography, and subsequently cleaved with tobacco etch virus protease. Purification protocols yielded ∼10-15mg of pure protein from 1L of culture. Proper folding of the shorter domains was confirmed by heteronuclear NMR spectra recorded on (15)N-labeled samples. A modified protocol for the native purification of the secreted 81kDa pro-protein of PrtV is provided. Proteolytic activity measurements suggest that the 37kDa catalytic metalloprotease domain alone is sufficient for activity.

Place, publisher, year, edition, pages
Elsevier, 2014
Keywords
Vibrio cholerae, Metalloprotease, PrtV, Fusion tag, Expression screen, Escherichia coli
National Category
Chemical Sciences
Identifiers
urn:nbn:se:umu:diva-87821 (URN)10.1016/j.pep.2014.01.012 (DOI)000332906300007 ()24492010 (PubMedID)
Funder
Swedish Research Council, K2013-67X-13001-15-3
Available from: 2014-04-10 Created: 2014-04-10 Last updated: 2018-06-08Bibliographically approved
Brännström, K., Öhman, A., Nilsson, L., Pihl, M., Sandblad, L. & Olofsson, A. (2014). The N-terminal Region of Amyloid β Controls the Aggregation Rate and Fibril Stability at Low pH Through a Gain of Function Mechanism. Journal of the American Chemical Society, 136(31), 10956-10964
Open this publication in new window or tab >>The N-terminal Region of Amyloid β Controls the Aggregation Rate and Fibril Stability at Low pH Through a Gain of Function Mechanism
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2014 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 136, no 31, p. 10956-10964Article in journal (Refereed) Published
Abstract [en]

Alzheimer's disease is linked to a pathological polymerization of the endogenous amyloid β-peptide (Aβ) that ultimately forms amyloid plaques within the human brain. We used surface plasmon resonance (SPR) to measure the kinetic properties of Aβ fibril formation under different conditions during the polymerization process. For all polymerization processes, a critical concentration of free monomers, as defined by the dissociation equilibrium constant (KD), is required for the buildup of the polymer, for example, amyloid fibrils. At concentrations below the KD, polymerization cannot occur. However, the KD for Aβ has previously been shown to be several orders of magnitude higher than the concentrations found in the cerebrospinal and interstitial fluids of the human brain, and the mechanism by which Aβ amyloid forms in vivo has been a matter of debate. Using SPR, we found that the KD of Aβ dramatically decreases as a result of lowering the pH. Importantly, this effect enables Aβ to polymerize within a picomolar concentration range that is close to the physiological Aβ concentration within the human brain. The stabilizing effect is dynamic, fully reversible, and notably pronounced within the pH range found within the endosomal and lysosomal pathways. Through sequential truncation, we show that the N-terminal region of Aβ contributes to the enhanced fibrillar stability due to a gain of function mechanism at low pH. Our results present a possible route for amyloid formation at very low Aβ concentrations and raise the question of whether amyloid formation in vivo is restricted to a low pH environment. These results have general implications for the development of therapeutic interventions.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2014
Keywords
Mediator, Med25, Dreb2a, VP16, conformational changes, NMR, ITC
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-91524 (URN)10.1021/ja503535m (DOI)000340079800030 ()25014209 (PubMedID)
Available from: 2014-08-11 Created: 2014-08-11 Last updated: 2018-06-07Bibliographically approved
Brännström, K., Öhman, A., Lindhagen-Persson, M. & Olofsson, A. (2013). Ca2+ enhances Aβ polymerization rate and fibrillar stability in a dynamic manner. Biochemical Journal, 450, 189-197
Open this publication in new window or tab >>Ca2+ enhances Aβ polymerization rate and fibrillar stability in a dynamic manner
2013 (English)In: Biochemical Journal, ISSN 0264-6021, E-ISSN 1470-8728, Vol. 450, p. 189-197Article in journal (Refereed) Published
Abstract [en]

Identifying factors that affect the self-assembly of the amyloid-β peptide (Aβ) is of utmost importance in the quest to understand the molecular mechanisms causing Alzheimer's disease (AD). Ca2+ has previously been shown to accelerate both Aβ fibril nucleation and maturation, and a dysregulated Ca2+ homeostasis frequently correlates with development of AD. The mechanisms regarding Ca2+ binding as well as its effect on fibril kinetics are not fully understood. Using a polymerization assay we show that Ca2+ in a dynamic and reversible manner enhances both the elongation rate and fibrillar stability, where specifically the "dock and lock" phase mechanism is enhanced. Through NMR analysis we found that Ca2+ affects the fibrillar architecture. In addition, and unexpectedly, we found that Ca2+ does not bind the free Aβ monomer. This implies that Ca2+ binding requires an architecture adopted by assembled peptides, and consequently is mediated through intermolecular interactions between adjacent peptides. This gives a mechanistic explanation to the enhancing effect on fibril maturation and indicates structural similarities between prefibrillar structures and mature amyloid. Taken together we expose how Ca2+ levels affect the delicate equilibrium between the monomeric and assembled Aβ and how fluctuations in vivo may contribute to development and progression of the disease.

Place, publisher, year, edition, pages
Portland Press, 2013
Keywords
amyloid, amyloid-beta peptide (A beta), atomic force microscopy (AFM), Ca2+, NMR, surface plasmon resonance (SPR)
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-64160 (URN)10.1042/BJ20121583 (DOI)000314322600019 ()23171033 (PubMedID)
Available from: 2013-01-17 Created: 2013-01-17 Last updated: 2018-06-08Bibliographically approved
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