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Liberta, F., Loerch, S., Rennegarbege, M., Schierhorn, A., Westermark, P., Westermark, G., . . . Schmidt, M. (2019). Cryo-EM fibril structures from systemic AA amyloidosis reveal the species complementarity of pathological amyloids. Nature Communications, 10, Article ID 1104.
Åpne denne publikasjonen i ny fane eller vindu >>Cryo-EM fibril structures from systemic AA amyloidosis reveal the species complementarity of pathological amyloids
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2019 (engelsk)Inngår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 10, artikkel-id 1104Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Systemic AA amyloidosis is a worldwide occurring protein misfolding disease of humans and animals. It arises from the formation of amyloid fibrils from the acute phase protein serum amyloid A. Here, we report the purification and electron cryo-microscopy analysis of amyloid fibrils from a mouse and a human patient with systemic AA amyloidosis. The obtained resolutions are 3.0 angstrom and 2.7 angstrom for the murine and human fibril, respectively. The two fibrils differ in fundamental properties, such as presence of right-hand or left-hand twisted cross-beta sheets and overall fold of the fibril proteins. Yet, both proteins adopt highly similar beta-arch conformations within the N-terminal similar to 21 residues. Our data demonstrate the importance of the fibril protein N-terminus for the stability of the analyzed amyloid fibril morphologies and suggest strategies of combating this disease by interfering with specific fibril polymorphs.

sted, utgiver, år, opplag, sider
NATURE PUBLISHING GROUP, 2019
HSV kategori
Forskningsprogram
Patologi
Identifikatorer
urn:nbn:se:uu:diva-379892 (URN)10.1038/s41467-019-09033-z (DOI)000460510000001 ()30846696 (PubMedID)
Forskningsfinansiär
EU, Horizon 2020German Research Foundation (DFG), FA 456/15-1German Research Foundation (DFG), SCHM 3276/1
Tilgjengelig fra: 2019-03-25 Laget: 2019-03-25 Sist oppdatert: 2019-03-29bibliografisk kontrollert
Panahi, A. V., Hultman, P., Ollinger, K., Westermark, G. T. & Lundmark, K. (2019). Lipid membranes accelerate amyloid formation in the mouse model of AA amyloidosis. Amyloid: Journal of Protein Folding Disorders, 26(1), 34-44
Åpne denne publikasjonen i ny fane eller vindu >>Lipid membranes accelerate amyloid formation in the mouse model of AA amyloidosis
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2019 (engelsk)Inngår i: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 26, nr 1, s. 34-44Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Introduction:

AA amyloidosis develops as a result of prolonged inflammation and is characterized by deposits of N-terminal proteolytic fragments of the acute phase reactant serum amyloid A (SAA). Macrophages are usually found adjacent to amyloid, suggesting their involvement in the formation and/or degradation of the amyloid fibrils. Furthermore, accumulating evidence suggests that lipid membranes accelerate the fibrillation of different amyloid proteins.

Methods:

Using an experimental mouse model of AA amyloidosis, we compared the amyloidogenic effect of liposomes and/or amyloid-enhancing factor (AEF). Inflammation was induced by subcutaneous injection of silver nitrate followed by intravenous injection of liposomes and/or AEF to accelerate amyloid formation.

Results:

We showed that liposomes accelerate amyloid formation in inflamed mice, but the amyloidogenic effect of liposomes was weaker compared with AEF. Regardless of the induction method, amyloid deposits were mainly found in the marginal zones of the spleen and coincided with the depletion of marginal zone macrophages, while red pulp macrophages and metallophilic marginal zone macrophages proved insensitive to amyloid deposition.

Conclusions:

We conclude that increased intracellular lipid content facilitates AA amyloid fibril formation and show that the mouse model of AA amyloidosis is a suitable system for further mechanistic studies.

Emneord
Amyloid, liposomes, lipid membrane, macrophages, AA amyloidosis
HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-383486 (URN)10.1080/13506129.2019.1576606 (DOI)000466218300001 ()30929476 (PubMedID)
Tilgjengelig fra: 2019-05-16 Laget: 2019-05-16 Sist oppdatert: 2019-05-16bibliografisk kontrollert
Westermark, G., Faendrich, M., Lundmark, K. & Westermark, P. (2018). Noncerebral Amyloidoses: Aspects on Seeding, Cross-Seeding, and Transmission. Cold Spring Harbor Perspectives in Medicine, 8(1), Article ID a024323.
Åpne denne publikasjonen i ny fane eller vindu >>Noncerebral Amyloidoses: Aspects on Seeding, Cross-Seeding, and Transmission
2018 (engelsk)Inngår i: Cold Spring Harbor Perspectives in Medicine, ISSN 0103-3247, E-ISSN 2157-1422, Vol. 8, nr 1, artikkel-id a024323Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

More than 30 proteins form amyloid in humans, most of them outside of the brain. Deposition of amyloid in extracerebral tissues is very common and seems inevitable for an aging person. Most deposits are localized, small, and probably without consequence, but in some instances, they are associated with diseases such as type 2 diabetes. Other extracerebral amyloidoses are systemic, with life-threatening effects on the heart, kidneys, and other organs. Here, we review how amyloid may spread through seeding and whether transmission of amyloid diseases may occur between humans. We also discuss whether cross-seeding is important in the development of amyloidosis, focusing specifically on the amyloid proteins AA, transthyretin, and islet amyloid polypeptide (IAPP).

sted, utgiver, år, opplag, sider
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT, 2018
HSV kategori
Forskningsprogram
Patologi
Identifikatorer
urn:nbn:se:uu:diva-351767 (URN)10.1101/cshperspect.a024323 (DOI)000429143200001 ()
Forskningsfinansiär
Swedish Research CouncilErik, Karin och Gösta Selanders FoundationSwedish Diabetes AssociationGerman Research Foundation (DFG), FA 456/15-1
Tilgjengelig fra: 2018-06-04 Laget: 2018-06-04 Sist oppdatert: 2019-03-29bibliografisk kontrollert
Rahman, M. M., Westermark, G., Zetterberg, H., Hard, T. & Sandgren, M. (2018). Protofibrillar and Fibrillar Amyloid-beta Binding Proteins in Cerebrospinal Fluid. Journal of Alzheimer's Disease, 66(3), 1053-1064
Åpne denne publikasjonen i ny fane eller vindu >>Protofibrillar and Fibrillar Amyloid-beta Binding Proteins in Cerebrospinal Fluid
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2018 (engelsk)Inngår i: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 66, nr 3, s. 1053-1064Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Aggregation and deposition of misfolded amyloid-beta (A beta) peptide in the brain is central to Alzheimer's disease (AD). Oligomeric, protofibrillar, and fibrillar forms of A beta are believed to be neurotoxic and cause neurodegeneration in AD, but the toxicity mechanisms are not well understood and may involve A beta-interacting molecular partners. In a previous study, we identified potential A beta(42) protofibrillar-binding proteins in serum and cerebrospinal fluid (CSF) using an engineered version of A beta(42) (A beta 42CC) that forms protofibrils, but not fibrils. Here we studied binding of proteins to A beta(42) fibrils in AD and non-AD CSF and compared these with protofibrillar A beta 42CC-binding partners. A beta(42) fibrils sequestered 2.4-fold more proteins than A beta 42CC protofibrils. Proteins with selective binding to fibrillar aggregates with low nanomolar affinity were identified. We also found that protofibrillar and fibrillar A beta-binding proteins represent distinct functional categories. A beta 42CC protofibrils triggered interactions with proteins involved in catalytic activities, like transferases and oxidoreductases, while A beta(42) fibrils were more likely involved in binding to proteoglycans, growth factors and neuron-associated proteins, e.g., neurexin-1, -2, and -3. Interestingly, 10 brain-enriched proteins were identified among the fibril-binding proteins, while protofibril-extracted proteins had more general expression patterns. Both types of A beta aggregates bound several extracellular proteins. Additionally, we list a set of CSF proteins that might have potential to discriminate between AD and non-AD CSF samples. The results may be of relevance both for biomarker studies and for studies of A beta-related toxicity mechanisms.

Emneord
Alzheimer's disease, amyloid-beta, biomolecular interaction, cerebrospinal fluid, fibrils, protofibrils
HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-372429 (URN)10.3233/JAD-180596 (DOI)000451225400015 ()30372682 (PubMedID)
Forskningsfinansiär
Swedish Research Council Formas, 942-2015-945Swedish Research CouncilEU, European Research CouncilKnut and Alice Wallenberg Foundation
Tilgjengelig fra: 2019-01-07 Laget: 2019-01-07 Sist oppdatert: 2019-01-07bibliografisk kontrollert
Oskarsson, M. E., Hermansson, E., Wang, Y., Welsh, N., Presto, J., Johansson, J. & Westermark, G. (2018). The BRICHOS domain of Bri2 inhibits islet amyloid polypeptide (IAPP) fibril formation and toxicity in human beta cells. Proceedings of the National Academy of Sciences of the United States of America, 115(12), E2752-E2761
Åpne denne publikasjonen i ny fane eller vindu >>The BRICHOS domain of Bri2 inhibits islet amyloid polypeptide (IAPP) fibril formation and toxicity in human beta cells
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2018 (engelsk)Inngår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 115, nr 12, s. E2752-E2761Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Aggregation of islet amyloid polypeptide (IAPP) into amyloid fibrils in islets of Langerhans is associated with type 2 diabetes, and formation of toxic IAPP species is believed to contribute to the loss of insulin-producing beta cells. The BRICHOS domain of integral membrane protein 2B (Bri2), a transmembrane protein expressed in several peripheral tissues and in the brain, has recently been shown to prevent fibril formation and toxicity of Aβ42, an amyloid-forming peptide in Alzheimer disease. In this study, we demonstrate expression of Bri2 in human islets and in the human beta-cell line EndoC-βH1. Bri2 colocalizes with IAPP intracellularly and is present in amyloid deposits in patients with type 2 diabetes. The BRICHOS domain of Bri2 effectively inhibits fibril formation in vitro and instead redirects IAPP into formation of amorphous aggregates. Reduction of endogenous Bri2 in EndoC-βH1 cells with siRNA increases sensitivity to metabolic stress leading to cell death while a concomitant overexpression of Bri2 BRICHOS is protective. Also, coexpression of IAPP and Bri2 BRICHOS in lateral ventral neurons of Drosophila melanogaster results in an increased cell survival. IAPP is considered to be the most amyloidogenic peptide known, and described findings identify Bri2, or in particular its BRICHOS domain, as an important potential endogenous inhibitor of IAPP aggregation and toxicity, with the potential to be a possible target for the treatment of type 2 diabetes.

Emneord
Bri2, BRICHOS, chaperone, IAPP, amyloid, islet amyloid, beta cells, type 2 diabetes
HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-265483 (URN)10.1073/pnas.1715951115 (DOI)000427829500014 ()
Forskningsfinansiär
Swedish Research CouncilSwedish Diabetes AssociationNovo NordiskErnfors Foundation
Tilgjengelig fra: 2015-10-29 Laget: 2015-10-29 Sist oppdatert: 2018-06-01bibliografisk kontrollert
Carlsson, P.-O., Espes, D., Sedigh, A., Rotem, A., Zimermann, B., Grinberg, H., . . . Korsgren, O. (2018). Transplantation of macroencapsulated human islets within the bioartificial pancreas βAir to patients with type 1 diabetes mellitus. American Journal of Transplantation, 18(7), 1735-1744
Åpne denne publikasjonen i ny fane eller vindu >>Transplantation of macroencapsulated human islets within the bioartificial pancreas βAir to patients with type 1 diabetes mellitus
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2018 (engelsk)Inngår i: American Journal of Transplantation, ISSN 1600-6135, E-ISSN 1600-6143, Vol. 18, nr 7, s. 1735-1744Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Macroencapsulation devices provide the dual possibility to immunoprotect transplanted cells while also being retrievable; the latter bearing importance for safety in future trials with stem-cell derived cells. However, macroencapsulation entails a problem with oxygen supply to the encapsulated cells. The βAir device solves this with an incorporated refillable oxygen tank. This phase 1 study evaluated the safety and efficacy of implanting the βAir device containing allogeneic human pancreatic islets to patients with type 1 diabetes. Four patients were transplanted with 1-2 βAir devices, each containing 155000-180000 IEQ (i.e. 1800-4600 IEQ per kg body weight), and monitored for 3-6 months, followed by the recovery of devices. Implantation of the βAir device was safe and successfully prevented immunization and rejection of the transplanted tissue. However, although beta cells survived in the device, only minute levels of circulating C-peptide were observed with no impact on metabolic control. Fibrotic tissue with immune cells was formed in capsule surroundings. Recovered devices displayed a blunted glucose-stimulated insulin response, and amyloid formation in the endocrine tissue. We conclude that the βAir device is safe and can support survival of allogeneic islets for several months, although the function of the transplanted cells was limited.

Emneord
cellular biology, clinical research, practice, diabetes: type 1, encapsulation, endocrinology, diabetology, islet transplantation, islets of Langerhans, translational research, science
HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-337701 (URN)10.1111/ajt.14642 (DOI)000437727800020 ()29288549 (PubMedID)
Forskningsfinansiär
Ernfors FoundationSwedish Diabetes AssociationSwedish Research Council, 921-2014-7054Swedish Research Council, K2013-55X-15043Swedish Research Council, K2015-54X-12219-19-4Swedish Research Council, K2016-01040Swedish Research Council, K2016-GTWNovo NordiskSwedish Child Diabetes FoundationEU, European Research Council, F4-2013-602889EU, European Research Council, 646075-ELASTISLETEXODIAB - Excellence of Diabetes Research in Sweden
Merknad

De två första författarna delar förstaförfattarskapet.

Tilgjengelig fra: 2018-01-03 Laget: 2018-01-03 Sist oppdatert: 2019-07-03bibliografisk kontrollert
Krizhanovskii, C., Fred, R. G., Oskarsson, M. E., Westermark, G. T. & Welsh, N. (2017). Addition of exogenous sodium palmitate increases the IAPP/insulin mRNA ratio via GPR40 in human EndoC-beta H1 cells. Upsala Journal of Medical Sciences, 122(3), 149-159
Åpne denne publikasjonen i ny fane eller vindu >>Addition of exogenous sodium palmitate increases the IAPP/insulin mRNA ratio via GPR40 in human EndoC-beta H1 cells
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2017 (engelsk)Inngår i: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 122, nr 3, s. 149-159Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Background: Enhanced IAPP production may contribute to islet amyloid formation in type 2 diabetes. The objective of this study was to determine the effects of the saturated fatty acid palmitate on IAPP levels in human beta-cells. Methods: EndoC-beta H1 cells and human islets were cultured in the presence of sodium palmitate. Effects on IAPP/insulin mRNA expression and secretion were determined using real-time qPCR/ELISA. Pharmacological activators and/or inhibitors and RNAi were used to determine the underlying mechanisms. Results: We observed that EndoC-beta H1 cells exposed to palmitate for 72 h displayed decreased expression of Pdx-1 and MafA and increased expression of thioredoxin-interacting protein (TXNIP), reduced insulin mRNA expression and glucose-induced insulin secretion, as well as increased IAPP mRNA expression and secretion. Further, these effects were independent of fatty acid oxidation, but abolished in response to GPR40 inhibition/downregulation. In human islets both a high glucose concentration and palmitate promoted increased IAPP mRNA levels, resulting in an augmented IAPP/insulin mRNA ratio. This was paralleled by elevated IAPP/insulin protein secretion and content ratios. Conclusions: Addition of exogenous palmitate to human beta-cells increased the IAPP/insulin expression ratio, an effect contributed to by activation of GPR40. These findings may be pertinent to our understanding of the islet amyloid formation process.

Emneord
Amyloid, fatty acids, insulin, islet amyloid polypeptide (IAPP), palmitate
HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-340975 (URN)10.1080/03009734.2017.1368745 (DOI)000414107800001 ()28980863 (PubMedID)
Tilgjengelig fra: 2018-02-06 Laget: 2018-02-06 Sist oppdatert: 2018-02-06bibliografisk kontrollert
Krotee, P., Rodriguez, J. A., Sawaya, M. R., Cascio, D., Reyes, F. E., Shi, D., . . . Eisenberg, D. S. (2017). Atomic structures of fibrillar segments of hIAPP suggest tightly mated beta-sheets are important or cytotoxicity. eLIFE, 6
Åpne denne publikasjonen i ny fane eller vindu >>Atomic structures of fibrillar segments of hIAPP suggest tightly mated beta-sheets are important or cytotoxicity
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2017 (engelsk)Inngår i: eLIFE, E-ISSN 2050-084X, Vol. 6Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

hIAPP fibrils are associated with Type-II Diabetes, but the link of hIAPP structure to islet cell death remains elusive. Here we observe that hIAPP fibrils are cytotoxic to cultured pancreatic beta-cells, leading us to determine the structure and cytotoxicity of protein segments composing the amyloid spine of hIAPP. Using the cryoEM method MicroED, we discover that one segment, 19-29 S20G, forms pairs of beta-sheets mated by a dry interface that share structural features with and are similarly cytotoxic to full-length hIAPP fibrils. In contrast, a second segment, 15-25 WT, forms non-toxic labile beta-sheets. These segments possess different structures and cytotoxic effects, however, both can seed full-length hIAPP, and cause hIAPP to take on the cytotoxic and structural features of that segment. These results suggest that protein segment structures represent polymorphs of their parent protein and that segment 19-29 S20G may serve as a model for the toxic spine of hIAPP.

HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-316042 (URN)10.7554/eLife.19273 (DOI)000392186000001 ()
Forskningsfinansiär
NIH (National Institute of Health), R01 AG029430
Tilgjengelig fra: 2017-02-24 Laget: 2017-02-24 Sist oppdatert: 2018-01-13bibliografisk kontrollert
Rostami, J., Holmqvist, S., Lindström, V., Sigvardson, J., Westermark, G., Ingelsson, M., . . . Erlandsson, A. (2017). Human Astrocytes Transfer Aggregated Alpha-Synuclein via Tunneling Nanotubes. Journal of Neuroscience, 37(49), 11835-11853
Åpne denne publikasjonen i ny fane eller vindu >>Human Astrocytes Transfer Aggregated Alpha-Synuclein via Tunneling Nanotubes
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2017 (engelsk)Inngår i: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 37, nr 49, s. 11835-11853Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Many lines of evidence suggest that the Parkinson's disease (PD)-related protein alpha-synuclein (alpha-SYN) can propagate from cell to cell in a prion-like manner. However, the cellular mechanisms behind the spreading remain elusive. Here, we show that human astrocytes derived from embryonic stem cells actively transfer aggregated alpha-SYN to nearby astrocytes via direct contact and tunneling nanotubes (TNTs). Failure in the astrocytes' lysosomal digestion of excess alpha-SYN oligomers results in alpha-SYN deposits in the trans-Golgi network followed by endoplasmic reticulum swelling and mitochondrial disturbances. The stressed astrocytes respond by conspicuously sending out TNTs, enabling intercellular transfer of alpha-SYN to healthy astrocytes, which in return deliver mitochondria, indicating a TNT-mediated rescue mechanism. Using a pharmacological approach to inhibit TNT formation, we abolished the transfer of both alpha-SYN and mitochondria. Together, our results highlight the role of astrocytes in alpha-SYN cell-to-cell transfer, identifying possible pathophysiological events in the PD brain that could be of therapeutic relevance.

sted, utgiver, år, opplag, sider
SOC NEUROSCIENCE, 2017
Emneord
alpha-synuclein, astrocytes, lysosomes, mitochondria, trans-Golgi, tunneling nanotubes
HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-340258 (URN)10.1523/JNEUROSCI.0983-17.2017 (DOI)000418053700007 ()29089438 (PubMedID)
Forskningsfinansiär
Swedish Research CouncilThe Crafoord FoundationÅke Wiberg Foundation
Tilgjengelig fra: 2018-01-31 Laget: 2018-01-31 Sist oppdatert: 2018-01-31bibliografisk kontrollert
Ullsten, S., Bohman, S., Oskarsson, M. E., Nilsson, K. P., Westermark, G. & Carlsson, P.-O. (2017). Islet amyloid deposits preferentially in the highly functional and most blood-perfused islets.. Endocrine Connections, 6(7), 458-468
Åpne denne publikasjonen i ny fane eller vindu >>Islet amyloid deposits preferentially in the highly functional and most blood-perfused islets.
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2017 (engelsk)Inngår i: Endocrine Connections, ISSN 2049-3614, E-ISSN 2049-3614, Vol. 6, nr 7, s. 458-468Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Islet amyloid and beta cell death in type 2 diabetes are heterogeneous events, where some islets are affected early in the disease process, whereas others remain visibly unaffected. This study investigated the possibility that inter-islet functional and vascular differences may explain the propensity for amyloid accumulation in certain islets. Highly blood-perfused islets were identified by microspheres in human islet amyloid polypeptide expressing mice fed a high-fat diet for three or 10 months. These highly blood-perfused islets had better glucose-stimulated insulin secretion capacity than other islets and developed more amyloid deposits after 10 months of high-fat diet. Similarly, human islets with a superior release capacity formed more amyloid in high glucose culture than islets with a lower release capacity. The amyloid formation in mouse islets was associated with a higher amount of prohormone convertase 1/3 and with a decreased expression of its inhibitor proSAAS when compared to islets with less amyloid. In contrast, levels of prohormone convertase 2 and expression of its inhibitor neuroendocrine protein 7B2 were unaltered. A misbalance in prohormone convertase levels may interrupt the normal processing of islet amyloid polypeptide and induce amyloid formation. Preferential amyloid load in the most blood-perfused and functional islets may accelerate the progression of type 2 diabetes.

Emneord
blood flow, heterogeneity, islet amyloid, pancreatic islets
HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-330801 (URN)10.1530/EC-17-0148 (DOI)000411647000007 ()28790139 (PubMedID)
Forskningsfinansiär
Swedish Research Council, 55X-15043Swedish Child Diabetes FoundationSwedish Diabetes AssociationNovo NordiskEXODIAB - Excellence of Diabetes Research in Sweden
Tilgjengelig fra: 2017-10-04 Laget: 2017-10-04 Sist oppdatert: 2017-12-18bibliografisk kontrollert
Organisasjoner
Identifikatorer
ORCID-id: ORCID iD iconorcid.org/0000-0003-1151-9986