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Fasching, Angelica
Publications (10 of 22) Show all publications
Sivertsson, E., Friederich Persson, M., Öberg, C. M., Fasching, A., Hansell, P., Rippe, B. & Palm, F. (2018). Inhibition of mammalian target of rapamycin decreases intrarenal oxygen availability and alters glomerular permeability. American Journal of Physiology - Renal Physiology, 314(5), F864-F872
Open this publication in new window or tab >>Inhibition of mammalian target of rapamycin decreases intrarenal oxygen availability and alters glomerular permeability
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2018 (English)In: American Journal of Physiology - Renal Physiology, ISSN 1931-857X, E-ISSN 1522-1466, Vol. 314, no 5, p. F864-F872Article in journal (Refereed) Published
Abstract [en]

An increased kidney oxygen consumption causing tissue hypoxia has been suggested to be a common pathway toward chronic kidney disease. The mammalian target of rapamycin (mTOR) regulates cell proliferation and mitochondrial function. mTOR inhibitors (e.g., rapamycin) are used clinically to prevent graft rejection. mTOR has been identified as a key player in diabetes, which has stimulated the use of mTOR inhibitors to counter diabetic nephropathy. However, the effect of mTOR inhibition on kidney oxygen consumption is unknown. Therefore, we investigated the effects of mTOR inhibition on in vivo kidney function, oxygen homeostasis, and glomerular permeability. Control and streptozotocin-induced diabetic rats were chronically treated with rapamycin, and the functional consequences were studied 14 days thereafter. In both groups, mTOR inhibition induced mitochondrial uncoupling, resulting in increased total kidney oxygen consumption and decreased intrarenal oxygen availability. Concomitantly, mTOR inhibition induced tubular injury, as estimated from urinary excretion of kidney injury molecule-1 (KIM-1) and reduced urinary protein excretion. The latter corresponded to reduced sieving coefficient for large molecules. In conclusion, mTOR inhibition induces mitochondrial dysfunction leading to decreased oxygen availability in normal and diabetic kidneys. which translates into increased KIM-1 in the urine. Reduced proteinuria after mTOR inhibition is an effect of reduced glomerular permeability for large molecules. Since hypoxia has been suggested as a common pathway in the development of chronic kidney disease, mTOR inhibition to patients with preexisting nephropathy should be used with caution, since it may accelerate the progression of the disease.

Place, publisher, year, edition, pages
AMER PHYSIOLOGICAL SOC, 2018
Keywords
glomerular permeability, hypoxia, mitochondrial function, mTOR, oxygen consumption, tubular injury
National Category
Physiology
Identifiers
urn:nbn:se:uu:diva-363076 (URN)10.1152/ajprenal.00033.2017 (DOI)000441089200019 ()28971989 (PubMedID)
Funder
Swedish Research CouncilSwedish Diabetes AssociationSwedish Society for Medical Research (SSMF)
Available from: 2018-10-12 Created: 2018-10-12 Last updated: 2018-10-12Bibliographically approved
Franzén, S., Pihl, L., Fasching, A. & Palm, F. (2018). Intrarenal activation of endothelin type B receptors improves kidney oxygenation in type 1 diabetic rats. American Journal of Physiology - Renal Physiology, 314(3), F439-F444
Open this publication in new window or tab >>Intrarenal activation of endothelin type B receptors improves kidney oxygenation in type 1 diabetic rats
2018 (English)In: American Journal of Physiology - Renal Physiology, ISSN 1931-857X, E-ISSN 1522-1466, Vol. 314, no 3, p. F439-F444Article in journal (Refereed) Published
Abstract [en]

About one-third of patients with type 1 diabetes develops kidney disease. The mechanism is largely unknown, but intrarenal hypoxia has been proposed as a unifying mechanism for chronic kidney disease, including diabetic nephropathy. The endothelin system has recently been demonstrated to regulate oxygen availability in the diabetic kidney via a pathway involving endothelin type A receptors (ETA-R). These receptors mainly mediate vasoconstriction and tubular sodium retention, and inhibition of ETA-R improves intrarenal oxygenation in the diabetic kidney. Endothelin type B receptors (ETB-R) can induce vasodilation of the renal vasculature and also regulate tubular sodium handling. However, the role of ETB-R in kidney oxygen homeostasis is unknown. The effects of acute intrarenal ETB-R activation (sarafotoxin 6c for 30-40 min; 0.78 pmol/h directly into the renal artery) on kidney function and oxygen metabolism were investigated in normoglycemic controls and insulinopenic male Sprague-Dawley rats administered streptozotocin (55 mg/kg) 2 wk before the acute experiments. Intrarenal activation of ETB-R improved oxygenation in the hypoxic diabetic kidney. However, the effects on diabetes-induced increased kidney oxygen consumption could not explain the improved oxygenation. Rather, the improved kidney oxygenation was due to hemodynamic effects increasing oxygen delivery without increasing glomerular filtration or tubular sodium load. In conclusion, increased ETB-R signaling in the diabetic kidney improves intrarenal tissue oxygenation due to increased oxygen delivery secondary to increased renal blood flow.

Place, publisher, year, edition, pages
AMER PHYSIOLOGICAL SOC, 2018
Keywords
diabetes, endothelin, kidney, oxygen consumption, oxygen tension
National Category
Physiology
Identifiers
urn:nbn:se:uu:diva-354369 (URN)10.1152/ajprenal.00498.2017 (DOI)000428517700014 ()29092848 (PubMedID)
Funder
Swedish Research CouncilSwedish Heart Lung FoundationSwedish Diabetes AssociationErnfors Foundation
Available from: 2018-06-19 Created: 2018-06-19 Last updated: 2018-06-19Bibliographically approved
Persson, P., Fasching, A., Teerlink, T., Hansell, P. & Palm, F. (2017). Cellular transport of L-Arginine determines renal medullary blood flow in control rats, but not in diabetic rats despite enhanced cellular uptake capacity. American Journal of Physiology - Renal Physiology, 312(2), F278-F283
Open this publication in new window or tab >>Cellular transport of L-Arginine determines renal medullary blood flow in control rats, but not in diabetic rats despite enhanced cellular uptake capacity
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2017 (English)In: American Journal of Physiology - Renal Physiology, ISSN 0363-6127, E-ISSN 1522-1466, Vol. 312, no 2, p. F278-F283Article in journal (Refereed) Published
Abstract [en]

Diabetes mellitus is associated with decreased nitric oxide bioavailability thereby affecting renal blood flow regulation. Previous reports have demonstrated that cellular uptake of L-arginine is rate limiting for nitric oxide production, and that plasma L-arginine concentration is decreased in diabetes. We therefore investigated if regional renal blood flow regulation is affected by cellular L-arginine uptake in streptozotocin-induced diabetic rats. Rats were anesthetized with thiobutabarbital and left kidney was exposed. Total, cortical and medullary renal blood flow was investigated before and after renal artery infusion of increasing doses of either L-homoarginine to inhibit cellular uptake of L-arginine, or L-NAME to inhibit nitric oxide synthase. L-homoarginine infusion did not affect total or cortical blood flow in any of the groups, but caused a dose-dependent reduction in medullary blood flow. L-NAME decreased total, cortical and medullary blood flow in both groups. However, the reductions in medullary blood flow in response to both L-homoarginine and L-NAME were more pronounced in the control groups compared to the diabetic groups. Isolated cortical tubular cells displayed similar L-arginine uptake capacity whereas medullary tubular cells isolated from diabetic rats had increased L-arginine uptake capacity. Diabetics had reduced L-arginine concentrations in plasma and medullary tissue but increased L-arginine concentration in cortical tissue. In conclusion, the reduced L-arginine availability in plasma and medullary tissue in diabetes results in reduced nitric oxide-mediated regulation of renal medullary hemodynamics. Cortical blood flow regulation displays less dependency on extracellular L-arginine and the upregulated cortical tissue L-arginine may protect cortical hemodynamics in diabetes.

Keywords
L-homoarginine, cortical blood flow, kidney, renal blood flow, streptozotocin
National Category
Physiology
Research subject
Physiology
Identifiers
urn:nbn:se:uu:diva-310400 (URN)10.1152/ajprenal.00335.2016 (DOI)000393897900006 ()27927650 (PubMedID)
Funder
Swedish Research CouncilÅke Wiberg FoundationSwedish Society for Medical Research (SSMF)Swedish Diabetes Association
Available from: 2016-12-15 Created: 2016-12-15 Last updated: 2018-01-13Bibliographically approved
Liss, P., Hansell, P., Fasching, A. & Palm, F. (2016). Iodinated contrast media inhibit oxygen consumption in freshly isolated proximal tubular cells from elderly humans and diabetic rats: Influence of nitric oxide.. Upsala Journal of Medical Sciences, 121(1), 12-16
Open this publication in new window or tab >>Iodinated contrast media inhibit oxygen consumption in freshly isolated proximal tubular cells from elderly humans and diabetic rats: Influence of nitric oxide.
2016 (English)In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 121, no 1, p. 12-16Article in journal (Refereed) Published
Abstract [en]

Objectives Mechanisms underlying contrast medium (CM)-induced nephropathy remain elusive, but recent attention has been directed to oxygen availability. The purpose of this study was to evaluate the effect of the low-osmolar CM iopromide and the iso-osmolar CM iodixanol on oxygen consumption (QO2) in freshly isolated proximal tubular cells (PTC) from kidneys ablated from elderly humans undergoing nephrectomy for renal carcinomas and from normoglycemic or streptozotocin-diabetic rats. Materials PTC were isolated from human kidneys, or kidneys of normoglycemic or streptozotocin-diabetic rats. QO2 was measured with Clark-type microelectrodes in a gas-tight chamber with and without each CM (10 mg I/mL medium). L-NAME was used to inhibit nitric oxide (NO) production caused by nitric oxide synthase. Results Both CM reduced QO2 in human PTC (about -35%) which was prevented by L-NAME. PTC from normoglycemic rats were unaffected by iopromide, whereas iodixanol decreased QO2 (-34%). Both CM decreased QO2 in PTC from diabetic rats (-38% and -36%, respectively). L-NAME only prevented the effect of iopromide in the diabetic rat PTC. Conclusions These observations demonstrate that CM can induce NO release from isolated PTC in vitro, which affects QO2. Our results suggest that the induction of NO release and subsequent effect on the cellular oxygen metabolism are dependent on several factors, including CM type and pre-existing risk factors for the development of CM-induced nephropathy.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-284721 (URN)10.3109/03009734.2016.1144664 (DOI)000372123700002 ()26933994 (PubMedID)
Funder
The Swedish Medical AssociationSwedish Diabetes AssociationSwedish Research Council
Available from: 2016-04-19 Created: 2016-04-19 Last updated: 2017-11-30Bibliographically approved
Nordquist, L., Friederich-Persson, M., Fasching, A., Liss, P., Shoji, K., Nangaku, M., . . . Palm, F. (2015). Activation of Hypoxia-Inducible Factors Prevents Diabetic Nephropathy. Journal of the American Society of Nephrology, 26(2), 328-338
Open this publication in new window or tab >>Activation of Hypoxia-Inducible Factors Prevents Diabetic Nephropathy
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2015 (English)In: Journal of the American Society of Nephrology, ISSN 1046-6673, E-ISSN 1533-3450, Vol. 26, no 2, p. 328-338Article in journal (Refereed) Published
Abstract [en]

Hyperglycemia results in increased oxygen consumption and decreased oxygen tension in the kidney. We tested the hypothesis that activation of hypoxia-inducible factors (HIFs) protects against diabetes-induced alterations in oxygen metabolism and kidney function. Experimental groups consisted of control and streptozotocin-induced diabetic rats treated with or without chronic cobalt chloride to activate HIFs. We elucidated the involvement of oxidative stress by studying the effects of acute administration of the superoxide dismutase mimetic tempol. Compared with controls, diabetic rats displayed tissue hypoxia throughout the kidney, glomerular hyperfiltration, increased oxygen consumption, increased total mitochondrial leak respiration, and decreased tubular sodium transport efficiency. Diabetic kidneys showed proteinuria and tubulointerstitial damage. Cobalt chloride activated HIFs, prevented the diabetes-induced alterations in oxygen metabolism, mitochondrial leak respiration, and kidney function, and reduced proteinuria and tubulointerstitial damage. The beneficial effects of tempol were less pronounced after activation of HIFs, indicating improved oxidative stress status. In conclusion, activation of HIFs prevents diabetes-induced alteration in kidney oxygen metabolism by normalizing glomerular filtration, which reduces tubular electrolyte load, preventing mitochondrial leak respiration and improving tubular transport efficiency. These improvements could be related to reduced oxidative stress and account for the reduced proteinuria and tubulointerstitial damage. Thus, pharmacologic activation of the HIF system may prevent development of diabetic nephropathy.

National Category
Clinical Medicine
Identifiers
urn:nbn:se:uu:diva-232171 (URN)10.1681/ASN.2013090990 (DOI)000348623700012 ()25183809 (PubMedID)
Available from: 2014-09-15 Created: 2014-09-15 Last updated: 2017-12-05Bibliographically approved
O'Neill, J., Fasching, A., Pihl, L., Patinha, D., Franzen, S. & Palm, F. (2015). Acute SGLT inhibition normalizes O-2 tension in the renal cortex but causes hypoxia in the renal medulla in anaesthetized control and diabetic rats. American Journal of Physiology - Renal Physiology, 309(3), F227-F234
Open this publication in new window or tab >>Acute SGLT inhibition normalizes O-2 tension in the renal cortex but causes hypoxia in the renal medulla in anaesthetized control and diabetic rats
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2015 (English)In: American Journal of Physiology - Renal Physiology, ISSN 0363-6127, E-ISSN 1522-1466, Vol. 309, no 3, p. F227-F234Article in journal (Refereed) Published
Abstract [en]

Early stage diabetic nephropathy is characterized by glomerular hyperfiltration and reduced renal tissue PO2. Recent observations have indicated that increased tubular Na+-glucose linked transport (SGLT) plays a role in the development of diabetes-induced hyperfiltration. The aim of the present study was to determine how inhibition of SLGT impacts upon PO2 in the diabetic rat kidney. Diabetes was induced by streptozotocin in Sprague-Dawley rats 2 wk before experimentation. Renal hemodynamics, excretory function, and renal O-2 homeostasis were measured in anesthetized control and diabetic rats during baseline and after acute SGLT inhibition using phlorizin (200 mg/kg ip). Baseline arterial pressure was similar in both groups and unaffected by SGLT inhibition. Diabetic animals displayed reduced baseline PO2 in both the cortex and medulla. SGLT inhibition improved cortical PO2 in the diabetic kidney, whereas it reduced medullary PO2 in both groups. SGLT inhibition reduced Na+ transport efficiency [tubular Na+ transport (TNa)/renal O-2 consumption (QO(2))] in the control kidney, whereas the already reduced TNa/QO(2) in the diabetic kidney was unaffected by SGLT inhibition. In conclusion, these data demonstrate that when SGLT is inhibited, renal cortex PO2 in the diabetic rat kidney is normalized, which implies that increased proximal tubule transport contributes to the development of hypoxia in the diabetic kidney. The reduction in medullary PO2 in both control and diabetic kidneys during the inhibition of proximal Na+ reabsorption suggests the redistribution of active Na+ transport to less efficient nephron segments, such as the medullary thick ascending limb, which results in medullary hypoxia.

Keywords
diabetes, oxgen consumption, renal hypoxia, sodium-glucose linked transport, sodium transport
National Category
Urology and Nephrology Physiology
Identifiers
urn:nbn:se:uu:diva-261965 (URN)10.1152/ajprenal.00689.2014 (DOI)000359731400005 ()
Funder
Swedish Heart Lung FoundationSwedish Diabetes AssociationSwedish Research Council
Available from: 2015-09-14 Created: 2015-09-07 Last updated: 2018-01-11Bibliographically approved
Persson, P., Friederich-Persson, M., Fasching, A., Hansell, P., Inagi, R. & Palm, F. (2015). Adenosine A2 a receptor stimulation prevents proteinuria in diabetic rats by promoting an anti-inflammatory phenotype without affecting oxidative stress. Acta Physiologica, 214(3), 311-318
Open this publication in new window or tab >>Adenosine A2 a receptor stimulation prevents proteinuria in diabetic rats by promoting an anti-inflammatory phenotype without affecting oxidative stress
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2015 (English)In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 214, no 3, p. 311-318Article in journal (Refereed) Published
Abstract [en]

AIM: Diabetic patients are at increased risk for kidney disease. There is presently no clinical treatment available that effectively protects kidney function in diabetics. The present study investigates if chronic stimulation of the adenosine A2a receptor (A2a AR) protects kidney function in insulinopenic diabetic rats.

METHODS: Streptozotocin-induced diabetic rats and corresponding controls were chronically treated with the adenosine A2a AR agonist CGS21680 throughout the four-week diabetes duration. Kidney function was thereafter investigated and urine and plasma samples were collected for analysis of protein, oxidative stress and inflammatory markers.

RESULTS: Glomerular filtration rate, renal blood flow, filtration fraction and diabetes-induced kidney hypoxia were all unaffected by chronic A2a AR stimulation. Furthermore, diabetic rats had increased oxidative stress, which was further increased by chronic A2a AR stimulation. However, the 10-fold increased urinary protein excretion observed in the diabetic rats was completely prevented by chronic A2a AR stimulation. These beneficial effects were accompanied by reduced levels of the pro-inflammatory TNF-α and increased levels of the anti-inflammatory IL-10 as well as decreased infiltration of macrophages, glomerular damage and basement membrane thickness.

CONCLUSION: Chronic A2a AR stimulation prevents proteinuria and glomerular damage in experimental diabetes via an anti-inflammatory mechanism independent of oxidative stress and kidney hypoxia.

National Category
Physiology
Identifiers
urn:nbn:se:uu:diva-252416 (URN)10.1111/apha.12511 (DOI)000356306300007 ()25891445 (PubMedID)
Funder
Swedish Heart Lung FoundationSwedish Research CouncilÅke Wiberg FoundationSwedish Diabetes Association
Available from: 2015-05-06 Created: 2015-05-06 Last updated: 2018-01-11Bibliographically approved
Franzen, S., Friederich-Persson, M., Fasching, A., Hansell, P., Nangaku, M. & Palm, F. (2014). Differences in susceptibility to develop parameters of diabetic nephropathy in four mouse strains with type 1 diabetes. American Journal of Physiology-Renal Physiology, 306(10), F1171-F1178
Open this publication in new window or tab >>Differences in susceptibility to develop parameters of diabetic nephropathy in four mouse strains with type 1 diabetes
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2014 (English)In: American Journal of Physiology-Renal Physiology, ISSN 1931-857X, Vol. 306, no 10, p. F1171-F1178Article in journal (Refereed) Published
Abstract [en]

One-third of diabetes mellitus patients develop diabetic nephropathy, and with underlying mechanisms unknown it is imperative that diabetic animal models resemble human disease. The present study investigated the susceptibility to develop diabetic nephropathy in four commonly used and commercially available mouse strains with type 1 diabetes to determine the suitability of each strain. Type 1 diabetes was induced in C57Bl/6, NMRI, BALB/c, and 129Sv mice by alloxan, and conscious glomerular filtration rate, proteinuria, and oxidative stress levels were measured in control and diabetic animals at baseline and after 5 and 10 wk. Histological alterations were analyzed using periodic acid-Schiff staining. Diabetic C57Bl/6 displayed increased glomerular filtration rate, i.e., hyperfiltration, whereas all other parameters remained unchanged. Diabetic NMRI developed the most pronounced hyperfiltration as well as increased oxidative stress and proteinuria but without glomerular damage. Diabetic BALB/c did not develop hyperfiltration but presented with pronounced proteinuria, increased oxidative stress, and glomerular damage. Diabetic 129Sv displayed proteinuria and increased oxidative stress without glomerular hyperfiltration or damage. However, all strains displayed intras-train correlation between oxidative stress and proteinuria. In conclusion, diabetic C57Bl/6 and NMRI both developed glomerular hyperfiltration but neither presented with histological damage, although NMRI developed low-degree proteinuria. Thus these strains may be suitable when investigating the mechanism causing hyperfiltration. Neither BALB/c nor 129Sv developed hyperfiltration although both developed pronounced proteinuria. However, only BALB/c developed detectable histological damage. Thus BALB/c may be suitable when studying the roles of proteinuria and histological alterations for the progression of diabetic nephropathy.

Keywords
C57Bl/6, NMRI, BALB/c, 129Sv, diabetic nephropathy, kidney function
National Category
Physiology Urology and Nephrology
Identifiers
urn:nbn:se:uu:diva-228483 (URN)10.1152/ajprenal.00595.2013 (DOI)000336846400007 ()
Available from: 2014-07-15 Created: 2014-07-15 Last updated: 2018-01-11Bibliographically approved
Persson, P., Fasching, A., Teerlink, T., Hansell, P. & Palm, F. (2014). L-Citrulline, But Not L-Arginine, Prevents Diabetes Mellitus–Induced Glomerular Hyperfiltration and Proteinuria in Rat. Hypertension, 64(2), 323-329
Open this publication in new window or tab >>L-Citrulline, But Not L-Arginine, Prevents Diabetes Mellitus–Induced Glomerular Hyperfiltration and Proteinuria in Rat
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2014 (English)In: Hypertension, ISSN 0194-911X, E-ISSN 1524-4563, Vol. 64, no 2, p. 323-329Article in journal (Refereed) Published
Abstract [en]

Diabetes mellitus–induced oxidative stress causes increased renal oxygen consumption and intrarenal tissue hypoxia. Nitric oxide is an important determinant of renal oxygen consumption and electrolyte transport efficiency. The present study investigates whether l-arginine or l-citrulline to promote nitric oxide production prevents the diabetes mellitus–induced kidney dysfunction. Glomerular filtration rate, renal blood flow, in vivo oxygen consumption, tissue oxygen tension, and proteinuria were investigated in control and streptozotocin-diabetic rats with and without chronic l-arginine or l-citrulline treatment for 3 weeks. Untreated and l-arginine–treated diabetic rats displayed increased glomerular filtration rate (2600±162 versus 1599±127 and 2290±171 versus 1739±138 µL/min per kidney), whereas l-citrulline prevented the increase (1227±126 versus 1375±88 µL/min per kidney). Filtration fraction was increased in untreated diabetic rats because of the increase in glomerular filtration rate but not in l-arginine– or l-citrulline–treated diabetic rats. Urinary protein excretion was increased in untreated and l-arginine–treated diabetic rats (142±25 versus 75±7 and 128±7 versus 89±7 µg/min per kidney) but not in diabetic rats administered l-citrulline (67±7 versus 61±5 µg/min per kidney). The diabetes mellitus–induced tissue hypoxia, because of elevated oxygen consumption, was unaltered by any of the treatments. l-citrulline administered to diabetic rats increases plasma l-arginine concentration, which prevents the diabetes mellitus–induced glomerular hyperfiltration, filtration fraction, and proteinuria, possibly by a vascular effect.

National Category
Physiology Basic Medicine
Research subject
Medical Science; Physiology
Identifiers
urn:nbn:se:uu:diva-195487 (URN)10.1161/HYPERTENSIONAHA.114.03519 (DOI)000339120700023 ()24866144 (PubMedID)
Available from: 2013-02-25 Created: 2013-02-25 Last updated: 2018-01-11Bibliographically approved
Persson, P., Fasching, A., Teerlink, T., Hansell, P. & Palm, F. (2014). L-citrulline, but not L-arginine, prevents diabetes-induced glomerular hyperfiltration and proteinuria. Paper presented at Experimental Biology Meeting, APR 26-30, 2014, San Diego, CA. The FASEB Journal, 28(1), Article ID 689.12.
Open this publication in new window or tab >>L-citrulline, but not L-arginine, prevents diabetes-induced glomerular hyperfiltration and proteinuria
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2014 (English)In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 28, no 1, article id 689.12Article in journal, Meeting abstract (Other academic) Published
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-246841 (URN)000346646703208 ()
Conference
Experimental Biology Meeting, APR 26-30, 2014, San Diego, CA
Available from: 2015-03-10 Created: 2015-03-10 Last updated: 2017-12-04Bibliographically approved
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