Publications by authors named "Alexander Weidemann"

39 Publications

[Long-term clinical outcomes of acute kidney failure].

Nephrologe 2020 Dec 22:1-3. Epub 2020 Dec 22.

Medizinische Klinik I Nephrologie, Transplantationsmedizin und internistische Intensivmedizin, Kliniken der Stadt Köln, Krankenhaus Merheim, Klinikum der Universität Witten/Herdecke, Ostmerheimer Str. 200, 51109 Köln, Deutschland.

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http://dx.doi.org/10.1007/s11560-020-00476-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7755118PMC
December 2020

Giant coronary aneurysm in a patient with autosomal dominant polycystic kidney disease.

Clin Res Cardiol 2021 01 14;110(1):148-150. Epub 2020 May 14.

Department of Cardiology, Rhythmology and Medical Intensive Care, Krankenhaus Koln-Merheim Medizinische Klinik I, Cologne, Germany.

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http://dx.doi.org/10.1007/s00392-020-01662-5DOI Listing
January 2021

Association of donor hypertension and recipient renal function in living donor kidney transplantation: A single-center retrospective study.

Clin Transplant 2019 10 12;33(10):e13697. Epub 2019 Sep 12.

Medizinische Klinik 4, Nephrologie und Hypertensiologie, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.

Transplant centers now accept living donors with well-controlled hypertension. Little is known whether hypertension in living donors affects recipient's kidney function. We aimed to examine potential differences in kidneys from hypertensive donors compared to normotensive donors with respect to renal function over 36 months and histologic findings at transplantation (T0) and 12 months after transplantation (T1). Retrospective single-center analysis of 174 living donor-recipient pairs (age > 18; transplantation date 1/2008-3/2016). Hypertension in donors was defined as being on antihypertensive medication. All biopsies were assessed by the same blinded, experienced renal pathologist. Biopsies were scored for glomerulosclerosis, IFTA, and arteriosclerosis. Regression models were used to examine the relationship of donor hypertension with renal function and histologic changes. Hypertensive donors were significantly older than normotensive donors. Chronic changes such as tubular atrophy and atherosclerosis were more evident in kidneys from hypertensive donors at T0 as well as T1. Donor hypertension was independently associated with histologic changes at T0 and T1 but not with renal function over the follow period. Despite more pronounced histologic changes in kidneys from hypertensive living donors, these grafts exhibited a similar functional outcome. However, they subsequently might be at a greater risk and warrant thorough follow-up care.
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http://dx.doi.org/10.1111/ctr.13697DOI Listing
October 2019

Mononuclear phagocytes orchestrate prolyl hydroxylase inhibition-mediated renoprotection in chronic tubulointerstitial nephritis.

Kidney Int 2019 08 5;96(2):378-396. Epub 2019 Mar 5.

Department of Internal Medicine 4-Nephrology and Hypertension, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen, Erlangen, Germany. Electronic address:

Prolyl hydroxylase domain enzyme inhibitors (PHDIs) stabilize hypoxia-inducible factors (HIFs), and are protective in models of acute ischemic and inflammatory kidney disease. Whether PHDIs also confer protection in chronic inflammatory kidney disease models remains unknown. Here we investigated long-term effects of PHDI treatment in adenine-induced nephropathy as a model for chronic tubulointerstitial nephritis. After three weeks, renal dysfunction and tubulointerstitial damage, including proximal and distal tubular injury, tubular dilation and renal crystal deposition were significantly attenuated in PHDI-treated (the isoquinoline derivative ICA and Roxadustat) compared to vehicle-treated mice with adenine-induced nephropathy. Crystal-induced renal fibrosis was only partially diminished by treatment with ICA. Renoprotective effects of ICA treatment could not be attributed to changes in adenine metabolism or urinary excretion of the metabolite 2,8-dihydroxyadenine. ICA treatment reduced inflammatory infiltrates of F4/80+ mononuclear phagocytes in the kidneys and supported a regulatory, anti-inflammatory immune response. Furthermore, interstitial deposition of complement C1q was decreased in ICA-treated mice fed an adenine-enriched diet. Tubular cell-specific HIF-1α and myeloid cell-specific HIF-1α and HIF-2α expression were not required for the renoprotective effects of ICA. In contrast, depletion of mononuclear phagocytes with clodronate largely abolished the nephroprotective effects of PHD inhibition. Thus, our findings indicate novel and potent systemic anti-inflammatory properties of PHDIs that confer preservation of kidney function and structure in chronic tubulointerstitial inflammation and might counteract kidney disease progression.
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http://dx.doi.org/10.1016/j.kint.2019.02.016DOI Listing
August 2019

Peritoneal dialysis catheter leakage following intermittent vacuum therapy.

Clin Kidney J 2018 Oct 21;11(5):724-725. Epub 2017 Dec 21.

Department of Nephrology, Transplantation and Medical Intensive Care, University Witten/Herdecke, Medical Centre Cologne-Merheim, Cologne, Germany.

Peripheral arterial disease and diabetic foot syndrome are common comorbidities in dialysis patients. These conditions are treated with intermittent vacuum therapy in order to increase angiogenesis and perfusion. Some devices encase the lower extremities up to the abdomen. Here we report the case of a patient who had performed peritoneal dialysis for 2 years without complications. Following postoperative intermittent vacuum therapy, he presented with extensive catheter leakage. Ultimately the patient had to be switched to haemodialysis and the catheter had to be removed. This case exemplifies that peritoneal dialysis patients have a substantial risk for noninfectious catheter-related complications using vacuum therapy.
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http://dx.doi.org/10.1093/ckj/sfx142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6165761PMC
October 2018

HIF-1α promotes cyst progression in a mouse model of autosomal dominant polycystic kidney disease.

Kidney Int 2018 11 30;94(5):887-899. Epub 2018 Aug 30.

Department of Nephrology and Hypertension, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany. Electronic address:

Autosomal dominant polycystic kidney disease (ADPKD) is mainly caused by mutations of the PKD1 gene and characterized by growth of bilateral renal cysts. Cyst growth is accompanied by regional hypoxia and induction of hypoxia-inducible factor (HIF)-1α in cyst-lining epithelial cells. To determine the relevance of HIF-1α for cyst growth in vivo we used an inducible kidney epithelium-specific knockout mouse to delete Pkd1 at postnatal day 20 or 35 to induce polycystic kidney disease of different severity and analyzed the effects of Hif-1α co-deletion and HIF-1α stabilization using a prolyl-hydroxylase inhibitor. HIF-1α expression was enhanced in kidneys with progressive cyst growth induced by early Pkd1 deletion, but unchanged in the milder phenotype induced by later Pkd1 deletion. Hif-1α co-deletion significantly attenuated cyst growth in the severe, but not in the mild, phenotype. Application of a prolyl-hydroxylase inhibitor resulted in severe aggravation of the mild phenotype with rapid loss of renal function. HIF-1α expression was associated with induction of genes that mediate calcium-activated chloride secretion. Thus, HIF-1α does not seem to play a role in early cyst formation, but accelerates cyst growth during progressive polycystic kidney disease. This novel mechanism of cyst growth may qualify as a therapeutic target.
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http://dx.doi.org/10.1016/j.kint.2018.06.008DOI Listing
November 2018

Delayed graft function is associated with an increased rate of renal allograft rejection: A retrospective single center analysis.

PLoS One 2018 21;13(6):e0199445. Epub 2018 Jun 21.

Medizinische Klinik 4, Nephrologie und Hypertensiologie, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.

Introduction: The association of delayed graft function (DGF) and biopsy proven acute rejection (BPAR) of renal allografts is controversial. Borderline rejections comprise a major portion of biopsy results but the significance of such histologic changes is debated. The present study explores the impact of DGF on BPAR with a special emphasis on discriminating the effects of borderline rejection.

Methods: Single center analysis of 417 deceased donor kidney recipients (age>18; transplantation date 1/2008-2/2015). Patients with primary non-function were excluded. DGF was defined as the need for dialysis within the first week after transplantation. Acute rejection was defined according to Banff criteria. Cox proportional hazards models were used to examine the relationship of DGF with BPAR within the first year.

Results: No graft loss was observed during the first year after transplantation. DGF significantly associated with BPAR in the first year, irrespective of whether borderline rejections were included (HR 1.71, 95%CI 1.16,2.53) or excluded (HR 1.79, 95%CI 1.13,2.84).

Conclusion: DGF is significantly associated with rejection-with or without borderline changes-within the first year.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0199445PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6013231PMC
April 2019

A randomized, phase 2 study of ASP0113, a DNA-based vaccine, for the prevention of CMV in CMV-seronegative kidney transplant recipients receiving a kidney from a CMV-seropositive donor.

Am J Transplant 2018 12 20;18(12):2945-2954. Epub 2018 Jun 20.

Immunology, Transplant, Inflammation & CNS/Pain, Astellas Pharma Global Development, Inc., Northbrook, IL, USA.

Cytomegalovirus (CMV) is a latent infection in most infected individuals, but can be pathogenic in immunocompromised kidney transplant recipients. ASP0113 is a DNA-based vaccine for the prevention of CMV-related mortality and end-organ disease in transplant recipients. The efficacy, safety, and immunogenicity of ASP0113 was assessed in a phase 2, double-blind, placebo-controlled study in CMV-seronegative kidney transplant recipients receiving a kidney from a CMV-seropositive donor. Transplant recipients were randomized (1:1) to receive 5 doses of ASP0113 (5 mg; n = 75) or placebo (n = 74) on Days 30/60/90/120/180 posttransplant, and they received prophylactic valganciclovir/ganciclovir 10-100 days posttransplant. The primary endpoint was the proportion of transplant recipients with CMV viremia ≥1000 IU/mL from Day 100 through to 1 year after the first study vaccine injection. There was no statistically significant difference in the primary endpoint between the ASP0113 and placebo groups (odds ratio 0.79, 95% confidence interval 0.43-1.47; P = .307). There were similar numbers of transplant recipients with treatment-emergent adverse events between groups; however, more transplant recipients reported injection site pain in the ASP0113 group compared with placebo. ASP0113 did not demonstrate efficacy in the prevention of CMV viremia in this CMV-seronegative kidney transplant population, but demonstrated a safety profile similar to placebo. ClinicalTrials.gov registration number: NCT01974206.
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http://dx.doi.org/10.1111/ajt.14925DOI Listing
December 2018

Hypoxia-inducible protein 2 Hig2/Hilpda mediates neutral lipid accumulation in macrophages and contributes to atherosclerosis in apolipoprotein E-deficient mice.

FASEB J 2017 11 31;31(11):4971-4984. Epub 2017 Jul 31.

Department of Nephrology and Hypertension, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany;

Recently we identified hypoxia-inducible protein 2 (HIG2)/hypoxia-inducible lipid droplet-associated (HILPDA) as lipid droplet (LD) protein. Because HILPDA is highly expressed in atherosclerotic plaques, we examined its regulation and function in murine macrophages, compared it to the LD adipose differentiation-related protein (Adrp)/perilipin 2 (Plin2), and investigated its effects on atherogenesis in apolipoprotein E-deficient () mice. -Cre-driven conditional knockout (cKO) did not affect viability, proliferation, and ATP levels in macrophages. proved to be a target of hypoxia-inducible factor 1 (Hif-1) and peroxisome proliferator-activated receptors. In contrast, was not induced by Hif-1. Hilpda localized to the endoplasmic reticulum-LD interface, the site of LD formation. Hypoxic lipid accumulation and storage of oxidized LDL, cholesteryl esters and triglycerides were abolished in cKO macrophages, independent of the glycolytic switch, fatty acid or lipoprotein uptake. Hilpda depletion reduced resistance against lipid overload and increased production of reactive oxygen species after reoxygenation. LPS-stimulated prostaglandin-E2 production was dysregulated in macrophages, demonstrating the substrate buffer and reservoir function of LDs for eicosanoid production. In cKO mice, total aortic plaque area, plaque macrophages and vascular expression were reduced. Thus, macrophage Hilpda is crucial to foam-cell formation and lipid deposition, and to controlled prostaglandin-E2 production. By these means Hilpda promotes lesion formation and progression of atherosclerosis.-Maier, A., Wu, H., Cordasic, N., Oefner, P., Dietel, B., Thiele, C., Weidemann, A., Eckardt, K.-U., Warnecke, C. Hypoxia-inducible protein 2 Hig2/Hilpda mediates neutral lipid accumulation in macrophages and contributes to atherosclerosis in apolipoprotein E-deficient mice.
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http://dx.doi.org/10.1096/fj.201700235RDOI Listing
November 2017

Transcriptional repressor ZEB2 promotes terminal differentiation of CD8+ effector and memory T cell populations during infection.

J Exp Med 2015 Nov 26;212(12):2027-39. Epub 2015 Oct 26.

Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093

ZEB2 is a multi-zinc-finger transcription factor known to play a significant role in early neurogenesis and in epithelial-mesenchymal transition-dependent tumor metastasis. Although the function of ZEB2 in T lymphocytes is unknown, activity of the closely related family member ZEB1 has been implicated in lymphocyte development. Here, we find that ZEB2 expression is up-regulated by activated T cells, specifically in the KLRG1(hi) effector CD8(+) T cell subset. Loss of ZEB2 expression results in a significant loss of antigen-specific CD8(+) T cells after primary and secondary infection with a severe impairment in the generation of the KLRG1(hi) effector memory cell population. We show that ZEB2, which can bind DNA at tandem, consensus E-box sites, regulates gene expression of several E-protein targets and may directly repress Il7r and Il2 in CD8(+) T cells responding to infection. Furthermore, we find that T-bet binds to highly conserved T-box sites in the Zeb2 gene and that T-bet and ZEB2 regulate similar gene expression programs in effector T cells, suggesting that T-bet acts upstream and through regulation of ZEB2. Collectively, we place ZEB2 in a larger transcriptional network that is responsible for the balance between terminal differentiation and formation of memory CD8(+) T cells.
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http://dx.doi.org/10.1084/jem.20150194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4647262PMC
November 2015

Kidney injury is independent of endothelial HIF-1α.

J Mol Med (Berl) 2015 Aug 11;93(8):891-904. Epub 2015 Mar 11.

Department of Nephrology and Hypertension, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Ulmenweg 18, 91054, Erlangen, Germany.

Unlabelled: Hypoxia-inducible transcription factors (HIFs) control cellular adaptation to low oxygen. In the kidney, activation of HIF is beneficial during injury; however, the specific contribution of HIF-1α in renal endothelial cells (EC) remains elusive. Since EC display tissue-specific heterogeneity, we investigated how HIF-1α affects key functions of glomerular EC in vitro and its contribution to renal development and pathophysiological adaptation to acute or chronic renal injury in vivo. Loss of HIF-1α in glomerular EC induces hypoxic cell death and reduces hypoxic adhesion of macrophages in vitro. In vivo, HIF-1α expression in EC in mouse kidneys is detectable but limited. Accordingly, EC-specific ablation of HIF-1α does not lead to developmental or phenotypical abnormalities in the kidney. Renal function and expression of adhesion molecules during acute ischemic kidney injury is independent of HIF-1α in EC. Likewise, inflammation and development of fibrosis after unilateral ureteric obstruction is not influenced by endothelial HIF-1α. Taken together, although HIF-1α exerts effects on glomerular EC in vitro, endothelial HIF-1α does not influence renal development and pathophysiological adaptation to kidney injury in vivo. This implies a profound difference of the hypoxic response of the renal vascular bed compared to other organs, such as the heart. This has implications for the development of pharmacological strategies targeting the endothelial hypoxic response pathways.

Key Message: HIF-1α controls hypoxic survival and adhesion on endothelial cells (EC) in vitro. In vivo, HIF-1α expression in renal EC is low. Deletion of HIF-1α in EC does not affect kidney development and function in mice. Renal function after acute and chronic kidney injury is independent of HIF-1α in EC. Data suggest organ-specific regulation of HIF-1α function in EC.
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http://dx.doi.org/10.1007/s00109-015-1264-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6592817PMC
August 2015

Inactivation of evenness interrupted (EVI) reduces experimental fibrosis by combined inhibition of canonical and non-canonical Wnt signalling.

Ann Rheum Dis 2014 Mar 20;73(3):624-7. Epub 2013 Nov 20.

Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, , Erlangen, Germany.

Objectives: Canonical as well as non-canonical Wnt signalling pathways have emerged as core pathways of fibrosis. Their profibrotic effects are mediated via distinct intracellular cascades independently of each other. Thus, inhibition of both pathways may have additive antifibrotic effects. Here, we knocked down evenness interrupted (EVI) to simultaneously target for the first time canonical and non-canonical Wnt signalling in experimental fibrosis.

Methods: The antifibrotic effects of siRNA-mediated knockdown of EVI were evaluated in the mouse models of bleomycin-induced skin fibrosis and in fibrosis induced by adenoviral overexpression of a constitutively active TGF-β receptor I (AdTBRI).

Results: Knockdown of EVI decreased the release of canonical and non-canonical Wnt ligands by fibroblasts and reduced the activation of canonical and non-canonical Wnt cascades in experimental fibrosis with decreased accumulation of β-catenin and phosphorylated JNK and cJun. Inactivation of EVI exerted potent antifibrotic effects and reduced dermal thickening, myofibroblast differentiation and accumulation of collagen in the mouse models of bleomycin-induced and AdTBR-induced fibrosis.

Conclusions: Inhibition of Wnt secretion by knockdown of EVI inhibits canonical and non-canonical Wnt signalling and effectively reduces experimental fibrosis in different preclinical models. Inhibition of Wnt secretion may thus be an interesting approach for the treatment of fibrosis.
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http://dx.doi.org/10.1136/annrheumdis-2013-203995DOI Listing
March 2014

HIF-1α activation results in actin cytoskeleton reorganization and modulation of Rac-1 signaling in endothelial cells.

Cell Commun Signal 2013 Oct 21;11:80. Epub 2013 Oct 21.

Department of Nephrology and Hypertension, Universitätsklinikum Erlangen, Universität Erlangen-Nürnberg, Loschgestrasse 8, 91054 Erlangen, Germany.

Background: Hypoxia is a major driving force in vascularization and vascular remodeling. Pharmacological inhibition of prolyl hydroxylases (PHDs) leads to an oxygen-independent and long-lasting activation of hypoxia-inducible factors (HIFs). Whereas effects of HIF-stabilization on transcriptional responses have been thoroughly investigated in endothelial cells, the molecular details of cytoskeletal changes elicited by PHD-inhibition remain largely unknown. To investigate this important aspect of PHD-inhibition, we used a spheroid-on-matrix cell culture model.

Results: Microvascular endothelial cells (glEND.2) were organized into spheroids. Migration of cells from the spheroids was quantified and analyzed by immunocytochemistry. The PHD inhibitor dimethyloxalyl glycine (DMOG) induced F-actin stress fiber formation in migrating cells, but only weakly affected microvascular endothelial cells firmly attached in a monolayer. Compared to control spheroids, the residual spheroids were larger upon PHD inhibition and contained more cells with tight VE-cadherin positive cell-cell contacts. Morphological alterations were dependent on stabilization of HIF-1α and not HIF-2α as shown in cells with stable knockdown of HIF-α isoforms. DMOG-treated endothelial cells exhibited a reduction of immunoreactive Rac-1 at the migrating front, concomitant with a diminished Rac-1 activity, whereas total Rac-1 protein remained unchanged. Two chemically distinct Rac-1 inhibitors mimicked the effects of DMOG in terms of F-actin fiber formation and orientation, as well as stabilization of residual spheroids. Furthermore, phosphorylation of p21-activated kinase PAK downstream of Rac-1 was reduced by DMOG in a HIF-1α-dependent manner. Stabilization of cell-cell contacts associated with decreased Rac-1 activity was also confirmed in human umbilical vein endothelial cells.

Conclusions: Our data demonstrates that PHD inhibition induces HIF-1α-dependent cytoskeletal remodeling in endothelial cells, which is mediated essentially by a reduction in Rac-1 signaling.
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http://dx.doi.org/10.1186/1478-811X-11-80DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895861PMC
October 2013

BK viremia and polyomavirus nephropathy in 352 kidney transplants; risk factors and potential role of mTOR inhibition.

BMC Nephrol 2013 Oct 2;14:207. Epub 2013 Oct 2.

Department of Nephrology and Hypertension, Friedrich-Alexander-University Erlangen-Nürnberg, Ulmenweg 18, 91054, Erlangen, Germany.

Background: Polyomavirus BK nephropathy (PyVAN) remains an important cause of early graft dysfunction and graft loss in kidney transplantation.

Methods: In this retrospective, single centre cohort study we studied the incidence and outcome of BK viral infection in 352 patients transplanted in 2008-2011.

Results: During follow-up viral replication was detected in 48 patients (13.6%); 22 patients (6.2%) had biopsy proven PyVAN.In multivariate logistic regression analyses risk factors for BK-viremia were lack of enrolment into randomized controlled trials (RCTs), biopsy proven acute rejections, cytomegaly virus (CMV) serostatus of both donor and recipient and previous transplantation.In patients without PyVAN reduction or switch of immunosuppression was associated with rapid viral clearance and stable graft function. In contrast, in most patients with PyVAN graft function deteriorated and 5 patients prematurely lost their allograft. Switch of immunosuppression to a low dose cyclosporine plus mTOR inhibitor based regimen in patients with PyVAN was safe, well tolerated and tended to be associated with a better short-term outcome in terms of graft function compared to reduction of existing immunosuppression alone.

Conclusions: With the lack of licensed anti-polyoma viral drugs reduction or conversion of immunosuppression remains the mainstay of therapy in patients with PyVAN. The combination of low dose cyclosporine plus mTOR inhibition appears to be safe and warrants further investigation.
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http://dx.doi.org/10.1186/1471-2369-14-207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3850699PMC
October 2013

Loss of epithelial hypoxia-inducible factor prolyl hydroxylase 2 accelerates skin wound healing in mice.

Mol Cell Biol 2013 Sep 24;33(17):3426-38. Epub 2013 Jun 24.

Emmy Noether Research Group, University of Technology, Dresden, Germany.

Skin wound healing in mammals is a complex, multicellular process that depends on the precise supply of oxygen. Hypoxia-inducible factor (HIF) prolyl hydroxylase 2 (PHD2) serves as a crucial oxygen sensor and may therefore play an important role during reepithelialization. Hence, this study was aimed at understanding the role of PHD2 in cutaneous wound healing using different lines of conditionally deficient mice specifically lacking PHD2 in inflammatory, vascular, or epidermal cells. Interestingly, PHD2 deficiency only in keratinocytes and not in myeloid or endothelial cells was found to lead to faster wound closure, which involved enhanced migration of the hyperproliferating epithelium. We demonstrate that this effect relies on the unique expression of β3-integrin in the keratinocytes around the tip of the migrating tongue in an HIF1α-dependent manner. Furthermore, we show enhanced proliferation of these cells in the stratum basale, which is directly related to their attenuated transforming growth factor β signaling. Thus, loss of the central oxygen sensor PHD2 in keratinocytes stimulates wound closure by prompting skin epithelial cells to migrate and proliferate. Inhibition of PHD2 could therefore offer novel therapeutic opportunities for the local treatment of cutaneous wounds.
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http://dx.doi.org/10.1128/MCB.00609-13DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3753847PMC
September 2013

HIF-1α is a protective factor in conditional PHD2-deficient mice suffering from severe HIF-2α-induced excessive erythropoiesis.

Blood 2013 Feb 20;121(8):1436-45. Epub 2012 Dec 20.

Emmy Noether Research Group, University of Technology, Dresden, Germany.

Erythropoiesis must be tightly balanced to guarantee adequate oxygen delivery to all tissues in the body. This process relies predominantly on the hormone erythropoietin (EPO) and its transcription factor hypoxia inducible factor (HIF). Accumulating evidence suggests that oxygen-sensitive prolyl hydroxylases (PHDs) are important regulators of this entire system. Here, we describe a novel mouse line with conditional PHD2 inactivation (cKO P2) in renal EPO producing cells, neurons, and astrocytes that displayed excessive erythrocytosis because of severe overproduction of EPO, exclusively driven by HIF-2α. In contrast, HIF-1α served as a protective factor, ensuring survival of cKO P2 mice with HCT values up to 86%. Using different genetic approaches, we show that simultaneous inactivation of PHD2 and HIF-1α resulted in a drastic PHD3 reduction with consequent overexpression of HIF-2α-related genes, neurodegeneration, and lethality. Taken together, our results demonstrate for the first time that conditional loss of PHD2 in mice leads to HIF-2α-dependent erythrocytosis, whereas HIF-1α protects these mice, providing a platform for developing new treatments of EPO-related disorders, such as anemia.
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http://dx.doi.org/10.1182/blood-2012-08-449181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3628111PMC
February 2013

Inactivation of tankyrases reduces experimental fibrosis by inhibiting canonical Wnt signalling.

Ann Rheum Dis 2013 Sep 12;72(9):1575-80. Epub 2012 Nov 12.

Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany.

Objectives: Canonical Wnt signalling has recently emerged as a key mediator of fibroblast activation and tissue fibrosis in systemic sclerosis. Here, we investigated tankyrases as novel molecular targets for inhibition of canonical Wnt signalling in fibrotic diseases.

Methods: The antifibrotic effects of the tankyrase inhibitor XAV-939 or of siRNA-mediated knockdown of tankyrases were evaluated in the mouse models of bleomycin-induced dermal fibrosis and in experimental fibrosis induced by adenoviral overexpression of a constitutively active TGF-β receptor I (Ad-TBRI).

Results: Inactivation of tankyrases prevented the activation of canonical Wnt signalling in experimental fibrosis and reduced the nuclear accumulation of β-catenin and the mRNA levels of the target gene c-myc. Treatment with XAV-939 or siRNA-mediated knockdown of tankyrases in the skin effectively reduced bleomycin-induced dermal thickening, differentiation of resting fibroblasts into myofibroblasts and accumulation of collagen. Potent antifibrotic effects were also observed in Ad-TBRI driven skin fibrosis. Inhibition of tankyrases was not limited by local or systemic toxicity.

Conclusions: Inactivation of tankyrases effectively abrogated the activation of canonical Wnt signalling and demonstrated potent antifibrotic effects in well-tolerated doses. Thus, tankyrases might be candidates for targeted therapies in fibrotic diseases.
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http://dx.doi.org/10.1136/annrheumdis-2012-202275DOI Listing
September 2013

Loss of fibroblast HIF-1α accelerates tumorigenesis.

Cancer Res 2012 Jul 3;72(13):3187-95. Epub 2012 May 3.

Molecular Biology Section, Division of Biological Sciences, Department of Medicine, University of California, San Diego, La Jolla, California, USA.

Solid tumors consist of malignant cells and associated stromal components, including fibroblastic cells that contribute to tumor growth and progression. Although tumor fibrosis and aberrant vascularization contribute to the hypoxia often found in advanced tumors, the contribution of hypoxic signaling within tumor-associated fibroblasts to tumorigenesis remains unknown. In this study, we used a fibroblast-specific promoter to create mice in which key hypoxia regulatory genes, including VHL, HIF-1α, HIF-2α, and VEGF-A, were knocked out specifically in tumor stromal fibroblasts. We found that loss of HIF-1α and its target gene VEGF-A accelerated tumor growth in murine model of mammary cancer. HIF-1α and VEGF-A loss also led to a reduction in vascular density and myeloid cell infiltration, which correlated with improved tumor perfusion. Together, our findings indicate that the fibroblast HIF-1α response is a critical component of tumor vascularization.
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http://dx.doi.org/10.1158/0008-5472.CAN-12-0534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4089958PMC
July 2012

Astrocyte hypoxic response is essential for pathological but not developmental angiogenesis of the retina.

Glia 2010 Aug;58(10):1177-85

Division of Biology, University of California, San Diego, La Jolla, California 92093, USA.

Vascular/parenchymal crosstalk is increasingly recognized as important in the development and maintenance of healthy vascularized tissues. The retina is an excellent model in which to study the role of cell type-specific contributions to the process of blood vessel and neuronal growth. During retinal vascular development, glial cells such as astrocytes provide the template over which endothelial cells migrate to form the retinal vascular network, and hypoxia-regulated vascular endothelial growth factor (VEGF) has been demonstrated to play a critical role in this process as well as pathological neovascularization. To investigate the nature of cell-specific contributions to this process, we deleted VEGF and its upstream regulators, the hypoxia-inducible transcription factors HIF-1 alpha and HIF-2 alpha, and the negative regulator of HIF alpha, von Hippel-Lindau protein (VHL), in astrocytes. We found that loss of hypoxic response and VEGF production in astrocytes does not impair normal development of retinal vasculature, indicating that astrocyte-derived VEGF is not essential for this process. In contrast, using a model of oxygen-induced ischemic retinopathy, we show that astrocyte-derived VEGF is essential for hypoxia-induced neovascularization. Thus, we demonstrate that astrocytes in the retina have highly divergent roles during developmental, physiological angiogenesis, and ischemia-driven, pathological neovascularization.
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http://dx.doi.org/10.1002/glia.20997DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2993327PMC
August 2010

Differential activation and antagonistic function of HIF-{alpha} isoforms in macrophages are essential for NO homeostasis.

Genes Dev 2010 Mar;24(5):491-501

University of California at San Diego, La Jolla, 92093, USA.

Hypoxic response and inflammation both involve the action of the hypoxia-inducible transcription factors HIF-1alpha and HIF-2alpha. Previous studies have revealed that both HIF-alpha proteins are in a number of aspects similarly regulated post-translationally. However, the functional interrelationship of these two isoforms remains largely unclear. The polarization of macrophages controls functionally divergent processes; one of these is nitric oxide (NO) production, which in turn is controlled in part by HIF factors. We show here that the HIF-alpha isoforms can be differentially activated: HIF-1alpha is induced by Th1 cytokines in M1 macrophage polarization, whereas HIF-2alpha is induced by Th2 cytokines during an M2 response. This differential response was most evident in polarized macrophages through HIF-alpha isoform-specific regulation of the inducible NO synthase gene by HIF-1alpha, and the arginase1 gene by HIF-2alpha. In silico modeling predicted that regulation of overall NO availability is due to differential regulation of HIF-1alpha versus HIF-2alpha, acting to, respectively, either increase or suppress NO synthesis. An in vivo model of endotoxin challenge confirmed this; thus, these studies reveal that the two homologous transcription factors, HIF-1alpha and HIF-2alpha, can have physiologically antagonistic functions, but that their antiphase regulation allows them to coordinately regulate NO production in a cytokine-induced and transcription-dependent fashion.
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http://dx.doi.org/10.1101/gad.1881410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2827844PMC
March 2010

Loss of myeloid cell-derived vascular endothelial growth factor accelerates fibrosis.

Proc Natl Acad Sci U S A 2010 Mar 8;107(9):4329-34. Epub 2010 Feb 8.

Molecular Biology Section, Division of Biological Sciences, University of California, San Diego, CA 92093, USA.

Tissue injury initiates a complex series of events that act to restore structure and physiological homeostasis. Infiltration of inflammatory cells and vascular remodeling are both keystones of this process. However, the role of inflammation and angiogenesis in general and, more specifically, the significance of inflammatory cell-derived VEGF in this context are unclear. To determine the role of inflammatory cell-derived VEGF in a clinically relevant and chronically inflamed injury, pulmonary fibrosis, we deleted the VEGF-A gene in myeloid cells. In a model of pulmonary fibrosis in mice, deletion of VEGF in myeloid cells resulted in significantly reduced formation of blood vessels; however, it causes aggravated fibrotic tissue damage. This was accompanied by a pronounced decrease in epithelial cell survival and a striking increase in myofibroblast invasion. The drastic increase in fibrosis following loss of myeloid VEGF in the damaged lungs was also marked by increased levels of hypoxia-inducible factor (HIF) expression and Wnt/beta-catenin signaling. This demonstrates that the process of angiogenesis, driven by myeloid cell-derived VEGF, is essential for the prevention of fibrotic damage.
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http://dx.doi.org/10.1073/pnas.0912766107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2840078PMC
March 2010

Improvement of the cardiac marker N-terminal-pro brain natriuretic peptide through adjustment for renal function: a stratified multicenter trial.

Clin Chem Lab Med 2010 ;48(1):121-8

Klinik und Poliklinik für Innere Medizin II, Klinikum der Universität Regensburg, Regensburg, Germany.

Background: N-terminal-pro brain natriuretic peptide (NT-proBNP) is a useful cardiac marker that is also influenced by renal dysfunction. It was our objective to assess the relationship between NT-proBNP concentrations in plasma and worsening renal function, and to attempt adjustment of NT-proBNP for renal dysfunction in a prospective, stratified multi-center study.

Methods: We stratified 203 male patients according to their cardiac status and the estimated glomerular filtration rate (eGFR). Cardiac disease was assessed by medical history, physical examination and standardized echocardiography. Patients were stratified according to the following: absence of cardiac history and abnormalities (control, CTRL, n=66), cardiac history without left ventricular hypertrophy (LVH) or left ventricular systolic dysfunction (LVD) (history, n=30), LVH without systolic dysfunction (LVH, n=68), and LVD [ejection fraction (EF) <40%, LVD, n=39]. Renal disease was stratified according to the eGFR: 15-30 mL/min (n=52), 31-75 mL/min (n=99), and >75 mL/min (n=52).

Results: NT-proBNP was correlated with eGFR in the entire study population and for all levels of cardiac disease (all p<0.01). Regression analysis allowed adjustment of NT-proBNP for eGFR in a continuous manner, and this adjustment significantly improved the predictive value (receiver operating characteristic curve for symptomatic LVD from 0.80 to 0.86, p<0.01; sensitivity from 74% to 83% and specificity from 68% to 79%).

Conclusions: NT-proBNP correlates inversely and significantly with eGFR throughout all levels of cardiac strata. We propose for the first time a continuous adjustment algorithm which markedly improves the predictive values of NT-proBNP in male patients with impaired renal function.
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http://dx.doi.org/10.1515/CCLM.2010.011DOI Listing
March 2010

The glial cell response is an essential component of hypoxia-induced erythropoiesis in mice.

J Clin Invest 2009 Nov 5;119(11):3373-83. Epub 2009 Oct 5.

Division of Biology, University of California, San Diego, La Jolla, California 92093, USA.

A key adaptation to environmental hypoxia is an increase in erythropoiesis, driven by the hormone erythropoietin (EPO) through what is traditionally thought to be primarily a renal response. However, both neurons and astrocytes (the largest subpopulation of glial cells in the CNS) also express EPO following ischemic injury, and this response is known to ameliorate damage to the brain. To investigate the role of glial cells as a component of the systemic response to hypoxia, we created astrocyte-specific deletions of the murine genes encoding the hypoxia-inducible transcription factors HIF-1alpha and HIF-2alpha and their negative regulator von Hippel-Lindau (VHL) as well as astrocyte-specific deletion of the HIF target gene Vegf. We found that loss of the hypoxic response in astrocytes does not cause anemia in mice but is necessary for approximately 50% of the acute erythropoietic response to hypoxic stress. In accord with this, erythroid progenitor cells and reticulocytes were substantially reduced in number in mice lacking HIF function in astrocytes following hypoxic stress. Thus, we have demonstrated that the glial component of the CNS is an essential component of hypoxia-induced erythropoiesis.
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http://dx.doi.org/10.1172/JCI39378DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2769183PMC
November 2009

HIF-prolyl hydroxylases in the rat kidney: physiologic expression patterns and regulation in acute kidney injury.

Am J Pathol 2009 May 6;174(5):1663-74. Epub 2009 Apr 6.

Department of Nephrology and Hypertension, Friedrich-Alexander-University Erlangen-Nuremberg,Erlangen, Germany.

Hypoxia-inducible transcription factors (HIFs) play important roles in the response of the kidney to systemic and regional hypoxia. Degradation of HIFs is mediated by three oxygen-dependent HIF-prolyl hydroxylases (PHDs), which have partially overlapping characteristics. Although PHD inhibitors, which can induce HIFs in the presence of oxygen, are already in clinical development, little is known about the expression and regulation of these enzymes in the kidney. Therefore, we investigated the expression levels of the three PHDs in both isolated tubular cells and rat kidneys. All three PHDs were present in the kidney and were expressed predominantly in three different cell populations: (a) in distal convoluted tubules and collecting ducts (PHD1,2,3), (b) in glomerular podocytes (PHD1,3), and (c) in interstitial fibroblasts (PHD1,3). Higher levels of PHDs were found in tubular segments of the inner medulla where oxygen tensions are known to be physiologically low. PHD expression levels were unchanged in HIF-positive tubular and interstitial cells after induction by systemic hypoxia. In rat models of acute renal injury, changes in PHD expression levels were variable; while cisplatin and ischemia/reperfusion led to significant decreases in PHD2 and 3 expression levels, no changes were seen in a model of contrast media-induced nephropathy. These results implicate the non-uniform expression of HIF-regulating enzymes that modify the hypoxic response in the kidney under both regional and temporal conditions.
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http://dx.doi.org/10.2353/ajpath.2009.080687DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2671255PMC
May 2009

Nonrenal regulation of EPO synthesis.

Kidney Int 2009 Apr 21;75(7):682-8. Epub 2009 Jan 21.

Division of Biology, University of California, San Diego, La Jolla, CA 92037-0377, USA.

Erythropoietin (EPO) is a circulating glycoprotein hormone whose principal function is thought to be red blood cell production. It is a classic example of a hypoxia-inducible gene, and studies of the induction of EPO synthesis by low oxygen led to the discovery of a widespread system of hypoxia-inducible transcription factors. Tissue-specific expression of the EPO gene is tightly controlled, and in the adult organism the kidney produces around 90% of systemic EPO. Before birth, the liver is the main site of EPO production; factors contributing to the liver-to-kidney switch are still elusive, but may provide clues to the tissue-specificity of EPO gene expression. EPO has also been detected in non-erythropoietic tissues such as the brain, where it is suggested to exert local protective effects. Apart from classical ways of regulating renal EPO during hypoxia and anemia, novel pathways have been discovered that demonstrate that other organ systems in the adult might not only be important for the production of EPO but also for modulating the hypoxic EPO response. Knowledge of the molecular bases of these non-renal pathways will eventually help to develop pharmacological strategies to induce endogenous EPO production when the main source, the kidney, is significantly impaired. This review will provide an overview of the molecular aspects of EPO gene regulation by hypoxia-inducible transcription factors and of the tissue-specific regulation of EPO production in adult mammals. Insights into the biology of EPO production in genetically modified animals, with an emphasis on recent advances in the understanding of non-renal EPO regulation, will be discussed.
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http://dx.doi.org/10.1038/ki.2008.687DOI Listing
April 2009

Mutual regulation of hypoxia-inducible factor and mammalian target of rapamycin as a function of oxygen availability.

Mol Cancer Res 2009 Jan;7(1):88-98

Interdisciplinary Centre for Clinical Research, Friedrich Alexander Universität Erlangen-Nürnberg, Nuremberg, Germany.

The mammalian target of rapamycin (mTOR) regulates cellular growth and proliferation, mainly by controlling cellular translation. Most tumors show constitutive activation of the mTOR pathway. In hypoxia, mTOR is inactivated, which is believed to be part of the program of the cell to maintain energy homeostasis. However, certain proteins are believed to be preferentially translated during hypoxia via 5' terminal oligopyrimidine tract mechanisms with controversial discussion about the involvement of the mTOR-dependent ribosomal protein S6 (rpS6). The hypoxia-inducible transcription factor (HIF) is the master regulator of hypoxic adaptation and itself strongly implicated in tumor growth. HIF is translationally regulated by mTOR. The regulatory features and the involvement of molecular oxygen itself in this regulation of HIF by mTOR are poorly understood. mTOR inhibition leads to profound attenuation of HIFalpha protein in the majority of primary and cancer cells studied. Under severe hypoxia, no influence of mTOR inhibitors was observed; thus, stimulation of HIFalpha by mTOR may only be relevant under mild hypoxia or even normoxia. HIF expression and phosphorylated rpS6 negatively correlate in experimental tumors. In cell culture, prolonged hypoxia abolishes rpS6 phosphorylation, which seems to be partly independent of the upstream p70S6 kinase. We show that hypoxic repression of rpS6 is largely dependent on HIF, implicating a negative feedback loop, which may influence cellular translational rates and metabolic homeostasis. These data implicate that the hypoxic microenvironment renders tumor cells resistant to mTOR inhibition, at least concerning hypoxic gene activation, which would add to the difficulties of other established therapeutic strategies in hypoxic cancer tissues.
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http://dx.doi.org/10.1158/1541-7786.MCR-08-0288DOI Listing
January 2009

Deletion of vascular endothelial growth factor in myeloid cells accelerates tumorigenesis.

Nature 2008 Dec 9;456(7223):814-8. Epub 2008 Nov 9.

Molecular Biology Section, Division of Biological Sciences, Moores Cancer Center, University of California, San Diego, San Diego, California 92093, USA.

Angiogenesis and the development of a vascular network are required for tumour progression, and they involve the release of angiogenic factors, including vascular endothelial growth factor (VEGF-A), from both malignant and stromal cell types. Infiltration by cells of the myeloid lineage is a hallmark of many tumours, and in many cases the macrophages in these infiltrates express VEGF-A. Here we show that the deletion of inflammatory-cell-derived VEGF-A attenuates the formation of a typical high-density vessel network, thus blocking the angiogenic switch in solid tumours in mice. Vasculature in tumours lacking myeloid-cell-derived VEGF-A was less tortuous, with increased pericyte coverage and decreased vessel length, indicating vascular normalization. In addition, loss of myeloid-derived VEGF-A decreases the phosphorylation of VEGF receptor 2 (VEGFR2) in tumours, even though overall VEGF-A levels in the tumours are unaffected. However, deletion of myeloid-cell VEGF-A resulted in an accelerated tumour progression in multiple subcutaneous isograft models and an autochthonous transgenic model of mammary tumorigenesis, with less overall tumour cell death and decreased tumour hypoxia. Furthermore, loss of myeloid-cell VEGF-A increased the susceptibility of tumours to chemotherapeutic cytotoxicity. This shows that myeloid-derived VEGF-A is essential for the tumorigenic alteration of vasculature and signalling to VEGFR2, and that these changes act to retard, not promote, tumour progression.
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http://dx.doi.org/10.1038/nature07445DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3103772PMC
December 2008

Activation of negative regulators of the hypoxia-inducible factor (HIF) pathway in human end-stage heart failure.

Biochem Biophys Res Commun 2008 Nov 7;376(2):315-20. Epub 2008 Sep 7.

Institute of Experimental and Clinical Pharmacology and Toxicology, University of Erlangen-Nuremberg, Fahrstr. 17, 91054 Erlangen, Germany.

The hypoxia-inducible transcription factor HIF is induced early in acute myocardial ischemia in humans, but it is unknown whether this activation of HIF persists during chronic heart failure. The HIF system was characterized in left ventricular myocardia from 18 explanted failing hearts and 11 non-failing donor hearts by quantitative RT-PCR and Western analysis. HIF-1alpha mRNA levels were significantly decreased while its natural antisense transcript aHIF was nearly twofold higher (p<0.01) in failing myocardia than in control hearts. Moreover, compared to donor hearts a significantly increased expression of HIF-3alpha, which may act as a competitive inhibitor of HIF-1/2alpha activity, and PHD3, which upon hydroxylation of prolyl residues directs HIF-alpha subunits towards proteasomal degradation, was observed in the failing myocardium. Although negative regulators of HIF were induced, the HIF pathway obviously remains activated in chronic human heart failure, because prototype HIF target genes, such as ABCG2, VEGF, and BNIP3, were significantly induced.
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http://dx.doi.org/10.1016/j.bbrc.2008.08.152DOI Listing
November 2008

Epidermal sensing of oxygen is essential for systemic hypoxic response.

Cell 2008 Apr;133(2):223-34

Molecular Biology Section, Division of Biological Sciences, UC San Diego, La Jolla, CA 92093, USA.

Skin plays an essential role, mediated in part by its remarkable vascular plasticity, in adaptation to environmental stimuli. Certain vertebrates, such as amphibians, respond to hypoxia in part through the skin; but it is unknown whether this tissue can influence mammalian systemic adaptation to low oxygen levels. We have found that epidermal deletion of the hypoxia-responsive transcription factor HIF-1alpha inhibits renal erythropoietin (EPO) synthesis in response to hypoxia. Conversely, mice with an epidermal deletion of the von Hippel-Lindau (VHL) factor, a negative regulator of HIF, have increased EPO synthesis and polycythemia. We show that nitric oxide release induced by the HIF pathway acts on cutaneous vascular flow to increase systemic erythropoietin expression. These results demonstrate that in mice the skin is a critical mediator of systemic responses to environmental oxygen.
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http://dx.doi.org/10.1016/j.cell.2008.02.038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2849644PMC
April 2008