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- Hale, L J, et al.
(författare)
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Insulin-like growth factor-II is produced by, signals to and is an important survival factor for the mature podocyte in man and mouse
- 2013
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Ingår i: Journal of Pathology. - : Wiley. - 0022-3417 .- 1096-9896. ; 230:1, s. 95-106
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Tidskriftsartikel (refereegranskat)abstract
- Podocytes are crucial for preventing the passage of albumin into the urine and, when lost, are associated with the development of albuminuria, renal failure and cardiovascular disease. Podocytes have limited capacity to regenerate, therefore pro-survival mechanisms are critically important. Insulin-like growth factor-II (IGF-II) is a potent survival and growth factor; however, its major function is thought to be in prenatal development, when circulating levels are high. IGF-II has only previously been reported to continue to be expressed in discrete regions of the brain into adulthood in rodents, with systemic levels being undetectable. Using conditionally immortalized human and ex vivo adult mouse cells of the glomerulus, we demonstrated the podocyte to be the major glomerular source and target of IGF-II; it signals to this cell via the IGF-I receptor via the PI3 kinase and MAPK pathways. Functionally, a reduction in IGF signalling causes podocyte cell death in vitro and glomerular disease in vivo in an aged IGF-II transgenic mouse that produces approximately 60% of IGF-II due to a lack of the P2 promoter of this gene. Collectively, this work reveals the fundamental importance of IGF-II in the mature podocyte for glomerular health across mammalian species.
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- Rivera, Corban G., et al.
(författare)
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Analysis of VEGF-A Regulated Gene Expression in Endothelial Cells to Identify Genes Linked to Angiogenesis
- 2011
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 6:9, s. e24887-
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Tidskriftsartikel (refereegranskat)abstract
- Angiogenesis is important for many physiological processes, diseases, and also regenerative medicine. Therapies that inhibit the vascular endothelial growth factor (VEGF) pathway have been used in the clinic for cancer and macular degeneration. In cancer applications, these treatments suffer from a "tumor escape phenomenon'' where alternative pathways are upregulated and angiogenesis continues. The redundancy of angiogenesis regulation indicates the need for additional studies and new drug targets. We aimed to (i) identify novel and missing angiogenesis annotations and (ii) verify their significance to angiogenesis. To achieve these goals, we integrated the human interactome with known angiogenesis-annotated proteins to identify a set of 202 angiogenesis-associated proteins. Across endothelial cell lines, we found that a significant fraction of these proteins had highly perturbed gene expression during angiogenesis. After treatment with VEGF-A, we found increasing expression of HIF-1 alpha, APP, HIV-1 tat interactive protein 2, and MEF2C, while endoglin, liprin beta 1 and HIF-2 alpha had decreasing expression across three endothelial cell lines. The analysis showed differential regulation of HIF-1 alpha and HIF-2 alpha. The data also provided additional evidence for the role of endothelial cells in Alzheimer's disease.
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- Graham, Lesley A, et al.
(författare)
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Validation of Uromodulin as a Candidate Gene for Human Essential Hypertension
- 2014
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Ingår i: Hypertension. - 0194-911X .- 1524-4563. ; 63:3, s. 551-558
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Tidskriftsartikel (refereegranskat)abstract
- A recent genome-wide association study identified a locus on chromosome 16 in the promoter region of the uromodulin (UMOD) gene that is associated with hypertension. Here, we examined the hypertension signal with functional studies in Umod knockout (KO) mice. Systolic blood pressure was significantly lower in KO versus wild-type (WT) mice under basal conditions (KO: 116.6±0.3 mm Hg versus WT: 136.2±0.4 mm Hg; P<0.0001). Administration of 2% NaCl did not alter systolic blood pressure in KO mice, whereas it increased in WT mice by ≈33%, P<0.001. The average 24-hour urinary sodium excretion in the KO was greater than that of WT mice (P<0.001). Chronic renal function curves demonstrate a leftward shift in KO mice, suggesting that the relationship between UMOD and blood pressure is affected by sodium. Creatinine clearance was increased during salt loading with 2% NaCl in the KO mice, leading to augmented filtered Na(+) excretion and further Na(+) loss. The difference in sodium uptake that exists between WT and KO strains was explored at the molecular level. Urinary tumor necrosis factor-α levels were significantly higher in KO mice compared with WT mice (P<0.0001). Stimulation of primary thick ascending limb of the loop of Henle cells with exogenous tumor necrosis factor-α caused a reduction in NKCC2A expression (P<0.001) with a concurrent rise in the levels of UMOD mRNA (P<0.001). Collectively, we demonstrate that UMOD regulates sodium uptake in the thick ascending limb of the loop of Henle by modulating the effect of tumor necrosis factor-α on NKCC2A expression, making UMOD an important determinant of blood pressure control.
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- Hjalmarsson, Håkan, 1962-, et al.
(författare)
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Identification of box-jenkins models using structured ARX models and nuclear norm relaxation
- 2012
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Ingår i: 16th IFAC Symposium on System Identification. - : IFAC. - 9783902823069 ; , s. 322-327
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Konferensbidrag (refereegranskat)abstract
- In this contribution we present a method to estimate structured high order ARX models. By this we mean that the estimated model, despite its high order is close to a low order model. This is achieved by adding two terms to the least-squares cost function. These two terms correspond to nuclear norms of two Hankel matrices. These Hankel matrices are constructed from the impulse response coefficients of the inverse noise model, and the numerator polynomial of the model dynamics, respectively. In a simulation study the method is shown to be competitive as compared to the prediction error method. In particular, in the study the performance degrades more gracefully than for the Prediction Error Method when the signal to noise ratio decreases.
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| 6. |
- Katselis, Dimitrios, et al.
(författare)
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Robust Experiment Design for System Identification via Semi-Infinite Programming Techniques
- 2012
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Ingår i: Proceedings of the 16th IFAC Symposium on System Identification (SYSID 2012). - 9783902823069 ; , s. 680-685
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Konferensbidrag (refereegranskat)abstract
- Robust optimal experiment design for dynamic system identification is cast as a minmax optimization problem, which is infinite-dimensional. If the input spectrum is discretized (either by considering a Riemmann approximation, or by restricting it to the span of a finite dimensional linear space), this problem falls within the class of semi-infinite convex programs. One approach to this optimization problem of infinite constraints is the so called "scenario approach", which is based on a probabilistic description of the uncertainty to deliver a finite program that attempts to approximate the optimal solution with a prescribed probability. In this paper, we propose as an alternative an exchange algorithm based on some recent advances in the field of semi-infinite programming to tackle the same problem. This method is compared with the scenario approach both from the aspects of accuracy and computational efficiency. Furthermore, the comparison includes the MATLAB semi-infinite solver fseminf to provide a general palette of methods approximating the robust optimal design problem.
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