| 11. |
- Padmanabhan, Sandosh, et al.
(författare)
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Genome-Wide Association Study of Blood Pressure Extremes Identifies Variant near UMOD Associated with Hypertension
- 2010
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Ingår i: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 6:10
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Tidskriftsartikel (refereegranskat)abstract
- Hypertension is a heritable and major contributor to the global burden of disease. The sum of rare and common genetic variants robustly identified so far explain only 1%-2% of the population variation in BP and hypertension. This suggests the existence of more undiscovered common variants. We conducted a genome-wide association study in 1,621 hypertensive cases and 1,699 controls and follow-up validation analyses in 19,845 cases and 16,541 controls using an extreme case-control design. We identified a locus on chromosome 16 in the 59 region of Uromodulin (UMOD; rs13333226, combined P value of 3.6x10(-11)). The minor G allele is associated with a lower risk of hypertension (OR [95% CI]: 0.87 [0.84-0.91]), reduced urinary uromodulin excretion, better renal function; and each copy of the G allele is associated with a 7.7% reduction in risk of CVD events after adjusting for age, sex, BMI, and smoking status (H.R. = 0.923, 95% CI 0.860-0.991; p = 0.027). In a subset of 13,446 individuals with estimated glomerular filtration rate (eGFR) measurements, we show that rs13333226 is independently associated with hypertension (unadjusted for eGFR: 0.89 [0.83-0.96], p = 0.004; after eGFR adjustment: 0.89 [0.83-0.96], p = 0.003). In clinical functional studies, we also consistently show the minor G allele is associated with lower urinary uromodulin excretion. The exclusive expression of uromodulin in the thick portion of the ascending limb of Henle suggests a putative role of this variant in hypertension through an effect on sodium homeostasis. The newly discovered UMOD locus for hypertension has the potential to give new insights into the role of uromodulin in BP regulation and to identify novel drugable targets for reducing cardiovascular risk.
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| 12. |
- Rojas, Cristian R., 1980-, et al.
(författare)
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Robustness in Experiment Design
- 2012
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Ingår i: IEEE Transactions on Automatic Control. - 0018-9286 .- 1558-2523. ; 57:4, s. 860-874
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Tidskriftsartikel (refereegranskat)abstract
- This paper focuses on the problem of robust experiment design, i.e., how to design an input signal which gives relatively good estimation performance over a large number of systems and model structures. Specifically, we formulate the robust experiment design problem utilizing fundamental limitations on the variance of estimated parametric models as constraints. Using this formulation we design an input signal for situations where only diffuse a priori information is known about the system. Furthermore, we present a robust version of the unprejudiced optimal input design problem. To achieve this, we first develop a closed form solution for the input spectrum which minimizes the maximum weighted integral of the variance of the frequency response estimate over all model structures.
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| 13. |
- Rojas, Cristian R., 1980-, et al.
(författare)
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The Cost of Complexity in System Identification: Frequency Function Estimation of Finite Impulse Response Systems
- 2010
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Ingår i: IEEE Transactions on Automatic Control. - 0018-9286 .- 1558-2523. ; 55:10, s. 2298-2309
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Tidskriftsartikel (refereegranskat)abstract
- In this paper, we consider full order modeling, i.e., when the true system belongs to the model set. We investigate the minimum amount of input energy required to estimate a given linear system with a full order model within a prescribed degree of accuracy gamma, as a function of the model complexity. This quantity we define to be the "cost of complexity." The degree of accuracy is measured by the inverse of the maximum variance of the discrete-time frequency function estimator over a given frequency range [-omega(B), omega(B)]. It is commonly believed that the cost increases as the model complexity increases. However, the amount of information that is to be extracted from the system also influences the cost. The objective of this paper is to quantify these dependencies for systems described by finite-impulse response models. It is shown that, asymptotically in the model order and sample size, the cost is well approximated by gamma sigma(2)(o)n omega(B)/pi where sigma(2)(o)is the noise variance. This expression can be used as a simple rule of thumb for assessing trade-offs that have to be made in a system identification project where full order models are used. For example, for given experiment duration, excitation level and desired accuracy, one can assess how the achievable frequency range depends on the required model order. This type of consideration is useful when formally planning experiments. In addition, we establish several properties of the cost of complexity. We find, for example, that if omega(B) is very close (but not necessarily equal) to pi, the optimal input satisfies the model quality constraint for all frequencies.
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| 14. |
- Rojas, Cristian R., 1980-, et al.
(författare)
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The cost of complexity in system identification: The Output Error case
- 2011
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Ingår i: Automatica. - : Elsevier BV. - 0005-1098 .- 1873-2836. ; 47:9, s. 1938-1948
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Tidskriftsartikel (refereegranskat)abstract
- In this paper we investigate the cost of complexity, which is defined as the minimum amount of input power required to estimate the frequency response of a given linear time invariant system of order n with a prescribed degree of accuracy. In particular we require that the asymptotic (in the data length) variance is less or equal to gamma over a prespecified frequency range [0, omega(B)]. The models considered here are Output Error models, with an emphasis on fixed denominator and Laguerre models. Several properties of the cost are derived. For instance, we present an expression which shows how the pole of the Laguerre model affects the cost. These results quantify how the cost of the system identification experiment depends on n and on the model structure. Also, they show the relation between the cost and the amount of information we would like to extract from the system (in terms of omega(B) and gamma). For simplicity we assume that there is no undermodelling.
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| 15. |
- Singh, A., et al.
(författare)
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High glucose causes dysfunction of the human glomerular endothelial glycocalyx
- 2011
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Ingår i: American journal of physiology. Renal physiology. - : American Physiological Society. - 1522-1466 .- 1931-857X. ; 300:1
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Tidskriftsartikel (refereegranskat)abstract
- The endothelial glycocalyx is a gel-like layer which covers the luminal side of blood vessels. The glomerular endothelial cell (GEnC) glycocalyx is composed of proteoglycan core proteins, glycosaminoglycan (GAG) chains, and sialoglycoproteins and has been shown to contribute to the selective sieving action of the glomerular capillary wall. Damage to the systemic endothelial glycocalyx has recently been associated with the onset of albuminuria in diabetics. In this study, we analyze the effects of high glucose on the biochemical structure of the GEnC glycocalyx and quantify functional changes in its protein-restrictive action. We used conditionally immortalized human GEnC. Proteoglycans were analyzed by Western blotting and indirect immunofluorescence. Biosynthesis of GAG was analyzed by radiolabeling and quantified by anion exchange chromatography. FITC-albumin was used to analyze macromolecular passage across GEnC monolayers using an established in vitro model. We observed a marked reduction in the biosynthesis of GAG by the GEnC under high-glucose conditions. Further analysis confirmed specific reduction in heparan sulfate GAG. Expression of proteoglycan core proteins remained unchanged. There was also a significant increase in the passage of albumin across GEnC monolayers under high-glucose conditions without affecting interendothelial junctions. These results reproduce changes in GEnC barrier properties caused by enzymatic removal of heparan sulfate from the GEnC glycocalyx. They provide direct evidence of high glucose-induced alterations in the GEnC glycocalyx and demonstrate changes to its function as a protein-restrictive layer, thus implicating glycocalyx damage in the pathogenesis of proteinuria in diabetes.
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| 16. |
- Singh, A., et al.
(författare)
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Reactive Oxygen Species Modulate the Barrier Function of the Human Glomerular Endothelial Glycocalyx
- 2013
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Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 8:2
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Tidskriftsartikel (refereegranskat)abstract
- Reactive oxygen species (ROS) play a key role in the pathogenesis of proteinuria in glomerular diseases like diabetic nephropathy. Glomerular endothelial cell (GEnC) glycocalyx covers the luminal aspect of the glomerular capillary wall and makes an important contribution to the glomerular barrier. ROS are known to depolymerise glycosaminoglycan (GAG) chains of proteoglycans, which are crucial for the barrier function of GEnC glycocalyx. The aim of this study is to investigate the direct effects of ROS on the structure and function of GEnC glycocalyx using conditionally immortalised human GEnC. ROS were generated by exogenous hydrogen peroxide. Biosynthesis and cleavage of GAG chains was analyzed by radiolabelling (S35 and 3H-glucosamine). GAG chains were quantified on GEnC surface and in the cell supernatant using liquid chromatography and immunofluorescence techniques. Barrier properties were estimated by measuring trans-endothelial passage of albumin. ROS caused a significant loss of WGA lectin and heparan sulphate staining from the surface of GEnC. This lead to an increase in trans-endothelial albumin passage. The latter could be inhibited by catalase and superoxide dismutase. The effect of ROS on GEnC was not mediated via the GAG biosynthetic pathway. Quantification of radiolabelled GAG fractions in the supernatant confirmed that ROS directly caused shedding of HS GAG. This finding is clinically relevant and suggests a mechanism by which ROS may cause proteinuria in clinical conditions associated with high oxidative stress.
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| 17. |
- Welsh, Allison W., et al.
(författare)
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Cytoplasmic Estrogen Receptor in Breast Cancer
- 2012
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Ingår i: Clinical Cancer Research. - 1078-0432. ; 18:1, s. 118-126
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: In addition to genomic signaling, it is accepted that estrogen receptor-alpha (ER alpha) has nonnuclear signaling functions, which correlate with tamoxifen resistance in preclinical models. However, evidence for cytoplasmic ER localization in human breast tumors is less established. We sought to determine the presence and implications of nonnuclear ER in clinical specimens. Experimental Design: A panel of ER alpha-specific antibodies (SP1, MC20, F10, 60c, and 1D5) was validated by Western blot and quantitative immunofluorescent (QIF) analysis of cell lines and patient controls. Then eight retrospective cohorts collected on tissue microarrays were assessed for cytoplasmic ER. Four cohorts were from Yale (YTMA 49, 107, 130, and 128) and four others (NCI YTMA 99, South Swedish Breast Cancer Group SBII, NSABP B14, and a Vietnamese Cohort) from other sites around the world. Results: Four of the antibodies specifically recognized ER by Western and QIF analysis, showed linear increases in amounts of ER in cell line series with progressively increasing ER, and the antibodies were reproducible on YTMA 49 with Pearson correlations (r(2) values) ranging from 0.87 to 0.94. One antibody with striking cytoplasmic staining (MC20) failed validation. We found evidence for specific cytoplasmic staining with the other four antibodies across eight cohorts. The average incidence was 1.5%, ranging from 0 to 3.2%. Conclusions: Our data show ER alpha is present in the cytoplasm in a number of cases using multiple antibodies while reinforcing the importance of antibody validation. In nearly 3,200 cases, cytoplasmic ER is present at very low incidence, suggesting its measurement is unlikely to be of routine clinical value. Clin Cancer Res; 18(1); 118-26. (C) 2011 AACR.
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| 18. |
- Welsh, James S., et al.
(författare)
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Sparse estimation techniques for basis function selection in wideband system identification
- 2012
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Ingår i: 16th IFAC Symposium on System Identification. - : IFAC. - 9783902823069 ; , s. 977-982
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Konferensbidrag (refereegranskat)abstract
- This paper considers the use of sparse estimation techniques to determine an appropriate set of basis functions, in terms of the number of poles and their respective location, to be used in a system identification problem. In particular, the problem cast in the paper is based on the identification of set of parameters to represent a system of large dynamic range. The proposed solution is based on a LASSO-type sparse estimator, which provides an automatic method for selecting both the number of poles and their location. A simulation example is provided that consists of a highly resonant system with eight resonances that extends over 9 decades of frequency.
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