| 1. |
- Elkin, Michael, et al.
(author)
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Energy Fluctuations Shape Free Energy of Nonspecific Biomolecular Interactions
- 2012
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In: Journal of Statistical Physics. - : Springer Science and Business Media LLC. - 1572-9613 .- 0022-4715. ; 146:4, s. 870-877
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Journal article (peer-reviewed)abstract
- Understanding design principles of biomolecular recognition is a key question of molecular biology. Yet the enormous complexity and diversity of biological molecules hamper the efforts to gain a predictive ability for the free energy of protein-protein, protein-DNA, and protein-RNA binding. Here, using a variant of the Derrida model, we predict that for a large class of biomolecular interactions, it is possible to accurately estimate the relative free energy of binding based on the fluctuation properties of their energy spectra, even if a finite number of the energy levels is known. We show that the free energy of the system possessing a wider binding energy spectrum is almost surely lower compared with the system possessing a narrower energy spectrum. Our predictions imply that low-affinity binding scores, usually wasted in protein-protein and protein-DNA docking algorithms, can be efficiently utilized to compute the free energy. Using the results of Rosetta docking simulations of protein-protein interactions from Andre et al. (Proc. Natl. Acad. Sci. USA 105: 16148, 2008), we demonstrate the power of our predictions.
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| 2. |
- Garsen, Marjolein, et al.
(author)
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Heparanase Is Essential for the Development of Acute Experimental Glomerulonephritis
- 2016
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In: American Journal of Pathology. - : Elsevier BV. - 0002-9440 .- 1525-2191. ; 186:4, s. 805-815
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Journal article (peer-reviewed)abstract
- Heparanase, a heparan sulfate (HS)-specific endoglucuronidase, mediates the onset of proteinuria and renal damage during experimental diabetic nephropathy. Glomerular heparanase expression is increased in most proteinuric diseases. Herein, we evaluated the role of heparanase in two models of experimental glomerulonephritis, being anti-glomerular basement membrane and lipopolysaccharide-induced glomerulonephritis, in wild-type and heparanase-deficient mice. Induction of experimental glomerulonephritis Led to an increased heparanase expression in wild-type mice, which was associated with a decreased glomerular expression of a highly sulfated HS domain, and albuminuria. Albuminuria was reduced in the heparanase-deficient mice in both models of experimental glomerulonephritis, which was accompanied by a better renal function and less renal damage. Notably, glomerular HS expression was preserved in the heparanase-deficient mice. Glomerular leukocyte and macrophage influx was reduced in the heparanase-deficient mice, which was accompanied by a reduced expression of both types 1 and 2 helper T-cell cytokines. In vitro, tumor necrosis factor-alpha and Lipopolysaccharide directly induced heparanase expression and increased transendothelial albumin passage. Our study shows that heparanase contributes to proteinuria and renal damage in experimental glomerulonephritis by decreasing glomerular HS expression, enhancing renal leukocyte and macrophage influx, and affecting the Local cytokine milieu.
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| 3. |
- Gil, Natali, et al.
(author)
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Heparanase Is Essential for the Development of Diabetic Nephropathy in Mice
- 2012
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In: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 61:1, s. 208-216
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Journal article (peer-reviewed)abstract
- Diabetic nephropathy (DN) is the major life-threatening complication of diabetes. Abnormal permselectivity of glomerular basement membrane (GBM) plays an important role in DN pathogenesis. Heparanase is the predominant enzyme that degrades heparan sulfate (HS), the main polysaccharide of the GBM. Loss of GBM HS in diabetic kidney was associated with increased glomerular expression of heparanase; however, the causal involvement of heparanase in the pathogenesis of DN has not been demonstrated. We report for the first time the essential involvement of heparanase in DN. With the use of Hpse-KO mice, we found that deletion of the heparanase gene protects diabetic mice from DN. Furthermore, by investigating the molecular mechanism underlying induction of the enzyme in DN, we found that transcription factor early growth response 1 (Egr1) is responsible for activation of heparanase promoter under diabetic conditions. The specific heparanase inhibitor SST0001 markedly decreased the extent of albuminuria and renal damage in mouse models of DN. Our results collectively underscore the crucial role of heparanase in the pathogenesis of DN and its potential as a highly relevant target for interventions in patients with DN.
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| 4. |
- Goldberg, Rachel, et al.
(author)
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Role of Heparanase-Driven Inflammatory Cascade in Pathogenesis of Diabetic Nephropathy
- 2014
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In: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 63:12, s. 4302-4313
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Journal article (peer-reviewed)abstract
- Renal involvement is a major medical concern in the diabetic population, and with the global epidemic of diabetes, diabetic nephropathy (DN) became the leading cause of end-stage renal failure in the Western world. Heparanase (the only known mammalian endoglycosidase that cleaves heparan sulfate) is essentially involved in DN pathogenesis. Nevertheless, the exact mode of heparanase action in sustaining the pathology of DN remains unclear. Here we describe a previously unrecognized combinatorial circuit of heparanase-driven molecular events promoting chronic inflammation and renal injury in individuals with DN. These events are fueled by heterotypic interactions among glomerular, tubular, and immune cell compartments, as well as diabetic milieu (DM) components. We found that under diabetic conditions latent heparanase, overexpressed by glomerular cells and posttranslationally activated by cathepsin L of tubular origin, sustains continuous activation of kidney-damaging macrophages by DM components, thus creating chronic inflammatory conditions and fostering macrophage-mediated renal injury. Elucidation of the mechanism underlying the enzyme action in diabetic kidney damage is critically important for the proper design and future implementation of heparanase-targeting therapeutic interventions (which are currently under intensive development and clinical testing) in individuals with DN and perhaps other complications of diabetes.
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| 5. |
- Hermano, Esther, et al.
(author)
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Dichotomic role of heparanase in a murine model of metabolic syndrome
- 2021
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In: Cellular and Molecular Life Sciences (CMLS). - : Springer. - 1420-682X .- 1420-9071. ; 78, s. 2771-2780
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Journal article (peer-reviewed)abstract
- Heparanase is the predominant enzyme that cleaves heparan sulfate, the main polysaccharide in the extracellular matrix. While the role of heparanase in sustaining the pathology of autoimmune diabetes is well documented, its association with metabolic syndrome/type 2 diabetes attracted less attention. Our research was undertaken to elucidate the significance of heparanase in impaired glucose metabolism in metabolic syndrome and early type 2 diabetes. Here, we report that heparanase exerts opposite effects in insulin-producing (i.e., islets) vs. insulin-target (i.e., skeletal muscle) compartments, sustaining or hampering proper regulation of glucose homeostasis depending on the site of action. We observed that the enzyme promotes macrophage infiltration into islets in a murine model of metabolic syndrome, and fosters beta-cell-damaging properties of macrophages activated in vitro by components of diabetogenic/obese milieu (i.e., fatty acids). On the other hand, in skeletal muscle (prototypic insulin-target tissue), heparanase is essential to ensure insulin sensitivity. Thus, despite a deleterious effect of heparanase on macrophage infiltration in islets, the enzyme appears to have beneficial role in glucose homeostasis in metabolic syndrome. The dichotomic action of the enzyme in the maintenance of glycemic control should be taken into account when considering heparanase-targeting strategies for the treatment of diabetes.
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| 6. |
- Hermano, Esther, et al.
(author)
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Heparanase Accelerates Obesity-Associated Breast Cancer Progression
- 2019
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In: Cancer Research. - 0008-5472 .- 1538-7445. ; 79:20, s. 5342-5354
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Journal article (peer-reviewed)abstract
- Obese women have higher risk of bearing breast tumors that are highly aggressive and resistant to therapies. Tumor-promoting effects of obesity occur locally via adipose inflammation and related alterations to the extracellular matrix (ECM) as well as systemically via circulating metabolic mediators (e.g., free fatty acids, FFA) associated with excess adiposity and implicated in toll-like receptor-mediated activation of macrophages-key cellular players in obesity-related cancer progression. Although the contribution of macrophages to proneoplastic effects of obesity is well documented, the role of ECM components and their enzymatic degradation is less appreciated. We show that heparanase, the sole mammalian endoglucuronidase that cleaves heparan sulfate in ECM, is preferentially expressed in clinical/experimental obesity-associated breast tumors. Heparanase deficiency abolished obesity-accelerated tumor progression in vivo. Heparanase orchestrated a complex molecular program that occurred concurrently in adipose and tumor tissue and sustained the cancer-promoting action of obesity. Heparanase was required for adipose tissue macrophages to produce inflammatory mediators responsible for local induction of aromatase, a rate-limiting enzyme in estrogen biosynthesis. Estrogen upregulated heparanase in hormone-responsive breast tumors. In subsequent stages, elevated levels of heparanase induced acquisition of procancerous phenotype by tumor-associated macrophages, resulting in activation of tumor-promoting signaling and acceleration of breast tumor growth under obese conditions. As techniques to screen for heparanase expression in tumors become available, these findings provide rational and a mechanistic basis for designing antiheparanase approaches to uncouple obesity and breast cancer in a rapidly growing population of obese patients. Significance: This study reveals the role of heparanase in promoting obesity-associated breast cancer and provides a mechanistically informed approach to uncouple obesity and breast cancer in a rapidly growing population of obese patients.
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| 7. |
- Kuligowski, Erica D., et al.
(author)
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Movement on Stairs During Building Evacuations
- 2014
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Reports (other academic/artistic)abstract
- The time that it takes an occupant population to reach safety when descending a stair during building evacuations is typically estimated by measureable engineering variables such as stair geometry, speed, stair density, and pre-observation delay. In turn, engineering models of building evacuation use these variables to predict the performance of egress systems for building design, emergency planning, or event reconstruction. As part of a program to better understand occupant movement and behavior during building emergencies, the Engineering Laboratory at the National Institute of Standards and Technology (NIST) has been collecting stair movement data during fire drill evacuations of office and residential buildings. These data collections are intended to provide a better understanding of this principal building egress feature and develop a technical foundation for future codes and standards requirements. NIST has collected fire drill evacuation data in 14 buildings (11 office buildings and 3 residential buildings) ranging from six to 62 stories in height that have included a range of stair widths and occupant densities. A total of more than 22000 individual measurements are included in the data set. This report provides details of the data collected, an analysis of the data, and examples of the use of the data. The intention is to better understand movement during stair evacuations and provide data to test the predictive capability of building egress models. While mean movement speeds in the current study of 0.44 m/s ± 0.19 m/s are observed to be quite similar to the range of values in previous studies, mean local movement speeds as occupants traverse down the stairs are seen to vary widely within a given stair, ranging from 0.10 m/s ± 0.008 m/s to 1.7 m/s ± 0.13 m/s. These data provide confirmation of the adequacy of existing literature values typically used for occupant movement speeds and provide updated data for use in egress modeling or other engineering calculations.
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| 8. |
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