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Sample records for adaptive outward remodeling

  1. Liposomal prednisolone inhibits vascular inflammation and enhances venous outward remodeling in a murine arteriovenous fistula model

    PubMed Central

    Wong, ChunYu; Bezhaeva, Taisiya; Rothuizen, Tonia C.; Metselaar, Josbert M.; de Vries, Margreet R.; Verbeek, Floris P. R.; Vahrmeijer, Alexander L.; Wezel, Anouk; van Zonneveld, Anton-Jan; Rabelink, Ton J.; Quax, Paul H. A.; Rotmans, Joris I.

    2016-01-01

    Arteriovenous fistulas (AVF) for hemodialysis access have a 1-year primary patency rate of only 60%, mainly as a result of maturation failure that is caused by insufficient outward remodeling and intimal hyperplasia. The exact pathophysiology remains unknown, but the inflammatory vascular response is thought to play an important role. In the present study we demonstrate that targeted liposomal delivery of prednisolone increases outward remodeling of the AVF in a murine model. Liposomes accumulate in the post-anastomotic area of the venous outflow tract in which the vascular pathology is most prominent in failed AVFs. On a histological level, we observed a reduction of lymphocytes and granulocytes in the vascular wall. In addition, a strong anti-inflammatory effect of liposomal prednisolone on macrophages was demonstrated in vitro. Therefore, treatment with liposomal prednisolone might be a valuable strategy to improve AVF maturation. PMID:27460883

  2. Resveratrol Improved Flow-Mediated Outward Arterial Remodeling in Ovariectomized Rats with Hypertrophic Effect at High Dose

    PubMed Central

    Petit, Marie; Guihot, Anne-Laure; Grimaud, Linda; Vessieres, Emilie; Toutain, Bertrand; Menet, Marie-Claude; Nivet-Antoine, Valérie; Arnal, Jean-François; Loufrani, Laurent; Procaccio, Vincent; Henrion, Daniel

    2016-01-01

    Objectives Chronic increases in blood flow in resistance arteries induce outward remodeling associated with increased wall thickness and endothelium-mediated dilatation. This remodeling is essential for collateral arteries growth following occlusion of a large artery. As estrogens have a major role in this remodeling, we hypothesized that resveratrol, described as possessing phytoestrogen properties, could improve remodeling in ovariectomized rats. Methods Blood flow was increased in vivo in mesenteric arteries after ligation of adjacent arteries in 3-month old ovariectomized rats treated with resveratrol (5 or 37.5 mg/kg per day: RESV5 or RESV37.5) or vehicle. After 2 weeks arterial structure and function were measured in vitro in high flow (HF) and normal flow (NF) arteries isolated from each rat. Results Arterial diameter was greater in HF than in NF arteries in ovariectomized rats treated with RESV5 or RESV37.5, not in vehicle-treated rats. In mice lacking estrogen receptor alpha diameter was equivalent in HF and NF arteries whereas in mice treated with RESV5 diameter was greater in HF than in NF vessels. A compensatory increase in wall thickness and a greater phenylephrine-mediated contraction were observed in HF arteries. This was more pronounced in HF arteries from RESV37.5-treated rats. ERK1/2 phosphorylation, involved in hypertrophy and contraction, were higher in RESV37.5-treated rats than in RESV5- and vehicle-treated rats. Endothelium-dependent relaxation was greater in HF than in NF arteries in RESV5-treated rats only. In HF arteries from RESV37.5-treated rats relaxation was increased by superoxide reduction and markers of oxidative stress (p67phox, GP91phox) were higher than in the 2 other groups. Conclusion Resveratrol improved flow-mediated outward remodeling in ovariectomized rats thus providing a potential therapeutic tool in menopause-associated ischemic disorders. This effect seems independent of the estrogen receptor alpha. Nevertheless

  3. [Effect of allitridum on remodeling of the transient outward potassium current of ventricular myocytes of spontaneously hypertensive rats].

    PubMed

    Dan, Qing; Zhao, Ying; Wu, Zhi-juan; Zhu, Chao; Liu, Li; Xu, Bin; Liu, Yu-qi; Chen, Qi; Li, Yang

    2015-01-01

    We aimed to study the effect of allitridum (All) on the transient outward potassium current (Ito) of ventricular myocytes of spontaneously hypertensive rats (SHR). Totally 30 male SHRs were randomly divided into three groups: low-dose All group (7.5 mg·kg(-1)), high-dose All group (15.0 mg·kg(-1)) and normal saline group. The other 10 sex and age matched Wistar-kyoto rats (WKY) were also taken as control group (WKY group). All animals received i.p. administration for 8 weeks. The dual enzymatic method was used to separate single ventricular myocyte from animals. Patch-clamp technique was used to record Ito and analyze the effect of All on the current. It was shown that the left ventricular hypertrophy of SHR was reversed significantly by All. Furthermore, the density of Ito was recovered in both high and low dose All groups. The peak current densities of Ito were enhanced from 18.23±3.64 to 25.17±2.86 pA/pF (P<0.01) and 36.47±5.42 pA/pF (P<0.01) at +50 mV by All 7.5 mg·kg(-1) and 15.0 mg·kg(-1), respectively, which was not significantly different with WKY group. The effect was associated with positive shift of the steady-state, close-state inactivation, and shortened recovery from inactivation of Ito. It is concluded that All decreases the remodeling of Ito of ventricular hypertrophic myocytes of SHR. PMID:25924473

  4. Adaptive scapula bone remodeling computational simulation: Relevance to regenerative medicine

    SciTech Connect

    Sharma, Gulshan B.; Robertson, Douglas D.

    2013-07-01

    Shoulder arthroplasty success has been attributed to many factors including, bone quality, soft tissue balancing, surgeon experience, and implant design. Improved long-term success is primarily limited by glenoid implant loosening. Prosthesis design examines materials and shape and determines whether the design should withstand a lifetime of use. Finite element (FE) analyses have been extensively used to study stresses and strains produced in implants and bone. However, these static analyses only measure a moment in time and not the adaptive response to the altered environment produced by the therapeutic intervention. Computational analyses that integrate remodeling rules predict how bone will respond over time. Recent work has shown that subject-specific two- and three dimensional adaptive bone remodeling models are feasible and valid. Feasibility and validation were achieved computationally, simulating bone remodeling using an intact human scapula, initially resetting the scapular bone material properties to be uniform, numerically simulating sequential loading, and comparing the bone remodeling simulation results to the actual scapula’s material properties. Three-dimensional scapula FE bone model was created using volumetric computed tomography images. Muscle and joint load and boundary conditions were applied based on values reported in the literature. Internal bone remodeling was based on element strain-energy density. Initially, all bone elements were assigned a homogeneous density. All loads were applied for 10 iterations. After every iteration, each bone element’s remodeling stimulus was compared to its corresponding reference stimulus and its material properties modified. The simulation achieved convergence. At the end of the simulation the predicted and actual specimen bone apparent density were plotted and compared. Location of high and low predicted bone density was comparable to the actual specimen. High predicted bone density was greater than

  5. Adaptive scapula bone remodeling computational simulation: Relevance to regenerative medicine

    NASA Astrophysics Data System (ADS)

    Sharma, Gulshan B.; Robertson, Douglas D.

    2013-07-01

    Shoulder arthroplasty success has been attributed to many factors including, bone quality, soft tissue balancing, surgeon experience, and implant design. Improved long-term success is primarily limited by glenoid implant loosening. Prosthesis design examines materials and shape and determines whether the design should withstand a lifetime of use. Finite element (FE) analyses have been extensively used to study stresses and strains produced in implants and bone. However, these static analyses only measure a moment in time and not the adaptive response to the altered environment produced by the therapeutic intervention. Computational analyses that integrate remodeling rules predict how bone will respond over time. Recent work has shown that subject-specific two- and three dimensional adaptive bone remodeling models are feasible and valid. Feasibility and validation were achieved computationally, simulating bone remodeling using an intact human scapula, initially resetting the scapular bone material properties to be uniform, numerically simulating sequential loading, and comparing the bone remodeling simulation results to the actual scapula's material properties. Three-dimensional scapula FE bone model was created using volumetric computed tomography images. Muscle and joint load and boundary conditions were applied based on values reported in the literature. Internal bone remodeling was based on element strain-energy density. Initially, all bone elements were assigned a homogeneous density. All loads were applied for 10 iterations. After every iteration, each bone element's remodeling stimulus was compared to its corresponding reference stimulus and its material properties modified. The simulation achieved convergence. At the end of the simulation the predicted and actual specimen bone apparent density were plotted and compared. Location of high and low predicted bone density was comparable to the actual specimen. High predicted bone density was greater than actual

  6. Outward Bound.

    ERIC Educational Resources Information Center

    Outward Bound, Inc., Andover, MA.

    The Outward Bound concept was developed in Germany and Great Britain with the saving of human life as the ultimate goal. Courses are designed to help students discover their true physical and mental limits through development of skills including emergency medical aid, firefighting, search and rescue, mountaineering, and sailing. Five Outward Bound…

  7. Cholestasis‐induced adaptive remodeling of interlobular bile ducts

    PubMed Central

    Damle‐Vartak, Amruta; Richter, Beate; Dirsch, Olaf; Dahmen, Uta; Hammad, Seddik

    2016-01-01

    Cholestasis is a common complication in liver diseases that triggers a proliferative response of the biliary tree. Bile duct ligation (BDL) is a frequently used model of cholestasis in rodents. To determine which changes occur in the three‐dimensional (3D) architecture of the interlobular bile duct during cholestasis, we used 3D confocal imaging, surface reconstructions, and automated image quantification covering a period up to 28 days after BDL. We show a highly reproducible sequence of interlobular duct remodeling, where cholangiocyte proliferation initially causes corrugation of the luminal duct surface, leading to an approximately five‐fold increase in surface area. This is analogous to the function of villi in the intestine or sulci in the brain, where an expansion of area is achieved within a restricted volume. The increase in surface area is further enhanced by duct branching, branch elongation, and loop formation through self‐joining, whereby an initially relatively sparse mesh surrounding the portal vein becomes five‐fold denser through elongation, corrugation, and ramification. The number of connections between the bile duct and the lobular bile canalicular network by the canals of Hering decreases proportionally to the increase in bile duct length, suggesting that no novel connections are established. The diameter of the interlobular bile duct remains constant after BDL, a response that is qualitatively distinct from that of large bile ducts, which tend to enlarge their diameters. Therefore, volume enhancement is only due to net elongation of the ducts. Because curvature and tortuosity of the bile duct are unaltered, this enlargement of the biliary tree is caused by branching and not by convolution. Conclusion: BDL causes adaptive remodeling that aims at optimizing the intraluminal surface area by way of corrugation and branching. (Hepatology 2016;63:951–964) PMID:26610202

  8. Restraint stress delays endometrial adaptive remodeling during mouse embryo implantation.

    PubMed

    Liu, Guanhui; Dong, Yulan; Wang, Zixu; Cao, Jing; Chen, Yaoxing

    2015-01-01

    In mice, previously, we showed that restraint stress reduces the number of embryo implantation sites in the endometrium. Here, we hypothesized that the uterine microenvironment is altered by restraint stress and consequently is suboptimal for embryo implantation. On embryonic day 1 (E1), 60 of 154 pregnant CD1 mice underwent restraint stress (4 h), repeated daily to E3, E5 or E7 (n = 10 mice per group). Restraint stress decreased food intake and suppressed body weight gain on E3, E5 and E7. Restraint stress decreased the actual and relative weight (percent body weight) of uterus and ovary on E5 (by 14.9%, p = 0.03; 16.1%, p = 0.004) and E7 (by 16.8%, p = 0.03; 20.0%, p = 0.01). Morphologically, restraint stress decreased relative endometrial area (by 8.94-18.8%, p = 0.003-0.021) and uterine gland area (by 30.6%, p < 0.01 on E3 and 44.5%, p < 0.01 on E5). Immunohistochemistry showed that restraint stress decreased microvessel density (by 12.9-70.5%, p < 0.01) and vascular endothelial growth factor expression (by 14.6-45.9%, p = 0.007-0.02). Restraint stress decreased by 32.4-39.8% (p = 0.002-0.01) the mean optical density ratio for proliferating cell nuclear antigen/terminal deoxynucleotidyl transferase dUTP nick end labeling. Methyl thiazolyl tetrazolium assay showed a dose-dependent decrease in proliferative activity of endometrial stromal cells (from 52 of 154 pregnant E5 control mice) incubated with H2O2 (100-1000 μM) in vitro. These findings supported the hypothesis that restraint stress negatively influences endometrial adaptive remodeling via an oxidative stress pathway, which resulted in fewer implantation sites.

  9. Impaired mitochondrial fat oxidation induces adaptive remodeling of muscle metabolism

    PubMed Central

    Wicks, Shawna E.; Vandanmagsar, Bolormaa; Haynie, Kimberly R.; Fuller, Scott E.; Warfel, Jaycob D.; Stephens, Jacqueline M.; Wang, Miao; Han, Xianlin; Zhang, Jingying; Noland, Robert C.; Mynatt, Randall L.

    2015-01-01

    The correlations between intramyocellular lipid (IMCL), decreased fatty acid oxidation (FAO), and insulin resistance have led to the hypothesis that impaired FAO causes accumulation of lipotoxic intermediates that inhibit muscle insulin signaling. Using a skeletal muscle-specific carnitine palmitoyltransferase-1 KO model, we show that prolonged and severe mitochondrial FAO inhibition results in increased carbohydrate utilization, along with reduced physical activity; increased circulating nonesterified fatty acids; and increased IMCLs, diacylglycerols, and ceramides. Perhaps more importantly, inhibition of mitochondrial FAO also initiates a local, adaptive response in muscle that invokes mitochondrial biogenesis, compensatory peroxisomal fat oxidation, and amino acid catabolism. Loss of its major fuel source (lipid) induces an energy deprivation response in muscle coordinated by signaling through AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) to maintain energy supply for locomotion and survival. At the whole-body level, these adaptations result in resistance to obesity. PMID:26056297

  10. Adaptive Remodeling of Achilles Tendon: A Multi-scale Computational Model

    PubMed Central

    Rubenson, Jonas; Umberger, Brian

    2016-01-01

    While it is known that musculotendon units adapt to their load environments, there is only a limited understanding of tendon adaptation in vivo. Here we develop a computational model of tendon remodeling based on the premise that mechanical damage and tenocyte-mediated tendon damage and repair processes modify the distribution of its collagen fiber lengths. We explain how these processes enable the tendon to geometrically adapt to its load conditions. Based on known biological processes, mechanical and strain-dependent proteolytic fiber damage are incorporated into our tendon model. Using a stochastic model of fiber repair, it is assumed that mechanically damaged fibers are repaired longer, whereas proteolytically damaged fibers are repaired shorter, relative to their pre-damage length. To study adaptation of tendon properties to applied load, our model musculotendon unit is a simplified three-component Hill-type model of the human Achilles-soleus unit. Our model results demonstrate that the geometric equilibrium state of the Achilles tendon can coincide with minimization of the total metabolic cost of muscle activation. The proposed tendon model independently predicts rates of collagen fiber turnover that are in general agreement with in vivo experimental measurements. While the computational model here only represents a first step in a new approach to understanding the complex process of tendon remodeling in vivo, given these findings, it appears likely that the proposed framework may itself provide a useful theoretical foundation for developing valuable qualitative and quantitative insights into tendon physiology and pathology. PMID:27684554

  11. Extensive remodeling of the presynaptic cytomatrix upon homeostatic adaptation to network activity silencing.

    PubMed

    Lazarevic, Vesna; Schöne, Cornelia; Heine, Martin; Gundelfinger, Eckart D; Fejtova, Anna

    2011-07-13

    Global changes of activity in neuronal networks induce homeostatic adaptations of synaptic strengths, which involve functional remodeling of both presynaptic and postsynaptic apparatuses. Despite considerable advances in understanding cellular properties of homeostatic synaptic plasticity, the underlying molecular mechanisms are not fully understood. Here, we explored the hypothesis that adaptive homeostatic adjustment of presynaptic efficacy involves molecular remodeling of the release apparatus including the presynaptic cytomatrix, which spatially and functionally coordinates neurotransmitter release. We found significant downregulation of cellular expression levels of presynaptic scaffolding proteins Bassoon, Piccolo, ELKS/CAST, Munc13, RIM, liprin-α, and synapsin upon prolonged (48 h) activity depletion in rat neuronal cultures. This was accompanied by a general reduction of Bassoon, Piccolo, ELKS/CAST, Munc13, and synapsin levels at synaptic sites. Interestingly, RIM was upregulated in a subpopulation of synapses. At the level of individual synapses, RIM quantities correlated well with synaptic activity, and a constant relationship between RIM levels and synaptic activity was preserved upon silencing. Silencing also induced synaptic enrichment of other previously identified regulators of presynaptic release probability, i.e., synaptotagmin1, SV2B, and P/Q-type calcium channels. Seeking responsible cellular mechanisms, we revealed a complex role of the ubiquitin-proteasome system in the functional presynaptic remodeling and enhanced degradation rates of Bassoon and liprin-α upon silencing. Together, our data indicate a significant molecular reorganization of the presynaptic release apparatus during homeostatic adaptation to network inactivity and identify RIM, synaptotagmin1, Ca(v)2.1, and SV2B as molecular candidates underlying the main silencing-induced functional hallmark at presynapse, i.e., increase of neurotransmitter release probability.

  12. Stress, sex and neural adaptation to a changing environment: mechanisms of neuronal remodeling

    PubMed Central

    McEwen, Bruce S.

    2010-01-01

    The adult brain is much more resilient and adaptable than previously believed, and adaptive structural plasticity involves growth and shrinkage of dendritic trees, turnover of synapses and limited amounts of neurogenesis in the forebrain, especially the dentate gyrus of the hippocampal formation. Stress and sex hormones help to mediate adaptive structural plasticity, which has been extensively investigated in hippocampus and to a lesser extent in prefrontal cortex and amygdala, all brain regions that are involved in cognitive and emotional functions. Stress and sex hormones exert their effects on brain structural remodeling through both classical genomic as well as non-genomic mechanisms, and they do so in collaboration with neurotransmitters and other intra- and extracellular mediators. This review will illustrate the actions of estrogen on synapse formation in the hippocampus and the process of stress-induced remodelling of dendrites and synapses in the hippocampus, amygdala and prefrontal cortex. The influence of early developmental epigenetic events, such as early life stress and brain sexual differentiation, is noted along with the interactions between sex hormones and the effects of stress on the brain. Because hormones influence brain structure and function and because hormone secretion is governed by the brain, applied molecular neuroscience techniques can begin to reveal the role of hormones in brain-related disorders and the treatment of these diseases. A better understanding of hormone-brain interactions should promote more flexible approaches to the treatment of psychiatric disorders, as well as their prevention through both behavioral and pharmaceutical interventions. PMID:20840167

  13. Girls Leading Outward

    ERIC Educational Resources Information Center

    Hamed, Heather; Reyes, Jazmin; Moceri, Dominic C.; Morana, Laura; Elias, Maurice J.

    2011-01-01

    The authors describe a program implemented in Red Bank Middle School in New Jersey to help at-risk, minority middle school girls realize their leadership potential. The GLO (Girls Leading Outward) program was developed by the Developing Safe and Civil Schools Project at Rutgers University and is facilitated by university students. Selected middle…

  14. Extracellular matrix remodeling and its contribution to protective adaptation following lengthening contractions in human muscle.

    PubMed

    Hyldahl, Robert D; Nelson, Brad; Xin, Ling; Welling, Tyson; Groscost, Logan; Hubal, Monica J; Chipkin, Stuart; Clarkson, Priscilla M; Parcell, Allen C

    2015-07-01

    This study determined the contribution of extracellular matrix (ECM) remodeling to the protective adaptation of human skeletal muscle known as the repeated-bout effect (RBE). Muscle biopsies were obtained 3 hours, 2 days, and 27 days following an initial bout (B1) of lengthening contractions (LCs) and 2 days following a repeated bout (B2) in 2 separate studies. Biopsies from the nonexercised legs served as controls. In the first study, global transcriptomic analysis indicated widespread changes in ECM structural, deadhesive, and signaling transcripts, 3 hours following LC. To determine if ECM remodeling is involved in the RBE, we conducted a second study by use of a repeated-bout paradigm. TNC immunoreactivity increased 10.8-fold following B1, was attenuated following B2, and positively correlated with LC-induced strength loss (r(2) = 0.45; P = 0.009). Expression of collagen I, III, and IV (COL1A1, COL3A1, COL4A1) transcripts was unchanged early but increased 5.7 ± 2.5-, 3.2 ± 0.9-, and 2.1 ± 0.4-fold (P < 0.05), respectively, 27 days post-B1 and were unaffected by B2. Likewise, TGF-β signaling demonstrated a delayed response following LC. Satellite cell content increased 80% (P < 0.05) 2 days post-B1 (P < 0.05), remained elevated 27 days post-B1, and was unaffected by B2. Collectively, the data suggest sequential ECM remodeling characterized by early deadhesion and delayed reconstructive activity that appear to contribute to the RBE. PMID:25808538

  15. Temperature adaptation in two bivalve species from different thermal habitats: energetics and remodelling of membrane lipids.

    PubMed

    Pernet, Fabrice; Tremblay, Réjean; Comeau, Luc; Guderley, Helga

    2007-09-01

    We compared lipid dynamics and the physiological responses of blue mussels Mytilus edulis, a cold-adapted species, and oysters Crassostrea virginica, a warmer-water species, during simulated overwintering and passage to spring conditions. To simulate overwintering, animals were held at 0 degrees C, 4 degrees C and 9 degrees C for 3 months and then gradually brought to and maintained at 20 degrees C for 5 weeks to simulate spring-summer conditions. Changes in lipid class and fatty acid composition were related to clearance rate and oxygen consumption. We found major differences between species in triglyceride (TAG) metabolism during overwintering. Mussels used digestive gland TAG stores for energy metabolism or reproductive processes during the winter, whereas oysters did not accumulate large TAG stores prior to overwintering. Mussel TAG contained high levels of 20:5n-3 compared to levels in oysters and in the diet. This may help to counteract the effect of low temperature by reducing the melting point of TAG and thus increasing the availability of storage fats at low temperature. Mussels seemed better able to mobilise 20:5n-3 and 18:4n-3 than other fatty acids. We also found that both bivalves underwent a major remodelling of membrane phospholipids. The unsaturation index decreased in the gills and digestive glands of both species during the early stages of warming, principally due to decreases in 22:6n-3 and 20:5n-3. In digestive glands, the unsaturation index did not increase with decreasing temperature beyond a threshold attained at 9 degrees C whereas a perfect negative relationship was observed in gills, as predicted by homeoviscous adaptation. The presence of digestive enzymes and acids in the digestive gland microenvironment may lead to specific requirements for membrane stability. That oysters had lower metabolic rates than mussels coincides with a lower unsaturation index of their lipids, as predicted by Hulbert's theory of membranes as metabolic

  16. Extensive Intestinal Resection Triggers Behavioral Adaptation, Intestinal Remodeling and Microbiota Transition in Short Bowel Syndrome

    PubMed Central

    Mayeur, Camille; Gillard, Laura; Le Beyec, Johanne; Bado, André; Joly, Francisca; Thomas, Muriel

    2016-01-01

    Extensive resection of small bowel often leads to short bowel syndrome (SBS). SBS patients develop clinical mal-absorption and dehydration relative to the reduction of absorptive area, acceleration of gastrointestinal transit time and modifications of the gastrointestinal intra-luminal environment. As a consequence of severe mal-absorption, patients require parenteral nutrition (PN). In adults, the overall adaptation following intestinal resection includes spontaneous and complex compensatory processes such as hyperphagia, mucosal remodeling of the remaining part of the intestine and major modifications of the microbiota. SBS patients, with colon in continuity, harbor a specific fecal microbiota that we called “lactobiota” because it is enriched in the Lactobacillus/Leuconostoc group and depleted in anaerobic micro-organisms (especially Clostridium and Bacteroides). In some patients, the lactobiota-driven fermentative activities lead to an accumulation of fecal d/l-lactates and an increased risk of d-encephalopathy. Better knowledge of clinical parameters and lactobiota characteristics has made it possible to stratify patients and define group at risk for d-encephalopathy crises.

  17. Extensive Intestinal Resection Triggers Behavioral Adaptation, Intestinal Remodeling and Microbiota Transition in Short Bowel Syndrome

    PubMed Central

    Mayeur, Camille; Gillard, Laura; Le Beyec, Johanne; Bado, André; Joly, Francisca; Thomas, Muriel

    2016-01-01

    Extensive resection of small bowel often leads to short bowel syndrome (SBS). SBS patients develop clinical mal-absorption and dehydration relative to the reduction of absorptive area, acceleration of gastrointestinal transit time and modifications of the gastrointestinal intra-luminal environment. As a consequence of severe mal-absorption, patients require parenteral nutrition (PN). In adults, the overall adaptation following intestinal resection includes spontaneous and complex compensatory processes such as hyperphagia, mucosal remodeling of the remaining part of the intestine and major modifications of the microbiota. SBS patients, with colon in continuity, harbor a specific fecal microbiota that we called “lactobiota” because it is enriched in the Lactobacillus/Leuconostoc group and depleted in anaerobic micro-organisms (especially Clostridium and Bacteroides). In some patients, the lactobiota-driven fermentative activities lead to an accumulation of fecal d/l-lactates and an increased risk of d-encephalopathy. Better knowledge of clinical parameters and lactobiota characteristics has made it possible to stratify patients and define group at risk for d-encephalopathy crises. PMID:27681910

  18. Extensive Intestinal Resection Triggers Behavioral Adaptation, Intestinal Remodeling and Microbiota Transition in Short Bowel Syndrome.

    PubMed

    Mayeur, Camille; Gillard, Laura; Le Beyec, Johanne; Bado, André; Joly, Francisca; Thomas, Muriel

    2016-01-01

    Extensive resection of small bowel often leads to short bowel syndrome (SBS). SBS patients develop clinical mal-absorption and dehydration relative to the reduction of absorptive area, acceleration of gastrointestinal transit time and modifications of the gastrointestinal intra-luminal environment. As a consequence of severe mal-absorption, patients require parenteral nutrition (PN). In adults, the overall adaptation following intestinal resection includes spontaneous and complex compensatory processes such as hyperphagia, mucosal remodeling of the remaining part of the intestine and major modifications of the microbiota. SBS patients, with colon in continuity, harbor a specific fecal microbiota that we called "lactobiota" because it is enriched in the Lactobacillus/Leuconostoc group and depleted in anaerobic micro-organisms (especially Clostridium and Bacteroides). In some patients, the lactobiota-driven fermentative activities lead to an accumulation of fecal d/l-lactates and an increased risk of d-encephalopathy. Better knowledge of clinical parameters and lactobiota characteristics has made it possible to stratify patients and define group at risk for d-encephalopathy crises. PMID:27681910

  19. Adaptive Remodeling of the Bacterial Proteome by Specific Ribosomal Modification Regulates Pseudomonas Infection and Niche Colonisation

    PubMed Central

    Little, Richard H.; Grenga, Lucia; Saalbach, Gerhard; Howat, Alexandra M.; Pfeilmeier, Sebastian; Trampari, Eleftheria; Malone, Jacob G.

    2016-01-01

    Post-transcriptional control of protein abundance is a highly important, underexplored regulatory process by which organisms respond to their environments. Here we describe an important and previously unidentified regulatory pathway involving the ribosomal modification protein RimK, its regulator proteins RimA and RimB, and the widespread bacterial second messenger cyclic-di-GMP (cdG). Disruption of rimK affects motility and surface attachment in pathogenic and commensal Pseudomonas species, with rimK deletion significantly compromising rhizosphere colonisation by the commensal soil bacterium P. fluorescens, and plant infection by the pathogens P. syringae and P. aeruginosa. RimK functions as an ATP-dependent glutamyl ligase, adding glutamate residues to the C-terminus of ribosomal protein RpsF and inducing specific effects on both ribosome protein complement and function. Deletion of rimK in P. fluorescens leads to markedly reduced levels of multiple ribosomal proteins, and also of the key translational regulator Hfq. In turn, reduced Hfq levels induce specific downstream proteomic changes, with significant increases in multiple ABC transporters, stress response proteins and non-ribosomal peptide synthetases seen for both ΔrimK and Δhfq mutants. The activity of RimK is itself controlled by interactions with RimA, RimB and cdG. We propose that control of RimK activity represents a novel regulatory mechanism that dynamically influences interactions between bacteria and their hosts; translating environmental pressures into dynamic ribosomal changes, and consequently to an adaptive remodeling of the bacterial proteome. PMID:26845436

  20. 17ß-Estradiol Regulates mTORC2 Sensitivity to Rapamycin in Adaptive Cardiac Remodeling

    PubMed Central

    Kusch, Angelika; Schmidt, Maria; Gürgen, Dennis; Postpieszala, Daniel; Catar, Rusan; Hegner, Björn; Davidson, Merci M.; Mahmoodzadeh, Shokoufeh; Dragun, Duska

    2015-01-01

    Adaptive cardiac remodeling is characterized by enhanced signaling of mTORC2 downstream kinase Akt. In females, 17ß-estradiol (E2), as well as Akt contribute essentially to sex-related premenopausal cardioprotection. Pharmacologic mTOR targeting with rapamycin is increasingly used for various clinical indications, yet burdened with clinical heterogeneity in therapy responses. The drug inhibits mTORC1 and less-so mTORC2. In male rodents, rapamycin decreases maladaptive cardiac hypertrophy whereas it leads to detrimental dilative cardiomyopathy in females. We hypothesized that mTOR inhibition could interfere with 17β-estradiol (E2)-mediated sexual dimorphism and adaptive cell growth and tested responses in murine female hearts and cultured female cardiomyocytes. Under physiological in vivo conditions, rapamycin compromised mTORC2 function only in female, but not in male murine hearts. In cultured female cardiomyocytes, rapamycin impaired simultaneously IGF-1 induced activation of both mTOR signaling branches, mTORC1 and mTORC2 only in presence of E2. Use of specific estrogen receptor (ER)α- and ERβ-agonists indicated involvement of both estrogen receptors (ER) in rapamycin effects on mTORC1 and mTORC2. Classical feedback mechanisms common in tumour cells with upregulation of PI3K signaling were not involved. E2 effect on Akt-pS473 downregulation by rapamycin was independent of ERK as shown by sequential mTOR and MEK-inhibition. Furthermore, regulatory mTORC2 complex defining component rictor phosphorylation at Ser1235, known to interfere with Akt-substrate binding to mTORC2, was not altered. Functionally, rapamycin significantly reduced trophic effect of E2 on cell size. In addition, cardiomyocytes with reduced Akt-pS473 under rapamycin treatment displayed decreased SERCA2A mRNA and protein expression suggesting negative functional consequences on cardiomyocyte contractility. Rictor silencing confirmed regulation of SERCA2A expression by mTORC2 in E2-cultured

  1. Northwest Outward Bound Instructor's Manual.

    ERIC Educational Resources Information Center

    Northwest Outward Bound School, Portland, OR.

    Instructor responsibilities, procedures for completing activities safely, and instructional methods and techniques are outlined to assist instructors in the Northwest Outward Bound School (Portland, Oregon) as they strive for teaching excellence. Information is organized into six chapters addressing: history and philosophy of Outward Bound; course…

  2. Lipid remodelling in the reef-building honeycomb worm, Sabellaria alveolata, reflects acclimation and local adaptation to temperature

    PubMed Central

    Muir, Anna P.; Nunes, Flavia L. D.; Dubois, Stanislas F.; Pernet, Fabrice

    2016-01-01

    Acclimation and adaptation, which are key to species survival in a changing climate, can be observed in terms of membrane lipid composition. Remodelling membrane lipids, via homeoviscous adaptation (HVA), counteracts membrane dysfunction due to temperature in poikilotherms. In order to assess the potential for acclimation and adaptation in the honeycomb worm, Sabellaria alveolata, a reef-building polychaete that supports high biodiversity, we carried out common-garden experiments using individuals from along its latitudinal range. Individuals were exposed to a stepwise temperature increase from 15 °C to 25 °C and membrane lipid composition assessed. Our results suggest that S. alveolata was able to acclimate to higher temperatures, as observed by a decrease in unsaturation index and 20:5n-3. However, over the long-term at 25 °C, lipid composition patterns are not consistent with HVA expectations and suggest a stress response. Furthermore, unsaturation index of individuals from the two coldest sites were higher than those from the two warmest sites, with individuals from the thermally intermediate site being in-between, likely reflecting local adaptation to temperature. Therefore, lipid remodelling appears limited at the highest temperatures in S. alveolata, suggesting that individuals inhabiting warm environments may be close to their upper thermal tolerance limits and at risk in a changing climate. PMID:27762300

  3. Ventricular structure, function, and mechanics at high altitude: chronic remodeling in Sherpa vs. short-term lowlander adaptation.

    PubMed

    Stembridge, Mike; Ainslie, Philip N; Hughes, Michael G; Stöhr, Eric J; Cotter, James D; Nio, Amanda Q X; Shave, Rob

    2014-08-01

    Short-term, high-altitude (HA) exposure raises pulmonary artery systolic pressure (PASP) and decreases left-ventricular (LV) volumes. However, relatively little is known of the long-term cardiac consequences of prolonged exposure in Sherpa, a highly adapted HA population. To investigate short-term adaptation and potential long-term cardiac remodeling, we studied ventricular structure and function in Sherpa at 5,050 m (n = 11; 31 ± 13 yr; mass 68 ± 10 kg; height 169 ± 6 cm) and lowlanders at sea level (SL) and following 10 ± 3 days at 5,050 m (n = 9; 34 ± 7 yr; mass 82 ± 10 kg; height 177 ± 6 cm) using conventional and speckle-tracking echocardiography. At HA, PASP was higher in Sherpa and lowlanders compared with lowlanders at SL (both P < 0.05). Sherpa had smaller right-ventricular (RV) and LV stroke volumes than lowlanders at SL with lower RV systolic strain (P < 0.05) but similar LV systolic mechanics. In contrast to LV systolic mechanics, LV diastolic, untwisting velocity was significantly lower in Sherpa compared with lowlanders at both SL and HA. After partial acclimatization, lowlanders demonstrated no change in the RV end-diastolic area; however, both RV strain and LV end-diastolic volume were reduced. In conclusion, short-term hypoxia induced a reduction in RV systolic function that was also evident in Sherpa following chronic exposure. We propose that this was consequent to a persistently higher PASP. In contrast to the RV, remodeling of LV volumes and normalization of systolic mechanics indicate structural and functional adaptation to HA. However, altered LV diastolic relaxation after chronic hypoxic exposure may reflect differential remodeling of systolic and diastolic LV function.

  4. The adaptive remodeling of endothelial glycocalyx in response to fluid shear stress.

    PubMed

    Zeng, Ye; Tarbell, John M

    2014-01-01

    The endothelial glycocalyx is vital for mechanotransduction and endothelial barrier integrity. We previously demonstrated the early changes in glycocalyx organization during the initial 30 min of shear exposure. In the present study, we tested the hypothesis that long-term shear stress induces further remodeling of the glycocalyx resulting in a robust layer, and explored the responses of membrane rafts and the actin cytoskeleton. After exposure to shear stress for 24 h, the glycocalyx components heparan sulfate, chondroitin sulfate, glypican-1 and syndecan-1, were enhanced on the apical surface, with nearly uniform spatial distributions close to baseline levels that differed greatly from the 30 min distributions. Heparan sulfate and glypican-1 still clustered near the cell boundaries after 24 h of shear, but caveolin-1/caveolae and actin were enhanced and concentrated across the apical aspects of the cell. Our findings also suggest the GM1-labelled membrane rafts were associated with caveolae and glypican-1/heparan sulfate and varied in concert with these components. We conclude that remodeling of the glycocalyx to long-term shear stress is associated with the changes in membrane rafts and the actin cytoskeleton. This study reveals a space- and time- dependent reorganization of the glycocalyx that may underlie alterations in mechanotransduction mechanisms over the time course of shear exposure.

  5. Adapting extracellular matrix proteomics for clinical studies on cardiac remodeling post-myocardial infarction.

    PubMed

    Lindsey, Merry L; Hall, Michael E; Harmancey, Romain; Ma, Yonggang

    2016-01-01

    Following myocardial infarction (MI), the left ventricle (LV) undergoes a series of cardiac wound healing responses that involve stimulation of robust inflammation to clear necrotic myocytes and tissue debris and induction of extracellular matrix (ECM) protein synthesis to generate a scar. Proteomic strategies provide us with a means to index the ECM proteins expressed in the LV, quantify amounts, determine functions, and explore interactions. This review will focus on the efforts taken in the proteomics research field that have expanded our understanding of post-MI LV remodeling, concentrating on the strengths and limitations of different proteomic approaches to glean information that is specific to ECM turnover in the post-MI setting. We will discuss how recent advances in sample preparation and labeling protocols increase our successes at detecting components of the cardiac ECM proteome. We will summarize how proteomic approaches, focusing on the ECM compartment, have progressed over time to current gel-free methods using decellularized fractions or labeling strategies that will be useful for clinical applications. This review will provide an overview of how cardiac ECM proteomics has evolved over the last decade and will provide insight into future directions that will drive forward our understanding of cardiac ECM turnover in the post-MI LV. PMID:27651752

  6. Differential remodelling of peroxisome function underpins the environmental and metabolic adaptability of diplonemids and kinetoplastids.

    PubMed

    Morales, Jorge; Hashimoto, Muneaki; Williams, Tom A; Hirawake-Mogi, Hiroko; Makiuchi, Takashi; Tsubouchi, Akiko; Kaga, Naoko; Taka, Hikari; Fujimura, Tsutomu; Koike, Masato; Mita, Toshihiro; Bringaud, Frédéric; Concepción, Juan L; Hashimoto, Tetsuo; Embley, T Martin; Nara, Takeshi

    2016-05-11

    The remodelling of organelle function is increasingly appreciated as a central driver of eukaryotic biodiversity and evolution. Kinetoplastids including Trypanosoma and Leishmania have evolved specialized peroxisomes, called glycosomes. Glycosomes uniquely contain a glycolytic pathway as well as other enzymes, which underpin the physiological flexibility of these major human pathogens. The sister group of kinetoplastids are the diplonemids, which are among the most abundant eukaryotes in marine plankton. Here we demonstrate the compartmentalization of gluconeogenesis, or glycolysis in reverse, in the peroxisomes of the free-living marine diplonemid, Diplonema papillatum Our results suggest that peroxisome modification was already under way in the common ancestor of kinetoplastids and diplonemids, and raise the possibility that the central importance of gluconeogenesis to carbon metabolism in the heterotrophic free-living ancestor may have been an important selective driver. Our data indicate that peroxisome modification is not confined to the kinetoplastid lineage, but has also been a factor in the success of their free-living euglenozoan relatives.

  7. Cardiac Remodeling, Adaptations and Associated Myocardial Mechanics in Hypertensive Heart Diseases

    PubMed Central

    Lai, Yau-Huei; Lo, Chi-In; Wu, Yih-Jer; Hung, Chung-Lieh; Yeh, Hung-I

    2013-01-01

    Hypertension is the leading cause of heart failure and cardiovascular comorbidities in developed countries. Left ventricular structural/functional alterations such as concentric remodeling or hypertrophy have been extensively studied in hypertensive heart diseases. Furthermore, it is also well-recognized that diastolic function actually deteriorates in hypertensive subjects prior to overt heart failure. Novel imaging modality techniques such as myocardial deformation have allowed for early detection of regional/global myocardial contractile dysfunction. Myocardial deformation, which can be quantified by measuring the systolic strain and strain rate in three different directions (longitudinal, circumferential and radial), has facilitated new insights into the understanding of cardiac systolic mechanics in subjects with early stage myocardial damage. Previous studies had shown that longitudinal function remains the most sensitive parameter in identifying hypertension-related myocardial dysfunction, particularly for those patients who had developed LV hypertrophy. Instead, preserved or enhanced short-axis function, when presented as circumferential or radial strains, may remain relatively preserved or enhanced in order to compensate for longitudinal functional decline. In this manner, global cardiac pumping in terms of ejection fraction may remain relatively unchanged. The early recognition of subclinical systolic dysfunction and associated mechanical compensation in the context of hypertension is crucial, which potentially helps to identify a disease stage that is still responsive to therapeutic intervention. PMID:27122686

  8. Differential remodelling of peroxisome function underpins the environmental and metabolic adaptability of diplonemids and kinetoplastids.

    PubMed

    Morales, Jorge; Hashimoto, Muneaki; Williams, Tom A; Hirawake-Mogi, Hiroko; Makiuchi, Takashi; Tsubouchi, Akiko; Kaga, Naoko; Taka, Hikari; Fujimura, Tsutomu; Koike, Masato; Mita, Toshihiro; Bringaud, Frédéric; Concepción, Juan L; Hashimoto, Tetsuo; Embley, T Martin; Nara, Takeshi

    2016-05-11

    The remodelling of organelle function is increasingly appreciated as a central driver of eukaryotic biodiversity and evolution. Kinetoplastids including Trypanosoma and Leishmania have evolved specialized peroxisomes, called glycosomes. Glycosomes uniquely contain a glycolytic pathway as well as other enzymes, which underpin the physiological flexibility of these major human pathogens. The sister group of kinetoplastids are the diplonemids, which are among the most abundant eukaryotes in marine plankton. Here we demonstrate the compartmentalization of gluconeogenesis, or glycolysis in reverse, in the peroxisomes of the free-living marine diplonemid, Diplonema papillatum Our results suggest that peroxisome modification was already under way in the common ancestor of kinetoplastids and diplonemids, and raise the possibility that the central importance of gluconeogenesis to carbon metabolism in the heterotrophic free-living ancestor may have been an important selective driver. Our data indicate that peroxisome modification is not confined to the kinetoplastid lineage, but has also been a factor in the success of their free-living euglenozoan relatives. PMID:27170716

  9. Changes of vessel-cells complex in zones of adaptive remodeling of the bone tissue under microgravity conditions

    NASA Astrophysics Data System (ADS)

    Rodionova, N.; Oganov, V.; Nosova, L.

    The development and differentiation of osteogenic cells in organism happen in closely topographical and functional connection with blood capillaries. We formerly proofed, that small-differentiated cells, which are in the population of perivascular cells are osteogenic cells -precursors . At the present time it is actually to clear up, how these biostructures react on conditions of less of biomechanical load on skeleton bones. We researched peculiarities of blood-bed structure and perivascular cells in metaphises of thighbones and tibial bones in rats, which were onboard the American space station SLS-2 and in experiments of modeling hypokinesia. There were used methods of cytochemistry, histology and electron microscopy. We established, that under the support and functional load decreasing in zones of bones adaptive remodeling, comparatively to control, on histosections the own volume of sinusoid capillaries reduces. The small vessels prevail here. The spaces of sinusoid capillaries are limited by 1 2 cells of the endothelia. Endotheliocytes in- general have the typical ultrastructure. Basal membranes are expressed not-distinctly. Perivascular cells don't create the unbroken layer. The population of these cells is not-homogeneous. It includes enclosed to endothelia small-differentiated forms and separating cells with sings of fibroblastic differentiation (the own volume of rough endoplasmic reticulum in cytoplasm induces). The part of these cells reacts on the alkaline phosphatase (the marker of the osteogenic differentiation). Under the conditions of support load decreasing (especially under the microgravity) there is a tendency to reducing of separating osteogenic cells number. We noted the priority of differentiating fibroblasts. It leads to further development in zones of bone remodeling of hearths of fibrous tissue, that doesn't mineralize. The obtained data are seen as one of mechanisms of osteoporosis and osteopenia development under the deficite of support

  10. Understanding How Space Travel Affects Blood Vessels: Arterial Remodeling and Functional Adaptations Induced by Microgravity

    NASA Technical Reports Server (NTRS)

    Delp, Michael; Vasques, Marilyn; Aquilina, Rudy (Technical Monitor)

    2002-01-01

    Ever rise quickly from the couch to get something from the kitchen and suddenly feel dizzy? With a low heart rate and relaxed muscles, the cardiovascular system does not immediately provide the resistance necessary to keep enough blood going to your head. Gravity wins, at least for a short time, before your heart and blood vessels can respond to the sudden change in position and correct the situation. Actually, the human cardiovascular system is quite well adapted to the constant gravitational force of the Earth. When standing, vessels in the legs constrict to prevent blood from collecting in the lower extremities. In the space environment, the usual head-to-foot blood pressure and tissue fluid gradients that exist during the upright posture on Earth are removed. The subsequent shift in fluids from the lower to the upper portions of the body triggers adaptations within the cardiovascular system to accommodate the new pressure and fluid gradients. In animal models that simulate microgravity, the vessels in the head become more robust while those in the lower limbs become thin and lax. Similar changes may also occur in humans during spaceflight and while these adaptations are appropriate for a microgravity environment, they can cause problems when the astronauts return to Earth or perhaps another planet. Astronauts often develop orthostatic intolerance which means they become dizzy or faint when standing upright. This dizziness can persist for a number of days making routine activities difficult. In an effort to understand the physiological details of these cardiovascular adaptations, Dr. Michael Delp at Texas A&M University, uses the rat as a model for his studies. For the experiment flown on STS-107, he will test the hypothesis that blood vessels in the rats' hindlimbs become thinner, weaker, and constrict less in response to pressure changes and to chemical signals when exposed to microgravity. In addition, he will test the hypothesis that arteries in the brain

  11. Effect of femoral canal shape on mechanical stress distribution and adaptive bone remodelling around a cementless tapered-wedge stem

    PubMed Central

    Oba, M.; Kobayashi, N.; Ike, H.; Tezuka, T.; Saito, T.

    2016-01-01

    Objectives In total hip arthroplasty (THA), the cementless, tapered-wedge stem design contributes to achieving initial stability and providing optimal load transfer in the proximal femur. However, loading conditions on the femur following THA are also influenced by femoral structure. Therefore, we determined the effects of tapered-wedge stems on the load distribution of the femur using subject-specific finite element models of femurs with various canal shapes. Patients and Methods We studied 20 femurs, including seven champagne flute-type femurs, five stovepipe-type femurs, and eight intermediate-type femurs, in patients who had undergone cementless THA using the Accolade TMZF stem at our institution. Subject–specific finite element (FE) models of pre- and post-operative femurs with stems were constructed and used to perform FE analyses (FEAs) to simulate single-leg stance. FEA predictions were compared with changes in bone mineral density (BMD) measured for each patient during the first post-operative year. Results Stovepipe models implanted with large-size stems had significantly lower equivalent stress on the proximal-medial area of the femur compared with champagne-flute and intermediate models, with a significant loss of BMD in the corresponding area at one year post-operatively. Conclusions The stovepipe femurs required a large-size stem to obtain an optimal fit of the stem. The FEA result and post-operative BMD change of the femur suggest that the combination of a large-size Accolade TMZF stem and stovepipe femur may be associated with proximal stress shielding. Cite this article: M. Oba, Y. Inaba, N. Kobayashi, H. Ike, T. Tezuka, T. Saito. Effect of femoral canal shape on mechanical stress distribution and adaptive bone remodelling around a cementless tapered-wedge stem. Bone Joint Res 2016;5:362–369. DOI: 10.1302/2046-3758.59.2000525. PMID:27601435

  12. Multiscale Mechanobiology of De Novo Bone Generation and Remodeling & Adaptation of Autograft in a Common Ovine Femur Model

    PubMed Central

    Knothe Tate, Melissa L.; Dolejs, Scott; McBride, Sarah; Miller, R. Matthew; Knothe, Ulf

    2013-01-01

    The link between mechanics and biology in generation and adaptation of bone has been studied for more than a century in the context of skeletal development and fracture healing. However, the interplay between mechanics and biology in de novo generation of bone in postnatal defects as well as healing of morcellized bone graft or massive cortical bone autografts is less well understood. To address this, here we integrate insights from our previously published studies describing the mechanobiology on both de novo bone generation and graft healing in a common ovine femoral defect model. Studying these effects in a common experimental model provides a unique opportunity to elucidate factors conducive to harnessing the regenerative power of the periosteum and ultimately to provide mechanistic insights into the multiscale mechanobiology of bone generation, remodeling and adaptation. Taken together, the studies indicate that, as long as adequate, directional transport of cells and molecules can be insured (e.g. with peristeum in situ or a delivery device), biological factors intrinsic to the periosteum suffice to bridge critical sized bone defects, even in the absence of a patent blood supply. Furthermore, mechanical stimuli are crucial for the success of periosteal bone generation and bone graft healing. Interestingly, areas of highest periosteal strain around defects correlate with highest areas albeit less mineralized areas of new bone. This may indicate a role for convection enhanced transport of cells and molecules in modulation of tissue generation by pluripotent cells that ingress into the defect center, away from the peristeum and toward the surface of the intramedullary nail that fills the medullary cavity. These insights bring us much closer to understanding the mechanobiological environment and stimuli that stimulate the proliferation and differentiation of periosteum derived progenitor cells and ultimately drive the generation of new bone tissue. Furthermore

  13. Outward Bound: An Innovative Patient Education Program.

    ERIC Educational Resources Information Center

    Stich, Thomas F.; Gaylor, Michael S.

    A 1975 Dartmouth Outward Bound Mental Health Project, begun with a pilot project for disturbed adolescents, has evolved into an ongoing treatment option in three separate clinical settings for psychiatric patients and recovering alcoholics. Outward Bound consists of a series of prescribed physical and social tasks where the presence of stress,…

  14. Determinants of cerebrovascular remodeling: Do large brain arteries accommodate stenosis?

    PubMed Central

    Gutierrez, Jose; Goldman, James; Honig, Lawrence S; Elkind, Mitchell SV; Morgello, Susan; Marshall, Randolph S

    2014-01-01

    Objective It is hypothesized that outward remodeling in systemic arteries is a compensatory mechanism for lumen area preservation in the face of increasing arterial stenosis. Large brain arteries have also been studied, but it remains unproven if all assumptions about arterial remodeling can be replicated in the cerebral circulation. Methods The sample included 196 autopsied subjects with a mean age of 55 years; 63 % were men, and 74 % non-Hispanic whites. From each of 1,396 dissected cadaveric large arteries of the circle of Willis, the areas of the lumen, intima, media, and adventitia were measured. Internal elastic lamina (IEL) area was defined as the area encircled by this layer. Stenosis was calculated by dividing the plaque area by the IEL area and multiplying by 100. Results Plotting stenosis against lumen area or stratified by arterial size showed no preservation of the lumen in the setting of growing stenosis. We could not find an association between greater IEL proportion and stenosis (B=0.44, P=0.86). Stratifying arteries by their size, we found that smaller arteries have greater lumen reduction at any degree of stenosis (B=−23.65, P=<0.0001), and although larger arteries show a positive association between IEL proportion and stenosis, this was no longer significant after adjusting for covariates (B=6.0, P=0.13). Conclusions We cannot confirm the hypothesis that large brain arteries undergo outward remodeling as an adaptive response to increasing degrees of stenosis. We found that the lumen decreases proportionally to the degree of stenosis. PMID:24929285

  15. microRNAs and Cardiovascular Remodeling.

    PubMed

    Ono, Koh

    2015-01-01

    Heart failure (HF) is associated with significant morbidity and mortality attributable largely to structural changes in the heart and with associated cardiac dysfunction. Remodeling is defined as alteration of the mass, dimensions, or shape of the heart (termed cardiac or ventricular remodeling) and vessels (vascular remodeling) in response to hemodynamic load and/or cardiovascular injury in association with neurohormonal activation. Remodeling may be described as physiologic or pathologic; alternatively, remodeling may be classified as adaptive or maladaptive. The importance of remodeling as a pathogenic mechanism has been controversial because factors leading to remodeling as well as the remodeling itself may be major determinants of patients' prognosis. The basic mechanisms of cardiovascular remodeling, and especially the roles of microRNAs in HF progression and vascular diseases, will be reviewed here.

  16. Logistics Handbook, 1976. Colorado Outward Bound School.

    ERIC Educational Resources Information Center

    Colorado Outward Bound School, Denver.

    Logistics, a support mission, is vital to the successful operation of the Colorado Outward Bound School (COBS) courses. Logistics is responsible for purchasing, maintaining, transporting, and replenishing a wide variety of items, i.e., food, mountaineering and camping equipment, medical and other supplies, and vehicles. The Logistics coordinator…

  17. An Outward-Looking Approach in Schools.

    ERIC Educational Resources Information Center

    Clausen, Sten Krog

    This report is based on the work of the international colloquy organized by the Council of Europe (Luxembourg, 1981). The aim of the colloquy was to explore how to foster an outward-looking approach in schools, and how to bring about a new approach to teaching man/environment relationships and ways in which people affect and are affected by their…

  18. Outward Bound as an Adjunct to Therapy.

    ERIC Educational Resources Information Center

    Chase, Nelson K.

    The Colorado Outward Bound School (COBS) provides successful adjunct programs for special populations undergoing therapy at the Adventure Home (Boulder, CO), the Juvenile Justice Program and the St. Luke's Hospital Alcoholism Recovery Unit (Denver, CO), and the Dartmouth-Hitchcock Medical Center Department of Psychiatry (Hanover, NH). The goals of…

  19. Colorado Outward Bound School River Rafters' Manual.

    ERIC Educational Resources Information Center

    Leachman, Mark

    Instructional sequences, safety rules, duties of crew members, and procedures for Colorado Outward Bound School river rafting trips are summarized in this manual. Designed to acquaint instructors with the duties expected of them on the trips, the information in the manual is presented in outline form and is intended for those with prior river…

  20. Calcium channel blockade prevents pressure-dependent inward remodeling in isolated subendocardial resistance vessels.

    PubMed

    Sorop, Oana; Bakker, Erik N T P; Pistea, Adrian; Spaan, Jos A E; VanBavel, Ed

    2006-09-01

    The capacity for myocardial perfusion depends on the structure of the coronary microvascular bed. Coronary microvessels may adapt their structure to various stimuli. We tested whether the local pressure profile affects tone and remodeling of porcine coronary microvessels. Subendocardial vessels (approximately 160 microm, n=53) were cannulated and kept in organoid culture for 3 days under different transvascular pressure profiles: Osc 80: mean 80 mmHg, 60 mmHg peak-peak sine wave pulsation amplitude at 1.5 Hz; St 80: steady 80 mmHg; Osc 40: mean 40 mmHg, 30 mmHg amplitude; St 40: steady 40 mmHg. Under the Osc 80 profile, modest tone developed, reducing the diameter to 81+/-14% (mean+/-SE, n=6) of the maximal, passive diameter. No inward remodeling was found here, as determined from the passive pressure-diameter relation after 3 days of culture. Under all other profiles, much more tone developed (e.g., Osc 40: to 26+/-3%, n=7). In addition, these vessels showed eutrophic (i.e., without a change in wall cross-sectional area) inward remodeling (e.g., Osc 40: passive diameter reduction by 24+/-3%). The calcium blocker amlodipine induced maintained dilation in St 40 vessels and reversed the 22+/-3% (n=6) inward remodeling to 15+/-3% (n=8) outward remodeling toward day 3. Vessels required a functional endothelium to maintain structural integrity in culture. Our data indicate that reduction of either mean pressure or pulse pressure leads to microvascular constriction followed by inward remodeling. These effects could be reversed by amlodipine. Although microvascular pressure profiles distal to stenoses are poorly defined, these data suggest that vasodilator therapy could improve subendocardial microvascular function and structure in coronary artery disease.

  1. Outward sodium current in beating heart cells.

    PubMed

    Wellis, D P; DeFelice, L J; Mazzanti, M

    1990-01-01

    This article is a study of the fast Na current during action potentials. We have investigated the outward Na current (Mazzanti, M., and L.J. DeFelice. 1987. Biophys. J. 52:95-100) in more detail, and we have asked whether it goes through the same channels associated with the rapid depolarization phase of action potentials. We address the question by patch clamping single, spontaneously beating, embryonic chick ventricle cells, using two electrodes to record the action potential and the patch current simultaneously. The chief limitation is the capacitive current, and in this article we describe a new method to subtract it. Varying the potential and the Na concentration in the patch pipette, and fitting the corrected currents to a standard model (Ebihara, L., and E.A. Johnson. 1980. Biophys. J. 32:779-790), provides evidence that the outward current is carried by the same channels that conduct the inward current. We compare the currents in beating cells to currents in nonbeating cells using whole-cell and cell-attached patch clamp recordings. The latter tend to show more positive Na reversal potentials, with the implication that internal Na is higher in beating cells. We propose that the plateau of the action potential, which is partly due to an inward Ca current, exceeds Na action current reversal potentials, and that this driving force gives rise to an outward movement of Na ions. The existence of such a current would imply that the fast repolarization phase after the upstroke of cardiac action potentials is partly due to the Na action current.

  2. Prostaglandin E2 Exerts Multiple Regulatory Actions on Human Obese Adipose Tissue Remodeling, Inflammation, Adaptive Thermogenesis and Lipolysis

    PubMed Central

    García-Alonso, Verónica; Titos, Esther; Alcaraz-Quiles, Jose; Rius, Bibiana; Lopategi, Aritz; López-Vicario, Cristina; Jakobsson, Per-Johan; Delgado, Salvadora; Lozano, Juanjo; Clària, Joan

    2016-01-01

    Obesity induces white adipose tissue (WAT) dysfunction characterized by unremitting inflammation and fibrosis, impaired adaptive thermogenesis and increased lipolysis. Prostaglandins (PGs) are powerful lipid mediators that influence the homeostasis of several organs and tissues. The aim of the current study was to explore the regulatory actions of PGs in human omental WAT collected from obese patients undergoing laparoscopic bariatric surgery. In addition to adipocyte hypertrophy, obese WAT showed remarkable inflammation and total and pericellular fibrosis. In this tissue, a unique molecular signature characterized by altered expression of genes involved in inflammation, fibrosis and WAT browning was identified by microarray analysis. Targeted LC-MS/MS lipidomic analysis identified increased PGE2 levels in obese fat in the context of a remarkable COX-2 induction and in the absence of changes in the expression of terminal prostaglandin E synthases (i.e. mPGES-1, mPGES-2 and cPGES). IPA analysis established PGE2 as a common top regulator of the fibrogenic/inflammatory process present in this tissue. Exogenous addition of PGE2 significantly reduced the expression of fibrogenic genes in human WAT explants and significantly down-regulated Col1α1, Col1α2 and αSMA in differentiated 3T3 adipocytes exposed to TGF-β. In addition, PGE2 inhibited the expression of inflammatory genes (i.e. IL-6 and MCP-1) in WAT explants as well as in adipocytes challenged with LPS. PGE2 anti-inflammatory actions were confirmed by microarray analysis of human pre-adipocytes incubated with this prostanoid. Moreover, PGE2 induced expression of brown markers (UCP1 and PRDM16) in WAT and adipocytes, but not in pre-adipocytes, suggesting that PGE2 might induce the trans-differentiation of adipocytes towards beige/brite cells. Finally, PGE2 inhibited isoproterenol-induced adipocyte lipolysis. Taken together, these findings identify PGE2 as a regulator of the complex network of interactions

  3. Outwardly Propagating Flames at Elevated Pressures

    NASA Technical Reports Server (NTRS)

    Law, C. K.; Rozenchan, G.; Tse, S. D.; Zhu, D. L.

    2001-01-01

    Spherical, outwardly-propagating flames of CH4-O2-inert and H2-O2-inert mixtures were experimentally studied in a high pressure apparatus. Stretch-free flame speeds and Markstein lengths were extracted for a wide range of pressures and equivalence ratios for spherically-symmetric, smooth flamefronts and compared to numerical computations with detailed chemistry and transport, as well as existing data in the literature. Wrinkle development was examined for propagating flames that were unstable under our experimental conditions. Hydrodynamic cells developed for most H2-air and CH4-air flames at elevated pressures, while thermal-diffusive instabilities were also observed for lean and near-stoichiometric hydrogen flames at pressures above atmospheric. Strategies in suppressing or delaying the onset of cell formation have been assessed. Buoyancy effects affected sufficiently off-stoichiometric CH4 mixtures at high pressures.

  4. Round ceiling detail, note tension wires working against outward forces ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    Round ceiling detail, note tension wires working against outward forces on the vertical columns while restoration of collapsed roof takes place. - Baltimore & Ohio Railroad, Mount Clare Passenger Car Shop, Southwest corner of Pratt & Poppleton Streets, Baltimore, Independent City, MD

  5. Frontiers in growth and remodeling

    PubMed Central

    Menzel, Andreas; Kuhl, Ellen

    2012-01-01

    Unlike common engineering materials, living matter can autonomously respond to environmental changes. Living structures can grow stronger, weaker, larger, or smaller within months, weeks, or days as a result of a continuous microstructural turnover and renewal. Hard tissues can adapt by increasing their density and grow strong. Soft tissues can adapt by increasing their volume and grow large. For more than three decades, the mechanics community has actively contributed to understand the phenomena of growth and remodeling from a mechanistic point of view. However, to date, there is no single, unified characterization of growth, which is equally accepted by all scientists in the field. Here we shed light on the continuum modeling of growth and remodeling of living matter, and give a comprehensive overview of historical developments and trends. We provide a state-of-the-art review of current research highlights, and discuss challenges and potential future directions. Using the example of volumetric growth, we illustrate how we can establish and utilize growth theories to characterize the functional adaptation of soft living matter. We anticipate this review to be the starting point for critical discussions and future research in growth and remodeling, with a potential impact on life science and medicine. PMID:22919118

  6. Frontiers in growth and remodeling.

    PubMed

    Menzel, Andreas; Kuhl, Ellen

    2012-06-01

    Unlike common engineering materials, living matter can autonomously respond to environmental changes. Living structures can grow stronger, weaker, larger, or smaller within months, weeks, or days as a result of a continuous microstructural turnover and renewal. Hard tissues can adapt by increasing their density and grow strong. Soft tissues can adapt by increasing their volume and grow large. For more than three decades, the mechanics community has actively contributed to understand the phenomena of growth and remodeling from a mechanistic point of view. However, to date, there is no single, unified characterization of growth, which is equally accepted by all scientists in the field. Here we shed light on the continuum modeling of growth and remodeling of living matter, and give a comprehensive overview of historical developments and trends. We provide a state-of-the-art review of current research highlights, and discuss challenges and potential future directions. Using the example of volumetric growth, we illustrate how we can establish and utilize growth theories to characterize the functional adaptation of soft living matter. We anticipate this review to be the starting point for critical discussions and future research in growth and remodeling, with a potential impact on life science and medicine. PMID:22919118

  7. Role of 5-HTTLPR polymorphism in the development of the inward/outward personality organization: a genetic association study.

    PubMed

    Nardi, Bernardo; Marini, Alessandra; Turchi, Chiara; Arimatea, Emidio; Tagliabracci, Adriano; Bellantuono, Cesario

    2013-01-01

    Reciprocity with primary caregivers affects subjects' adaptive abilities toward the construction of the most useful personal meaning organization (PMO) with respect to their developmental environment. Within cognitive theory the post-rationalist approach has outlined two basic categories of identity construction and of regulation of cognitive and emotional processes: the Outward and the Inward PMO. The presence of different, consistent clinical patterns in Inward and Outward subjects is paralleled by differences in cerebral activation during emotional tasks on fMRI and by different expression of some polymorphisms in serotonin pathways. Since several lines of evidence support a role for the 5-HTTLPR polymorphism in mediating individual susceptibility to environmental emotional stimuli, this study was conducted to investigate its influence in the development of the Inward/Outward PMO. PMO was assessed and the 5-HTTLPR polymorphism investigated in 124 healthy subjects who were subdivided into an Inward (n = 52) and an Outward (n = 72) group. Case-control comparisons of short allele (S) frequencies showed significant differences between Inwards and Outwards (p = 0.036, χ2 test; p = 0.026, exact test). Genotype frequencies were not significantly different although values slightly exceeded p ≤ 0.05 (p = 0.056, χ2 test; p = 0.059, exact test). Analysis of the 5-HTTLPR genotypes according to the recessive inheritance model showed that the S/S genotype increased the likelihood of developing an Outward PMO (p = 0.0178, χ2 test; p = 0.0143, exact test; OR = 3.43, CI (95%) = 1.188-9.925). A logistic regression analysis confirmed the association between short allele and S/S genotypes with the Outward PMO also when gender and age were considered. However none of the differences remained significant after correction for multiple testing, even though using the recessive model they approach significance. Overall our data seem to suggest a putative genetic basis for

  8. Role of 5-HTTLPR polymorphism in the development of the inward/outward personality organization: a genetic association study.

    PubMed

    Nardi, Bernardo; Marini, Alessandra; Turchi, Chiara; Arimatea, Emidio; Tagliabracci, Adriano; Bellantuono, Cesario

    2013-01-01

    Reciprocity with primary caregivers affects subjects' adaptive abilities toward the construction of the most useful personal meaning organization (PMO) with respect to their developmental environment. Within cognitive theory the post-rationalist approach has outlined two basic categories of identity construction and of regulation of cognitive and emotional processes: the Outward and the Inward PMO. The presence of different, consistent clinical patterns in Inward and Outward subjects is paralleled by differences in cerebral activation during emotional tasks on fMRI and by different expression of some polymorphisms in serotonin pathways. Since several lines of evidence support a role for the 5-HTTLPR polymorphism in mediating individual susceptibility to environmental emotional stimuli, this study was conducted to investigate its influence in the development of the Inward/Outward PMO. PMO was assessed and the 5-HTTLPR polymorphism investigated in 124 healthy subjects who were subdivided into an Inward (n = 52) and an Outward (n = 72) group. Case-control comparisons of short allele (S) frequencies showed significant differences between Inwards and Outwards (p = 0.036, χ2 test; p = 0.026, exact test). Genotype frequencies were not significantly different although values slightly exceeded p ≤ 0.05 (p = 0.056, χ2 test; p = 0.059, exact test). Analysis of the 5-HTTLPR genotypes according to the recessive inheritance model showed that the S/S genotype increased the likelihood of developing an Outward PMO (p = 0.0178, χ2 test; p = 0.0143, exact test; OR = 3.43, CI (95%) = 1.188-9.925). A logistic regression analysis confirmed the association between short allele and S/S genotypes with the Outward PMO also when gender and age were considered. However none of the differences remained significant after correction for multiple testing, even though using the recessive model they approach significance. Overall our data seem to suggest a putative genetic basis for

  9. Outward Migration of Giant Planets in Orbital Resonance

    NASA Astrophysics Data System (ADS)

    D'Angelo, G.; Marzari, F.

    2013-05-01

    A pair of giant planets interacting with a gaseous disk may be subject to convergent orbital migration and become locked into a mean motion resonance. If the orbits are close enough, the tidal gaps produced by the planets in the disk may overlap. This represents a necessary condition to activate the outward migration of the pair. However, a number of other conditions must also be realized in order for this mechanism to operate. We have studied how disk properties, such as turbulence viscosity, temperature, surface density gradient, mass, and age, may affect the outcome of the outward migration process. We have also investigated the implications on this mechanism of the planets' gas accretion. If the pair resembles Jupiter and Saturn, the 3:2 orbital resonance may drive them outward until they reach stalling radii for migration, which are within ~10 AU of the star for disks representative of the early proto-solar nebula. However, planet post-formation conditions in the disk indicate that such planets become typically locked in the 1:2 orbital resonance, which does not lead to outward migration. Planet growth via gas accretion tends to alter the planets' mass-ratio and/or the disk accretion rate toward the star, reducing or inhibiting outward migration. Support from NASA Outer Planets Research Program and NASA Origins of Solar Systems Program is gratefully acknowledged.

  10. Mitochondria, myocardial remodeling, and cardiovascular disease.

    PubMed

    Verdejo, Hugo E; del Campo, Andrea; Troncoso, Rodrigo; Gutierrez, Tomás; Toro, Barbra; Quiroga, Clara; Pedrozo, Zully; Munoz, Juan Pablo; Garcia, Lorena; Castro, Pablo F; Lavandero, Sergio

    2012-12-01

    The process of muscle remodeling lies at the core of most cardiovascular diseases. Cardiac adaptation to pressure or volume overload is associated with a complex molecular change in cardiomyocytes which leads to anatomic remodeling of the heart muscle. Although adaptive at its beginnings, the sustained cardiac hypertrophic remodeling almost unavoidably ends in progressive muscle dysfunction, heart failure and ultimately death. One of the features of cardiac remodeling is a progressive impairment in mitochondrial function. The heart has the highest oxygen uptake in the human body and accordingly it has a large number of mitochondria, which form a complex network under constant remodeling in order to sustain the high metabolic rate of cardiac cells and serve as Ca(2+) buffers acting together with the endoplasmic reticulum (ER). However, this high dependence on mitochondrial metabolism has its costs: when oxygen supply is threatened, high leak of electrons from the electron transport chain leads to oxidative stress and mitochondrial failure. These three aspects of mitochondrial function (Reactive oxygen species signaling, Ca(2+) handling and mitochondrial dynamics) are critical for normal muscle homeostasis. In this article, we will review the latest evidence linking mitochondrial morphology and function with the process of myocardial remodeling and cardiovascular disease.

  11. Mitochondria, myocardial remodeling, and cardiovascular disease.

    PubMed

    Verdejo, Hugo E; del Campo, Andrea; Troncoso, Rodrigo; Gutierrez, Tomás; Toro, Barbra; Quiroga, Clara; Pedrozo, Zully; Munoz, Juan Pablo; Garcia, Lorena; Castro, Pablo F; Lavandero, Sergio

    2012-12-01

    The process of muscle remodeling lies at the core of most cardiovascular diseases. Cardiac adaptation to pressure or volume overload is associated with a complex molecular change in cardiomyocytes which leads to anatomic remodeling of the heart muscle. Although adaptive at its beginnings, the sustained cardiac hypertrophic remodeling almost unavoidably ends in progressive muscle dysfunction, heart failure and ultimately death. One of the features of cardiac remodeling is a progressive impairment in mitochondrial function. The heart has the highest oxygen uptake in the human body and accordingly it has a large number of mitochondria, which form a complex network under constant remodeling in order to sustain the high metabolic rate of cardiac cells and serve as Ca(2+) buffers acting together with the endoplasmic reticulum (ER). However, this high dependence on mitochondrial metabolism has its costs: when oxygen supply is threatened, high leak of electrons from the electron transport chain leads to oxidative stress and mitochondrial failure. These three aspects of mitochondrial function (Reactive oxygen species signaling, Ca(2+) handling and mitochondrial dynamics) are critical for normal muscle homeostasis. In this article, we will review the latest evidence linking mitochondrial morphology and function with the process of myocardial remodeling and cardiovascular disease. PMID:22972531

  12. OUTWARD MIGRATION OF JUPITER AND SATURN IN EVOLVED GASEOUS DISKS

    SciTech Connect

    D'Angelo, Gennaro; Marzari, Francesco E-mail: francesco.marzari@pd.infn.it

    2012-09-20

    The outward migration of a pair of resonant-orbit planets, driven by tidal interactions with a gas-dominated disk, is studied in the context of evolved solar nebula models. The planets' masses, M{sub 1} and M{sub 2}, correspond to those of Jupiter and Saturn. Hydrodynamical calculations in two and three dimensions are used to quantify the migration rates and analyze the conditions under which the outward migration mechanism may operate. The planets are taken to be fully formed after 10{sup 6} and before 3 Multiplication-Sign 10{sup 6} years. The orbital evolution of the planets in an evolving disk is then calculated until the disk's gas is completely dissipated. Orbital locking in the 3:2 mean motion resonance may lead to outward migration under appropriate conditions of disk viscosity and temperature. However, resonance locking does not necessarily result in outward migration. This is the case, for example, if convergent migration leads to locking in the 2:1 mean motion resonance, as post-formation disk conditions seem to suggest. Accretion of gas on the planets may deactivate the outward migration mechanism by raising the mass ratio M{sub 2}/M{sub 1} and/or by reducing the accretion rate toward the star, and hence depleting the inner disk. For migrating planets locked in the 3:2 mean motion resonance, there are stalling radii that depend on disk viscosity and on stellar irradiation, when it determines the disk's thermal balance. Planets locked in the 3:2 orbital resonance that start moving outward from within 1-2 AU may reach beyond Almost-Equal-To 5 AU only under favorable conditions. However, within the explored space of disk parameters, only a small fraction-less than a few percent-of the models predict that the interior planet reaches beyond Almost-Equal-To 4 AU.

  13. Outward Bound...Into the Mainstream of Education.

    ERIC Educational Resources Information Center

    Outward Bound, Inc., Andover, MA.

    Outward Bound schools have instituted advanced courses designed specifically for adults engaged in education and youth work. Benefits for teachers include greater development of capacitites and potentialities, greater confidence in their abilities, and the ability to relate more effectively to others. Some of the specific training elements in an…

  14. Instructor's Field Manual: North Carolina Outward Bound School.

    ERIC Educational Resources Information Center

    Outward Bound, Morganton, NC.

    A supplement to the North Carolina Outward Bound School's Instructor's Handbook, this field manual presents useful, but not required, information gleaned from old timers and resource books which may enable the instructor to conduct a better course. Section one considers advantages and disadvantages and provides directions and topographical maps…

  15. To Know By Experience: Outward Bound, North Carolina.

    ERIC Educational Resources Information Center

    Meyer, Dan; Meyer, Diane

    Directed at discovering one's inner resources and the dignity of one's fellow man, the Outward Bound experience seeks to instill self-reliance, physical fitness, and compassion as fundamental values recognizing there are few opportunities to formulate such values in an increasingly technological and urbanized society. For 3 1/2 weeks, people from…

  16. The Career Beginnings Outward Bound Component: An Empirical Evaluation.

    ERIC Educational Resources Information Center

    Outward Bound USA, Greenwich, CT.

    This paper summarizes the results of the empirical evaluation of the Outward Bound component of the 1987 Career Beginnings Program. Career Beginnings is a national, privately funded program designed to increase the probability that minority high school youth will either attend college or find good jobs following high school graduation. The Outward…

  17. Academic Perspectives on the Outcomes of Outward Student Mobility

    ERIC Educational Resources Information Center

    Bridger, Kath

    2015-01-01

    This research project was commissioned by the UK Higher Education International Unit (IU) and the Higher Education Academy (HEA) in June 2014 to explore academic perspectives on the outcomes of outward mobility at undergraduate, postgraduate and research levels for UK domiciled students, and to consider how best to facilitate the take up as well…

  18. Outwards migration for planets in stellar irradiated 3D discs

    NASA Astrophysics Data System (ADS)

    Lega, E.; Morbidelli, A.; Bitsch, B.; Crida, A.; Szulágyi, J.

    2015-09-01

    For the very first time we present 3D simulations of planets embedded in stellar irradiated discs. It is well known that thermal effects could reverse the direction of planetary migration from inwards to outwards, potentially saving planets in the inner, optically thick parts of the protoplanetary disc. When considering stellar irradiation in addition to viscous friction as a source of heating, the outer disc changes from a shadowed to a flared structure. Using a suited analytical formula it has been shown that in the flared part of the disc the migration is inwards; planets can migrate outwards only in shadowed regions of the disc, because the radial gradient of entropy is stronger there. In order to confirm this result numerically, we have computed the total torque acting on planets held on fixed orbits embedded in stellar irradiated 3D discs using the hydrodynamical code FARGOCA. We find qualitatively good agreement between the total torque obtained with numerical simulations and the one predicted by the analytical formula. For large masses (>20 M⊕) we find quantitative agreement, and we obtain outwards migration regions for planets up to 60 M⊕ in the early stages of accretional discs. We find nevertheless that the agreement with the analytic formula is quite fortuitous because the formula underestimates the size of the horseshoe region; this error is compensated by imperfect estimates of other terms, most likely the cooling rate and the saturation.

  19. Periprosthetic Bone Remodelling in Total Knee Arthroplasty

    PubMed Central

    GEORGEANU, Vlad; ATASIEI, Tudor; GRUIONU, Lucian

    2014-01-01

    Introduction: The clinical studies have shown that the displacement of the prosthesis components, especially of the tibial one is higher during the first year, after which it reaches an equilibrum position compatible with a good long term functioning. This displacement takes place due to bone remodelling close to the implant secondary to different loading concentrations over different areas of bone. Material and Method: Our study implies a simulation on a computational model using the finite element analysis. The simulation started taking into account arbitrary points because of non-linear conditions of bone-prosthesis interface and it was iterative.. A hundred consecutive situations corresponding to intermediate bone remodelling phases have been calculated according to given loadings. Bone remodelling was appreciated as a function of time and bone density for each constitutive element of the computational model created by finite element method. For each constitutive element a medium value of stress during the walking cycle was applied. Results: Analyse of proximal epiphysis-prosthesis complex slices showed that bone density increase is maintained all over the stem in the immediately post-operative period. At 10 months, the moment considered to be the end of bone remodelling, areas with increased bone density are fewer and smaller. Meanwhile, their distribution with a concentration toward the internal compartment in the distal metaphysis is preserved. Conclusions: After the total knee arthroplasty the tibial bone suffered a process of remodelling adapted to the new stress conditions. This bone remodelling can influence, sometimes negatively, especially in the cases with tibial component varus malposition, the fixation, respectively the survival of the prosthesis. This process has been demonstrated both by clinical trials and by simulation, using the finite elements method of periprosthetic bone remodelling. PMID:25553127

  20. The Arabidopsis outward K+ channel GORK is involved in regulation of stomatal movements and plant transpiration

    PubMed Central

    Hosy, Eric; Vavasseur, Alain; Mouline, Karine; Dreyer, Ingo; Gaymard, Frédéric; Porée, Fabien; Boucherez, Jossia; Lebaudy, Anne; Bouchez, David; Véry, Anne-Aliénor; Simonneau, Thierry; Thibaud, Jean-Baptiste; Sentenac, Hervé

    2003-01-01

    Microscopic pores present in the epidermis of plant aerial organs, called stomata, allow gas exchanges between the inner photosynthetic tissue and the atmosphere. Regulation of stomatal aperture, preventing excess transpirational vapor loss, relies on turgor changes of two highly differentiated epidermal cells surrounding the pore, the guard cells. Increased guard cell turgor due to increased solute accumulation results in stomatal opening, whereas decreased guard cell turgor due to decreased solute accumulation results in stomatal closing. Here we provide direct evidence, based on reverse genetics approaches, that the Arabidopsis GORK Shaker gene encodes the major voltage-gated outwardly rectifying K+ channel of the guard cell membrane. Expression of GORK dominant negative mutant polypeptides in transgenic Arabidopsis was found to strongly reduce outwardly rectifying K+ channel activity in the guard cell membrane, and disruption of the GORK gene (T-DNA insertion knockout mutant) fully suppressed this activity. Bioassays on epidermal peels revealed that disruption of GORK activity resulted in impaired stomatal closure in response to darkness or the stress hormone azobenzenearsonate. Transpiration measurements on excised rosettes and intact plants (grown in hydroponic conditions or submitted to water stress) revealed that absence of GORK activity resulted in increased water consumption. The whole set of data indicates that GORK is likely to play a crucial role in adaptation to drought in fluctuating environments. PMID:12671068

  1. Rhizobium leguminosarum bv. viciae 3841 Adapts to 2,4-Dichlorophenoxyacetic Acid with "Auxin-Like" Morphological Changes, Cell Envelope Remodeling and Upregulation of Central Metabolic Pathways.

    PubMed

    Bhat, Supriya V; Booth, Sean C; McGrath, Seamus G K; Dahms, Tanya E S

    2014-01-01

    There is a growing need to characterize the effects of environmental stressors at the molecular level on model organisms with the ever increasing number and variety of anthropogenic chemical pollutants. The herbicide 2,4-dichlorophenoxyacetic acid (2,4-D), as one of the most widely applied pesticides in the world, is one such example. This herbicide is known to have non-targeted undesirable effects on humans, animals and soil microbes, but specific molecular targets at sublethal levels are unknown. In this study, we have used Rhizobium leguminosarum bv. viciae 3841 (Rlv) as a nitrogen fixing, beneficial model soil organism to characterize the effects of 2,4-D. Using metabolomics and advanced microscopy we determined specific target pathways in the Rlv metabolic network and consequent changes to its phenotype, surface ultrastructure, and physical properties during sublethal 2,4-D exposure. Auxin and 2,4-D, its structural analogue, showed common morphological changes in vitro which were similar to bacteroids isolated from plant nodules, implying that these changes are related to bacteroid differentiation required for nitrogen fixation. Rlv showed remarkable adaptation capabilities in response to the herbicide, with changes to integral pathways of cellular metabolism and the potential to assimilate 2,4-D with consequent changes to its physical and structural properties. This study identifies biomarkers of 2,4-D in Rlv and offers valuable insights into the mode-of-action of 2,4-D in soil bacteria. PMID:25919284

  2. Rhizobium leguminosarum bv. viciae 3841 Adapts to 2,4-Dichlorophenoxyacetic Acid with “Auxin-Like” Morphological Changes, Cell Envelope Remodeling and Upregulation of Central Metabolic Pathways

    PubMed Central

    Bhat, Supriya V.; Booth, Sean C.; McGrath, Seamus G. K.; Dahms, Tanya E. S.

    2015-01-01

    There is a growing need to characterize the effects of environmental stressors at the molecular level on model organisms with the ever increasing number and variety of anthropogenic chemical pollutants. The herbicide 2,4-dichlorophenoxyacetic acid (2,4-D), as one of the most widely applied pesticides in the world, is one such example. This herbicide is known to have non-targeted undesirable effects on humans, animals and soil microbes, but specific molecular targets at sublethal levels are unknown. In this study, we have used Rhizobium leguminosarum bv. viciae 3841 (Rlv) as a nitrogen fixing, beneficial model soil organism to characterize the effects of 2,4-D. Using metabolomics and advanced microscopy we determined specific target pathways in the Rlv metabolic network and consequent changes to its phenotype, surface ultrastructure, and physical properties during sublethal 2,4-D exposure. Auxin and 2,4-D, its structural analogue, showed common morphological changes in vitro which were similar to bacteroids isolated from plant nodules, implying that these changes are related to bacteroid differentiation required for nitrogen fixation. Rlv showed remarkable adaptation capabilities in response to the herbicide, with changes to integral pathways of cellular metabolism and the potential to assimilate 2,4-D with consequent changes to its physical and structural properties. This study identifies biomarkers of 2,4-D in Rlv and offers valuable insights into the mode-of-action of 2,4-D in soil bacteria. PMID:25919284

  3. Rhizobium leguminosarum bv. viciae 3841 Adapts to 2,4-Dichlorophenoxyacetic Acid with "Auxin-Like" Morphological Changes, Cell Envelope Remodeling and Upregulation of Central Metabolic Pathways.

    PubMed

    Bhat, Supriya V; Booth, Sean C; McGrath, Seamus G K; Dahms, Tanya E S

    2014-01-01

    There is a growing need to characterize the effects of environmental stressors at the molecular level on model organisms with the ever increasing number and variety of anthropogenic chemical pollutants. The herbicide 2,4-dichlorophenoxyacetic acid (2,4-D), as one of the most widely applied pesticides in the world, is one such example. This herbicide is known to have non-targeted undesirable effects on humans, animals and soil microbes, but specific molecular targets at sublethal levels are unknown. In this study, we have used Rhizobium leguminosarum bv. viciae 3841 (Rlv) as a nitrogen fixing, beneficial model soil organism to characterize the effects of 2,4-D. Using metabolomics and advanced microscopy we determined specific target pathways in the Rlv metabolic network and consequent changes to its phenotype, surface ultrastructure, and physical properties during sublethal 2,4-D exposure. Auxin and 2,4-D, its structural analogue, showed common morphological changes in vitro which were similar to bacteroids isolated from plant nodules, implying that these changes are related to bacteroid differentiation required for nitrogen fixation. Rlv showed remarkable adaptation capabilities in response to the herbicide, with changes to integral pathways of cellular metabolism and the potential to assimilate 2,4-D with consequent changes to its physical and structural properties. This study identifies biomarkers of 2,4-D in Rlv and offers valuable insights into the mode-of-action of 2,4-D in soil bacteria.

  4. Catalytic properties of Phr family members of cell wall glucan remodeling enzymes: implications for the adaptation of Candida albicans to ambient pH.

    PubMed

    Kováčová, Kristína; Degani, Genny; Stratilová, Eva; Farkaš, Vladimír; Popolo, Laura

    2015-03-01

    Fungal wall formation is a dynamic process involving several categories of enzymes. The GH72 family of β(1,3)-glucanosyltransferases is essential for the determination of cell shape, for cell integrity and for virulence in pathogenic fungi. Candida albicans has five GH72 genes: PHR1 and PHR2 are pH dependent, the first being expressed at pH ≥ 6 and repressed at lower pH and the second regulated in the opposite manner, PGA4 is transcribed independently of pH whereas PHR3 and PGA5 have low expression levels. To characterize the catalytic properties of Phr1p-2p and probe the activity of Pga4p, we heterologously expressed these proteins and used a fluorescent assay based on the transfer of oligosaccharyl units from a donor to a sulforhodamine-labeled acceptor. Phr1p-2p used exclusively β-1,3-glucan or cell wall glucan as donor and laminarin-derived oligosaccharides as acceptor. The acceptor efficiency increased with the length of the oligosaccharide. The temperature optimum was 30°C. The pH optimum was 5.8 for Phr1p and 3 for Phr2p. Overall, adaptation to pH of C. albicans appears to involve a fine interplay among the pH-dependent activity of Phr1p and Phr2p, the pH-regulated expression of their genes and protein stability. Unexpectedly, Pga4p was inactive suggesting that it turned into a structural mannoprotein.

  5. Fireplace adapters

    SciTech Connect

    Hunt, R.L.

    1983-12-27

    An adapter is disclosed for use with a fireplace. The stove pipe of a stove standing in a room to be heated may be connected to the flue of the chimney so that products of combustion from the stove may be safely exhausted through the flue and outwardly of the chimney. The adapter may be easily installed within the fireplace by removing the damper plate and fitting the adapter to the damper frame. Each of a pair of bolts has a portion which hooks over a portion of the damper frame and a threaded end depending from the hook portion and extending through a hole in the adapter. Nuts are threaded on the bolts and are adapted to force the adapter into a tight fit with the adapter frame.

  6. Adrenocortical Zonation, Renewal, and Remodeling

    PubMed Central

    Pihlajoki, Marjut; Dörner, Julia; Cochran, Rebecca S.; Heikinheimo, Markku; Wilson, David B.

    2015-01-01

    The adrenal cortex is divided into concentric zones. In humans the major cortical zones are the zona glomerulosa, zona fasciculata, and zona reticularis. The adrenal cortex is a dynamic organ in which senescent cells are replaced by newly differentiated ones. This constant renewal facilitates organ remodeling in response to physiological demand for steroids. Cortical zones can reversibly expand, contract, or alter their biochemical profiles to accommodate needs. Pools of stem/progenitor cells in the adrenal capsule, subcapsular region, and juxtamedullary region can differentiate to repopulate or expand zones. Some of these pools appear to be activated only during specific developmental windows or in response to extreme physiological demand. Senescent cells can also be replenished through direct lineage conversion; for example, cells in the zona glomerulosa can transform into cells of the zona fasciculata. Adrenocortical cell differentiation, renewal, and function are regulated by a variety of endocrine/paracrine factors including adrenocorticotropin, angiotensin II, insulin-related growth hormones, luteinizing hormone, activin, and inhibin. Additionally, zonation and regeneration of the adrenal cortex are controlled by developmental signaling pathways, such as the sonic hedgehog, delta-like homolog 1, fibroblast growth factor, and WNT/β-catenin pathways. The mechanisms involved in adrenocortical remodeling are complex and redundant so as to fulfill the offsetting goals of organ homeostasis and stress adaptation. PMID:25798129

  7. The effect of stress concentration on bone remodeling: theoretical predictions.

    PubMed

    Firoozbakhsh, K; Aleyaasin, M

    1989-11-01

    Theoretical predictions of internal bone remodeling around an elliptical hole are studied. The internal remodeling theory due to Cowin and Hegedus is employed. The bone is modeled as an initially homogeneous adaptive elastic plate with an elliptical hole under a superposed steady compressive load. It is shown that there will exist a final inhomogeneous remodeling distribution around the hole that will disappear away from the hole. The remodeling is such that the compressive stress concentration causes the bone structure to evolve to one of greater density and stiffer elastic coefficients. The speed of remodeling around the hole and its variation with respect to distance is investigated and discussed. It is shown that the rate of bone reinforcement in the area of compressive stress concentration is much higher than the rate of bone resorption in the area of existing tensile stress. Special cases of a circular hole and vertical and horizontal slots are studied and discussed.

  8. Serotonin modulates outward potassium currents in mouse olfactory receptor neurons.

    PubMed

    Gao, S; Guo, X; Liu, T; Liu, J; Chen, W; Xia, Q; Chen, Y; Tang, Y

    2013-01-01

    Monoaminergic neurotransmitter 5-hydroxytryptamine (5-HT), also known as serotonin, plays important roles in modulating the function of the olfactory system. However, thus far, the knowledge about 5-HT and its receptors in olfactory receptor neurons (ORNs) and their physiological role have not been fully characterized. In the present study, reverse transcription-polymerase chain reaction (RT-PCR) analysis revealed the presence of 5-HT(1A) and 5-HT(1B) receptor subtypes in mouse olfactory epithelium at the mRNA level. With subtype selective antibodies and standard immunohistochemical techniques, both receptor subtypes were found to be positively labeled. To further elucidate the molecular mechanisms of 5-HT act on the peripheral olfactory transduction, the whole-cell patch clamp techniques were used on freshly isolated ORNs. We found that 5-HT decreased the magnitude of outward K(+) current in a dose-dependent manner and these inhibitory effects were markedly attenuated by the 5-HT(1A) receptor blocker WAY-100635 and the 5-HT(1B) receptor antagonist GR55562. These data suggested that 5-HT may play a role in the modulation of peripheral olfactory signals by regulating outward potassium currents, both 5-HT(1A) and 5-HT(1B) receptors were involved in this regulation.

  9. Adapt

    NASA Astrophysics Data System (ADS)

    Bargatze, L. F.

    2015-12-01

    Active Data Archive Product Tracking (ADAPT) is a collection of software routines that permits one to generate XML metadata files to describe and register data products in support of the NASA Heliophysics Virtual Observatory VxO effort. ADAPT is also a philosophy. The ADAPT concept is to use any and all available metadata associated with scientific data to produce XML metadata descriptions in a consistent, uniform, and organized fashion to provide blanket access to the full complement of data stored on a targeted data server. In this poster, we present an application of ADAPT to describe all of the data products that are stored by using the Common Data File (CDF) format served out by the CDAWEB and SPDF data servers hosted at the NASA Goddard Space Flight Center. These data servers are the primary repositories for NASA Heliophysics data. For this purpose, the ADAPT routines have been used to generate data resource descriptions by using an XML schema named Space Physics Archive, Search, and Extract (SPASE). SPASE is the designated standard for documenting Heliophysics data products, as adopted by the Heliophysics Data and Model Consortium. The set of SPASE XML resource descriptions produced by ADAPT includes high-level descriptions of numerical data products, display data products, or catalogs and also includes low-level "Granule" descriptions. A SPASE Granule is effectively a universal access metadata resource; a Granule associates an individual data file (e.g. a CDF file) with a "parent" high-level data resource description, assigns a resource identifier to the file, and lists the corresponding assess URL(s). The CDAWEB and SPDF file systems were queried to provide the input required by the ADAPT software to create an initial set of SPASE metadata resource descriptions. Then, the CDAWEB and SPDF data repositories were queried subsequently on a nightly basis and the CDF file lists were checked for any changes such as the occurrence of new, modified, or deleted

  10. Lymphoid Tissue Mesenchymal Stromal Cells in Development and Tissue Remodeling

    PubMed Central

    2016-01-01

    Secondary lymphoid organs (SLOs) are sites that facilitate cell-cell interactions required for generating adaptive immune responses. Nonhematopoietic mesenchymal stromal cells have been shown to play a critical role in SLO function, organization, and tissue homeostasis. The stromal microenvironment undergoes profound remodeling to support immune responses. However, chronic inflammatory conditions can promote uncontrolled stromal cell activation and aberrant tissue remodeling including fibrosis, thus leading to tissue damage. Despite recent advancements, the origin and role of mesenchymal stromal cells involved in SLO development and remodeling remain unclear. PMID:27190524

  11. Clustering of metabolic syndrome traits is associated with maladaptive carotid remodeling and stiffening: a 6-year longitudinal study.

    PubMed

    Ferreira, Isabel; Beijers, Hanneke J; Schouten, Fleur; Smulders, Yvo M; Twisk, Jos W; Stehouwer, Coen D

    2012-08-01

    Maladaptive arterial remodeling may constitute a mechanism underlying the risk of stroke in individuals with the metabolic syndrome (MetS), but evidence supporting this contention derives from cross-sectional studies only. We, therefore, investigated, in apparently healthy adults, whether changes in MetS status between the ages of 36 and 42 years (never [n=207, reference group], incident [n=31], recovery [n=23], and persistent [n=32]) were associated with changes in carotid interadventitial diameter, lumen diameter, intima-media thickness, circumferential wall tension and stress, and Young's elastic modulus. All data analyses were adjusted for sex, height, and (changes in) age, lifestyle variables, low-density lipoprotein cholesterol, and use of antihypertensive medication. At baseline and as compared with the reference group, individuals with persistent MetS had significantly higher interadventitial diameter, circumferential wall tension, circumferential wall stress, and Young's elastic modulus but not intima-media thickness. In the course of follow-up, these individuals (versus reference group) displayed significantly steeper increases in intima-media thickness (0.011 versus 0.005 mm/y), which were accompanied by significantly steeper increases in interadventitial diameter (0.077 versus 0.032 mm/y) and lumen diameter (0.055 versus 0.023 mm/y) but not circumferential wall stress, which decreased (-0.34 versus 0.12 kPa/y). These findings suggest that increases in intima-media thickness in young adults with the MetS may primarily reflect an adaptive mechanism that attempts to restore local hemodynamic conditions to an equilibrium rather than atherosclerosis, per se. However, carotid adaptations did not restore circumferential wall stress to levels comparable with those of the reference group, and, therefore, outward remodeling was maladaptive. Importantly, individuals who recovered from the MetS restored carotid properties to levels comparable to the reference group

  12. Finite element prediction of endosteal and periosteal bone remodelling in the turkey ulna: effect of remodelling signal and dead-zone definition.

    PubMed

    Taylor, W R; Warner, M D; Clift, S E

    2003-01-01

    Bone remodelling is the adaptation of bone mass in response to localized changes in loading conditions. The nature of the mechanical signal governing remodelling, however, remains the subject of continued investigation. The aims of this study were to use an iterative finite element (FE) bone remodelling technique to explore the effect of different remodelling signals in the prediction of bone remodelling behaviour. A finite element model of the turkey ulna, following that of Brown et al., was analysed using the ABAQUS package. The model was validated against the static predictions of the Brown et al. study. A bone remodelling technique, based on swelling algorithms given by Taylor and Clift, was then applied to predict the dramatic change in loading conditions imposed. The resulting changes in FE mid-shaft bone geometry were compared with the remodelling observed experimentally and showed good agreement. The tensile principal stress was found to be the best remodelling signal under the imposed conditions. Localized sensitivities in the remodelling patterns were found, however, and the definition of the dead zone was modified as a result. Remodelling with the new dead-zone definition showed that both the tensile principal stress and the tensile principal strain produced the remodelling patterns that agreed most closely with experiment.

  13. Nucleosome Remodeling and Epigenetics

    PubMed Central

    Becker, Peter B.; Workman, Jerry L.

    2013-01-01

    Eukaryotic chromatin is kept flexible and dynamic to respond to environmental, metabolic, and developmental cues through the action of a family of so-called “nucleosome remodeling” ATPases. Consistent with their helicase ancestry, these enzymes experience conformation changes as they bind and hydrolyze ATP. At the same time they interact with DNA and histones, which alters histone–DNA interactions in target nucleosomes. Their action may lead to complete or partial disassembly of nucleosomes, the exchange of histones for variants, the assembly of nucleosomes, or the movement of histone octamers on DNA. “Remodeling” may render DNA sequences accessible to interacting proteins or, conversely, promote packing into tightly folded structures. Remodeling processes participate in every aspect of genome function. Remodeling activities are commonly integrated with other mechanisms such as histone modifications or RNA metabolism to assemble stable, epigenetic states. PMID:24003213

  14. Rate of outward growth of the Mediterranean ridge accretionary complex

    NASA Astrophysics Data System (ADS)

    Kastens, Kim A.

    1991-12-01

    The position as a function time of the deformation front on the southwest flank of the Mediterranean Ridge accretionary complex is constrained as follows: (a) the deformation front is now active; (b) the site of core BAN84-05GC was still near the abyssal plain when displaced shallow water benthic foraminifera of inferred African provenance were redeposited within an upper Pliocene age unit; (c) the site of core BAN84-05GC on the outer flank of the Mediterranean Ridge was already within the topographically rugged accretionary complex when a Pliocene debris flow was emplaced; (d) DSDP Site 125 had already been uplifted into a topographically elevated position when lower Pliocene pelagic ooze was deposited; (e) a gypsum-bearing breccia in DSDP Site 125 requires that the site was either on the abyssal plain or within the tectonically active outer perimeter of the accretionary complex during the Messinian salinity crisis; (f) DSDP Site 377 had already been uplifted into a topographically elevated position when middle Miocene age pelagic marl was deposited; (g) DSDP Site 377 was still on or near the abyssal plain when early to lower-middle Miocene age, smectite-bearing turbidites of inferred African provenance were deposited; and (h) the Mediterranean Ridge began to grow by offscraping against a backstop formed by the Alpine nappes of the Hellenic Arc at the time that subduction began (> 33 Ma). Together, these constraints define a range of potential growth curves for the Mediterranean Ridge, with a rate of outward growth of approximately 0.5 to 2 cm/yr. This growth rate is faster than that inferred for most other modern accretionary prisms, both as an absolute value, and as a fraction of the subduction velocity. An unusually thick incoming section and/or an unusually weak (evaporitic) décollement may contribute to the rapid growth rate. The inferred age of accretion does not increase linearly with distance from the deformation front; rather, there is an apparent

  15. Peak outward acceleration and ball release in cricket.

    PubMed

    Spratford, Wayne; Portus, Marc; Wixted, Andrew; Leadbetter, Raymond; James, Daniel A

    2015-01-01

    The purpose of this study was to investigate the utility of peak outward acceleration (POA) measured from an inertial sensor worn at the wrist as an indicator of the critical end point of the bowling action – ball release, a critical element when assessing illegal actions. Twenty-one finger-spin and fast bowlers from nine countries were recruited from the ICC under-19 Cricket World Cup to take part in this research. Bowlers delivered a cross section of their standard deliveries while wearing an inertial sensor placed on their wrists. Ball release was determined by a validated motional analysis ball release (MABR) protocol and compared to the simultaneously collected POA. POA was shown to be highly correlated with MABR (R(2) = 0.98) and a Bland-Altman plot indicated that all 148 trials were within the 3.42 frame (0.014 s) limits of agreement. POA when measured by an inertial sensor worn on the wrist during bowling had a close relationship with an established method of identifying ball release in a biomechanical laboratory regardless of bowler and delivery type. Further, accuracy can be achieved with the adoption of a simple regression equation applied to the POA and as such is a valid measure of ball release in cricket bowlers.

  16. Allicin inhibits transient outward potassium currents in mouse ventricular myocytes

    PubMed Central

    CAO, HONG; HUANG, CONGXIN; WANG, XIN

    2016-01-01

    Allicin is the active constituent of garlic, a widely used spice and food. The remedial properties of garlic have also been extensively researched and it has been demonstrated that allicin is able to inhibit the transient outward potassium current (Ito) in atrial myocytes. However, the direct effect of allicin on Ito in ventricular myocytes has yet to be elucidated. In the present study, the effects of allicin on Ito in ventricular myocytes isolated from mice were investigated, using the whole-cell patch recording technique. The results revealed that Ito current was not significantly suppressed by allicin in the low-dose group (10 µmol/l; P>0.05). However, Ito was significantly inhibited by higher doses of allicin (30, 100 and 300 µmol/l; P<0.05 vs. control; n=6) in a concentration-dependent manner (IC50=41.6 µmol/l). In addition, a high concentration of allicin (≥100 µmol/l) was able to accelerate the voltage-dependent inactivation of Ito in mouse ventricular myocytes. In conclusion, the present study revealed that allicin inhibited the Ito in mouse ventricular myocytes, which may be the mechanism through which allicin exerts its antiarrhythmic effect. PMID:27168824

  17. Remodeling and Shuttling

    PubMed Central

    Rodrigueza, Wendi V.; Williams, Kevin Jon; Rothblat, George H.; Phillips, Michael C.

    2016-01-01

    In normal physiology, cells are exposed to cholesterol acceptors of different sizes simultaneously. The current study examined the possible interactions between two different classes of acceptors, one large (large unilamellar phospholipid vesicles, LUVs) and one small (HDL or other small acceptors), added separately or in combination to Fu5AH rat hepatoma cells. During a 24-hour incubation, LUVs of palmitoyl-oleoyl phosphatidylcholine at 1 mg phospholipid (PL) per milliliter extracted ≈20% of cellular unesterified cholesterol (UC) label and mass in a slow, continuous fashion (half-time [t½] for UC efflux was ≈50 hours) and human HDL3 at 25 μg PL per milliliter extracted ≈15% cellular UC label with no change in cellular cholesterol mass (t½ of ≈8 hours). In contrast, the combination of LUVs and HDL3 extracted over 90% of UC label (t½ of ≈4 hours) and ≈50% of the UC mass, indicating synergy. To explain this synergy, specific particle interactions were examined, namely, remodeling, in which the two acceptors alter each other’s composition and thus the ability to mobilize cellular cholesterol, and shuttling, in which the small acceptor ferries cholesterol from cells to the large acceptor. To examine remodeling, LUVs and HDL were coincubated and reisolated before application to cells. This HDL became UC depleted, PL enriched, and lost a small amount of apolipoprotein A-I. Compared with equivalent numbers of control HDL particles, remodeled HDL caused faster efflux (t½ ≈4 hours) and exhibited a greater capacity to sequester cellular cholesterol over 24 hours (≈38% versus ≈15% for control HDL), consistent with their enrichment in PL. Remodeled LUVs still extracted ≈20% of cellular UC. Thus, remodeling accounted for some but not all of the synergy between LUVs and HDL. To examine shuttling, several approaches were used. First, reisolation of particles after an 8-hour exposure to cells revealed that HDL contained very little of the cellular UC

  18. Innovative Adolescent Chemical Dependency Treatment and Its Outcome: A Model Based on Outward Bound Programming.

    ERIC Educational Resources Information Center

    McPeake, John D.; And Others

    1991-01-01

    Describes adolescent chemical dependency treatment model developed at Beech Hill Hospital (New Hampshire) which integrated Twelve Step-oriented alcohol and drug rehabilitation program with experiential education school, Hurricane Island Outward Bound School. Describes Beech Hill Hurricane Island Outward Bound School Adolescent Chemical Dependency…

  19. American Indian World View and the Outward Bound Concept: A Comparison.

    ERIC Educational Resources Information Center

    Lev, Peter

    To establish a philosophical meeting ground between Indians and white men, this document compares the Indian world view with the concept of Outward Bound. Part 1 points out the similarity between the Indian world view and the thinking behind the white man's interest in wilderness experience as a character builder, and compares the Outward Bound…

  20. 19 CFR 192.14 - Electronic information for outward cargo required in advance of departure.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... shipped. The proof of electronic filing citation, low-risk exporter citation, or exemption statement, will... 19 Customs Duties 2 2010-04-01 2010-04-01 false Electronic information for outward cargo required... Information Through the Automated Export System (AES) § 192.14 Electronic information for outward...

  1. Remodeling with the sun

    SciTech Connect

    Bodzin, S.

    1997-05-01

    Remodeling is the perfect time to improve daylighting, direct gain heating and shading with passive solar techniques. It can also provide the best opportunity to add solar water heating or even photoboltaics to a home. This article describes addition of such energy efficient plans to a home in terms of what is needed and what the benefits are: adding windows, North glass, east and west glass, south glass, daylighting, the roof, shingles and roofing tiles, walls and floors, solar hot water, photovoltaics. Two side bars discuss the sunplace: a passive solar room and angles and overhangs.

  2. [Focus on the effect of orthognathic surgery on condylar remodeling].

    PubMed

    Boulétreau, P; Frey, R; Breton, P; Freidel, M

    2004-11-01

    Condylar remodeling is a physiologic process that aims to adapt the structure of the temporo-mandibular joint (TMJ) to meet the functional demands. It is based on an interaction between the mechanical forces sustained by the TMJ and the adaptative capacities of the condyle. Orthognathic surgery can sometimes be responsible for an excessive physical stress to the articular surfaces. In these cases, normal functional condylar remodelling shifts to the process of progressive condylar resorption. Effect of orthognathic surgery on condylar remodeling is a poorly understood and controversial issue. It is however considered as an etiology of postoperative skeletal relapse following orthognathic surgery. Based on two case reports, etiopathogenic hypotheses of this process are discussed as well as predisposing factors to condylar resorption following orthognathic surgery.

  3. To Remodel or To Build?

    ERIC Educational Resources Information Center

    Rosenblum, Todd

    2009-01-01

    The question of remodeling an existing house to make it wheelchair accessible or building a new barrier-free house is a difficult decision. This article presents some initial questions and considerations followed by a list of pros and cons for remodeling an existing house vs. building a new house.

  4. No-Regrets Remodeling, 2nd Edition

    SciTech Connect

    2013-12-01

    No-Regrets Remodeling, sponsored by Oak Ridge National Laboratory, is an informative publication that walks homeowners and/or remodelers through various home remodeling projects. In addition to remodeling information, the publication provides instruction on how to incorporate energy efficiency into the remodeling process. The goal of the publication is to improve homeowner satisfaction after completing a remodeling project and to provide the homeowner with a home that saves energy and is comfortable and healthy.

  5. Molecular analysis of arterial remodeling: a novel application of infrared imaging

    NASA Astrophysics Data System (ADS)

    Herman, Brad C.; Kundi, Rishi; Yamanouchi, Dai; Kent, K. Craig; Liu, Bo; Pleshko, Nancy

    2009-02-01

    Arterial remodeling, i.e. changes in size and/or structure of arteries, plays an important role in vascular disease. Conflicting findings have been reported as to whether an abundance of collagen causes inward or outward remodeling, phenomena that result in either a smaller or larger lumen, respectively. We hypothesize that the amount, type and quality of collagen influence the remodeling response. Here, we create mechanical injury to the rat carotid artery using a balloon catheter, and this leads to inward remodeling. Treatment of the artery with Connective Tissue Growth Factor (CTGF) causes outward remodeling. We investigated the arterial composition in injured CTGF-treated and non-CTGF-treated and sham CTGF-treated and non-CTGF treated arteries 14 days post-injury (n = 7-8 per group) using infrared imaging. A Perkin Elmer Spotlight Spectrum 300 FT-IR microscope was used for data collection. Cross-sections of paraffinembedded arteries were scanned at 2 cm-1 spectral resolution with spatial resolution of 6.25 μm/pixel, and data analyzed using Malvern Instruments ISys 5.0. Post-injury, we found a nearly 50% reduction in the average 1338/AM2 area ratio (correlated to collagen helical integrity). The most dramatic change was a 600% increase in the 1660/1690 peak height ratio, which has previously been related to collagen crosslink maturity. In all cases, CTGF treatment resulted in the observed changes in peak parameters normalized back to control values. Overall, these preliminary studies demonstrate that infrared imaging can provide insight into the underlying molecular changes that contribute to arterial disease.

  6. Removal of periaxonal potassium accumulation in a squid giant axon by outward osmotic water flow.

    PubMed Central

    Kukita, F

    1988-01-01

    1. Periaxonal potassium accumulation does not occur in a squid giant axon when outward water flow is maintained by an osmotic gradient across the axolemma. Potassium concentrations in the periaxonal space were calculated from the potassium potentials (EK) for the tail K+ current. With outward water flow, the periaxonal K+ concentration was maintained at values less than or close to the K+ concentration in the bathing solution. 2. Outward osmotic water flow was produced by adding 1 M-urea to the isotonic external solution. This was sufficient to prevent K+ accumulation, but it had no effect if applied to both sides of the axolemma. 3. The thickness of the periaxonal space (theta s) and the permeability of the extracellular barrier (Ps) were estimated using a three-compartment model. Under isotonic conditions they were 25 nm and 3.7 micron/s, respectively. With outward water flow, either Ps or theta s or both must increase by a large factor, since K+ accumulation is prevented. 4. Instantaneous I-V relations with outward water flow showed outward rectification and no time-dependent changes in their shape. When external K+ concentration was increased, the curves became more linear. PMID:3404471

  7. Extraction (DSX) from Erigeron breviscapus modulates outward potassium currents in rat retinal ganglion cells

    PubMed Central

    Yin, Shuo; Wang, Zhong-Feng; Duan, Jun-Guo; Ji, Lu; Lu, Xue-Jing

    2015-01-01

    AIM To investigate the effect of DSX, an active component extracted from Erigeron breviscapus, on the voltage-gated outward K+ channel currents in rat retinal ganglion cells (RGCs) by using electrophysiological method, and to explore the possible mechanisms of DSX on optic nerve protection. METHODS Outward K+ currents were recorded by using whole-cell patch-clamp techniques on acutely isolated rat RGCs. Outward K+ currents were induced by a series of depolarizing voltage pulses from a holding potential of -70 mV to +20 mV in an increment of 10 mV. RESULTS Extracellular application of DSX voltage-dependently suppressed both the steady-state and peak current amplitudes of outward K+ currents in rat RGCs. Furthermore, DSX reversibly and dose-dependently inhibited the amplitudes of outward K+ currents of the cells. At +20 mV membrane potential DSX at the concentrations of 0.02 g/L and 0.05 g/L showed no significant effects on the currents. In contrast, DSX at higher concentrations (0.1 g/L, 0.2 g/L and 0.5 g/L) significantly suppressed the current amplitudes. CONCLUSION These results suggest that DSX reversibly and dose-dependently suppress outward K+ channel currents in rat RGCs, which may be one of the possible mechanisms underlying Erigeron breviscapus prevents vision loss and RGC damage caused by glaucoma. PMID:26682155

  8. Inward and outward membrane tubes pulled from giant vesicles

    NASA Astrophysics Data System (ADS)

    Dasgupta, Raktim; Dimova, Rumiana

    2014-07-01

    Membrane nanotubes are extruded from giant unilamellar lipid vesicles using a controlled hydrodynamic flow and membrane-attached beads manipulated via optical tweezers. Within a single experiment, the technique can be used to assess various important mechanical and rheological characteristics of the membrane such as the bending rigidity, tension and intermonolayer slip. The application of small flow velocities leads to the extrusion of tubes with sufficiently large diameters conveniently measurable under an optical microscope. For the first time, we show that by suitably controlling the medium flow, inward tubes inside the vesicles can be formed. This approach offers great potential for studying tubulation mechanisms in membrane systems, exhibiting positive as well as negative spontaneous curvatures and should offer a more realistic model for biomembranes because the vesicle membrane tension can adapt freely.

  9. Passive ventricular remodeling in cardiac disease: focus on heterogeneity

    PubMed Central

    Kessler, Elise L.; Boulaksil, Mohamed; van Rijen, Harold V. M.; Vos, Marc A.; van Veen, Toon A. B.

    2014-01-01

    Passive ventricular remodeling is defined by the process of molecular ventricular adaptation to different forms of cardiac pathophysiology. It includes changes in tissue architecture, such as hypertrophy, fiber disarray, alterations in cell size and fibrosis. Besides that, it also includes molecular remodeling of gap junctions, especially those composed by Connexin43 proteins (Cx43) in the ventricles that affect cell-to-cell propagation of the electrical impulse, and changes in the sodium channels that modify excitability. All those alterations appear mainly in a heterogeneous manner, creating irregular and inhomogeneous electrical and mechanical coupling throughout the heart. This can predispose to reentry arrhythmias and adds to a further deterioration into heart failure. In this review, passive ventricular remodeling is described in Hypertrophic Cardiomyopathy (HCM), Dilated Cardiomyopathy (DCM), Ischemic Cardiomyopathy (ICM), and Arrhythmogenic Cardiomyopathy (ACM), with a main focus on the heterogeneity of those alterations mentioned above. PMID:25566084

  10. Physiological remodelling of the maternal uterine circulation during pregnancy.

    PubMed

    Mandala, Maurizio; Osol, George

    2012-01-01

    Sufficient uteroplacental blood flow is essential for normal pregnancy outcome and is accomplished by the coordinated growth and remodelling of the entire maternal uterine vasculature. The main focus of this MiniReview is to provide information on upstream (pre-placental) maternal uterine vascular remodelling that facilitates gestational increases in uterine blood flow. Consideration of the three-dimensional pattern of remodelling (circumferential enlargement versus axial elongation), changes in vessel biomechanical properties, and underlying mechanisms [shear stress, nitric oxide, vascular endothelial growth factor (VEGF)/placental growth factor (PlGF), the renin-angiotensin system] and pathways (local versus systemic; venoarterial exchange) are provided using the rat as the principal animal model, although findings from other species are incorporated wherever possible to provide a comparative perspective. The process of maternal gestational uterine vascular remodelling involves a number of cellular processes and mechanisms, including trophoblast invasion, hyperplasia and hypertrophy, and changes in extracellular matrix composition. In addition, changes in cellular function, e.g. the secretory and contractile properties of smooth muscle and an up-regulation of endothelial vasodilatory influences may contribute to uteroplacental blood flow increases through changes in tone as well as in structure. Future studies aimed at better understanding the inter-relationship between changes in vessel structure (remodelling) and function (reactivity) would likely generate new mechanistic insights into the fascinating process of maternal gestational uterine vascular adaptation and provide a more physiological perspective of the underlying cellular processes involved in its regulation.

  11. Helical unwinding and side-chain unlocking unravel the outward open conformation of the melibiose transporter

    PubMed Central

    Wang, Li-Ying; Ravi, Vidhya M.; Leblanc, Gérard; Padrós, Esteve; Cladera, Josep; Perálvarez-Marín, Alex

    2016-01-01

    Molecular dynamics simulations have been used to study the alternate access mechanism of the melibiose transporter from Escherichia coli. Starting from the outward-facing partially occluded form, 2 out of 12 simulations produced an outward full open form and one partially open, whereas the rest yielded fully or partially occluded forms. The shape of the outward-open form resembles other outward-open conformations of secondary transporters. During the transporter opening, conformational changes in some loops are followed by changes in the periplasm region of transmembrane helix 7. Helical curvature relaxation and unlocking of hydrophobic and ionic locks promote the outward opening of the transporter making accessible the substrate binding site. In particular, FRET studies on mutants of conserved aromatic residues of extracellular loop 4 showed lack of substrate binding, emphasizing the importance of this loop for making crucial interactions that control the opening of the periplasmic side. This study indicates that the alternate access mechanism for the melibiose transporter fits better into a flexible gating mechanism rather than the archetypical helical rigid-body rocker-switch mechanism. PMID:27658476

  12. Locus of spatial attention determines inward-outward anisotropy in crowding.

    PubMed

    Petrov, Yury; Meleshkevich, Olga

    2011-04-01

    It has long been known that an outward mask is much more disruptive than an inward mask in crowding (H. Bouma, 1973). We show that the locus of attention strongly affects this inward-outward anisotropy, removing it in some conditions and reversing it in others. In a 2AFC paradigm, subjects identified whether a high-contrast Gabor target of a given orientation was presented left or right of fixation. When a fixed eccentricity (8°) was used, the outward plaid mask produced much stronger crowding than the inward mask. When 7°, 8°, and 9° eccentricities were interleaved within the same run, diffusing attention, the inward and outward masks produced the same amount of crowding for all three eccentricities. When target identification was contingent on a foveal cue, biasing attention inward, the inward mask produced stronger crowding. Finally, a new contrast-detection paradigm was used to demonstrate that attention is generally mislocalized outward of the target, which may explain the commonly observed anisotropy in crowding. Our results suggest that spatial attention is intimately involved in the mechanism of crowding.

  13. Ethanol modulates facial stimulation-evoked outward currents in cerebellar Purkinje cells in vivo in mice

    PubMed Central

    Wu, Mao-Cheng; Bing, Yan-Hua; Chu, Chun-Ping; Qiu, De-Lai

    2016-01-01

    Acute ethanol overdose can induce dysfunction of cerebellar motor regulation and cerebellar ataxia. In this study, we investigated the effect of ethanol on facial stimulation-evoked inhibitory synaptic responses in cerebellar Purkinje cells (PCs) in urethane-anesthetized mice, using in vivo patch-clamp recordings. Under voltage-clamp conditions, ethanol (300 mM) decreased the amplitude, half-width, rise time and decay time of facial stimulation-evoked outward currents in PCs. The ethanol-induced inhibition of facial stimulation-evoked outward currents was dose-dependent, with an IC50 of 148.5 mM. Notably, the ethanol-induced inhibition of facial stimulation-evoked outward currents were significantly abrogated by cannabinoid receptor 1 (CB1) antagonists, AM251 and O-2050, as well as by the CB1 agonist WIN55212-2. Moreover, the ethanol-induced inhibition of facial stimulation-evoked outward currents was prevented by cerebellar surface perfusion of the PKA inhibitors H-89 and Rp-cAMP, but not by intracellular administration of the PKA inhibitor PKI. Our present results indicate that ethanol inhibits the facial stimulation-evoked outward currents by activating presynaptic CB1 receptors via the PKA signaling pathway. These findings suggest that ethanol overdose impairs sensory information processing, at least in part, by inhibiting GABA release from molecular layer interneurons onto PCs. PMID:27489024

  14. Ethanol modulates facial stimulation-evoked outward currents in cerebellar Purkinje cells in vivo in mice.

    PubMed

    Wu, Mao-Cheng; Bing, Yan-Hua; Chu, Chun-Ping; Qiu, De-Lai

    2016-01-01

    Acute ethanol overdose can induce dysfunction of cerebellar motor regulation and cerebellar ataxia. In this study, we investigated the effect of ethanol on facial stimulation-evoked inhibitory synaptic responses in cerebellar Purkinje cells (PCs) in urethane-anesthetized mice, using in vivo patch-clamp recordings. Under voltage-clamp conditions, ethanol (300 mM) decreased the amplitude, half-width, rise time and decay time of facial stimulation-evoked outward currents in PCs. The ethanol-induced inhibition of facial stimulation-evoked outward currents was dose-dependent, with an IC50 of 148.5 mM. Notably, the ethanol-induced inhibition of facial stimulation-evoked outward currents were significantly abrogated by cannabinoid receptor 1 (CB1) antagonists, AM251 and O-2050, as well as by the CB1 agonist WIN55212-2. Moreover, the ethanol-induced inhibition of facial stimulation-evoked outward currents was prevented by cerebellar surface perfusion of the PKA inhibitors H-89 and Rp-cAMP, but not by intracellular administration of the PKA inhibitor PKI. Our present results indicate that ethanol inhibits the facial stimulation-evoked outward currents by activating presynaptic CB1 receptors via the PKA signaling pathway. These findings suggest that ethanol overdose impairs sensory information processing, at least in part, by inhibiting GABA release from molecular layer interneurons onto PCs. PMID:27489024

  15. Densitometric evaluation of periprosthetic bone remodeling

    PubMed Central

    Parchi, Paolo Domenico; Cervi, Valentina; Piolanti, Nicola; Ciapini, Gianluca; Andreani, Lorenzo; Castellini, Iacopo; Poggetti, Andrea; Lisanti, Michele

    2014-01-01

    Summary The application of Dual-energy X-ray absorptiometry (DEXA) in orthopaedic surgery gradually has been extended from the study of osteoporosis to different areas of interest like the study of the relation between bone and prosthetic implants. Aim of this review is to analyze changes that occur in periprosthetic bone after the implantation of a total hip arthroplasty (THA) or a total knee arthroplasty (TKA). In THA the pattern of adaptive bone remodeling with different cementless femoral stems varies and it appears to be strictly related to the design and more specifically to where the femoral stem is fixed on bone. Short stems with metaphyseal fixation allow the maintenance of a more physiologic load transfer to the proximal femur decreasing the entity of bone loss. Femoral bone loss after TKA seems to be related to the stress shielding induced by the implants while tibial bone remodeling seems to be related to postoperative changes in knee alignment (varus/valgus) and consequently in tibial load transfer. After both THA and TKA stress shielding seems to be an inevitable phenomenon that occurs mainly in the first year after surgery. PMID:25568658

  16. Obesity and carotid artery remodeling

    PubMed Central

    Kozakova, M; Palombo, C; Morizzo, C; Højlund, K; Hatunic, M; Balkau, B; Nilsson, P M; Ferrannini, E

    2015-01-01

    Background/Objective: The present study tested the hypothesis that obesity-related changes in carotid intima-media thickness (IMT) might represent not only preclinical atherosclerosis but an adaptive remodeling meant to preserve circumferential wall stress (CWS) in altered hemodynamic conditions characterized by body size-dependent increase in stroke volume (SV) and blood pressure (BP). Subjects/Methods: Common carotid artery (CCA) luminal diameter (LD), IMT and CWS were measured in three different populations in order to study: (A) cross-sectional associations between SV, BP, anthropometric parameters and CCA LD (266 healthy subjects with wide range of body weight (24–159 kg)); (B) longitudinal associations between CCA LD and 3-year IMT progression rate (ΔIMT; 571 healthy non-obese subjects without increased cardiovascular (CV) risk); (C) the impact of obesity on CCA geometry and CWS (88 obese subjects without CV complications and 88 non-obese subjects matched for gender and age). Results: CCA LD was independently associated with SV that was determined by body size. In the longitudinal study, baseline LD was an independent determinant of ΔIMT, and ΔIMT of subjects in the highest LD quartile was significantly higher (28±3 μm) as compared with those in the lower quartiles (8±3, 16±4 and 16±3 μm, P=0.001, P<0.05 and P=0.01, respectively). In addition, CCA CWS decreased during the observational period in the highest LD quartile (from 54.2±8.6 to 51.6±7.4 kPa, P<0.0001). As compared with gender- and age-matched lean individuals, obese subjects had highly increased CCA LD and BP (P<0.0001 for both), but only slightly higher CWS (P=0.05) due to a significant increase in IMT (P=0.005 after adjustment for confounders). Conclusions: Our findings suggest that in obese subjects, the CCA wall thickens to compensate the luminal enlargement caused by body size-induced increase in SV, and therefore, to normalize the wall stress. CCA diameter in obesity could

  17. Special Report: The Rush to Remodel

    ERIC Educational Resources Information Center

    Nation's Schools, 1973

    1973-01-01

    As more and more districts scurry to remodel outdated buildings and individual rooms, the detailed how-to-do-it sometimes gets lost in the overall planning. This article furnishes specific help in ways to remodel economically. (Author/JN)

  18. Brain arterial remodeling contribution to nonembolic brain infarcts in patients with HIV

    PubMed Central

    Goldman, James; Dwork, Andrew J.; Elkind, Mitchell S.V.; Marshall, Randolph S.; Morgello, Susan

    2015-01-01

    Background: Cerebrovascular disease is a cause of morbidity in HIV-infected populations. The relationship among HIV infection, brain arterial remodeling, and stroke is unclear. Methods: Large brain arteries (n = 1,878 segments) from 284 brain donors with and without HIV were analyzed to obtain media and wall thickness and lumen-to-wall ratio, and to determine the presence of atherosclerosis and dolichoectasia (arterial remodeling extremes). Neuropathologic assessment was used to characterize brain infarcts. Multilevel models were used to assess for associations between arterial characteristics and HIV. Associations between arterial characteristics and brain infarcts were examined in HIV+ individuals only. Results: Adjusting for vascular risk factors, HIV infection was associated with thicker arterial walls and smaller lumen-to-wall ratios. Cerebral atherosclerosis accounted for one-quarter of the brain infarcts in HIV+ cases, and was more common with aging, diabetes, a lower CD4 nadir, and a higher antemortem CD4 count. In contrast, a higher lumen-to-wall ratio was the only arterial predictor of unexplained infarcts in HIV+ cases. Dolichoectasia was more common in HIV+ cases with smoking and media thinning, and with protracted HIV infection and a detectable antemortem viral load. Conclusions: HIV infection may predispose to inward remodeling compared to uninfected controls. However, among HIV+ cases with protracted immunosuppression, outward remodeling is the defining arterial phenotype. Half of all brain infarcts in this sample were attributed to the extremes of brain arterial remodeling: atherosclerosis and dolichoectasia. Understanding the mechanisms influencing arterial remodeling will be important in controlling cerebrovascular disease in the HIV-infected population. PMID:26320196

  19. A Planning Guide for Short Backpacking and Ski Touring Courses with Colorado Outward Bound School.

    ERIC Educational Resources Information Center

    McLeod, Ricki

    Outward Bound (OB) backpacking and Nordic ski programs aim to integrate humanistic goals (i.e., personal awareness and understanding and compassion for others) with the school's curriculum. Program goals fall in three areas--personal, group, and academic. In designing a successful course which will achieve the goals, there are several phases, all…

  20. Exploring Familial Relationship Growth and Negotiation: A Case Study of Outward Bound Family Courses

    ERIC Educational Resources Information Center

    Overholt, Jillisa R.

    2013-01-01

    This study explored the phenomenon of father-child relationship development within the context of an Outward Bound (OB) family course, an environment that may both disrupt the ordinary aspects of an established relationship, and provide activities to purposefully encourage relationship development through a variety of aspects inherent to the…

  1. Protonation of Glu135 Facilitates the Outward-to-Inward Structural Transition of Fucose Transporter

    PubMed Central

    Liu, Yufeng; Ke, Meng; Gong, Haipeng

    2015-01-01

    Major facilitator superfamily (MFS) transporters typically need to alternatingly sample the outward-facing and inward-facing conformations, in order to transport the substrate across membrane. To understand the mechanism, in this work, we focused on one MFS member, the L-fucose/H+ symporter (FucP), whose crystal structure exhibits an outward-open conformation. Previous experiments imply several residues critical to the substrate/proton binding and structural transition of FucP, among which Glu135, located in the periplasm-accessible vestibule, is supposed as being involved in both proton translocation and conformational change of the protein. Here, the structural transition of FucP in presence of substrate was investigated using molecular-dynamics simulations. By combining the equilibrium and accelerated simulations as well as thermodynamic calculations, not only was the large-scale conformational change from the outward-facing to inward-facing state directly observed, but also the free energy change during the structural transition was calculated. The simulations confirm the critical role of Glu135, whose protonation facilitates the outward-to-inward structural transition both by energetically favoring the inward-facing conformation in thermodynamics and by reducing the free energy barrier along the reaction pathway in kinetics. Our results may help the mechanistic studies of both FucP and other MFS transporters. PMID:26244736

  2. An Analysis of the Impact of Outward Bound on Twelve High Schools.

    ERIC Educational Resources Information Center

    Schulze, Joseph R.

    Describing and analyzing the impact of Outward Bound (OB) programs on 12 high schools which reflect OB involvement varying from 1 to 5 years and include urban, suburban, and rural (public, private, boarding, and day) schools, this 1970-71 report is aimed at furthering OB philosophy and method. The report presents OB program: background; evaluation…

  3. 19 CFR 4.63 - Outward cargo declaration; shippers' export declarations.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... of the section in the Census Regulations (see 15 CFR 30.39, 30.50 through 30.57) where the particular... 19 Customs Duties 1 2014-04-01 2014-04-01 false Outward cargo declaration; shippers' export declarations. 4.63 Section 4.63 Customs Duties U.S. CUSTOMS AND BORDER PROTECTION, DEPARTMENT OF...

  4. Outward Foreign Direct Investment and Human Capital Development: A Small Country Perspective

    ERIC Educational Resources Information Center

    McDonnell, Anthony

    2008-01-01

    Purpose: The purpose of this paper is to examine the pattern of outward foreign direct investment (FDI) by Irish MNCs, and more specifically, to investigate their approach to human capital development and how these correspond to foreign MNCs in Ireland. In particular, it seeks to investigate training and development expenditure, adoption of…

  5. Streptococcus equi with truncated M-proteins isolated from outwardly healthy horses.

    PubMed

    Chanter, N; Talbot, N C; Newton, J R; Hewson, D; Verheyen, K

    2000-06-01

    The M-protein genes of Streptococcus equi isolated from 17 outwardly healthy horses after 4 strangles outbreaks had ended, including a quarantined animal, were compared with those of S. equi isolates from 167 active cases of strangles across 4 countries. The healthy horses included 16 persistent S. equi carriers, at least one from each of the four outbreaks. These carriers, despite being outwardly healthy, had empyema of the guttural pouch(es), an enlargement of the equine Eustachian tube. A persistent carrier from two of these outbreaks, the quarantined animal and a healthy animal with normal guttural pouches, from which S. equi was isolated only once, were colonized by variant S. equi with truncated M-protein genes (24% of outwardly healthy animals with S. equi). The truncated M-protein genes had in-frame deletions in slightly different positions between the signal sequence and the central repeat region, equivalent to approximately 20% of the mature expressed protein. Immunoblotting with antibody to recombinant M-protein confirmed that the variants expressed a truncated form of the M-protein. In contrast to the outwardly healthy S. equi carriers, only 1/167 of S. equi isolates from strangles cases possessed a truncated M-protein gene (<1%; Fisher's exact test, P=0.0002). Compared with isolates from healthy horses with a truncated M-protein, much more of the N terminus of the truncated M-protein was retained in the variant S. equi from a strangles case. Variant S. equi from outwardly healthy animals were more susceptible to phagocytosis by neutrophils in vitro than typical isolates. This is the first report of detection of S. equi with a truncated M-protein. The distribution of the variants between strangles cases and carriers suggests that the 80% of the M-protein retained in the variants may contribute to colonization whilst the deleted portion of the gene may be needed for full virulence.

  6. Bone remodeling induced by dental implants of functionally graded materials.

    PubMed

    Lin, Daniel; Li, Qing; Li, Wei; Swain, Michael

    2010-02-01

    Functionally graded material (FGM) had been developed as a potential implant material to replace titanium for its improved capability of initial osseointegration. The idea behind FGM dental implant is that its properties can be tailored in accordance with the biomechanical needs at different regions adapting to its hosting bony tissues, therefore creating an improved overall integration and stability in the entire restoration. However, there have been very few reports available so far on predicting bone remodeling induced by FGM dental implants. This article aims to evaluate bone remodeling when replacing the titanium with a hydroxyapatite/collagen (HAP/Col) FGM model. A finite element model was constructed in the buccal-lingual section of a dental implant-bone structure generated from in vivo CT scan images. The remodeling simulation was performed over a 4 year healing period. Comparisons were made between the titanium implant and various FGM implants of this model. The FGM implants showed an improved bone remodeling outcome. The study is expected to provide a basis for future development of FGM implants.

  7. Transcriptional coactivator PGC-1alpha promotes peroxisomal remodeling and biogenesis.

    PubMed

    Bagattin, Alessia; Hugendubler, Lynne; Mueller, Elisabetta

    2010-11-23

    Mitochondria and peroxisomes execute some analogous, nonredundant functions including fatty acid oxidation and detoxification of reactive oxygen species, and, in response to select metabolic cues, undergo rapid remodeling and division. Although these organelles share some components of their division machinery, it is not known whether a common regulator coordinates their remodeling and biogenesis. Here we show that in response to thermogenic stimuli, peroxisomes in brown fat tissue (BAT) undergo selective remodeling and expand in number and demonstrate that ectopic expression of the transcriptional coactivator PGC-1α recapitulates these effects on the peroxisomal compartment, both in vitro and in vivo. Conversely, β-adrenergic stimulation of PGC-1α(-/-) cells results in blunted induction of peroxisomal gene expression. Surprisingly, PPARα was not required for the induction of critical biogenesis factors, suggesting that PGC-1α orchestrates peroxisomal remodeling through a PPARα-independent mechanism. Our data suggest that PGC-1α is critical to peroxisomal physiology, establishing a role for this factor as a fundamental orchestrator of cellular adaptation to energy demands.

  8. Hierarchical Structure and Repair of Bone: Deformation, Remodelling, Healing

    NASA Astrophysics Data System (ADS)

    Fratzl, Peter; Weinkamer, Richard

    The design of natural materials follows a radically different paradigm as compared to engineering materials: organs are growing rather than being fabricated. As a main consequence, adaptation to changing conditions remains possible during the whole lifetime of a biological material. As a typical example of such a biological material, bone is constantly laid down by bone forming cells, osteoblasts, and removed by bone resorbing cells, osteoclasts. With this remodelling cycle of bone resorption and formation, the skeleton is able to adapt to changing needs at all levels of structural hierarchy. The hierarchical structure of bone is summarized in the second part of this chapter.

  9. Heart failure duration progressively modulates the arrhythmia substrate through structural and electrical remodeling

    PubMed Central

    Long, Victor P.; Bonilla, Ingrid M.; Vargas-Pinto, Pedro; Nishijima, Yoshinori; Sridhar, Arun; Li, Chun; Mowrey, Kent; Wright, Patrick; Velayutham, Murugesan; Kumar, Sanjay; Lee, Nam; Zweier, Jay L; Mohler, Peter J.; Györke, Sandor; Carnes, Cynthia A.

    2016-01-01

    AIMS Ventricular arrhythmias are a common cause of death in patients with heart failure (HF). Structural and electrical abnormalities in the heart provide a substrate for such arrhythmias. Canine tachypacing-induced HF models of 4–6 weeks duration are often used to study pathophysiology and therapies for HF. We hypothesized that a chronic canine model of HF would result in greater electrical and structural remodeling than a short term model, leading to a more arrhythmogenic substrate. MAIN METHODS HF was induced by ventricular tachypacing for one (short-term) or four (chronic) months to study remodeling. KEY FINDINGS Left ventricular contractility was progressively reduced, while ventricular hypertrophy and interstitial fibrosis were evident at 4 month but not 1 month of HF. Left ventricular myocyte action potentials were prolonged after 4 (p<0.05) but not 1 month of HF. Repolarization instability and early afterdepolarizations were evident only after 4 months of HF (p<0.05), coinciding with a prolonged QTc interval (p<0.05). The transient outward potassium current was reduced in both HF groups (p<0.05). The outward component of the inward rectifier potassium current was reduced only in the 4 month HF group (p<0.05). The delayed rectifier potassium currents were reduced in 4 (p<0.05) but not 1 month of HF. Reactive oxygen species were increased at both 1 and 4 months of HF (p<0.05). SIGNIFICANCE Reduced Ito, outward IK1, IKs, and IKr in HF contribute to EAD formation. Chronic, but not short term canine HF, results in the altered electrophysiology and repolarization instability characteristic of end-stage human HF. PMID:25596015

  10. Neural remodeling in retinal degeneration.

    PubMed

    Marc, Robert E; Jones, Bryan W; Watt, Carl B; Strettoi, Enrica

    2003-09-01

    Mammalian retinal degenerations initiated by gene defects in rods, cones or the retinal pigmented epithelium (RPE) often trigger loss of the sensory retina, effectively leaving the neural retina deafferented. The neural retina responds to this challenge by remodeling, first by subtle changes in neuronal structure and later by large-scale reorganization. Retinal degenerations in the mammalian retina generally progress through three phases. Phase 1 initiates with expression of a primary insult, followed by phase 2 photoreceptor death that ablates the sensory retina via initial photoreceptor stress, phenotype deconstruction, irreversible stress and cell death, including bystander effects or loss of trophic support. The loss of cones heralds phase 3: a protracted period of global remodeling of the remnant neural retina. Remodeling resembles the responses of many CNS assemblies to deafferentation or trauma, and includes neuronal cell death, neuronal and glial migration, elaboration of new neurites and synapses, rewiring of retinal circuits, glial hypertrophy and the evolution of a fibrotic glial seal that isolates the remnant neural retina from the surviving RPE and choroid. In early phase 2, stressed photoreceptors sprout anomalous neurites that often reach the inner plexiform and ganglion cell layers. As death of rods and cones progresses, bipolar and horizontal cells are deafferented and retract most of their dendrites. Horizontal cells develop anomalous axonal processes and dendritic stalks that enter the inner plexiform layer. Dendrite truncation in rod bipolar cells is accompanied by revision of their macromolecular phenotype, including the loss of functioning mGluR6 transduction. After ablation of the sensory retina, Müller cells increase intermediate filament synthesis, forming a dense fibrotic layer in the remnant subretinal space. This layer invests the remnant retina and seals it from access via the choroidal route. Evidence of bipolar cell death begins in

  11. The Cooperstown Outward Bound Summer Program: An Informal Look at the Program's Impact on the Lives of Students.

    ERIC Educational Resources Information Center

    Sakofs, Mitchell S.; And Others

    During the summer of 1987, 29 students from the Cooperstown High School in New York received scholarships and participated in an Outward Bound course. This report presents the results of a study assessing the impact of the Outward Bound experience on these students. Data gathering instruments included: the Self Report Survey (SRS), developed by…

  12. Vascular Remodeling in Pulmonary Hypertension

    PubMed Central

    Shimoda, Larissa A; Laurie, Steven S.

    2013-01-01

    Pulmonary hypertension is a complex, progressive condition arising from a variety of genetic and pathogenic causes. Patients present with a spectrum of histologic and pathophysiological features, likely reflecting the diversity in underlying pathogenesis. It is widely recognized that structural alterations in the vascular wall contribute to all forms of pulmonary hypertension. Features characteristic of the remodeled vasculature in patients with pulmonary hypertension include increased stiffening of the elastic proximal pulmonary arteries, thickening of the intimal and/or medial layer of muscular arteries, development of vaso-occlusive lesions and the appearance of cells expressing smooth muscle specific markers in normally non-muscular small diameter vessels, resulting from proliferation and migration of pulmonary arterial smooth muscle cells and cellular trans-differentiation. The development of several animal models of pulmonary hypertension has provided the means to explore the mechanistic underpinnings of pulmonary vascular remodeling, although none of the experimental models currently used entirely replicates the pulmonary arterial hypertension observed in patients. Herein, we provide an overview of the histological abnormalities observed in humans with pulmonary hypertension and in preclinical models and discuss insights gained regarding several key signaling pathways contributing to the remodeling process. In particular, we will focus on the roles of ion homeostasis, endothelin-1, serotonin, bone morphogenetic proteins, Rho kinase and hypoxia-inducible factor 1 in pulmonary arterial smooth muscle and endothelial cells, highlighting areas of cross-talk between these pathways and potentials for therapeutic targeting. PMID:23334338

  13. Chromatin remodeling in plant development.

    PubMed

    Jarillo, José A; Piñeiro, Manuel; Cubas, Pilar; Martínez-Zapater, José M

    2009-01-01

    Plant development results from specific patterns of gene expression that are tightly regulated in a spatio-temporal manner. Chromatin remodeling plays a central role in establishing these expression patterns and maintaining epigenetic transcriptional states through successive rounds of mitosis that take place within a cell lineage. Plant epigenetic switches occur not only at the embryo stage, but also during postembryonic developmental transitions, suggesting that chromatin remodeling activities in plants can provide a higher degree of regulatory flexibility which probably underlies their developmental plasticity. Here, we highlight recent progress in the understanding of plant chromatin dynamic organization, facilitating the activation or repression of specific sets of genes involved in different developmental programs and integrating them with the response to environmental signals. Chromatin conformation controls gene expression both in actively dividing undifferentiated cells and in those already fate-determined. In this context, we first describe chromatin reorganization activities required to maintain meristem function stable through DNA replication and cell division. Organ initiation at the apex, with emphasis on reproductive development, is next discussed to uncover the chromatin events involved in the establishment and maintenance of expression patterns associated with differentiating cells; this is illustrated with the complex epigenetic regulation of the Arabidopsis floral repressor FLOWERING LOCUS C (FLC). Finally, we discuss the involvement of chromatin remodeling in plant responses to environmental cues and to different types of stress conditions.

  14. Effects of spironolactone towards rabbit atrial remodeling with rapid pacing.

    PubMed

    Wang, Lian-Fa; Gu, Lei; Huang, Meng-Xun; Zhou, Wen-Bing; Li, Hua; Zhang, Bang-Zhu

    2016-01-01

    This study aimed to observe the effects of spironolactone towards the rabbit atrial remodeling with rapid atrial pacing (RAP). 30 rabbits were randomly divided into control group, RAP group and spironolactone group, with 10 rabbits in each group. RAP was performed at the speed of 800 beats/min for 8 h, atrial effective refractory period (AERP) was determined before and at the 1(st), 2(nd), 4(th), 6(th) and 8(th) of the pacing, the expressions of atrial muscular calcium channel α1C subunit and β1 subunit mRNA were performed the RT-PCR detection, and ultrastructural changes of atrial myocytes were observed. AERP of RAP group shortened, with poor frequency adaptability; the expressions of calcium channel α1C subunit and β1 subunit mRNA decreased 22% and 26%, respectively, when compared with the control group; ultrastructure of atrial myocytes changed significantly. AERP of spironotlactone group shortened less that RAP group, and the frequency adaptability was maintained, the decreased expressions of calcium channel α1C subunit and β1 subunit mRNA significantly reduced. RAP could cause atrial remodeling, while spironolactone could inhibit RAP-induced atrial remodeling. PMID:26826809

  15. Right heart structural and functional remodeling in athletes.

    PubMed

    D'Andrea, Antonello; La Gerche, Andrè; Golia, Enrica; Teske, Arco J; Bossone, Eduardo; Russo, Maria Giovanna; Calabrò, Raffaele; Baggish, Aaron L

    2015-01-01

    Long-term intensive exercise training programs lead to numerous progressive cardiac adaptations, which are collectively termed "athlete's heart." Noninvasive diagnostic techniques, such as color Doppler echocardiography, have been widely used in the analysis of the athlete's heart. Initial experiences focused mainly on left heart adaptations to training. However, in recent years, substantial structural and functional adaptations of the right heart have been documented. The present review article focuses on recent data defining right heart adaptation to short- and long-term periods of exercise training. Right ventricular (RV) morphology and function may be more profoundly affected by intense exercise and, in some cases, functional recovery may be incomplete. Moreover, there is speculation that such changes may represent a substrate for proarrhythmic RV remodeling in some highly trained athletes, even in the absence of a known familial redisposition.

  16. Outward K+ channels in Brassica chinensis pollen protoplasts are regulated by external and internal pH.

    PubMed

    Fan, L-M; Wang, Y-F; Wu, W-H

    2003-03-01

    Patch-clamp whole-cell and single-channel recording techniques were used to investigate the regulation of outward K(+) channels by external and internal protons in Brassica chinensispollen protoplasts. Outward K(+) currents and conductance were insensitive to external pH (pH(o)) except at pH 4.5. Maximal conductance (G(max)) for the outward K(+) currents was inhibited at acidic external pH. Half-activation voltage ( E(1/2)) for the outward K(+) currents shifted to more positive voltages along with the decrease in pH(o). E(1/2) can be described by a modified Henderson-Hasselbalch equation expected from a single titratable binding site. The activation kinetics of the outward K(+) channels was largely insensitive to pH(o). An internal pH (pH(i)) of 4.5 significantly increased outward K(+) currents and conductance. G(max) for the outward K(+) currents decreased with elevations in pH(i). In contrast to the effect of pH(o), E(1/2) was shifted to more positive voltages with elevations in pH(i). The outward K(+) currents, G(max) and E(1/2) can be described by the modified Henderson-Hasselbalch equation. Furthermore, acidifying pH(i) accelerated the activation of the outward K(+) currents significantly. The differences in electro-physiological properties among previously reported and currently described plant outward K(+) channels may reflect differences in the structure of these channels.

  17. Numerical modeling of inward and outward melting of high temperature PCM in a vertical cylinder

    NASA Astrophysics Data System (ADS)

    Riahi, S.; Saman, W. Y.; Bruno, F.; Tay, N. H. S.

    2016-05-01

    Numerical study of inward and outward melting of a high temperature PCM in cylindrical enclosures were performed, using FLUENT 15. For validation purposes, numerical modeling of inward melting of a low temperature PCM was initially conducted and the predicted results were compared with the experimental data from the literature. The validated model for the low temperature PCM was used for two high temperature cases; inward melting of a high temperature PCM in a cylindrical enclosure and outward melting in a cylindrical case with higher aspect ratio. The results of this study show that the numerical model developed is capable of capturing the details of melting process with buoyancy driven convection for Ra<108, i.e. laminar flow, for a high temperature PCM and can be used for the design and optimization of a latent heat thermal storage unit.

  18. Dynamics of Lung Defense in Pneumonia: Resistance, Resilience, and Remodeling

    PubMed Central

    Quinton, Lee J.; Mizgerd, Joseph P.

    2015-01-01

    Pneumonia is initiated by microbes in the lung, but physiological processes integrating responses across diverse cell types and organ systems dictate the outcome of respiratory infection. Resistance, or actions of the host to eradicate living microbes, in the lungs involves a combination of innate and adaptive immune responses triggered by air-space infection. Resilience, or the ability of the host tissues to withstand the physiologically damaging effects of microbial and immune activities, is equally complex, precisely regulated, and determinative. Both immune resistance and tissue resilience are dynamic and change throughout the lifetime, but we are only beginning to understand such remodeling and how it contributes to the incidence of severe pneumonias, which diminishes as childhood progresses and then increases again among the elderly. Here, we review the concepts of resistance, resilience, and remodeling as they apply to pneumonia, highlighting recent advances and current significant knowledge gaps. PMID:25148693

  19. Perspectives on biomechanical growth and remodeling mechanisms in glaucoma⋆

    PubMed Central

    Grytz, Rafael; Girkin, Christopher A.; Libertiaux, Vincent; Downs, J. Crawford

    2012-01-01

    Glaucoma is a blinding diseases in which damage to the axons results in loss of retinal ganglion cells. Experimental evidence indicates that chronic intraocular pressure elevation initiates axonal insult at the level of the lamina cribrosa. The lamina cribrosa is a porous collagen structure through which the axons pass on their path from the retina to the brain. Recent experimental studies revealed the extensive structural changes of the lamina cribrosa and its surrounding tissues during the development and progression of glaucoma. In this perspective paper we review the experimental evidence for growth and remodeling mechanisms in glaucoma including adaptation of tissue anisotropy, tissue thickening/thinning, tissue elongation/shortening and tissue migration. We discuss the existing predictive computational approaches that try to elucidate the potential biomechanical basis of theses growth and remodeling mechanisms and highlight open questions, challenges, and avenues for further development. PMID:23109748

  20. Structure of an antibacterial peptide ATP-binding cassette transporter in a novel outward occluded state

    PubMed Central

    Choudhury, Hassanul G.; Tong, Zhen; Mathavan, Indran; Li, Yanyan; Iwata, So; Zirah, Séverine; Rebuffat, Sylvie; van Veen, Hendrik W.; Beis, Konstantinos

    2014-01-01

    Enterobacteriaceae produce antimicrobial peptides for survival under nutrient starvation. Microcin J25 (MccJ25) is an antimicrobial peptide with a unique lasso topology. It is secreted by the ATP-binding cassette (ABC) exporter McjD, which ensures self-immunity of the producing strain through efficient export of the toxic mature peptide from the cell. Here we have determined the crystal structure of McjD from Escherichia coli at 2.7-Å resolution, which is to the authors’ knowledge the first structure of an antibacterial peptide ABC transporter. Our functional and biochemical analyses demonstrate McjD-dependent immunity to MccJ25 through efflux of the peptide. McjD can directly bind MccJ25 and displays a basal ATPase activity that is stimulated by MccJ25 in both detergent solution and proteoliposomes. McjD adopts a new conformation, termed nucleotide-bound outward occluded. The new conformation defines a clear cavity; mutagenesis and ligand binding studies of the cavity have identified Phe86, Asn134, and Asn302 as important for recognition of MccJ25. Comparisons with the inward-open MsbA and outward-open Sav1866 structures show that McjD has structural similarities with both states without the intertwining of transmembrane (TM) helices. The occluded state is formed by rotation of TMs 1 and 2 toward the equivalent TMs of the opposite monomer, unlike Sav1866 where they intertwine with TMs 3–6 of the opposite monomer. Cysteine cross-linking studies on the McjD dimer in inside-out membrane vesicles of E. coli confirmed the presence of the occluded state. We therefore propose that the outward-occluded state represents a transition intermediate between the outward-open and inward-open conformation of ABC exporters. PMID:24920594

  1. OUTWARD MOTION OF POROUS DUST AGGREGATES BY STELLAR RADIATION PRESSURE IN PROTOPLANETARY DISKS

    SciTech Connect

    Tazaki, Ryo; Nomura, Hideko

    2015-02-01

    We study the dust motion at the surface layer of protoplanetary disks. Dust grains in the surface layer migrate outward owing to angular momentum transport via gas-drag force induced by the stellar radiation pressure. In this study we calculate the mass flux of the outward motion of compact grains and porous dust aggregates by the radiation pressure. The radiation pressure force for porous dust aggregates is calculated using the T-Matrix Method for the Clusters of Spheres. First, we confirm that porous dust aggregates are forced by strong radiation pressure even if they grow to be larger aggregates, in contrast to homogeneous and spherical compact grains, for which radiation pressure efficiency becomes lower when their sizes increase. In addition, we find that the outward mass flux of porous dust aggregates with monomer size of 0.1 μm is larger than that of compact grains by an order of magnitude at the disk radius of 1 AU, when their sizes are several microns. This implies that large compact grains like calcium-aluminum-rich inclusions are hardly transported to the outer region by stellar radiation pressure, whereas porous dust aggregates like chondritic-porous interplanetary dust particles are efficiently transported to the comet formation region. Crystalline silicates are possibly transported in porous dust aggregates by stellar radiation pressure from the inner hot region to the outer cold cometary region in the protosolar nebula.

  2. Revealing an outward-facing open conformational state in a CLC Cl – /H + exchange transporter

    DOE PAGES

    Khantwal, Chandra M.; Abraham, Sherwin J.; Han, Wei; Jiang, Tao; Chavan, Tanmay S.; Cheng, Ricky C.; Elvington, Shelley M.; Liu, Corey W.; Mathews, Irimpan I.; Stein, Richard A.; et al

    2016-01-22

    CLC secondary active transporters exchange Cl - for H + . Crystal structures have suggested that the conformational change from occluded to outward-facing states is unusually simple, involving only the rotation of a conserved glutamate (Glu ex ) upon its protonation. Using 19 F NMR, we show that as [H + ] is increased to protonate Glu ex and enrich the outward-facing state, a residue ~20 Å away from Glu ex , near the subunit interface, moves from buried to solvent-exposed. Consistent with functional relevance of this motion, constriction via inter-subunit cross-linking reduces transport. Molecular dynamics simulations indicate thatmore » the cross-link dampens extracellular gate-opening motions. In support of this model, mutations that decrease steric contact between Helix N (part of the extracellular gate) and Helix P (at the subunit interface) remove the inhibitory effect of the cross-link. Together, these results demonstrate the formation of a previously uncharacterized 'outward-facing open' state, and highlight the relevance of global structural changes in CLC function.« less

  3. Revealing an outward-facing open conformational state in a CLC Cl–/H+ exchange transporter

    PubMed Central

    Khantwal, Chandra M; Abraham, Sherwin J; Han, Wei; Jiang, Tao; Chavan, Tanmay S; Cheng, Ricky C; Elvington, Shelley M; Liu, Corey W; Mathews, Irimpan I; Stein, Richard A; Mchaourab, Hassane S; Tajkhorshid, Emad; Maduke, Merritt

    2016-01-01

    CLC secondary active transporters exchange Cl- for H+. Crystal structures have suggested that the conformational change from occluded to outward-facing states is unusually simple, involving only the rotation of a conserved glutamate (Gluex) upon its protonation. Using 19F NMR, we show that as [H+] is increased to protonate Gluex and enrich the outward-facing state, a residue ~20 Å away from Gluex, near the subunit interface, moves from buried to solvent-exposed. Consistent with functional relevance of this motion, constriction via inter-subunit cross-linking reduces transport. Molecular dynamics simulations indicate that the cross-link dampens extracellular gate-opening motions. In support of this model, mutations that decrease steric contact between Helix N (part of the extracellular gate) and Helix P (at the subunit interface) remove the inhibitory effect of the cross-link. Together, these results demonstrate the formation of a previously uncharacterized 'outward-facing open' state, and highlight the relevance of global structural changes in CLC function. DOI: http://dx.doi.org/10.7554/eLife.11189.001 PMID:26799336

  4. Musculoskeletal work preceding the outward and inward Tkachev on uneven bars in artistic gymnastics.

    PubMed

    Kerwin, David G; Irwin, Gareth

    2010-03-01

    Outward facing Tkachevs on uneven bars have been the traditional technique employed by artistic gymnasts. Changes in bar spacing and judging have increased the popularity of the inward version of the skill, in which the gymnast faces towards the low bar as she straddles over the high bar. The purpose of this study was to compare these two variants of the women's Tkachev to examine the influence of the positioning of the low bar on the musculoskeletal demands placed on the gymnast. 3-D DLT reconstructed data sets from digitised video images of straddle Tkachevs performed at the 2000 Sydney Olympics were analysed. Five performances of each variant were compared using kinematics and inverse dynamics. Mean hip and shoulder kinematics were similar for both variants of the Tkachev, but for the inward, gymnasts released later, travelled higher and re-grasped earlier than for the outward. Hip joint moments were similar for both variants while shoulder moments were different. Total musculoskeletal demands were similar for both variants, although the distribution was markedly different with the shoulders contributing positively for the outward and negatively for the inward. Implications for training specificity, along with potential future developments for the inward variant, have been highlighted. PMID:20446636

  5. Gender differences in cardiac hypertrophic remodeling.

    PubMed

    Patrizio, Mario; Marano, Giuseppe

    2016-01-01

    Cardiac remodeling is a complex process that occurs in response to different types of cardiac injury such as ischemia and hypertension, and that involves cardiomyocytes, fibroblasts, vascular smooth muscle cells, vascular endothelial cells, and inflammatory cells. The end result is cardiomyocyte hypertrophy, fibrosis, inflammation, vascular, and electrophysiological remodeling. This paper reviews a large number of studies on the influence of gender on pathological cardiac remodeling and shows how sex differences result in different clinical outcomes and therapeutic responses, with males which generally develop greater cardiac remodeling responses than females. Although estrogens appear to have an important role in attenuating adverse cardiac remodeling, the mechanisms through which gender modulates myocardial remodeling remain to be identified. PMID:27364397

  6. Pulsatile Fluid Shear in Bone Remodeling

    NASA Technical Reports Server (NTRS)

    Frangos, John A.

    1997-01-01

    The objective of this investigation was to elucidate the sensitivity to transients in fluid shear stress in bone remodeling. Bone remodeling is clearly a function of the local mechanical environment which includes interstitial fluid flow. Traditionally, load-induced remodeling has been associated with low frequency (1-2 Hz) signals attributed to normal locomotion. McLeod and Rubin, however, demonstrated in vivo remodeling events associated with high frequency (15-30 Hz) loading. Likewise, other in vivo studies demonstrated that slowly applied strains did not trigger remodeling events. We therefore hypothesized that the mechanosensitive pathways which control bone maintenance and remodeling are differentially sensitive to varying rates of applied fluid shear stress.

  7. A remodelling metric for angular fibre distributions and its application to diseased carotid bifurcations.

    PubMed

    Creane, Arthur; Maher, Eoghan; Sultan, Sherif; Hynes, Niamh; Kelly, Daniel J; Lally, Caitríona

    2012-07-01

    Many soft biological tissues contain collagen fibres, which act as major load bearing constituents. The orientation and the dispersion of these fibres influence the macroscopic mechanical properties of the tissue and are therefore of importance in several areas of research including constitutive model development, tissue engineering and mechanobiology. Qualitative comparisons between these fibre architectures can be made using vector plots of mean orientations and contour plots of fibre dispersion but quantitative comparison cannot be achieved using these methods. We propose a 'remodelling metric' between two angular fibre distributions, which represents the mean rotational effort required to transform one into the other. It is an adaptation of the earth mover's distance, a similarity measure between two histograms/signatures used in image analysis, which represents the minimal cost of transforming one distribution into the other by moving distribution mass around. In this paper, its utility is demonstrated by considering the change in fibre architecture during a period of plaque growth in finite element models of the carotid bifurcation. The fibre architecture is predicted using a strain-based remodelling algorithm. We investigate the remodelling metric's potential as a clinical indicator of plaque vulnerability by comparing results between symptomatic and asymptomatic carotid bifurcations. Fibre remodelling was found to occur at regions of plaque burden. As plaque thickness increased, so did the remodelling metric. A measure of the total predicted fibre remodelling during plaque growth, TRM, was found to be higher in the symptomatic group than in the asymptomatic group. Furthermore, a measure of the total fibre remodelling per plaque size, TRM/TPB, was found to be significantly higher in the symptomatic vessels. The remodelling metric may prove to be a useful tool in other soft tissues and engineered scaffolds where fibre adaptation is also present. PMID:22086167

  8. Membrane currents in cat myocardium: separation of inward and outward components.

    PubMed

    McDonald, T F; Trautwein, W

    1978-01-01

    1. The single sucrose gap method was used to control the membrane potential of cat ventricular fibres.2. Following the early rapid events (capacitive, Na and slow inward (si) current spikes) the membrane current on depolarization contained three time-dependent components which appeared attributable to the inactivation of I(si) and the activation of two outward currents labelled I(K) and I(x).3. Tail currents were analysed with a view to confirming these conductance changes. At -60 mV the tail progressed from being predominantly inward in direction after short (30-50 msec) depolarizations to being predominantly outward after long (> 300 msec) depolarizations. Inward and outward components decayed exponentially with time constants independent of previous membrane history. The Q(10)s were about 3.4. Experiments with D600 and variations of the driving force identified the inward tail component (tau approximately 55 msec at -60 mV) as I(si). The major outward tail component (tau approximately 300 msec) appears to be carried primarily by potassium. A second outward tail component (tau approximately 3 sec) of much smaller amplitude than I(K) was observed after long depolarizations and is tentatively labelled I(x).5. Membrane currents at 0 mV can be described as the sum of three exponential processes: I(si) inactivation (tau approximately 90 msec), I(K) activation (tau approximately 370 msec) and I(x) activation (tau approximately 3 sec). Conductance measurements (envelops of I(si) and I(K) tails) supported these time courses. I(si) time constants increased from 50 msec at -40 mV to 120 msec at +40 mV. I(K) time constants increased from 400 msec at -40 to about 520 msec at -25 mV before declining to 300 msec at +40 mV.6. I(si) amplitudes measured visually (difference between peak I(si) and current level after 200-500 msec) were compared with those measured graphically (semilog plots, subtraction of I(K) and I(x)). As a consequence of the relative amplitudes and time

  9. Adipose Tissue Remodeling: Its Role in Energy Metabolism and Metabolic Disorders.

    PubMed

    Choe, Sung Sik; Huh, Jin Young; Hwang, In Jae; Kim, Jong In; Kim, Jae Bum

    2016-01-01

    The adipose tissue is a central metabolic organ in the regulation of whole-body energy homeostasis. The white adipose tissue functions as a key energy reservoir for other organs, whereas the brown adipose tissue accumulates lipids for cold-induced adaptive thermogenesis. Adipose tissues secrete various hormones, cytokines, and metabolites (termed as adipokines) that control systemic energy balance by regulating appetitive signals from the central nerve system as well as metabolic activity in peripheral tissues. In response to changes in the nutritional status, the adipose tissue undergoes dynamic remodeling, including quantitative and qualitative alterations in adipose tissue-resident cells. A growing body of evidence indicates that adipose tissue remodeling in obesity is closely associated with adipose tissue function. Changes in the number and size of the adipocytes affect the microenvironment of expanded fat tissues, accompanied by alterations in adipokine secretion, adipocyte death, local hypoxia, and fatty acid fluxes. Concurrently, stromal vascular cells in the adipose tissue, including immune cells, are involved in numerous adaptive processes, such as dead adipocyte clearance, adipogenesis, and angiogenesis, all of which are dysregulated in obese adipose tissue remodeling. Chronic overnutrition triggers uncontrolled inflammatory responses, leading to systemic low-grade inflammation and metabolic disorders, such as insulin resistance. This review will discuss current mechanistic understandings of adipose tissue remodeling processes in adaptive energy homeostasis and pathological remodeling of adipose tissue in connection with immune response.

  10. Adipose Tissue Remodeling: Its Role in Energy Metabolism and Metabolic Disorders

    PubMed Central

    Choe, Sung Sik; Huh, Jin Young; Hwang, In Jae; Kim, Jong In; Kim, Jae Bum

    2016-01-01

    The adipose tissue is a central metabolic organ in the regulation of whole-body energy homeostasis. The white adipose tissue functions as a key energy reservoir for other organs, whereas the brown adipose tissue accumulates lipids for cold-induced adaptive thermogenesis. Adipose tissues secrete various hormones, cytokines, and metabolites (termed as adipokines) that control systemic energy balance by regulating appetitive signals from the central nerve system as well as metabolic activity in peripheral tissues. In response to changes in the nutritional status, the adipose tissue undergoes dynamic remodeling, including quantitative and qualitative alterations in adipose tissue-resident cells. A growing body of evidence indicates that adipose tissue remodeling in obesity is closely associated with adipose tissue function. Changes in the number and size of the adipocytes affect the microenvironment of expanded fat tissues, accompanied by alterations in adipokine secretion, adipocyte death, local hypoxia, and fatty acid fluxes. Concurrently, stromal vascular cells in the adipose tissue, including immune cells, are involved in numerous adaptive processes, such as dead adipocyte clearance, adipogenesis, and angiogenesis, all of which are dysregulated in obese adipose tissue remodeling. Chronic overnutrition triggers uncontrolled inflammatory responses, leading to systemic low-grade inflammation and metabolic disorders, such as insulin resistance. This review will discuss current mechanistic understandings of adipose tissue remodeling processes in adaptive energy homeostasis and pathological remodeling of adipose tissue in connection with immune response. PMID:27148161

  11. The contribution of HIV infection to intracranial arterial remodeling: A pilot study

    PubMed Central

    Gutierrez, Jose; Elkind, Mitchell S. V.; Petito, Carol; Chung, David Y; Dwork, Andrew J.; Marshall, Randolph S

    2015-01-01

    Pathological arterial wall changes have been cited as potential mechanisms of cerebrovascular disease in the HIV population. We hypothesize that dilatation would be present in arterial walls of patients with HIV compared to controls. Fifty-one intracranial arteries, obtained from autopsies of five individuals with HIV infection and 13 without, were fixed, embedded, stained, and digitally photographed. Cross-sectional areas of intima, media, adventitia and lumen were measured by preset color thresholding. A measure of arterial remodeling was obtained by calculating the ratio between the lumen diameter and the thickness of the arterial wall. Higher numbers indicate arterial dilatation, while lower numbers indicate arterial narrowing. HIV-infected brain donors were more frequently black (80% vs. 15%, P = 0.02) compared with uninfected donors. Inter and intra-reader agreement measures were excellent. The continuous measure of vascular remodeling was significantly higher in the arteries from HIV donors (β = 2.8, P = 0.02). Adjustments for demographics and clinical covariates strengthen this association (β = 9.3, P = 0.01). We found an association of HIV infection with outward brain arterial remodeling. This association might be mediated by a thinner media layer. The reproduction of these results and the implications of this proposed pathophysiology merits further study. PMID:23067346

  12. Intracranial pressure and skull remodeling

    PubMed Central

    McCulley, Timothy J.; Jordan Piluek, W.; Chang, Jessica

    2014-01-01

    In this article we review bony changes resulting from alterations in intracranial pressure (ICP) and the implications for ophthalmologists and the patients for whom we care. Before addressing ophthalmic implications, we will begin with a brief overview of bone remodeling. Bony changes seen with chronic intracranial hypotension and hypertension will be discussed. The primary objective of this review was to bring attention to bony changes seen with chronic intracranial hypotension. Intracranial hypotension skull remodeling can result in enophthalmos. In advanced disease enophthalmos develops to a degree that is truly disfiguring. The most common finding for which subjects are referred is ocular surface disease, related to loss of contact between the eyelids and the cornea. Other abnormalities seen include abnormal ocular motility and optic atrophy. Recognition of such changes is important to allow for diagnosis and treatment prior to advanced clinical deterioration. Routine radiographic assessment of bony changes may allow for the identification of patient with abnormal ICP prior to the development of clinically significant disease. PMID:25859141

  13. HDL biogenesis, remodeling, and catabolism.

    PubMed

    Zannis, Vassilis I; Fotakis, Panagiotis; Koukos, Georgios; Kardassis, Dimitris; Ehnholm, Christian; Jauhiainen, Matti; Chroni, Angeliki

    2015-01-01

    In this chapter, we review how HDL is generated, remodeled, and catabolized in plasma. We describe key features of the proteins that participate in these processes, emphasizing how mutations in apolipoprotein A-I (apoA-I) and the other proteins affect HDL metabolism. The biogenesis of HDL initially requires functional interaction of apoA-I with the ATP-binding cassette transporter A1 (ABCA1) and subsequently interactions of the lipidated apoA-I forms with lecithin/cholesterol acyltransferase (LCAT). Mutations in these proteins either prevent or impair the formation and possibly the functionality of HDL. Remodeling and catabolism of HDL is the result of interactions of HDL with cell receptors and other membrane and plasma proteins including hepatic lipase (HL), endothelial lipase (EL), phospholipid transfer protein (PLTP), cholesteryl ester transfer protein (CETP), apolipoprotein M (apoM), scavenger receptor class B type I (SR-BI), ATP-binding cassette transporter G1 (ABCG1), the F1 subunit of ATPase (Ecto F1-ATPase), and the cubulin/megalin receptor. Similarly to apoA-I, apolipoprotein E and apolipoprotein A-IV were shown to form discrete HDL particles containing these apolipoproteins which may have important but still unexplored functions. Furthermore, several plasma proteins were found associated with HDL and may modulate its biological functions. The effect of these proteins on the functionality of HDL is the topic of ongoing research. PMID:25522986

  14. A microsphere-based remodelling formulation for anisotropic biological tissues.

    PubMed

    Menzel, Andreas; Waffenschmidt, Tobias

    2009-09-13

    Biological tissues possess the ability to adapt according to the respective local loading conditions, which results in growth and remodelling phenomena. The main goal of this work is the development of a new remodelling approach that, on the one hand, reflects the alignment of fibrous soft biological tissue with respect to representative loading directions. On the other hand, the continuum approach proposed is based on a sound micro-mechanically motivated formulation. To be specific, use of a worm-like chain model is made to describe the behaviour of long-chain molecules as present in, for instance, collageneous tissues. The extension of such a one-dimensional constitutive equation to the three-dimensional macroscopic level is performed by means of a microsphere formulation. Inherent with the algorithmic treatment of this type of modelling approach, a finite number of unit vectors is considered for the numerical integration over the domain of the unit sphere. As a key aspect of this contribution, remodelling is incorporated by setting up evolution equations for the referential orientations of these integration directions. Accordingly, the unit vectors considered now allow interpretation as internal variables, which characterize the material's anisotropic properties. Several numerical studies underline the applicability of the model that, moreover, nicely fits into iterative finite element formulations so that general boundary value problems can be solved. PMID:19657009

  15. Transient outward currents and action potential alterations in rabbit ventricular myocytes.

    PubMed

    Kawano, S; Hiraoka, M

    1991-06-01

    To clarify ionic mechanisms underlying successive changes in action potential repolarization upon sudden increase in driving rate or initiation of rapid drive after a rest, membrane potentials and currents were recorded from isolated rabbit ventricular myocytes using the suction-pipette whole-cell clamp method. When 20 action potentials were elicited with a stimulus frequency of 2.0 Hz after a rest period of 20 s, the plateau and action potential duration showed complex changes in successive beats, whereas they were nearly constant with stimulation at 0.1 Hz. There were only weak correlations between changes in action potential parameters and preceding diastolic intervals. The changes were prominent in the first 10 beats but subsided gradually thereafter, attaining nearly steady configurations of action potentials. When depolarizing pulses were applied at a fast rate, under the voltage clamp, the amplitudes of the initial inward current in the presence of tetrodotoxin changed greatly depending on the pulse numbers and diastolic intervals, whereas the delayed outward K+ current changed little. Variations of the initial inward current in successive pulses were caused by different degrees of activation and recovery from inactivation in the Ca2+ current, the Ca(2+)-sensitive and -insensitive transient outward current. While inhibition of either one or two current components decreased the action potential alterations, blocking the three components completely abolished them. These results indicate that alterations of the Ca(2+)-sensitive and -insensitive transient outward current together with the Ca2+ current contribute to the action potential alterations after initiation of rapid drive or an increase in driving rates.

  16. Potassium channels cloned from neuroblastoma cells display slowly inactivating outward currents in Xenopus oocytes.

    PubMed

    Ito, Y; Yokoyama, S; Higashida, H

    1992-05-22

    Messenger RNAs (mRNAs) specific for NGK1 and NGK2 potassium channels were synthesized from complementary DNAs (cDNAs) that had been cloned from mouse neuroblastoma x rat glioma hybrid NG108-15 cells. Outward pottasium currents were evoked by 5 s depolarizing voltage commands in Xenopus oocytes injected with NGK1- or NGK2-specific mRNAs. The NGK1 or NGK2 currents showed different activation and inactivation kinetics, and different pharmacological sensitivities. The threshold potential for activation of the NGK2 current (-14 mV) was more positive than that for the NGK1 (-36 mV). The NGK2 current showed faster inactivation during a 5 s depolarizing pulse than did the NGK1 current. Inactivation was best fit by time constants of 0.37, 1.5 and 19 s for the NGK2 current and 4.4 and 19 s for NGK1. Extracellularly applied tetraethylammonium chloride (TEA) was 1000 times more potent on the NGK2 current than the NGK1 current. Furthermore we examined outward current following co-injection of an equal amount of mRNAs for NGK1 and NGK2. The timecourse of inactivation differed from either alone or from a simple sum of the two individual currents. TEA sensitivity could not be explained by summation of the two homomultimeric channels. These findings suggest that both NGK1 and NGK2 proteins assemble to form heteromultimeric K+ channels in addition to homomultimeric K+ channels. NGK2 channels and the heteromultimeric channels may be responsible for the native transient outward current with slow inactivation in NG108-15 hybrid cells.

  17. Stochastic lattice model for bone remodeling and aging.

    PubMed

    Weinkamer, Richard; Hartmann, Markus A; Brechet, Yves; Fratzl, Peter

    2004-11-26

    We investigate the remodeling process of trabecular bone inside a human vertebral body using a stochastic lattice model, in which the ability of living bone to adapt to mechanical stimuli is incorporated. Our simulations show the emergence of a networklike structure similar to real trabecular bone. With time, the bone volume fraction reaches a steady state. The microstructure, however, coarsens with a typical length in the system following a power law. The simulation results suggest that a coarsening of the trabecular structure should occur as a natural aging phenomenon, not related to disease.

  18. Bone remodeling and silicon deficiency in rats

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Alveolar bone undergoes continuous remodeling to meet physiologic and functional demands. The aim of the present work was to evaluate histologically and histomorphometrically the effect of silicon deficiency on bone modeling and remodeling in the periodontal cortical plate. Two groups of weaning mal...

  19. Chromatin Remodelers: From Function to Dysfunction.

    PubMed

    Längst, Gernot; Manelyte, Laura

    2015-01-01

    Chromatin remodelers are key players in the regulation of chromatin accessibility and nucleosome positioning on the eukaryotic DNA, thereby essential for all DNA dependent biological processes. Thus, it is not surprising that upon of deregulation of those molecular machines healthy cells can turn into cancerous cells. Even though the remodeling enzymes are very abundant and a multitude of different enzymes and chromatin remodeling complexes exist in the cell, the particular remodeling complex with its specific nucleosome positioning features must be at the right place at the right time in order to ensure the proper regulation of the DNA dependent processes. To achieve this, chromatin remodeling complexes harbor protein domains that specifically read chromatin targeting signals, such as histone modifications, DNA sequence/structure, non-coding RNAs, histone variants or DNA bound interacting proteins. Recent studies reveal the interaction between non-coding RNAs and chromatin remodeling complexes showing importance of RNA in remodeling enzyme targeting, scaffolding and regulation. In this review, we summarize current understanding of chromatin remodeling enzyme targeting to chromatin and their role in cancer development. PMID:26075616

  20. A numerical calculation of outward propagation of solar disturbances. [solar atmospheric model with shock wave propagation

    NASA Technical Reports Server (NTRS)

    Wu, S. T.

    1974-01-01

    The responses of the solar atmosphere due to an outward propagation shock are examined by employing the Lax-Wendroff method to solve the set of nonlinear partial differential equations in the model of the solar atmosphere. It is found that this theoretical model can be used to explain the solar phenomena of surge and spray. A criterion to discriminate the surge and spray is established and detailed information concerning the density, velocity, and temperature distribution with respect to the height and time is presented. The complete computer program is also included.

  1. Nucleosome dynamics during chromatin remodeling in vivo

    PubMed Central

    Ramachandran, Srinivas; Henikoff, Steven

    2016-01-01

    ABSTRACT Precise positioning of nucleosomes around regulatory sites is achieved by the action of chromatin remodelers, which use the energy of ATP to slide, evict or change the composition of nucleosomes. Chromatin remodelers act to bind nucleosomes, disrupt histone-DNA interactions and translocate the DNA around the histone core to reposition nucleosomes. Hence, remodeling is expected to involve nucleosomal intermediates with a structural organization that is distinct from intact nucleosomes. We describe the identification of a partially unwrapped nucleosome structure using methods that map histone-DNA contacts genome-wide. This alternative nucleosome structure is likely formed as an intermediate or by-product during nucleosome remodeling by the RSC complex. Identification of the loss of histone-DNA contacts during chromatin remodeling by RSC in vivo has implications for the regulation of transcriptional initiation. PMID:26933790

  2. Lipid Acyl Chain Remodeling in Yeast

    PubMed Central

    Renne, Mike F.; Bao, Xue; De Smet, Cedric H.; de Kroon, Anton I. P. M.

    2015-01-01

    Membrane lipid homeostasis is maintained by de novo synthesis, intracellular transport, remodeling, and degradation of lipid molecules. Glycerophospholipids, the most abundant structural component of eukaryotic membranes, are subject to acyl chain remodeling, which is defined as the post-synthetic process in which one or both acyl chains are exchanged. Here, we review studies addressing acyl chain remodeling of membrane glycerophospholipids in Saccharomyces cerevisiae, a model organism that has been successfully used to investigate lipid synthesis and its regulation. Experimental evidence for the occurrence of phospholipid acyl chain exchange in cardiolipin, phosphatidylcholine, phosphatidylinositol, and phosphatidylethanolamine is summarized, including methods and tools that have been used for detecting remodeling. Progress in the identification of the enzymes involved is reported, and putative functions of acyl chain remodeling in yeast are discussed. PMID:26819558

  3. Age‐related remodeling of small arteries is accompanied by increased sphingomyelinase activity and accumulation of long‐chain ceramides

    PubMed Central

    Ohanian, Jacqueline; Liao, Aiyin; Forman, Simon P.; Ohanian, Vasken

    2014-01-01

    Abstract The structure and function of large arteries alters with age leading to increased risk of cardiovascular disease. Age‐related large artery remodeling and arteriosclerosis is associated with increased collagen deposition, inflammation, and endothelial dysfunction. Bioactive sphingolipids are known to regulate these processes, and are also involved in aging and cellular senescence. However, less is known about age‐associated alterations in small artery morphology and function or whether changes in arterial sphingolipids occur in aging. We show that mesenteric small arteries from old sheep have increased lumen diameter and media thickness without a change in media to lumen ratio, indicative of outward hypertrophic remodeling. This remodeling occurred without overt changes in blood pressure or pulse pressure indicating it was a consequence of aging per se. There was no age‐associated change in mechanical properties of the arteries despite an increase in total collagen content and deposition of collagen in a thickened intima layer in arteries from old animals. Analysis of the sphingolipid profile showed an increase in long‐chain ceramide (C14–C20), but no change in the levels of sphingosine or sphingosine‐1‐phosphate in arteries from old compared to young animals. This was accompanied by a parallel increase in acid and neutral sphingomyelinase activity in old arteries compared to young. This study demonstrates remodeling of small arteries during aging that is accompanied by accumulation of long‐chain ceramides. This suggests that sphingolipids may be important mediators of vascular aging. PMID:24872355

  4. Chromatin remodeling in nuclear cloning.

    PubMed

    Wade, Paul A; Kikyo, Nobuaki

    2002-05-01

    Nuclear cloning is a procedure to create new animals by injecting somatic nuclei into unfertilized oocytes. Recent successes in mammalian cloning with differentiated adult nuclei strongly indicate that oocyte cytoplasm contains unidentified remarkable reprogramming activities with the capacity to erase the previous memory of cell differentiation. At the heart of this nuclear reprogramming lies chromatin remodeling as chromatin structure and function define cell differentiation through regulation of the transcriptional activities of the cells. Studies involving the modification of chromatin elements such as selective uptake or release of binding proteins, covalent histone modifications including acetylation and methylation, and DNA methylation should provide significant insight into the molecular mechanisms of nuclear dedifferentiation and redifferentiation in oocyte cytoplasm.

  5. Thyroid Hormone and Vascular Remodeling.

    PubMed

    Ichiki, Toshihiro

    2016-01-01

    Both hyperthyroidism and hypothyroidism affect the cardiovascular system. Hypothyroidism is known to be associated with enhanced atherosclerosis and ischemic heart diseases. The accelerated atherosclerosis in the hypothyroid state has been traditionally ascribed to atherogenic lipid profile, diastolic hypertension, and impaired endothelial function. However, recent studies indicate that thyroid hormone has direct anti-atherosclerotic effects, such as production of nitric oxide and suppression of smooth muscle cell proliferation. These data suggest that thyroid hormone inhibits atherogenesis through direct effects on the vasculature as well as modification of risk factors for atherosclerosis. This review summarizes the basic and clinical studies on the role of thyroid hormone in vascular remodeling. The possible application of thyroid hormone mimetics to the therapy of hypercholesterolemia and atherosclerosis is also discussed. PMID:26558400

  6. H3K4 monomethylation dictates nucleosome dynamics and chromatin remodeling at stress-responsive genes.

    PubMed

    Nadal-Ribelles, Mariona; Mas, Glòria; Millán-Zambrano, Gonzalo; Solé, Carme; Ammerer, Gustav; Chávez, Sebastián; Posas, Francesc; de Nadal, Eulàlia

    2015-05-26

    Chromatin remodeling is essential for proper adaptation to extracellular stimuli. The p38-related Hog1 SAPK is an important regulator of transcription that mediates chromatin remodeling upon stress. Hog1 targets the RSC chromatin remodeling complex to stress-responsive genes and rsc deficient cells display reduced induction of gene expression. Here we show that the absence of H3K4 methylation, either achieved by deletion of the SET1 methyltransferase or by amino acid substitution of H3K4, bypasses the requirement of RSC for stress-responsive gene expression. Monomethylation of H3K4 is specifically inhibiting RSC-independent chromatin remodeling and thus, it prevents osmostress-induced gene expression. The absence of H3K4 monomethylation permits that the association of alternative remodelers with stress-responsive genes and the Swr1 complex (SWR-C) is instrumental in the induction of gene expression upon stress. Accordingly, the absence of SWR-C or histone H2A.Z results in compromised chromatin remodeling and impaired gene expression in the absence of RSC and H3K4 methylation. These results indicate that expression of stress-responsive genes is controlled by two remodeling mechanisms: RSC in the presence of monomethylated H3K4, and SWR-C in the absence of H3K4 monomethylation. Our findings point to a novel role for H3K4 monomethylation in dictating the specificity of chromatin remodeling, adding an extra layer of regulation to the transcriptional stress response.

  7. Outward Rectification of Voltage-Gated K+ Channels Evolved at Least Twice in Life History.

    PubMed

    Riedelsberger, Janin; Dreyer, Ingo; Gonzalez, Wendy

    2015-01-01

    Voltage-gated potassium (K+) channels are present in all living systems. Despite high structural similarities in the transmembrane domains (TMD), this K+ channel type segregates into at least two main functional categories-hyperpolarization-activated, inward-rectifying (Kin) and depolarization-activated, outward-rectifying (Kout) channels. Voltage-gated K+ channels sense the membrane voltage via a voltage-sensing domain that is connected to the conduction pathway of the channel. It has been shown that the voltage-sensing mechanism is the same in Kin and Kout channels, but its performance results in opposite pore conformations. It is not known how the different coupling of voltage-sensor and pore is implemented. Here, we studied sequence and structural data of voltage-gated K+ channels from animals and plants with emphasis on the property of opposite rectification. We identified structural hotspots that alone allow already the distinction between Kin and Kout channels. Among them is a loop between TMD S5 and the pore that is very short in animal Kout, longer in plant and animal Kin and the longest in plant Kout channels. In combination with further structural and phylogenetic analyses this finding suggests that outward-rectification evolved twice and independently in the animal and plant kingdom.

  8. Outward atmospheric scintillation effects and inward atmospheric scintillation effects comparisons for direct detection ladar applications

    NASA Astrophysics Data System (ADS)

    Youmans, Douglas G.

    2014-06-01

    Atmospheric turbulence produces intensity modulation or "scintillation" effects on both on the outward laser-mode path and on the return backscattered radiation path. These both degrade laser radar (ladar) target acquisition, ranging, imaging, and feature estimation. However, the finite sized objects create scintillation averaging on the outgoing path and the finite sized telescope apertures produce scintillation averaging on the return path. We expand on previous papers going to moderate to strong turbulence cases by starting from a 20kft altitude platform and propagating at 0° elevation (with respect to the local vertical) for 100km range to a 1 m diameter diffuse sphere. The outward scintillation and inward scintillation effects, as measured at the focal plane detector array of the receiving aperture, will be compared. To eliminate hard-body surface speckle effects in order to study scintillation, Goodman's M-parameter is set to 106 in the analytical equations and the non-coherent imaging algorithm is employed in Monte Carlo realizations. The analytical equations of the signal-to-noise ratio (SNRp), or mean squared signal over a variance, for a given focal plane array pixel window of interest will be summarized and compared to Monte Carlo realizations of a 1m diffuse sphere.

  9. Effects of calcium on the steady outward currents at the equator of the rat lens.

    PubMed

    Parmelee, J T; Robinson, K R; Patterson, J W

    1985-10-01

    The relationships between calcium and the steady outward currents at the equator of the rat lens were studied using the vibrating probe technique. In a calcium-free medium, the current was greatly increased and it returned to its original level when calcium was restored to the medium. The Ca-free effect was not observed in Na-free medium. Iodoacetate (IAA) inhibited the initial current, but a current then returned which is referred to as a secondary current. The secondary current was not observed in a Ca-free medium and, therefore, it is thought to be a calcium-dependent potassium current. These responses are consistent with effects on potassium efflux measured by others and lend support to the interpretation that the outward currents observed at the equator of the rat lens are potassium currents. The currents are partially inhibited but not abolished in Na-free bathing medium. This is consistent with the view that the inward currents at the optical poles may be related to the influx of sodium.

  10. Moderate Hypoxia Influences Potassium Outward Currents in Adipose-Derived Stem Cells

    PubMed Central

    Prasad, Mayuri; Zachar, Vladimir; Fink, Trine; Pennisi, Cristian Pablo

    2014-01-01

    Moderate hypoxic preconditioning of adipose-derived stem cells (ASCs) enhances properties such as proliferation and secretion of growth factors, representing a valuable strategy to increase the efficiency of cell-based therapies. In a wide variety of cells potassium (K+) channels are key elements involved in the cellular responses to hypoxia, suggesting that ASCs cultured under low oxygen conditions may display altered electrophysiological properties. Here, the effects of moderate hypoxic culture on proliferation, whole-cell currents, and ion channel expression were investigated using human ASCs cultured at 5% and 20% oxygen. Although cell proliferation was greatly enhanced, the dose-dependent growth inhibition by the K+ channel blocker tetraethylammonium (TEA) was not significantly affected by hypoxia. Under both normoxic and hypoxic conditions, ASCs displayed outward K+ currents composed by Ca2+-activated, delayed rectifier, and transient components. Hypoxic culture reduced the slope of the current-voltage curves and caused a negative shift in the voltage activation threshold of the whole-cell currents. However, the TEA-mediated shift of voltage activation threshold was not affected by hypoxia. Semiquantitative real-time RT-PCR revealed that expression of genes encoding for various ion channels subunits related to oxygen sensing and proliferation remained unchanged after hypoxic culture. In conclusion, outward currents are influenced by moderate hypoxia in ASCs through a mechanism that is not likely the result of modulation of TEA-sensitive K+ channels. PMID:25115627

  11. Outward bound, diabetes and motivation: experiential education in a wilderness setting.

    PubMed

    Herskowitz, R D

    1990-08-01

    Effective diabetes management requires the commitment to take charge of one's life, and the strength to face the daily challenges the illness presents on a long-term basis. Outward Bound Programmes utilize challenging experiences in a wilderness setting to foster personal growth and responsibility, and to encourage the participants to reach beyond their limitations. Six Outward Bound courses were taught, to a total of 56 students with Type 1 diabetes, 14 to 42 years old. With appropriate precautions, the fairly strenuous programme was conducted safely. A battery of psychosocial measures, administered to the initial pilot group of eight students before the course, and again 7 to 11 months after returning home, indicated a statistically significant improvement in problem scores on the Achenbach Youth Self-Report Profile, and suggested modest improvements in diabetes adjustment, locus of control, and self-esteem. Other course participants report having had an exhilarating experience, which helped to increase their self-confidence and determination to take charge. A few have begun to break previous patterns of dysfunction. Many have acquired new insights into the causes of fluctuating blood sugars, and into the options at their disposal to optimize self-care. PMID:2146073

  12. Compensatory saccade differences between outward versus inward head impulses in chronic unilateral vestibular hypofunction.

    PubMed

    Lee, Seung-Han; Newman-Toker, David E; Zee, David S; Schubert, Michael C

    2014-10-01

    The horizontal head impulse test (HIT) is a valuable clinical tool that can help identify peripheral vestibular hypofunction by the refixation (compensatory) saccade that returns the eyes to the target of interest after the head has stopped. We asked if there were differences in the compensatory saccade responses during the HIT when the head was rotated away or toward straight ahead (outward versus inward). We also investigated the influence of a fixation target. Using scleral search-coils, we tested five patients with chronic unilateral vestibular hypofunction (UVH) and three healthy control subjects. In UVH patients, the latencies of both overt and covert saccades were longer when the head was rotated inward from an initially eccentric position, regardless of a visual target. The proportion of HIT with covert saccades was independent of a visual target. In control subjects no compensatory saccades were observed and there were no differences in either angular vestibulo-ocular reflex gain or latency between inward and outward HIT. Our data suggest that inward applied HIT in chronic UVH is more likely to include an overt compensatory saccade based on its lengthened latency. Neither latency nor the occurrence of covert compensatory saccades during HIT depended on a visual target, suggesting they have become a learned behavior in response to chronic UVH.

  13. Outward Rectification of Voltage-Gated K+ Channels Evolved at Least Twice in Life History.

    PubMed

    Riedelsberger, Janin; Dreyer, Ingo; Gonzalez, Wendy

    2015-01-01

    Voltage-gated potassium (K+) channels are present in all living systems. Despite high structural similarities in the transmembrane domains (TMD), this K+ channel type segregates into at least two main functional categories-hyperpolarization-activated, inward-rectifying (Kin) and depolarization-activated, outward-rectifying (Kout) channels. Voltage-gated K+ channels sense the membrane voltage via a voltage-sensing domain that is connected to the conduction pathway of the channel. It has been shown that the voltage-sensing mechanism is the same in Kin and Kout channels, but its performance results in opposite pore conformations. It is not known how the different coupling of voltage-sensor and pore is implemented. Here, we studied sequence and structural data of voltage-gated K+ channels from animals and plants with emphasis on the property of opposite rectification. We identified structural hotspots that alone allow already the distinction between Kin and Kout channels. Among them is a loop between TMD S5 and the pore that is very short in animal Kout, longer in plant and animal Kin and the longest in plant Kout channels. In combination with further structural and phylogenetic analyses this finding suggests that outward-rectification evolved twice and independently in the animal and plant kingdom. PMID:26356684

  14. Outward Rectification of Voltage-Gated K+ Channels Evolved at Least Twice in Life History

    PubMed Central

    Riedelsberger, Janin; Dreyer, Ingo; Gonzalez, Wendy

    2015-01-01

    Voltage-gated potassium (K+) channels are present in all living systems. Despite high structural similarities in the transmembrane domains (TMD), this K+ channel type segregates into at least two main functional categories—hyperpolarization-activated, inward-rectifying (Kin) and depolarization-activated, outward-rectifying (Kout) channels. Voltage-gated K+ channels sense the membrane voltage via a voltage-sensing domain that is connected to the conduction pathway of the channel. It has been shown that the voltage-sensing mechanism is the same in Kin and Kout channels, but its performance results in opposite pore conformations. It is not known how the different coupling of voltage-sensor and pore is implemented. Here, we studied sequence and structural data of voltage-gated K+ channels from animals and plants with emphasis on the property of opposite rectification. We identified structural hotspots that alone allow already the distinction between Kin and Kout channels. Among them is a loop between TMD S5 and the pore that is very short in animal Kout, longer in plant and animal Kin and the longest in plant Kout channels. In combination with further structural and phylogenetic analyses this finding suggests that outward-rectification evolved twice and independently in the animal and plant kingdom. PMID:26356684

  15. Tethys and Dione as sources of outward-flowing plasma in Saturn's magnetosphere.

    PubMed

    Burch, J L; Goldstein, J; Lewis, W S; Young, D T; Coates, A J; Dougherty, M K; André, N

    2007-06-14

    Rotating at over twice the angular speed of Earth, Saturn imposes a rapid spin on its magnetosphere. As a result, cold, dense plasma is believed to be flung outward from the inner magnetosphere by centrifugal force and replaced by hotter, more tenuous plasma from the outer magnetosphere. The centrifugal interchange of plasmas in rotating magnetospheres was predicted many years ago and was conclusively demonstrated by observations in Jupiter's magnetosphere, which--like that of Saturn (but unlike that of Earth)--is rotationally dominated. Recent observations in Saturn's magnetosphere have revealed narrow injections of hot, tenuous plasma believed to be the inward-moving portion of the centrifugal interchange cycle. Here we report observations of the distribution of the angle between the electron velocity vector and the magnetic field vector ('pitch angle') obtained in the cold, dense plasma adjacent to these inward injection regions. The observed pitch-angle distributions are indicative of outward plasma flow and consistent with centrifugal interchange in Saturn's magnetosphere. Further, we conclude that the observed double-peaked ('butterfly') pitch-angle distributions result from the transport of plasma from regions near the orbits of Dione and Tethys, supporting the idea of distinct plasma tori associated with these moons.

  16. Classical confinement and outward convection of impurity ions in the MST RFP

    NASA Astrophysics Data System (ADS)

    Kumar, S. T. A.; Den Hartog, D. J.; Mirnov, V. V.; Caspary, K. J.; Magee, R. M.; Brower, D. L.; Chapman, B. E.; Craig, D.; Ding, W. X.; Eilerman, S.; Fiksel, G.; Lin, L.; Nornberg, M.; Parke, E.; Reusch, J. A.; Sarff, J. S.

    2012-05-01

    Impurity ion dynamics measured with simultaneously high spatial and temporal resolution reveal classical ion transport in the reversed-field pinch. The boron, carbon, oxygen, and aluminum impurity ion density profiles are obtained in the Madison Symmetric Torus [R. N. Dexter et al., Fusion Technol. 19, 131 (1991)] using a fast, active charge-exchange-recombination-spectroscopy diagnostic. Measurements are made during improved-confinement plasmas obtained using inductive control of tearing instability to mitigate stochastic transport. At the onset of the transition to improved confinement, the impurity ion density profile becomes hollow, with a slow decay in the core region concurrent with an increase in the outer region, implying an outward convection of impurities. Impurity transport from Coulomb collisions in the reversed-field pinch is classical for all collisionality regimes, and analysis shows that the observed hollow profile and outward convection can be explained by the classical temperature screening mechanism. The profile agrees well with classical expectations. Experiments performed with impurity pellet injection provide further evidence for classical impurity ion confinement.

  17. Relationship between transient outward K+ current and Ca2+ influx in rat cardiac myocytes of endo- and epicardial origin

    PubMed Central

    Volk, Tilmann; Nguyen, Thi Hong-Diep; Schultz, Jobst-Hendrik; Ehmke, Heimo

    1999-01-01

    The transient outward K+ current (Ito) is a major repolarizing ionic current in ventricular myocytes of several mammals. Recently it has been found that its magnitude depends on the origin of the myocyte and is regulated by a number of physiological and pathophysiological signals. The relationship between the magnitude of Ito, action potential duration (APD) and Ca2+ influx (QCa) was studied in rat left ventricular myocytes of endo- and epicardial origin using whole-cell recordings and the action potential voltage-clamp method. Under control conditions, in response to a depolarizing voltage step to +40 mV, Ito averaged 12.1 ± 2.6 pA pF−1 in endocardial (n = 11) and 24.0 ± 2.6 pA pF−1 in epicardial myocytes (n = 12; P < 0.01). APD90 (90 % repolarization) was twice as long in endocardial myocytes, whereas QCa inversely depended on the magnitude of Ito. L-type Ca2+ current density was similar in myocytes from both regions. To determine the effects of controlled reductions of Ito on QCa, recordings were repeated in the presence of increasing concentrations of the Ito inhibitor 4-aminopyridine. Inhibition of Ito by as little as 20 % more than doubled QCa in epicardial myocytes, whereas it had only a minor effect on QCa in myocytes of endocardial origin. Further inhibition of Ito led to a progressive increase in QCa in epicardial myocytes; at 90 % inhibition of Ito, QCa was four times larger than the control value. We conclude that moderate changes in the magnitude of Ito strongly affect QCa primarily in epicardial regions. An alteration of Ito might therefore allow for a regional regulation of contractility during physiological and pathophysiological adaptations. PMID:10457095

  18. Maternal uterine vascular remodeling during pregnancy.

    PubMed

    Osol, George; Mandala, Maurizio

    2009-02-01

    Sufficient uteroplacental blood flow is essential for normal pregnancy outcome and is accomplished by the coordinated growth and remodeling of the entire uterine circulation, as well as the creation of a new fetal vascular organ: the placenta. The process of remodeling involves a number of cellular processes, including hyperplasia and hypertrophy, rearrangement of existing elements, and changes in extracellular matrix. In this review, we provide information on uterine blood flow increases during pregnancy, the influence of placentation type on the distribution of uterine vascular resistance, consideration of the patterns, nature, and extent of maternal uterine vascular remodeling during pregnancy, and what is known about the underlying cellular mechanisms.

  19. Reverse Cardiac Remodeling: A Marker of Better Prognosis in Heart Failure

    PubMed Central

    Reis, José Rosino de Araújo Rocha; Cardoso, Juliano Novaes; Cardoso, Cristina Martins dos Reis; Pereira-Barretto, Antonio Carlos

    2015-01-01

    In heart failure syndrome, myocardial dysfunction causes an increase in neurohormonal activity, which is an adaptive and compensatory mechanism in response to the reduction in cardiac output. Neurohormonal activity is initially stimulated in an attempt to maintain compensation; however, when it remains increased, it contributes to the intensification of clinical manifestations and myocardial damage. Cardiac remodeling comprises changes in ventricular volume as well as the thickness and shape of the myocardial wall. With optimized treatment, such remodeling can be reversed, causing gradual improvement in cardiac function and consequently improved prognosis. PMID:26131706

  20. Overaluminizing of a CoNiCrAlY Coating by Inward and Outward Diffusion Treatments

    NASA Astrophysics Data System (ADS)

    Bababdani, Samira Mohseni; Nogorani, Farhad Shahriari

    2014-04-01

    Overaluminizing is a commercially accepted treatment to enhance high temperature oxidation resistance of MCrAlY overlay coatings. In the current investigation, a low pressure plasma-sprayed CoNiCrAlY coating was aluminized by two different growth modes: outward growth and inward growth. The resultant microstructures were characterized by means of scanning electron microscopy, energy dispersive spectroscopy, and X-ray diffraction analysis. The results showed that the final microstructure of both types of overaluminized coatings was similar and included Al-rich NiAl and Ni-rich NiAl zones from the top to the bottom. The details of the microstructures are discussed and compared with the results of simple aluminizing of the nickel-based substrate.

  1. Raise the Floor When Remodeling Science Labs

    ERIC Educational Resources Information Center

    Nation's Schools, 1972

    1972-01-01

    A new remodeling idea adopts the concept of raised floor covering gas, water, electrical, and drain lines. The accessible floor has removable panels set into an adjustable support frame 24 inches above a concrete subfloor. (Author)

  2. Lead Poisoning in Remodeling of Old Homes

    ERIC Educational Resources Information Center

    Barnes, Bart

    1973-01-01

    An article based on Dr. Muriel D. Wolf's study of elevated blood lead levels in children and adults present during the remodeling of old homes. Lead poisoning examples, symptoms, and precautions are given. (ST)

  3. Enhancement of an outwardly rectifying chloride channel in hippocampal pyramidal neurons after cerebral ischemia.

    PubMed

    Li, Jianguo; Chang, Quanzhong; Li, Xiaoming; Li, Xiawen; Qiao, Jiantian; Gao, Tianming

    2016-08-01

    Cerebral ischemia induces delayed, selective neuronal death in the CA1 region of the hippocampus. The underlying molecular mechanisms remain unclear, but it is known that apoptosis is involved in this process. Chloride efflux has been implicated in the progression of apoptosis in various cell types. Using both the inside-out and whole-cell configurations of the patch-clamp technique, the present study characterized an outwardly rectifying chloride channel (ORCC) in acutely dissociated pyramid neurons in the hippocampus of adult rats. The channel had a nonlinear current-voltage relationship with a conductance of 42.26±1.2pS in the positive voltage range and 18.23±0.96pS in the negative voltage range, indicating an outward rectification pattern. The channel is Cl(-) selective, and the open probability is voltage-dependent. It can be blocked by the classical Cl(-) channel blockers DIDS, SITS, NPPB and glibenclamide. We examined the different changes in ORCC activity in CA1 and CA3 pyramidal neurons at 6, 24 and 48h after transient forebrain ischemia. In the vulnerable CA1 neurons, ORCC activity was persistently enhanced after ischemic insult, whereas in the invulnerable CA3 neurons, no significant changes occurred. Further analysis of channel kinetics suggested that multiple openings are a major contributor to the increase in channel activity after ischemia. Pharmacological blockade of the ORCC partly attenuated cell death in the hippocampal neurons. We propose that the enhanced activity of ORCC might contribute to selective neuronal damage in the CA1 region after cerebral ischemia, and that ORCC may be a therapeutic target against ischemia-induced cell death. PMID:27181516

  4. Bone Remodeling Under Pathological Conditions.

    PubMed

    Xiao, Wenmei; Li, Shuai; Pacios, Sandra; Wang, Yu; Graves, Dana T

    2016-01-01

    Bone is masterfully programmed to repair itself through the coupling of bone formation following bone resorption, a process referred to as coupling. In inflammatory or other conditions, the balance between bone resorption and bone formation shifts so that a net bone loss results. This review focuses on four pathologic conditions in which remodeling leads to net loss of bone, postmenopausal osteoporosis, arthritis, periodontal disease, and disuse bone loss, which is similar to bone loss associated with microgravity. In most of these there is an acceleration of the resorptive process due to increased formation of bone metabolic units. This initially leads to a net bone loss since the time period of resorption is much faster than the time needed for bone formation that follows. In addition, each of these processes is characterized by an uncoupling that leads to net bone loss. Mechanisms responsible for increased rates of bone resorption, i.e. the formation of more bone metabolic units, involve enhanced expression of inflammatory cytokines and increased expression of RANKL. Moreover, the reasons for uncoupling are discussed which range from a decrease in expression of growth factors and bone morphogenetic proteins to increased expression of factors that inhibit Wnt signaling. PMID:26599114

  5. Remodeling kitchens: A smorgasbord of energy savings

    SciTech Connect

    Sullivan, B.

    1995-09-01

    The kitchen is often the busiest room in the house and is most likely to remodeled repeatedly over the life of a house. The kitchen also represents a concentration of household energy use. Remodeling a kitchen can mean introducing a host of new energy-saving features or making major energy blunders. This article discusses ways to utilized the best features: layout and design; appliances; lighting; windows and skylights; ventilation; insulation and air sealing; water; household recycling; green building materials.

  6. [Bone remodelling using the boundary element method].

    PubMed

    Martínez, Gabriela; Cerrolaza, Miguel

    2003-01-01

    An algorithm for the mathematical representation of external bone remodeling is proposed. The Boundary element method is used for the numerical analysis of trabecular bone, together with the remodeling algorithm presented by Fridez. The versatility and power of the algorithm discussed herein are shown by some numerical examples. As well, the method converges very fast to the solution, which is one of the main advantages of the proposed numerical scheme.

  7. Biomechanics of vascular mechanosensation and remodeling

    PubMed Central

    Baeyens, Nicolas; Schwartz, Martin A.

    2016-01-01

    Flowing blood exerts a frictional force, fluid shear stress (FSS), on the endothelial cells that line the blood and lymphatic vessels. The magnitude, pulsatility, and directional characteristics of FSS are constantly sensed by the endothelium. Sustained increases or decreases in FSS induce vessel remodeling to maintain proper perfusion of tissue. In this review, we discuss these mechanisms and their relevance to physiology and disease, and propose a model for how information from different mechanosensors might be integrated to govern remodeling. PMID:26715421

  8. Physiology and pathophysiology of bone remodeling.

    PubMed

    Raisz, L G

    1999-08-01

    The skeleton is a metabolically active organ that undergoes continuous remodeling throughout life. This remodeling is necessary both to maintain the structural integrity of the skeleton and to subserve its metabolic functions as a storehouse of calcium and phosphorus. These dual functions often come into conflict under conditions of changing mechanical forces or metabolic and nutritional stress. The bone remodeling cycle involves a complex series of sequential steps that are highly regulated. The "activation" phase of remodeling is dependent on the effects of local and systemic factors on mesenchymal cells of the osteoblast lineage. These cells interact with hematopoietic precursors to form osteoclasts in the "resorption" phase. Subsequently, there is a "reversal" phase during which mononuclear cells are present on the bone surface. They may complete the resorption process and produce the signals that initiate formation. Finally, successive waves of mesenchymal cells differentiate into functional osteoblasts, which lay down matrix in the "formation" phase. The effects of calcium-regulating hormones on this remodeling cycle subserve the metabolic functions of the skeleton. Other systemic hormones control overall skeletal growth. The responses to changes in mechanical force and repair of microfractures, as well as the maintenance of the remodeling cycle, are determined locally by cytokines, prostaglandins, and growth factors. Interactions between systemic and local factors are important in the pathogenesis of osteoporosis as well as the skeletal changes in hyperparathyroidism and hyperthyroidism. Local factors are implicated in the pathogenesis of the skeletal changes associated with immobilization, inflammation, and Paget disease of bone. PMID:10430818

  9. Epigenomic regulation of oncogenesis by chromatin remodeling.

    PubMed

    Kumar, R; Li, D-Q; Müller, S; Knapp, S

    2016-08-25

    Disruption of the intricate gene expression program represents one of major driving factors for the development, progression and maintenance of human cancer, and is often associated with acquired therapeutic resistance. At the molecular level, cancerous phenotypes are the outcome of cellular functions of critical genes, regulatory interactions of histones and chromatin remodeling complexes in response to dynamic and persistent upstream signals. A large body of genetic and biochemical evidence suggests that the chromatin remodelers integrate the extracellular and cytoplasmic signals to control gene activity. Consequently, widespread dysregulation of chromatin remodelers and the resulting inappropriate expression of regulatory genes, together, lead to oncogenesis. We summarize the recent developments and current state of the dysregulation of the chromatin remodeling components as the driving mechanism underlying the growth and progression of human tumors. Because chromatin remodelers, modifying enzymes and protein-protein interactions participate in interpreting the epigenetic code, selective chromatin remodelers and bromodomains have emerged as new frontiers for pharmacological intervention to develop future anti-cancer strategies to be used either as single-agent or in combination therapies with chemotherapeutics or radiotherapy. PMID:26804164

  10. Seasonal and post-trauma remodeling in cone-dominant ground squirrel retina.

    PubMed

    Merriman, Dana K; Sajdak, Benjamin S; Li, Wei; Jones, Bryan W

    2016-09-01

    With a photoreceptor mosaic containing ∼85% cones, the ground squirrel is one of the richest known mammalian sources of these important retinal cells. It also has a visual ecology much like the human's. While the ground squirrel retina is understandably prominent in the cone biochemistry, physiology, and circuitry literature, far less is known about the remodeling potential of its retinal pigment epithelium, neurons, macroglia, or microglia. This review aims to summarize the data from ground squirrel retina to this point in time, and to relate them to data from other brain areas where appropriate. We begin with a survey of the ground squirrel visual system, making comparisons with traditional rodent models and with human. Because this animal's status as a hibernator often goes unnoticed in the vision literature, we then present a brief primer on hibernation biology. Next we review what is known about ground squirrel retinal remodeling concurrent with deep torpor and with rapid recovery upon re-warming. Notable here is rapidly-reversible, temperature-dependent structural plasticity of cone ribbon synapses, as well as pre- and post-synaptic plasticity throughout diverse brain regions. It is not yet clear if retinal cell types other than cones engage in torpor-associated synaptic remodeling. We end with the small but intriguing literature on the ground squirrel retina's remodeling responses to insult by retinal detachment. Notable for widespread loss of (cone) photoreceptors, there is surprisingly little remodeling of the RPE or Müller cells. Microglial activation appears minimal, and remodeling of surviving second- and third-order neurons seems absent, but both require further study. In contrast, traumatic brain injury in the ground squirrel elicits typical macroglial and microglial responses. Overall, the data to date strongly suggest a heretofore unrecognized, natural checkpoint between retinal deafferentiation and RPE and Müller cell remodeling events. As we

  11. Computational biomechanics of bone's responses to dental prostheses - osseointegration, remodeling and resorption

    NASA Astrophysics Data System (ADS)

    Li, Wei; Rungsiyakull, Chaiy; Field, Clarice; Lin, Daniel; Zhang, Leo; Li, Qing; Swain, Michael

    2010-06-01

    Clinical and experimental studies showed that human bone has the ability to remodel itself to better adapt to its biomechanical environment by changing both its material properties and geometry. As a consequence of the rapid development and extensive applications of major dental restorations such as implantation and fixed partial denture (FPD), the effect of bone remodeling on the success of a dental restorative surgery is becoming critical for prosthetic design and pre-surgical assessment. This paper aims to provide a computational biomechanics framework to address dental bone's responses as a result of dental restoration. It explored three important issues of resorption, apposition and osseointegration in terms of remodeling simulation. The published remodeling data in long bones were regulated to drive the computational remodeling prediction for the dental bones by correlating the results to clinical data. It is anticipated that the study will provide a more predictive model of dental bone response and help develop a new design methodology for patient-specific dental prosthetic restoration.

  12. ATP-dependent chromatin remodeling in the DNA-damage response

    PubMed Central

    2012-01-01

    The integrity of DNA is continuously challenged by metabolism-derived and environmental genotoxic agents that cause a variety of DNA lesions, including base alterations and breaks. DNA damage interferes with vital processes such as transcription and replication, and if not repaired properly, can ultimately lead to premature aging and cancer. Multiple DNA pathways signaling for DNA repair and DNA damage collectively safeguard the integrity of DNA. Chromatin plays a pivotal role in regulating DNA-associated processes, and is itself subject to regulation by the DNA-damage response. Chromatin influences access to DNA, and often serves as a docking or signaling site for repair and signaling proteins. Its structure can be adapted by post-translational histone modifications and nucleosome remodeling, catalyzed by the activity of ATP-dependent chromatin-remodeling complexes. In recent years, accumulating evidence has suggested that ATP-dependent chromatin-remodeling complexes play important, although poorly characterized, roles in facilitating the effectiveness of the DNA-damage response. In this review, we summarize the current knowledge on the involvement of ATP-dependent chromatin remodeling in three major DNA repair pathways: nucleotide excision repair, homologous recombination, and non-homologous end-joining. This shows that a surprisingly large number of different remodeling complexes display pleiotropic functions during different stages of the DNA-damage response. Moreover, several complexes seem to have multiple functions, and are implicated in various mechanistically distinct repair pathways. PMID:22289628

  13. Cardiac remodelling and RAS inhibition.

    PubMed

    Ferrario, Carlos M

    2016-06-01

    Risk factors such as hypertension and diabetes are known to augment the activity and tissue expression of angiotensin II (Ang II), the major effector peptide of the renin-angiotensin system (RAS). Overstimulation of the RAS has been implicated in a chain of events that contribute to the pathogenesis of cardiovascular (CV) disease, including the development of cardiac remodelling. This chain of events has been termed the CV continuum. The concept of CV disease existing as a continuum was first proposed in 1991 and it is believed that intervention at any point within the continuum can modify disease progression. Treatment with antihypertensive agents may result in regression of left ventricular hypertrophy, with different drug classes exhibiting different degrees of efficacy. The greatest decrease in left ventricular mass is observed following treatment with angiotensin converting enzyme inhibitors (ACE-Is), which inhibit Ang II formation. Although ACE-Is and angiotensin receptor blockers (ARBs) provide significant benefits in terms of CV events and stroke, mortality remains high. This is partly due to a failure to completely suppress the RAS, and, as our knowledge has increased, an escape phenomenon has been proposed whereby the human sequence of the 12 amino acid substrate angiotensin-(1-12) is converted to Ang II by the mast cell protease, chymase. Angiotensin-(1-12) is abundant in a wide range of organs and has been shown to increase blood pressure in animal models, an effect abolished by the presence of ACE-Is or ARBs. This review explores the CV continuum, in addition to examining the influence of the RAS. We also consider novel pathways within the RAS and how new therapeutic approaches that target this are required to further reduce Ang II formation, and so provide patients with additional benefits from a more complete blockade of the RAS. PMID:27105891

  14. Structural remodeling of bacteriophage T4 and host membranes during infection initiation

    PubMed Central

    Hu, Bo; Margolin, William; Molineux, Ian J.; Liu, Jun

    2015-01-01

    The first stages of productive bacteriophage infections of bacterial host cells require efficient adsorption to the cell surface followed by ejection of phage DNA into the host cytoplasm. To achieve this goal, a phage virion must undergo significant structural remodeling. For phage T4, the most obvious change is the contraction of its tail. Here, we use skinny E. coli minicells as a host, along with cryo-electron tomography and mutant phage virions, to visualize key structural intermediates during initiation of T4 infection. We show for the first time that most long tail fibers are folded back against the tail sheath until irreversible adsorption, a feature compatible with the virion randomly walking across the cell surface to find an optimal site for infection. Our data confirm that tail contraction is triggered by structural changes in the baseplate, as intermediates were found with remodeled baseplates and extended tails. After contraction, the tail tube penetrates the host cell periplasm, pausing while it degrades the peptidoglycan layer. Penetration into the host cytoplasm is accompanied by a dramatic local outward curvature of the cytoplasmic membrane as it fuses with the phage tail tip. The baseplate hub protein gp27 and/or the ejected tape measure protein gp29 likely form the transmembrane channel for viral DNA passage into the cell cytoplasm. Building on the wealth of prior biochemical and structural information, this work provides new molecular insights into the mechanistic pathway of T4 phage infection. PMID:26283379

  15. Structural remodeling of bacteriophage T4 and host membranes during infection initiation.

    PubMed

    Hu, Bo; Margolin, William; Molineux, Ian J; Liu, Jun

    2015-09-01

    The first stages of productive bacteriophage infections of bacterial host cells require efficient adsorption to the cell surface followed by ejection of phage DNA into the host cytoplasm. To achieve this goal, a phage virion must undergo significant structural remodeling. For phage T4, the most obvious change is the contraction of its tail. Here, we use skinny E. coli minicells as a host, along with cryo-electron tomography and mutant phage virions, to visualize key structural intermediates during initiation of T4 infection. We show for the first time that most long tail fibers are folded back against the tail sheath until irreversible adsorption, a feature compatible with the virion randomly walking across the cell surface to find an optimal site for infection. Our data confirm that tail contraction is triggered by structural changes in the baseplate, as intermediates were found with remodeled baseplates and extended tails. After contraction, the tail tube penetrates the host cell periplasm, pausing while it degrades the peptidoglycan layer. Penetration into the host cytoplasm is accompanied by a dramatic local outward curvature of the cytoplasmic membrane as it fuses with the phage tail tip. The baseplate hub protein gp27 and/or the ejected tape measure protein gp29 likely form the transmembrane channel for viral DNA passage into the cell cytoplasm. Building on the wealth of prior biochemical and structural information, this work provides new molecular insights into the mechanistic pathway of T4 phage infection.

  16. Chromatin remodelling initiation during human spermiogenesis

    PubMed Central

    De Vries, Marieke; Ramos, Liliana; Housein, Zjwan; De Boer, Peter

    2012-01-01

    Summary During the last phase of spermatogenesis, spermiogenesis, haploid round spermatids metamorphose towards spermatozoa. Extensive cytoplasmic reduction and chromatin remodelling together allow a dramatic decrease of cellular, notably nuclear volume. DNA packing by a nucleosome based chromatin structure is largely replaced by a protamine based one. At the cytoplasmic level among others the acrosome and perinuclear theca (PNT) are formed. In this study we describe the onset of chromatin remodelling to occur concomitantly with acrosome and PNT development. In spread human round spermatid nuclei, we show development of a DAPI-intense doughnut-like structure co-localizing with the acrosomal sac and sub acrosomal PNT. At this structure we observe the first gradual decrease of nucleosomes and several histones. Histone post-translational modifications linked to chromatin remodelling such as H4K8ac and H4K16ac also delineate the doughnut, that is furthermore marked by H3K9me2. During the capping phase of acrosome development, the size of the doughnut-like chromatin domain increases, and this area often is marked by uniform nucleosome loss and the first appearance of transition protein 2 and protamine 1. In the acrosome phase at nuclear elongation, chromatin remodelling follows the downward movement of the marginal ring of the acrosome. Our results indicate that acrosome development and chromatin remodelling are interacting processes. In the discussion we relate chromatin remodelling to the available data on the nuclear envelope and the linker of nucleoskeleton and cytoskeleton (LINC) complex of spermatids, suggesting a signalling route for triggering chromatin remodelling. PMID:23213436

  17. Outward growth of Tibetan Plateau: Insights from joint inversion of lithosphere structure

    NASA Astrophysics Data System (ADS)

    Song, X.; Li, J.; Bao, X.; Zhu, L.

    2014-12-01

    Models for the growth of the Tibetan plateau have been a subject of great debate for decades. Here we add to the debate with new insights from an advanced imaging of the lithosphere structure of the western China. To resolve the ambiguity of model parameters and to improve resolution in seismic imaging, a combination of different data sets that have sensitivities to different parameters is required. We've recently developed joint-inversion methods involving Pn travel times, receiver functions, and surface wave dispersion measurements and applied them systematically to seismic stations in western China to obtain improved 3D P and S lithosphere models. Our models show significantly higher Vp/Vs ratios in northern Himalaya Block and southern Qiangtang Block than in the Lhasa Block. Mid-crustal low velocity zone (LVZ) is observed under much of the Tibetan Plateau. However, it is much more pronounced under the outer regions of the plateau (the Himalaya and Qiangtang Blocks) than under its interior (the Lhasa Block). The location of pronounced mid-crustal LVZ correlates (anti-correlates) with the distribution of seismicity in the plateau; the low seismicity areas have more pronounced LVZs and greater Vp/Vs values and the high seismic areas have less pronounced LVZs and smaller Vp/Vs values. The observations support the existence of a proto-Tibetan Plateau core and the outward growth of the margins at a later stage after the India-Eurasian collision (Wang C.S. et al., PNAS, 2008). The proto-plateau is more rigid and can sustain stress to cause brittle failure of earthquakes while the materials at the margins are weaker and can be subject to plastic deformation with much less seismicity. In this model, the proto-plateau core acts as an efficient medium for the stress transfer from the collision front to the margins for the outward growth of the plateau. The crust and mantle lithosphere act as a coherent unit as indicated by the consistent pattern of seismic anomalies with

  18. Connecting mechanics and bone cell activities in the bone remodeling process: an integrated finite element modeling.

    PubMed

    Hambli, Ridha

    2014-01-01

    Bone adaptation occurs as a response to external loadings and involves bone resorption by osteoclasts followed by the formation of new bone by osteoblasts. It is directly triggered by the transduction phase by osteocytes embedded within the bone matrix. The bone remodeling process is governed by the interactions between osteoblasts and osteoclasts through the expression of several autocrine and paracrine factors that control bone cell populations and their relative rate of differentiation and proliferation. A review of the literature shows that despite the progress in bone remodeling simulation using the finite element (FE) method, there is still a lack of predictive models that explicitly consider the interaction between osteoblasts and osteoclasts combined with the mechanical response of bone. The current study attempts to develop an FE model to describe the bone remodeling process, taking into consideration the activities of osteoclasts and osteoblasts. The mechanical behavior of bone is described by taking into account the bone material fatigue damage accumulation and mineralization. A coupled strain-damage stimulus function is proposed, which controls the level of autocrine and paracrine factors. The cellular behavior is based on Komarova et al.'s (2003) dynamic law, which describes the autocrine and paracrine interactions between osteoblasts and osteoclasts and computes cell population dynamics and changes in bone mass at a discrete site of bone remodeling. Therefore, when an external mechanical stress is applied, bone formation and resorption is governed by cells dynamic rather than adaptive elasticity approaches. The proposed FE model has been implemented in the FE code Abaqus (UMAT routine). An example of human proximal femur is investigated using the model developed. The model was able to predict final human proximal femur adaptation similar to the patterns observed in a human proximal femur. The results obtained reveal complex spatio-temporal bone

  19. A fly's view of neuronal remodeling.

    PubMed

    Yaniv, Shiri P; Schuldiner, Oren

    2016-09-01

    Developmental neuronal remodeling is a crucial step in sculpting the final and mature brain connectivity in both vertebrates and invertebrates. Remodeling includes degenerative events, such as neurite pruning, that may be followed by regeneration to form novel connections during normal development. Drosophila provides an excellent model to study both steps of remodeling since its nervous system undergoes massive and stereotypic remodeling during metamorphosis. Although pruning has been widely studied, our knowledge of the molecular and cellular mechanisms is far from complete. Our understanding of the processes underlying regrowth is even more fragmentary. In this review, we discuss recent progress by focusing on three groups of neurons that undergo stereotypic pruning and regrowth during metamorphosis, the mushroom body γ neurons, the dendritic arborization neurons and the crustacean cardioactive peptide peptidergic neurons. By comparing and contrasting the mechanisms involved in remodeling of these three neuronal types, we highlight the common themes and differences as well as raise key questions for future investigation in the field. WIREs Dev Biol 2016, 5:618-635. doi: 10.1002/wdev.241 For further resources related to this article, please visit the WIREs website. PMID:27351747

  20. Pay attention to cardiac remodeling in cancer cachexia.

    PubMed

    Zheng, Yawen; Chen, Han; Li, Xiaoqing; Sun, Yuping

    2016-07-01

    Cancer cachexia is a complex and multifaceted disease state characterized by fatigue, weakness, and loss of skeletal muscle and adipose tissue. Recently, the profound negative effects of cancer cachexia on cardiac tissue draw much attention, which is likely to contribute to mortality in tumor-bearing animals. The mechanism of cardiac remodeling is not so clear and involved with a series of molecular alterations. In cancer cachexia model, progressive loss of left ventricular mass and decrease in myocardial function is observed and cardiac autonomic functions are altered. Levels of several emerging cardiovascular neurohormones are found elevating in patients with cancer, but it is still controversial whether the changes could reflect the heart injury accurately. The remedy for cardiac remodeling has been explored. It is showed that exercise can modulate signaling pathways activated by wasting cytokines and impact on the resulting outcomes on heart adaptation. Some drugs, such as bisoprolol, spironolactone, perindopril, tandospirone, and simvastatin, can mitigate adverse effects of the tumor on the heart and prolong survival. PMID:27108265

  1. Equilibrated Atomic Models of Outward-Facing P-glycoprotein and Effect of ATP Binding on Structural Dynamics

    PubMed Central

    Pan, Lurong; Aller, Stephen G.

    2015-01-01

    P-glycoprotein (Pgp) is an ATP-binding cassette (ABC) transporter that alternates between inward- and outward-facing conformations to capture and force substrates out of cells like a peristaltic pump. The high degree of similarity in outward-facing structures across evolution of ABC transporters allowed construction of a high-confidence outward-facing Pgp atomic model based on crystal structures of outward-facing Sav1866 and inward-facing Pgp. The model adhered to previous experimentally determined secondary- and tertiary- configurations during all-atom molecular dynamics simulations in the presence or absence of MgATP. Three long lasting (>100 ns) meta-stable states were apparent in the presence of MgATP revealing new insights into alternating access. The two ATP-binding pockets are highly asymmetric resulting in differential control of overall structural dynamics and allosteric regulation of the drug-binding pocket. Equilibrated Pgp has a considerably different electrostatic profile compared to Sav1866 that implicates significant kinetic and thermodynamic differences in transport mechanisms. PMID:25600711

  2. A comparison of the delayed outward potassium current between the nucleus ambiguus and hippocampus: sensitivity to paeonol.

    PubMed

    Yang, Chin-Tsang; Leung, Yuk-Man; Hsu, Sheng-Feng; MacDonald, Iona; Wang, Mei-Ling; Lin, Jaung-Geng; Hung, Shih-Ya; Chen, Yi-Hung

    2016-08-01

    Whole-cell patch-clamp recordings investigated the electrophysiological effects of 2'-hydroxy-4'-methoxyacetophenone (paeonol), one of the major components of Moutan Cortex, in hippocampal CA1 neurons and nucleus ambiguus (NA) neurons from neonatal rats as well as in lung epithelial H1355 cells expressing Kv2.1 or Kv1.2. Extracellular application of paeonol at 100μM did not significantly affect the spontaneous action potential frequency, whereas paeonol at 300μM increased the frequency of spontaneous action potentials in hippocampal CA1 neurons. Paeonol (300μM) significantly decreased the tetraethylammonium-sensitive outward current in hippocampal CA1 neurons, but had no effect upon the fast-inactivating potassium current (IA). Extracellular application of paeonol at 300μM did not affect action potentials or the delayed outward currents in NA neurons. Paeonol (100μM) reduced the Kv2.1 current in H1355 cells, but not the Kv1.2 current. The inhibitor of Kv2, guangxitoxin-1E, reduced the delayed outward potassium currents in hippocampal neurons, but had only minimal effects in NA neurons. We demonstrated that paeonol decreased the delayed outward current and increased excitability in hippocampal CA1 neurons, whereas these effects were not observed in NA neurons. These effects may be associated with the inhibitory effects on Kv2.1 currents.

  3. Adolph Coors - Outward Bound Manpower Challenge Program. A Study of an Innovative Program to Train the Hardcore Unemployed.

    ERIC Educational Resources Information Center

    Harmon Associates, San Francisco, CA.

    Initiated in 1968 for "hardcore unemployables," the Adolph Coors Manpower Challenge Program combines a modified Outward Bound Course with a period of work in the Coors Recycling Yard, followed by permanent placement in the Coors Brewery. Based on changing participants' attitudes, the program eases transition to full employment in four phases…

  4. Equilibrated atomic models of outward-facing P-glycoprotein and effect of ATP binding on structural dynamics.

    PubMed

    Pan, Lurong; Aller, Stephen G

    2015-01-20

    P-glycoprotein (Pgp) is an ATP-binding cassette (ABC) transporter that alternates between inward- and outward-facing conformations to capture and force substrates out of cells like a peristaltic pump. The high degree of similarity in outward-facing structures across evolution of ABC transporters allowed construction of a high-confidence outward-facing Pgp atomic model based on crystal structures of outward-facing Sav1866 and inward-facing Pgp. The model adhered to previous experimentally determined secondary- and tertiary- configurations during all-atom molecular dynamics simulations in the presence or absence of MgATP. Three long lasting (>100 ns) meta-stable states were apparent in the presence of MgATP revealing new insights into alternating access. The two ATP-binding pockets are highly asymmetric resulting in differential control of overall structural dynamics and allosteric regulation of the drug-binding pocket. Equilibrated Pgp has a considerably different electrostatic profile compared to Sav1866 that implicates significant kinetic and thermodynamic differences in transport mechanisms.

  5. Cultivating Environmental Virtue among 7th and 8th Graders in an Expeditionary Learning Outward Bound School

    ERIC Educational Resources Information Center

    Martin, Bruce; Bright, Alan; Cafaro, Philip; Mittelstaedt, Robin; Bruyere, Brett

    2008-01-01

    This study attempted to assess the development of environmental virtue in 7th and 8th grade students in an Expeditionary Learning Outward Bound school. The purpose of this study was twofold. First, the researchers were interested in introducing a virtue ethics perspective into their teaching of environmental ethics. Second, the researchers were…

  6. Studies on the Outwardly and Inwardly Propagating Spherical Flames with Radiative Loss

    SciTech Connect

    Chen, Zheng; Gou, Xiaolong; Ju, Yiguang

    2010-01-29

    Outwardly and inwardly propagating spherical flames (OPF and IPF) with radiative loss are studied analytically and numerically. Emphasis is placed on investigating the effects of radiation on flame propagating speed, Markstein length, and flame extinction, as well as on examining whether the reactant can be completely consumed via an IPF. A general correlation between flame propagating speed and flame radius for OPF and IPF of large flame radii is derived and utilized to study the effects of radiative loss and Lewis number on flame propagation and extinction. A correlation for Markstein length at different Lewis numbers and radiative loss is also presented. It is shown that the Markstein length is strongly affected by radiative loss as well as Lewis number, and that only for mixtures not close to their flammability limits and without CO{sub 2} dilution is the effect of radiation on the Markstein length measured from expanding spherical flames negligible. Furthermore, the theoretical results are validated by numerical simulations. It is found that when radiative loss is considered, there exists unconsumed reactant after the extinction of IPF for mixture with Lewis number less than unity.

  7. Some aspects of the cosmogonic outward migration of Neptune. Co-planar migration

    NASA Astrophysics Data System (ADS)

    Neslušan, L.; Jakubík, M.

    2013-10-01

    Considering a simple model of the cosmogonic outward migration of Neptune, we investigate if the assumption of an extremely low orbital inclination of small bodies in a once-existing proto-planetary disk could influence the structure of reservoirs of the objects in the trans-Neptunian region. We found no significant influence. Our models predict only the existence of the mean-motion resonances (MMRs) with Neptune 2:3, 3:5, 1:2, and an anemic scattered disk (MMRs 3:4, 5:7, and 9:11 are also indicated). To explain the classical Edgeworth-Kuiper belt, relatively abundant 4:7 and 2:5 MMRs, and the more numerous scattered disk, we need to assume that, e.g., the outer boundary of the original proto-planetary disk considerably exceeded the distance of the current Neptune's orbit (Neptune probably ended its migration at the distance, where the disk's density started to be sub-critical), or that some Pluto-sized objects resided inside the MMRs and in the distant parts of the original proto-planetary disk.

  8. A proton-activated, outwardly rectifying chloride channel in human umbilical vein endothelial cells

    SciTech Connect

    Ma Zhiyong; Zhang Wei; Chen Liang; Wang Rong; Kan Xiaohong; Sun Guizhen; Liu Chunxi; Li Li Zhang Yun

    2008-07-04

    Extracellular acidic pH-activated chloride channel I{sub Cl,acid}, has been characterized in HEK 293 cells and mammalian cardiac myocytes. This study was designed to characterize I{sub Cl,acid} in human umbilical vein endothelial cells(HUVECs). The activation and deactivation of the current rapidly and repeatedly follows the change of the extracellular solution at pH 4.3, with the threshold pH 5.3. In addition, at very positive potentials, the current displays a time-dependent facilitation. pH-response relationship for I{sub Cl,acid} revealed that EC{sub 50} is pH 4.764 with a threshold pH value of pH 5.3 and nH of 14.545. The current can be blocked by the Cl{sup -} channel inhibitor DIDS (100 {mu}M). In summary, for the first time we report the presence of proton-activated, outwardly rectifying chloride channel in HUVECs. Because an acidic environment can develop in local myocardium under pathological conditions such as myocardial ischemia, I{sub Cl,acid} would play a role in regulation of EC function under these pathological conditions.

  9. Tuning the Outward to Inward Swelling in Lithiated Silicon Nanotubes via Surface Oxide Coating.

    PubMed

    Wang, Jiangwei; Luo, Hao; Liu, Yang; He, Yang; Fan, Feifei; Zhang, Ze; Mao, Scott X; Wang, Chongmin; Zhu, Ting

    2016-09-14

    Electrochemically induced mechanical degradation hinders the application of Si anodes in advanced lithium-ion batteries. Hollow structures and surface coatings have been often used to mitigate the degradation of Si-based anodes. However, the structural change and degradation mechanism during lithiation/delithiation of hollow Si structures with coatings remain unclear. Here, we combine in situ TEM experiment and chemomechanical modeling to study the electrochemically induced swelling of amorphous-Si (a-Si) nanotubes with different thicknesses of surface SiOx layers. Surprisingly, we find that no inward expansion occurs at the inner surface during lithiation of a-Si nanotubes with native oxides. In contrast, inward expansion can be induced by increasing the thickness of SiOx on the outer surface, thus reducing the overall outward swelling of the lithiated nanotube. Moreover, both the sandwich lithiation mechanism and the two-stage lithiation process in a-Si nanotubes remain unchanged with the increasing thickness of surface coatings. Our chemomechanical modeling reveals the mechanical confinement effects in lithiated a-Si nanotubes with and without SiOx coatings. This work not only provides insights into the degradation of nanotube anodes with surface coatings but also sheds light onto the optimal design of hollow anodes for high-performance lithium-ion batteries. PMID:27536960

  10. Cloning, functional expression and brain localization of a novel unconventional outward rectifier K+ channel.

    PubMed Central

    Fink, M; Duprat, F; Lesage, F; Reyes, R; Romey, G; Heurteaux, C; Lazdunski, M

    1996-01-01

    Human TWIK-1, which has been cloned recently, is a new structural type of weak inward rectifier K+ channel. Here we report the structural and functional properties of TREK-1, a mammalian TWIK-1-related K+ channel. Despite a low amino acid identity between TWIK-1 and TREK-1 (approximately 28%), both channel proteins share the same overall structural arrangement consisting of two pore-forming domains and four transmembrane segments (TMS). This structural similarity does not give rise to a functional analogy. K+ currents generated by TWIK-1 are inwardly rectifying while K+ currents generated by TREK-1 are outwardly rectifying. These channels have a conductance of 14 pS. TREK-1 currents are insensitive to pharmacological agents that block TWIK-1 activity such as quinine and quinidine. Extensive inhibitions of TREK-1 activity are observed after activation of protein kinases A and C. TREK-1 currents are sensitive to extracellular K+ and Na+. TREK-1 mRNA is expressed in most tissues and is particularly abundant in the lung and in the brain. Its localization in this latter tissue has been studied by in situ hybridization. TREK-1 expression is high in the olfactory bulb, hippocampus and cerebellum. These results provide the first evidence for the existence of a K+ channel family with four TMS and two pore domains in the nervous system of mammals. They also show that different members in this structural family can have totally different functional properties. Images PMID:9003761

  11. Impacts of intense inward and outward ULF wave radial diffusion on the Van Allen belts

    NASA Astrophysics Data System (ADS)

    Mann, Ian; Ozeke, Louis; Rae, I. Jonathan; Murphy, Kyle

    2016-07-01

    During geomagnetic storms, the power in ultra-low frequency (ULF) waves can be orders of magnitude larger than that predicted by statistics determined from an entire solar cycle. This is especially true during the main phase and early recovery phase. These periods of enhanced storm-time ULF wave power can have significant impacts on the morphology and structure of the Van Allen belts. Either fast inward or outward radial diffusion can result, depending on the profiles of the electron phase space density and the outer boundary condition at the edge of the belts. Small changes in the time sequence of powerful ULF waves, and the time sequence of any magnetopause shadowing or the recovery of plamasheet sources relative to the ULF wave occurrence, have a remarkable impact on the resulting structure of the belts. The overall impact of the enhanced ULF wave power is profound, but the response can be very different depending on the available source flux in the plasmasheet. We review these impacts by examining ultra-relativistic electron dynamics during seemingly different storms during the Van Allen Probe era, including during the Baker et al. third radiation belt, and show the observed behaviour can be largely explained by differences in the time sequence of events described above.

  12. Interfacial failure via encapsulation of external particulates in an outward-growing thermal oxide

    NASA Astrophysics Data System (ADS)

    Jung, Keeyoung; Kim, Chang-Soo; Pettit, Frederick S.; Meier, Gerald H.

    2011-05-01

    A Cr2O3-forming Ni-base superalloy and this alloy coated with a Pt-modified aluminide coating were exposed to SiO2 powder and cyclically oxidized at 950 °C. The uncoated alloy showed a considerable amount of spallation and buckling whereas the Pt-NiAl coated alloy remained protective throughout hundred 1 h-cycles. The interfacial failure is mainly ascribed to the increased thermal strain by the encapsulation of external SiO2 particulates in an outward-growing Cr2O3 layer. However, the particles were not embedded in the thermally grown oxide of the Pt-NiAl coated alloy due to the slow inward-growing characteristics of Al2O3 scales. The buckling of the Cr2O3 scale with embedded SiO2 was analyzed with (1) a classical buckling criterion using the instantaneous coefficients of thermal expansion of the constituents, and (2) finite element analyses (FEA) to estimate the local interfacial shear stresses. It turns out that the thermal strain with embedded SiO2 is larger than the experimentally determined critical thermal strain (ɛb) explaining the buckling of the oxide scale observed in the experiment. The FEA results demonstrate that local shear stresses at the metal/oxide interface are significantly amplified near the SiO2 particles showing that the buckling of oxide can be readily initiated especially in the vicinity of the embedded particles.

  13. Tuning the Outward to Inward Swelling in Lithiated Silicon Nanotubes via Surface Oxide Coating.

    PubMed

    Wang, Jiangwei; Luo, Hao; Liu, Yang; He, Yang; Fan, Feifei; Zhang, Ze; Mao, Scott X; Wang, Chongmin; Zhu, Ting

    2016-09-14

    Electrochemically induced mechanical degradation hinders the application of Si anodes in advanced lithium-ion batteries. Hollow structures and surface coatings have been often used to mitigate the degradation of Si-based anodes. However, the structural change and degradation mechanism during lithiation/delithiation of hollow Si structures with coatings remain unclear. Here, we combine in situ TEM experiment and chemomechanical modeling to study the electrochemically induced swelling of amorphous-Si (a-Si) nanotubes with different thicknesses of surface SiOx layers. Surprisingly, we find that no inward expansion occurs at the inner surface during lithiation of a-Si nanotubes with native oxides. In contrast, inward expansion can be induced by increasing the thickness of SiOx on the outer surface, thus reducing the overall outward swelling of the lithiated nanotube. Moreover, both the sandwich lithiation mechanism and the two-stage lithiation process in a-Si nanotubes remain unchanged with the increasing thickness of surface coatings. Our chemomechanical modeling reveals the mechanical confinement effects in lithiated a-Si nanotubes with and without SiOx coatings. This work not only provides insights into the degradation of nanotube anodes with surface coatings but also sheds light onto the optimal design of hollow anodes for high-performance lithium-ion batteries.

  14. Effects of allocryptopine on outward potassium current and slow delayed rectifier potassium current in rabbit myocardium

    PubMed Central

    Fu, Yi-Cheng; Zhang, Yu; Tian, Liu-Yang; Li, Nan; Chen, Xi; Cai, Zhong-Qi; Zhu, Chao; Li, Yang

    2016-01-01

    Objective Allocryptopine (ALL) is an effective alkaloid of Corydalis decumbens (Thunb.) Pers. Papaveraceae and has proved to be anti-arrhythmic. The purpose of our study is to investigate the effects of ALL on transmural repolarizing ionic ingredients of outward potassium current (Ito) and slow delayed rectifier potassium current (IKs). Methods The monophasic action potential (MAP) technique was used to record the MAP duration of the epicardium (Epi), myocardium (M) and endocardium (Endo) of the rabbit heart and the whole cell patch clamp was used to record Ito and IKs in cardiomyocytes of Epi, M and Endo layers that were isolated from rabbit ventricles. Results The effects of ALL on MAP of Epi, M and Endo layers were disequilibrium. ALL could effectively reduce the transmural dispersion of repolarization (TDR) in rabbit transmural ventricular wall. ALL decreased the current densities of Ito and IKs in a voltage and concentration dependent way and narrowed the repolarizing differences among three layers. The analysis of gating kinetics showed ALL accelerated the channel activation of Ito in M layers and partly inhibit the channel openings of Ito in Epi, M and Endo cells. On the other hand, ALL mainly slowed channel deactivation of IKs channel in Epi and Endo layers without affecting its activation. Conclusions Our study gives partially explanation about the mechanisms of transmural inhibition of Ito and IKs channels by ALL in rabbit myocardium. These findings provide novel perspective regarding the anti-arrhythmogenesis application of ALL in clinical settings. PMID:27403141

  15. Enhanced ion particle flux and momentum outward of a plasma ball

    NASA Astrophysics Data System (ADS)

    Makrinich, Gennady; Fruchtman, Amnon

    2013-09-01

    A plasma ball has been produced near the anode in a configuration that, when magnetized, operates as a radial plasma source (RPS). Plasma balls have been studied recently in different configurations. We find that the plasma particle flux outward of the plasma ball is larger than that expected by the Langmuir relation in double layers. The frequency of oscillations of a pendulum is larger than due to gravity only, reflecting the force by the plasma ball. The force by the plasma ball is larger than expected by the model. We address these two questions: the increased ion flux and the increased force relative to the model. We suggest that the Langmuir relation underestimates the ratio of ion to electron flux. We also suggest that the ions gain most of the momentum in the quasi-neutral plasma rather than in the double layer; the impulse enhancement is suggested to result from ion-neutral collisions in the plasma. Partially supported by the Israel Science Foundation, Grant 765/11.

  16. Vega's hot dust from icy planetesimals scattered inwards by an outward-migrating planetary system

    NASA Astrophysics Data System (ADS)

    Raymond, Sean N.; Bonsor, Amy

    2014-07-01

    Vega has been shown to host multiple dust populations, including both hot exozodiacal dust at sub-au radii and a cold debris disc extending beyond 100 au. We use dynamical simulations to show how Vega's hot dust can be created by long-range gravitational scattering of planetesimals from its cold outer regions. Planetesimals are scattered progressively inwards by a system of 5-7 planets from 30 to 60 au to very close-in. In successful simulations, the outermost planets are typically Neptune mass. The back-reaction of planetesimal scattering causes these planets to migrate outwards and continually interact with fresh planetesimals, replenishing the source of scattered bodies. The most favourable cases for producing Vega's exozodi have negative radial mass gradients, with sub-Saturn- to Jupiter-mass inner planets at 5-10 au and outer planets of 2.5 - 20 M⊕ . The mechanism fails if a Jupiter-sized planet exists beyond ˜15 au because the planet preferentially ejects planetesimals before they can reach the inner system. Direct-imaging planet searches can therefore directly test this mechanism.

  17. Scar remodeling after strabismus surgery.

    PubMed Central

    Ludwig, I H

    1999-01-01

    limitation of versions, less separation of the tendons from sclera, and thicker appearance of the scar segments. The use of nonabsorbable sutures in the repair procedure reduced the recurrence rate. Histologic examination of the clinical stretched scar specimens showed dense connective tissue that was less well organized compared with normal tendon. In the tissue culture studies, cells cultured from the stretched scar specimens grew rapidly and were irregularly shaped. A high-molecular-weight protein was identified in the culture medium. By contrast, cells cultured from normal tendon (controls) grew more slowly and regularly, stopped growing at 4 days, and produced less total protein than cultured stretched scar specimens. In the animal model studies, the collagenase-treated sites showed elongated scars with increased collagen between the muscle and the sclera, as well as increased collagen creep rates, compared with the saline-treated controls. The use of nonabsorbable sutures in collagenase-treated animal model surgery sites was associated with shorter, thicker scars compared with similar sites sutured with absorbable sutures. CONCLUSIONS: A lengthened or stretched, remodeled scar between an operated muscle tendon and sclera is a common occurrence and is a factor contributing to the variability of outcome after strabismus repair, even years later. This abnormality may be revealed by careful exploration of previously operated muscles. Definitive repair requires firm reattachment of tendon to sclera with nonabsorbable suture support. Images FIGURE 3 FIGURE 4 FIGURE 5 FIGURE 6 FIGURE 7 FIGURE 8 FIGURE 9 FIGURE 10 FIGURE 11 FIGURE 12 FIGURE 13 FIGURE 14 FIGURE 15 FIGURE 16 FIGURE 17 FIGURE 18 FIGURE 19 FIGURE 20 FIGURE 21 FIGURE 22 FIGURE 23 FIGURE 24 FIGURE 25 FIGURE 26 FIGURE 27 FIGURE 28 FIGURE 29 FIGURE 30 FIGURE 31 FIGURE 32 FIGURE 33 FIGURE 34 FIGURE 35 FIGURE 36 FIGURE 37 FIGURE 38 FIGURE 39 FIGURE 40 FIGURE 41 FIGURE 42 FIGURE 43 FIGURE 44 FIGURE 45 FIGURE 46 FIGURE 52

  18. mAKAP – A Master Scaffold for Cardiac Remodeling

    PubMed Central

    Passariello, Catherine L.; Li, Jinliang; Dodge-Kafka, Kimberly; Kapiloff, Michael S.

    2014-01-01

    Cardiac remodeling is regulated by an extensive intracellular signal transduction network. Each of the many signaling pathways in this network contributes uniquely to the control of cellular adaptation. In the last few years, it has become apparent that multimolecular signaling complexes or ‘signalosomes’ are important for fidelity in intracellular signaling and for mediating crosstalk between the different signaling pathways. These complexes integrate upstream signals and control downstream effectors. In the cardiac myocyte, the protein mAKAPβ serves as a scaffold for a large signalosome that is responsive to cAMP, calcium, hypoxia, and mitogen-activated protein kinase signaling. The main function of mAKAPβ signalosomes is to modulate stress-related gene expression regulated by the transcription factors NFATc, MEF2 and HIF-1α and type II histone deacetylases that control pathological cardiac hypertrophy. PMID:25551320

  19. Stress-induced remodeling of hippocampal CA3 pyramidal neurons.

    PubMed

    McEwen, Bruce S

    2016-08-15

    The discovery of steroid hormone receptors in brain regions that mediate virtually every aspect of brain function has broadened the definition of 'neuroendocrinology' to include the reciprocal communication between the brain and the body via hormonal and neural pathways. The brain is the central organ of stress and adaptation to stress because it perceives and determines what is threatening, as well as determining the behavioral and physiological responses to the stressor. The adult and developing brain possess remarkable structural and functional plasticity in response to stress, including neurogenesis leading to neuronal replacement, dendritic remodeling, and synapse turnover. Stress causes an imbalance of neural circuitry subserving cognition, decision-making, anxiety and mood that can alter expression of those behaviors and behavioral states. The two Brain Research papers noted in this review played an important role in triggering these advances. This article is part of a Special Issue entitled SI:50th Anniversary Issue. PMID:26740399

  20. Strategies for Energy Efficient Remodeling: SEER 2003 Case Study Report

    SciTech Connect

    2004-11-01

    The goal of the Strategies for Energy Efficiency in Remodeling (SEER) project is to provide information, based on research and case studies, to remodelers and consumers about opportunities to increase home energy performance.

  1. Interfacial failure via incapsulation of external particulates in an outward-growing thermal oxide

    SciTech Connect

    Jung, Keeyoung; Kim, Chang-Soo; Pettit, Frederick S; Meier, Gerald H

    2011-05-15

    A Cr{sub 2}O{sub 3}-forming Ni-base superalloy and this alloy coated with a Pt-modified aluminide coating were exposed to SiO{sub 2} powder and cyclically oxidized at 950 °C. The uncoated alloy showed a considerable amount of spallation and buckling whereas the Pt–NiAl coated alloy remained protective throughout hundred 1 h-cycles. The interfacial failure is mainly ascribed to the increased thermal strain by the encapsulation of external SiO{sub 2} particulates in an outward-growing Cr{sub 2}O{sub 3} layer. However, the particles were not embedded in the thermally grown oxide of the Pt–NiAl coated alloy due to the slow inward-growing characteristics of Al{sub 2}O{sub 3} scales. The buckling of the Cr{sub 2}O{sub 3} scale with embedded SiO{sub 2} was analyzed with (1) a classical buckling criterion using the instantaneous coefficients of thermal expansion of the constituents, and (2) finite element analyses (FEA) to estimate the local interfacial shear stresses. It turns out that the thermal strain with embedded SiO{sub 2} is larger than the experimentally determined critical thermal strain (ɛ{sub b}) explaining the buckling of the oxide scale observed in the experiment. The FEA results demonstrate that local shear stresses at the metal/oxide interface are significantly amplified near the SiO{sub 2} particles showing that the buckling of oxide can be readily initiated especially in the vicinity of the embedded particles.

  2. HIV-1 Tat Protein Increases Microglial Outward K+ Current and Resultant Neurotoxic Activity

    PubMed Central

    Liu, Jianuo; Xu, Peng; Collins, Cory; Liu, Han; Zhang, Jingdong; Keblesh, James P.; Xiong, Huangui

    2013-01-01

    Microglia plays a crucial role in the pathogenesis of HIV-1-associated neurocognitive disorders. Increasing evidence indicates the voltage-gated potassium (Kv) channels are involved in the regulation of microglia function, prompting us to hypothesize Kv channels may also be involved in microglia-mediated neurotoxic activity in HIV-1-infected brain. To test this hypothesis, we investigated the involvement of Kv channels in the response of microglia to HIV-1 Tat protein. Treatment of rat microglia with HIV-1 Tat protein (200 ng/ml) resulted in pro-inflammatory microglial activation, as indicated by increases in TNF-α, IL-1β, reactive oxygen species, and nitric oxide, which were accompanied by enhanced outward K+ current and Kv1.3 channel expression. Suppression of microglial Kv1.3 channel activity, either with Kv1.3 channel blockers Margatoxin, 5-(4-Phenoxybutoxy)psoralen, or broad-spectrum K+ channel blocker 4-Aminopyridine, or by knockdown of Kv1.3 expression via transfection of microglia with Kv1.3 siRNA, was found to abrogate the neurotoxic activity of microglia resulting from HIV-1 Tat exposure. Furthermore, HIV-1 Tat-induced neuronal apoptosis was attenuated with the application of supernatant collected from K+ channel blocker-treated microglia. Lastly, the intracellular signaling pathways associated with Kv1.3 were investigated and enhancement of microglial Kv1.3 was found to correspond with an increase in Erk1/2 mitogen-activated protein kinase activation. These data suggest targeting microglial Kv1.3 channels may be a potential new avenue of therapy for inflammation-mediated neurological disorders. PMID:23738010

  3. HIV-1 gp120 enhances outward potassium current via CXCR4 and cAMP-dependent PKA signaling in cultured rat microglia

    PubMed Central

    Xu, Changshui; Liu, Jianuo; Chen, Lina; Liang, Shangdong; Fujii, Nobutaka; Tamamura, Hirokazu; Xiong, Huangui

    2011-01-01

    Microglia are critical cells in mediating the pathophysiology of neurodegenerative disorders such as HIV-associated neurocognitive disorders. We hypothesize that HIV-1 glycoprotein 120 (gp120) activates microglia by enhancing outward K+ currents, resulting in microglia secretion of neurotoxins and consequent neuronal dysfunction and death. To test this hypothesis, we studied the effects of gp120 on outward K+ current in cultured rat microglia. Application of gp120 enhanced outward K+ current in a dose-dependent manner, which was blocked by voltage-gated K+ (Kv) channel blockers. Western blot analysis revealed that gp120 produced an elevated expression of Kv channel proteins. Examination of activation and inactivation of outward K+ currents showed that gp120 shifted membrane potentials for activation and steady-state inactivation. The gp120-associated enhancement of outward K+ current was blocked by a CXCR4 receptor antagonist T140 or by a specific protein kinase A (PKA) inhibitor H89, suggesting the involvement of chemokine receptor CXCR4 and PKA in gp120-mediated enhancement of outward K+ current. Biological significance of gp120-induced enhancement of microglia outward K+ current was demonstrated by experimental results showing the neurotoxic activity of gp120-stimulated microglia, evaluated by TUNEL staining and MTT assay, was significantly attenuated by Kv channel blockers. Taken together, these results suggest that gp120 induces microglia neurotoxic activity by enhancing microglia outward K+ current and that microglia Kv channels may function as a potential target for the development of therapeutic strategies. PMID:21438014

  4. Epigenetic regulation of aortic remodeling in hyperhomocysteinemia

    PubMed Central

    Narayanan, Nithya; Pushpakumar, Sathnur Basappa; Givvimani, Srikanth; Kundu, Sourav; Metreveli, Naira; James, Dexter; Bratcher, Adrienne P.; Tyagi, Suresh C.

    2014-01-01

    Hyperhomocysteinemia (HHcy) is prevalent in patients with hypertension and is an independent risk factor for aortic pathologies. HHcy is known to cause an imbalance between matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs), leading to the accumulation of collagen in the aorta and resulting in stiffness and development of hypertension. Although the exact mechanism of extracellular matrix (ECM) remodeling is unclear, emerging evidence implicates epigenetic regulation involving DNA methylation. Our purpose was to investigate whether 5-aza-2′-deoxycytidine (Aza), a DNA methyltransferase (DNMT1) inhibitor, reduces high blood pressure (BP) by regulating aortic ECM remodeling in HHcy. Wild-type and cystathionine β-synthase (CBS)+/− HHcy mice were treated with Aza (0.5 mg/kg body weight). In HHcy mice, Aza treatment normalized the plasma homocysteine (Hcy) level and BP. Thoracic and abdominal aorta ultrasound revealed a reduction in the resistive index and wall-to-lumen ratio. Vascular response to phenylephrine, acetylcholine, and sodium nitroprusside improved after Aza in HHcy mice. Histology showed a marked reduction in collagen deposition in the aorta. Aza treatment decreased the expression of DNMT1, MMP9, TIMP1, and S-adenosyl homocysteine hydrolase (SAHH) and upregulated methylene tetrahydrofolate reductase (MTHFR). We conclude that reduction of DNA methylation by Aza in HHcy reduces adverse aortic remodeling to mitigate hypertension.—Narayanan, N., Pushpakumar, S. B., Givvimani, S., Kundu, S., Metreveli, N., James, D., Bratcher, A. P., Tyagi, S. C. Epigenetic regulation of aortic remodeling in hyperhomocysteinemia. PMID:24739303

  5. Retinal remodeling in human retinitis pigmentosa.

    PubMed

    Jones, B W; Pfeiffer, R L; Ferrell, W D; Watt, C B; Marmor, M; Marc, R E

    2016-09-01

    Retinitis Pigmentosa (RP) in the human is a progressive, currently irreversible neural degenerative disease usually caused by gene defects that disrupt the function or architecture of the photoreceptors. While RP can initially be a disease of photoreceptors, there is increasing evidence that the inner retina becomes progressively disorganized as the outer retina degenerates. These alterations have been extensively described in animal models, but remodeling in humans has not been as well characterized. This study, using computational molecular phenotyping (CMP) seeks to advance our understanding of the retinal remodeling process in humans. We describe cone mediated preservation of overall topology, retinal reprogramming in the earliest stages of the disease in retinal bipolar cells, and alterations in both small molecule and protein signatures of neurons and glia. Furthermore, while Müller glia appear to be some of the last cells left in the degenerate retina, they are also one of the first cell classes in the neural retina to respond to stress which may reveal mechanisms related to remodeling and cell death in other retinal cell classes. Also fundamentally important is the finding that retinal network topologies are altered. Our results suggest interventions that presume substantial preservation of the neural retina will likely fail in late stages of the disease. Even early intervention offers no guarantee that the interventions will be immune to progressive remodeling. Fundamental work in the biology and mechanisms of disease progression are needed to support vision rescue strategies. PMID:27020758

  6. Revealing remodeler function: Varied and unique

    NASA Astrophysics Data System (ADS)

    Eastlund, Allen

    Chromatin remodelers perform a necessary and required function for the successful expression of our genetic code. By modifying, shifting, or ejecting nucleosomes from the chromatin structure they allow access to the underlying DNA to the rest of the cell's machinery. This research has focused on two major remodeler motors from major families of chromatin remodelers: the trimeric motor domain of RSC and the motor domain of the ISWI family, ISWI. Using primarily stopped-flow spectrofluorometry, I have categorized the time-dependent motions of these motor domains along their preferred substrate, double-stranded DNA. Combined with collected ATP utilization data, I present the subsequent analysis and associated conclusions that stem from the underlying assumptions and models. Interestingly, there is little in common between the investigated proteins aside from their favored medium. While RSC exhibits modest translocation characteristics and highly effective motion with the ability for large molecular forces, ISWI is not only structurally different but highly inefficient in its motion leading to difficulties in determining its specific translocation mechanics. While chromatin remodeling is a ubiquitous facet of eukaryotic life, there remains much to be understood about their general mechanisms.

  7. Chromatin remodelers: We are the drivers!!

    PubMed

    Tyagi, Monica; Imam, Nasir; Verma, Kirtika; Patel, Ashok K

    2016-07-01

    Chromatin is a highly dynamic structure that imparts structural organization to the genome and regulates the gene expression underneath. The decade long research in deciphering the significance of epigenetics in maintaining cellular integrity has embarked the focus on chromatin remodeling enzymes. These drivers have been categorized as readers, writers and erasers with each having significance of their own. Largely, on the basis of structure, ATP dependent chromatin remodelers have been grouped into 4 families; SWI/SNF, ISWI, IN080 and CHD. It is still unclear to what degree these enzymes are swayed by local DNA sequences when shifting a nucleosome to different positions. The ability of regulating active and repressive transcriptional state via open and close chromatin architecture has been well studied however, the significance of chromatin remodelers in regulating transcription at each step i.e. initiation, elongation and termination require further attention. The authors have highlighted the significance and role of different chromatin remodelers in transcription, DNA repair and histone variant deposition. PMID:27429206

  8. Challenging Modernization: Remodelling the Education Workforce

    ERIC Educational Resources Information Center

    Butt, Graham; Gunter, Helen

    2005-01-01

    This special edition enables an in-depth look at the process of modernization of education in England, in relation to other international developments. In particular we focus on the reform of teachers? work by examining the antecedence of the current policy of remodelling through three articles based on the Evaluation of the Department for…

  9. Arterial Remodeling Associates with CKD Progression

    PubMed Central

    Collin, Cédric; Karras, Alexandre; Laurent, Stéphane; Bozec, Erwan; Jacquot, Christian; Stengel, Bénédicte; Houillier, Pascal; Froissart, Marc; Boutouyrie, Pierre

    2011-01-01

    In CKD, large arteries remodel and become increasingly stiff. The greater pulsatile pressure reaching the glomerulus as a result of increased aortic stiffness could induce renal damage, suggesting that the stiffening and remodeling of large arteries could affect the progression of CKD. We measured carotid-femoral pulse wave velocity, aortic pressure and carotid remodeling and stiffness parameters in 180 patients with CKD (mean measured GFR, 32 ml/min per 1.73 m2) and followed them prospectively for a mean of 3.1 years. During follow-up, carotid stiffness significantly increased (+0.28 ± 0.05 m/s; P < 0.0001) but aortic stiffness did not. Carotid intima-media thickness decreased significantly during follow-up and the internal diameter of the carotid increased, producing increased circumferential wall stress (+2.08 ± 0.43 kPa/yr; P < 0.0001). In a linear mixed model, circumferential wall stress significantly associated with faster GFR decline after adjustment for risk factors of cardiovascular disease and progression of CKD. In a multivariable Cox model, carotid circumferential wall stress and pulse pressure independently associated with higher risk for ESRD. None of the arterial stiffness parameters associated with progression of CKD. In conclusion, maladaptive remodeling of the carotid artery and increased pulse pressure independently associate with faster decline of renal function and progression to ESRD. PMID:21493771

  10. Remodeling and vascular spaces in bone.

    PubMed

    Eriksen, Erik Fink; Eghbali-Fatourechi, Guiti Z; Khosla, Sundeep

    2007-01-01

    In recent years, we have come to appreciate that the close association between bone and vasculature plays a pivotal role in the regulation of bone remodeling and fracture repair. In 2001, Hauge et al. characterized a specialized vascular structure, the bone remodeling compartment (BRC), and showed that the outer lining of this compartment was made up of flattened cells, displaying all the characteristics of lining cells in bone. A decrease in bone turnover leads to a decrease in surfaces covered with remodeling compartments, whereas increased turnover causes an increase. Immunoreactivity for all major osteotropic growth factors and cytokines including osteoprotegerin (OPG) and RANKL has been shown in the cells lining the BRC, which makes the BRC the structure of choice for coupling between resorption and formation. The secretion of these factors inside a confined space separated from the bone marrow would facilitate local regulation of the remodeling process without interference from growth factors secreted by blood cells in the marrow space. The BRC creates an environment where cells inside the structure are exposed to denuded bone, which may enable direct cellular interactions with integrins and other matrix factors known to regulate osteoclast/osteoblast activity. However, the denuded bone surface inside the BRC also constitutes an ideal environment for the seeding of bone metastases, known to have high affinity for bone matrix. Reduction in BRC space brought about by antiresorptive therapies such as bisphosphonates reduce the number of skeletal events in advanced cancer, whereas an increase in BRC space induced by remodeling activators like PTH may increase the bone metastatic burden. The BRC has only been characterized in detail in trabecular bone; there is, however, evidence that a similar structure may exist in cortical bone, but further characterization is needed.

  11. Simulated Microgravity and Recovery-Induced Remodeling of the Left and Right Ventricle.

    PubMed

    Zhong, Guohui; Li, Yuheng; Li, Hongxing; Sun, Weijia; Cao, Dengchao; Li, Jianwei; Zhao, Dingsheng; Song, Jinping; Jin, Xiaoyan; Song, Hailin; Yuan, Xinxin; Wu, Xiaorui; Li, Qi; Xu, Qing; Kan, Guanghan; Cao, Hongqing; Ling, Shukuan; Li, Yingxian

    2016-01-01

    Physiological adaptations to microgravity involve alterations in cardiovascular systems. These adaptations result in cardiac remodeling and orthostatic hypotension. However, the response of the left ventricle (LV) and right ventricle (RV) following hindlimb unloading (HU) and hindlimb reloading (HR) is not clear and the underlying mechanism remains to be understood. In this study, three groups of mice were subjected to HU by tail suspension for 28 days. Following this, two groups were allowed to recover for 7 or 14 days. The control group was treated equally, with the exception of tail suspension. Echocardiography was performed to detect the structure and function changes of heart. Compared with the control, the HU group of mice showed reduced LV-EF (ejection fraction), and LV-FS (fractional shortening). However, mice that were allowed to recover for 7 days after HU (HR-7d) showed increased LVIDs (systolic LV internal diameter) and LV Vols (systolic LV volume). Mice that recovered for 14 days (HR-14d) returned to the normal state. In comparison, RV-EF and RV-FS didn't recover to the normal conditions till being reloaded for 14 days. Compared with the control, RVIDd (diastolic RV internal diameter), and RV Vold (diastolic RV volume) were reduced in HU group and recovered to the normal conditions in HR-7d and HR-14d groups, in which groups RVIDs (systolic RV internal diameter) and RV Vols (systolic RV volume) were increased. Histological analysis and cardiac remodeling gene expression results indicated that HU induces left and right ventricular remodeling. Western blot demonstrated that the phosphorylation of HDAC4 and ERK1/2 and the ratio of LC3-II / LC3-I, were increased following HU and recovered following HR in both LV and RV, and the phosphorylation of AMPK was inhibited in both LV and RV following HU, but only restored in LV following HR for 14 days. These results indicate that simulated microgravity leads to cardiac remodeling, and the remodeling changes can

  12. Simulated Microgravity and Recovery-Induced Remodeling of the Left and Right Ventricle

    PubMed Central

    Zhong, Guohui; Li, Yuheng; Li, Hongxing; Sun, Weijia; Cao, Dengchao; Li, Jianwei; Zhao, Dingsheng; Song, Jinping; Jin, Xiaoyan; Song, Hailin; Yuan, Xinxin; Wu, Xiaorui; Li, Qi; Xu, Qing; Kan, Guanghan; Cao, Hongqing; Ling, Shukuan; Li, Yingxian

    2016-01-01

    Physiological adaptations to microgravity involve alterations in cardiovascular systems. These adaptations result in cardiac remodeling and orthostatic hypotension. However, the response of the left ventricle (LV) and right ventricle (RV) following hindlimb unloading (HU) and hindlimb reloading (HR) is not clear and the underlying mechanism remains to be understood. In this study, three groups of mice were subjected to HU by tail suspension for 28 days. Following this, two groups were allowed to recover for 7 or 14 days. The control group was treated equally, with the exception of tail suspension. Echocardiography was performed to detect the structure and function changes of heart. Compared with the control, the HU group of mice showed reduced LV-EF (ejection fraction), and LV-FS (fractional shortening). However, mice that were allowed to recover for 7 days after HU (HR-7d) showed increased LVIDs (systolic LV internal diameter) and LV Vols (systolic LV volume). Mice that recovered for 14 days (HR-14d) returned to the normal state. In comparison, RV-EF and RV-FS didn't recover to the normal conditions till being reloaded for 14 days. Compared with the control, RVIDd (diastolic RV internal diameter), and RV Vold (diastolic RV volume) were reduced in HU group and recovered to the normal conditions in HR-7d and HR-14d groups, in which groups RVIDs (systolic RV internal diameter) and RV Vols (systolic RV volume) were increased. Histological analysis and cardiac remodeling gene expression results indicated that HU induces left and right ventricular remodeling. Western blot demonstrated that the phosphorylation of HDAC4 and ERK1/2 and the ratio of LC3-II / LC3-I, were increased following HU and recovered following HR in both LV and RV, and the phosphorylation of AMPK was inhibited in both LV and RV following HU, but only restored in LV following HR for 14 days. These results indicate that simulated microgravity leads to cardiac remodeling, and the remodeling changes can

  13. β Integrins Mediate FAK Y397 Autophosphorylation of Resistance Arteries during Eutrophic Inward Remodeling in Hypertension

    PubMed Central

    Heerkens, Egidius H.J; Quinn, Lisa; Withers, Sarah B; Heagerty, Anthony M

    2014-01-01

    Human essential hypertension is characterized by eutrophic inward remodeling of the resistance arteries with little evidence of hypertrophy. Upregulation of αVβ3 integrin is crucial during this process. In order to investigate the role of focal adhesion kinase (FAK) activation in this process, the level of FAK Y397 autophosphorylation was studied in small blood vessels from young TGR(mRen2)27 animals as blood pressure rose and eutrophic inward remodeling took place. Between weeks 4 and 5, this process was completed and accompanied by a significant increase in FAK phosphorylation compared with normotensive control animals. Phosphorylated (p)FAK Y397 was coimmunoprecipitated with both β1- and β3-integrin-specific antibodies. In contrast, only a fraction (<10-fold) was coprecipitated with the β3 integrin subunit in control vessels. Inhibition of eutrophic remodeling by cRGDfV treatment of TGR(mRen2)27 rats resulted in the development of smooth-muscle-cell hypertrophy and a significant further enhancement of FAK Y397 phosphorylation, but this time with exclusive coassociation of pFAK Y397 with integrin β1. We established that phosphorylation of FAK Y397 with association with β1 and β3 integrins occurs with pressure-induced eutrophic remodeling. Inhibiting this process leads to an adaptive hypertrophic vascular response induced by a distinct β1-mediated FAK phosphorylation pattern. PMID:25300309

  14. Toll-like receptor 4 activation promotes cardiac arrhythmias by decreasing the transient outward potassium current (Ito) through an IRF3-dependent and MyD88-independent pathway.

    PubMed

    Monnerat-Cahli, Gustavo; Alonso, Hiart; Gallego, Monica; Alarcón, Micaela Lopez; Bassani, Rosana A; Casis, Oscar; Medei, Emiliano

    2014-11-01

    Cardiac arrhythmias are one of the main causes of death worldwide. Several studies have shown that inflammation plays a key role in different cardiac diseases and Toll-like receptors (TLRs) seem to be involved in cardiac complications. In the present study, we investigated whether the activation of TLR4 induces cardiac electrical remodeling and arrhythmias, and the signaling pathway involved in these effects. Membrane potential was recorded in Wistar rat ventricle. Ca(2+) transients, as well as the L-type Ca(2+) current (ICaL) and the transient outward K(+) current (Ito), were recorded in isolated myocytes after 24 h exposure to the TLR4 agonist, lipopolysaccharide (LPS, 1 μg/ml). TLR4 stimulation in vitro promoted a cardiac electrical remodeling that leads to action potential prolongation associated with arrhythmic events, such as delayed afterdepolarization and triggered activity. After 24 h LPS incubation, Ito amplitude, as well as Kv4.3 and KChIP2 mRNA levels were reduced. The Ito decrease by LPS was prevented by inhibition of interferon regulatory factor 3 (IRF3), but not by inhibition of interleukin-1 receptor-associated kinase 4 (IRAK4) or nuclear factor kappa B (NF-κB). Extrasystolic activity was present in 25% of the cells, but apart from that, Ca(2+) transients and ICaL were not affected by LPS; however, Na(+)/Ca(2+) exchanger (NCX) activity was apparently increased. We conclude that TLR4 activation decreased Ito, which increased AP duration via a MyD88-independent, IRF3-dependent pathway. The longer action potential, associated with enhanced Ca(2+) efflux via NCX, could explain the presence of arrhythmias in the LPS group.

  15. The RSC chromatin remodeling complex has a crucial role in the complete remodeler set for yeast PHO5 promoter opening.

    PubMed

    Musladin, Sanja; Krietenstein, Nils; Korber, Philipp; Barbaric, Slobodan

    2014-04-01

    Although yeast PHO5 promoter chromatin opening is a founding model for chromatin remodeling, the complete set of involved remodelers remained unknown for a long time. The SWI/SNF and INO80 remodelers cooperate here, but nonessentially, and none of the many tested single or combined remodeler gene mutations could prevent PHO5 promoter opening. RSC, the most abundant and only remodeler essential for viability, was a controversial candidate for the unrecognized remodeling activity but unassessed in vivo. Now we show that remodels the structure of chromatin (RSC) is crucially involved in PHO5 promoter opening. Further, the isw1 chd1 double deletion also delayed chromatin remodeling. Strikingly, combined absence of RSC and Isw1/Chd1 or Snf2 abolished for the first time promoter opening on otherwise sufficient induction in vivo. Together with previous findings, we recognize now a surprisingly complex network of five remodelers (RSC, SWI/SNF, INO80, Isw1 and Chd1) from four subfamilies (SWI/SNF, INO80, ISWI and CHD) as involved in PHO5 promoter chromatin remodeling. This is likely the first described complete remodeler set for a physiological chromatin transition. RSC was hardly involved at the coregulated PHO8 or PHO84 promoters despite cofactor recruitment by the same transactivator and RSC's presence at all three promoters. Therefore, promoter-specific chromatin rather than transactivators determine remodeler requirements.

  16. Role of reactive oxygen species in myocardial remodeling.

    PubMed

    Zhang, Min; Shah, Ajay M

    2007-03-01

    Adverse cardiac remodeling is a fundamental process in the progression to chronic heart failure. Although the mechanisms underlying cardiac remodeling are multi-factorial, a significant body of evidence points to the crucial roles of increased reactive oxygen species. This article reviews recent advances in delineating the different sources of production for reactive oxygen species (namely mitochondria, xanthine oxidase, uncoupled nitric oxide synthases, and NADPH oxidases) that may be involved in cardiac remodeling and the aspects of the remodeling process that they affect. These data could suggest new ways of targeting redox pathways for the prevention and treatment of adverse cardiac remodeling.

  17. Role of reactive oxygen species in myocardial remodeling.

    PubMed

    Zhang, Min; Shah, Ajay M

    2007-03-01

    Adverse cardiac remodeling is a fundamental process in the progression to chronic heart failure. Although the mechanisms underlying cardiac remodeling are multi-factorial, a significant body of evidence points to the crucial roles of increased reactive oxygen species. This article reviews recent advances in delineating the different sources of production for reactive oxygen species (namely mitochondria, xanthine oxidase, uncoupled nitric oxide synthases, and NADPH oxidases) that may be involved in cardiac remodeling and the aspects of the remodeling process that they affect. These data could suggest new ways of targeting redox pathways for the prevention and treatment of adverse cardiac remodeling. PMID:17386182

  18. Role of G-proteins in muscarinic receptor inward and outward currents in rabbit jejunal smooth muscle.

    PubMed Central

    Komori, S; Bolton, T B

    1990-01-01

    1. Single smooth muscle cells obtained by enzymic dispersion of the longitudinal muscle layer of rabbit jejunum were held under voltage clamp using patch pipettes and membrane currents measured. The effects of carbachol or caffeine applied externally were examined in cells dialysed with normal pipette solutions or with a solution containing heparin (which blocks receptors for D-myo-inositol 1,4,5-trisphosphate, InsP3), guanosine 5-O-(gamma-thio)triphosphate (GTP gamma S) or guanosine 5-O-(beta-thio)diphosphate (GDP beta S). 2. Outward current in response to application of carbachol or caffeine was considered to represent the opening of calcium-activated potassium channels in response to a localized rise in the free ionized calcium concentration occasioned by the rapid discharge of stored calcium (Ca) by these agents. 3. Heparin included in the pipette solution blocked outward current to muscarinic receptor activation by carbachol but not that to caffeine, suggesting that receptor-evoked discharge of stored cellular Ca is caused by InsP3 action. However, heparin did not affect muscarinic-receptor inward current. 4. After dialysis with 0.1-0.5 mM-GTP gamma S, carbachol inward current was evoked in two out of three of the cells; after dialysis with 0.1-0.2 mM-GTP gamma S for an average of 7.7 min it was 80% of the normal response; after dialysis for an average of 8.6 min with 0.5 mM-GTP gamma S it was 31% of the normal response. In contrast, 0.1 mM-GTP gamma S reduced caffeine outward current by 93% after an average 4.5 min dialysis and spontaneous transient outward currents (STOCs) were abolished in 2.9 min on average. 5. Carbachol inward current (at -40 or -50 mV) and carbachol outward current (at 0 mV) in responding cells were reduced only by half after 8-10 min dialysis with 1 mM-GDP beta S which has been shown in portal vein cells to antagonize the depletion of Ca stores by intracellular GTP gamma S (Komori & Bolton, 1989). After 8-10 min dialysis with 5 m

  19. [Remodeling of Cardiovascular System: Causes and Consequences].

    PubMed

    Lopatina, E V; Kipenko, A V; Penniyaynen, V A; Pasatetckaia, N A; Tsyrline, V A

    2016-01-01

    Literature and our data suggest the regulatory action of a number of biologically active substances (catecholamines, cardiac glycosides, β-blockers, angiotensin-converting-enzyme inhibitor) on the growth and proliferation of heart cells. By using of organotypic tissue culture has proved that the basis of this regulation is the ability of test substances, receptor- or transducer-mediated signaling to modulate the function of Na⁺, K⁺-ATPase. There is a delay in the development of vascular smooth muscle in the late postnatal period in rats with the blockade of the sympathetic nervous system in the prenatal period. The relationship between vascular remodeling and contractile activity is described. It seems that one of the causes of high blood pressure is a remodeling of the cardiovascular system, which precedes the development of hypertension. PMID:27530043

  20. Chromatin Remodeling, DNA Damage Repair and Aging

    PubMed Central

    Liu, Baohua; Yip, Raymond KH; Zhou, Zhongjun

    2012-01-01

    Cells are constantly exposed to a variety of environmental and endogenous conditions causing DNA damage, which is detected and repaired by conserved DNA repair pathways to maintain genomic integrity. Chromatin remodeling is critical in this process, as the organization of eukaryotic DNA into compact chromatin presents a natural barrier to all DNA-related events. Studies on human premature aging syndromes together with normal aging have suggested that accumulated damages might lead to exhaustion of resources that are required for physiological functions and thus accelerate aging. In this manuscript, combining the present understandings and latest findings, we focus mainly on discussing the role of chromatin remodeling in the repair of DNA double-strand breaks (DSBs) and regulation of aging. PMID:23633913

  1. Metabolic remodeling in chronic heart failure.

    PubMed

    Wang, Jing; Guo, Tao

    2013-08-01

    Although the management of chronic heart failure (CHF) has made enormous progress over the past decades, CHF is still a tremendous medical and societal burden. Metabolic remodeling might play a crucial role in the pathophysiology of CHF. The characteristics and mechanisms of metabolic remodeling remained unclear, and the main hypothesis might include the changes in the availability of metabolic substrate and the decline of metabolic capability. In the early phases of the disease, metabolism shifts toward carbohydrate utilization from fatty acids (FAs) oxidation. Along with the progress of the disease, the increasing level of the hyperadrenergic state and insulin resistance cause the changes that shift back to a greater FA uptake and oxidation. In addition, a growing body of experimental and clinical evidence suggests that the improvement in the metabolic capability is likely to be more significant than the selection of the substrate.

  2. [Remodeling of Cardiovascular System: Causes and Consequences].

    PubMed

    Lopatina, E V; Kipenko, A V; Penniyaynen, V A; Pasatetckaia, N A; Tsyrline, V A

    2016-01-01

    Literature and our data suggest the regulatory action of a number of biologically active substances (catecholamines, cardiac glycosides, β-blockers, angiotensin-converting-enzyme inhibitor) on the growth and proliferation of heart cells. By using of organotypic tissue culture has proved that the basis of this regulation is the ability of test substances, receptor- or transducer-mediated signaling to modulate the function of Na⁺, K⁺-ATPase. There is a delay in the development of vascular smooth muscle in the late postnatal period in rats with the blockade of the sympathetic nervous system in the prenatal period. The relationship between vascular remodeling and contractile activity is described. It seems that one of the causes of high blood pressure is a remodeling of the cardiovascular system, which precedes the development of hypertension.

  3. Remodeling of Calcium Entry Pathways in Cancer.

    PubMed

    Villalobos, Carlos; Sobradillo, Diego; Hernández-Morales, Miriam; Núñez, Lucía

    2016-01-01

    Ca(2+) entry pathways play important roles in control of many cellular functions, including long-term proliferation, migration and cell death. In recent years, it is becoming increasingly clear that, in some types of tumors, remodeling of Ca(2+) entry pathways could contribute to cancer hallmarks such as excessive proliferation, cell migration and invasion as well as resistance to cell death or survival. In this chapter we briefly review findings related to remodeling of Ca(2+) entry pathways in cancer with emphasis on the mechanisms that contribute to increased store-operated Ca(2+) entry (SOCE) and store-operated currents (SOCs) in colorectal cancer cells. Finally, since SOCE appears critically involved in colon tumorogenesis, the inhibition of SOCE by aspirin and other NSAIDs and its possible contribution to colon cancer chemoprevention is reviewed.

  4. Remodeling of Calcium Entry Pathways in Cancer.

    PubMed

    Villalobos, Carlos; Sobradillo, Diego; Hernández-Morales, Miriam; Núñez, Lucía

    2016-01-01

    Ca(2+) entry pathways play important roles in control of many cellular functions, including long-term proliferation, migration and cell death. In recent years, it is becoming increasingly clear that, in some types of tumors, remodeling of Ca(2+) entry pathways could contribute to cancer hallmarks such as excessive proliferation, cell migration and invasion as well as resistance to cell death or survival. In this chapter we briefly review findings related to remodeling of Ca(2+) entry pathways in cancer with emphasis on the mechanisms that contribute to increased store-operated Ca(2+) entry (SOCE) and store-operated currents (SOCs) in colorectal cancer cells. Finally, since SOCE appears critically involved in colon tumorogenesis, the inhibition of SOCE by aspirin and other NSAIDs and its possible contribution to colon cancer chemoprevention is reviewed. PMID:27161240

  5. Phase field approaches of bone remodeling based on TIP

    NASA Astrophysics Data System (ADS)

    Ganghoffer, Jean-François; Rahouadj, Rachid; Boisse, Julien; Forest, Samuel

    2016-01-01

    The process of bone remodeling includes a cycle of repair, renewal, and optimization. This adaptation process, in response to variations in external loads and chemical driving factors, involves three main types of bone cells: osteoclasts, which remove the old pre-existing bone; osteoblasts, which form the new bone in a second phase; osteocytes, which are sensing cells embedded into the bone matrix, trigger the aforementioned sequence of events. The remodeling process involves mineralization of the bone in the diffuse interface separating the marrow, which contains all specialized cells, from the newly formed bone. The main objective advocated in this contribution is the setting up of a modeling and simulation framework relying on the phase field method to capture the evolution of the diffuse interface between the new bone and the marrow at the scale of individual trabeculae. The phase field describes the degree of mineralization of this diffuse interface; it varies continuously between the lower value (no mineral) and unity (fully mineralized phase, e.g. new bone), allowing the consideration of a diffuse moving interface. The modeling framework is the theory of continuous media, for which field equations for the mechanical, chemical, and interfacial phenomena are written, based on the thermodynamics of irreversible processes. Additional models for the cellular activity are formulated to describe the coupling of the cell activity responsible for bone production/resorption to the kinetics of the internal variables. Kinetic equations for the internal variables are obtained from a pseudo-potential of dissipation. The combination of the balance equations for the microforce associated to the phase field and the kinetic equations lead to the Ginzburg-Landau equation satisfied by the phase field with a source term accounting for the dissipative microforce. Simulations illustrating the proposed framework are performed in a one-dimensional situation showing the evolution of

  6. REACTIVE OXYGEN SPECIES IN PULMONARY VASCULAR REMODELING

    PubMed Central

    Aggarwal, Saurabh; Gross, Christine M.; Sharma, Shruti; Fineman, Jeffrey R.; Black, Stephen M.

    2014-01-01

    The pathogenesis of pulmonary hypertension is a complex multifactorial process that involves the remodeling of pulmonary arteries. This remodeling process encompasses concentric medial thickening of small arterioles, neomuscularization of previously nonmuscular capillary-like vessels, and structural wall changes in larger pulmonary arteries. The pulmonary arterial muscularization is characterized by vascular smooth muscle cell (SMC) hyperplasia and hypertrophy. In addition, in uncontrolled pulmonary hypertension, the clonal expansion of apoptosis-resistant endothelial cells leads to the formation of plexiform lesions. Based upon a large number of studies in animal models, the three major stimuli that drive the vascular remodeling process are inflammation, shear stress and hypoxia. Although, the precise mechanisms by which these stimuli impair pulmonary vascular function and structure are unknown, reactive oxygen species (ROS)-mediated oxidative damage appears to play an important role. ROS are highly reactive due to their unpaired valence shell electron. Oxidative damage occurs when the production of ROS exceeds the quenching capacity of the anti-oxidant mechanisms of the cell. ROS can be produced from complexes in the cell membrane (nicotinamide adenine dinucleotide phosphate-oxidase), cellular organelles (peroxisomes and mitochondria), and in the cytoplasm (xanthine oxidase). Furthermore, low levels of tetrahydrobiopterin (BH4) and L-arginine the rate limiting co-factor and substrate for endothelial nitric oxide synthase (eNOS), can cause the uncoupling of eNOS, resulting in decreased NO production and increased ROS production. This review will focus on the ROS generation systems, scavenger antioxidants, and oxidative stress associated alterations in vascular remodeling in pulmonary hypertension. PMID:23897679

  7. Perspectives on biological growth and remodeling

    PubMed Central

    Ambrosi, D.; Ateshian, G. A.; Arruda, E. M.; Cowin, S. C.; Dumais, J.; Goriely, A.; Holzapfel, G. A.; Humphrey, J. D.; Kemkemer, R.; Kuhl, E.; Olberding, J. E.; Taber, L. A.; Garikipati, K.

    2011-01-01

    The continuum mechanical treatment of biological growth and remodeling has attracted considerable attention over the past fifteen years. Many aspects of these problems are now well-understood, yet there remain areas in need of significant development from the standpoint of experiments, theory, and computation. In this perspective paper we review the state of the field and highlight open questions, challenges, and avenues for further development. PMID:21532929

  8. Application of Petri Nets in Bone Remodeling

    PubMed Central

    Li, Lingxi; Yokota, Hiroki

    2009-01-01

    Understanding a mechanism of bone remodeling is a challenging task for both life scientists and model builders, since this highly interactive and nonlinear process can seldom be grasped by simple intuition. A set of ordinary differential equations (ODEs) have been built for simulating bone formation as well as bone resorption. Although solving ODEs numerically can provide useful predictions for dynamical behaviors in a continuous time frame, an actual bone remodeling process in living tissues is driven by discrete events of molecular and cellular interactions. Thus, an event-driven tool such as Petri nets (PNs), which may dynamically and graphically mimic individual molecular collisions or cellular interactions, seems to augment the existing ODE-based systems analysis. Here, we applied PNs to expand the ODE-based approach and examined discrete, dynamical behaviors of key regulatory molecules and bone cells. PNs have been used in many engineering areas, but their application to biological systems needs to be explored. Our PN model was based on 8 ODEs that described an osteoprotegerin linked molecular pathway consisting of 4 types of bone cells. The models allowed us to conduct both qualitative and quantitative evaluations and evaluate homeostatic equilibrium states. The results support that application of PN models assists understanding of an event-driven bone remodeling mechanism using PN-specific procedures such as places, transitions, and firings. PMID:19838338

  9. Stepwise nucleosome translocation by RSC remodeling complexes

    PubMed Central

    Harada, Bryan T; Hwang, William L; Deindl, Sebastian; Chatterjee, Nilanjana; Bartholomew, Blaine; Zhuang, Xiaowei

    2016-01-01

    The SWI/SNF-family remodelers regulate chromatin structure by coupling the free energy from ATP hydrolysis to the repositioning and restructuring of nucleosomes, but how the ATPase activity of these enzymes drives the motion of DNA across the nucleosome remains unclear. Here, we used single-molecule FRET to monitor the remodeling of mononucleosomes by the yeast SWI/SNF remodeler, RSC. We observed that RSC primarily translocates DNA around the nucleosome without substantial displacement of the H2A-H2B dimer. At the sites where DNA enters and exits the nucleosome, the DNA moves largely along or near its canonical wrapping path. The translocation of DNA occurs in a stepwise manner, and at both sites where DNA enters and exits the nucleosome, the step size distributions exhibit a peak at approximately 1–2 bp. These results suggest that the movement of DNA across the nucleosome is likely coupled directly to DNA translocation by the ATPase at its binding site inside the nucleosome. DOI: http://dx.doi.org/10.7554/eLife.10051.001 PMID:26895087

  10. Stepwise nucleosome translocation by RSC remodeling complexes.

    PubMed

    Harada, Bryan T; Hwang, William L; Deindl, Sebastian; Chatterjee, Nilanjana; Bartholomew, Blaine; Zhuang, Xiaowei

    2016-02-19

    The SWI/SNF-family remodelers regulate chromatin structure by coupling the free energy from ATP hydrolysis to the repositioning and restructuring of nucleosomes, but how the ATPase activity of these enzymes drives the motion of DNA across the nucleosome remains unclear. Here, we used single-molecule FRET to monitor the remodeling of mononucleosomes by the yeast SWI/SNF remodeler, RSC. We observed that RSC primarily translocates DNA around the nucleosome without substantial displacement of the H2A-H2B dimer. At the sites where DNA enters and exits the nucleosome, the DNA moves largely along or near its canonical wrapping path. The translocation of DNA occurs in a stepwise manner, and at both sites where DNA enters and exits the nucleosome, the step size distributions exhibit a peak at approximately 1-2 bp. These results suggest that the movement of DNA across the nucleosome is likely coupled directly to DNA translocation by the ATPase at its binding site inside the nucleosome.

  11. Mio-Pliocene morphotectonic evolution of the Iranian Plateau: from outward expansion to incision and excavation

    NASA Astrophysics Data System (ADS)

    Ballato, Paolo; Heidarzadeh, Ghasem; Zeilinger, Gerold; Ghassemi, Mohammad; Cifelli, Francesca; Mattei, Massimo; Hassanzadeh, Jamshid; Balling, Philipp; Dunkl, István; Sudo, Masafumi; Mulch, Andreas; Strecker, Manfred

    2015-04-01

    .5 and 12.5 Ma. At ~10.5 Ma an increase in sediment flux into the basin occurred as documented by an extensive progradation (> 50 km of distance) of conglomerates in the distal sectors of the basin. This event was followed by basin uplift and erosion with a shift of the basin depocenter toward the outer margin of the plateau (to the N and NE; Zanjan and Mianeh basins). There, sedimentation lasted until fluvial incision and basin excavation of sub-horizontal sediments started sometime during the last 4 Ma. Overall, our data suggest that sedimentation took place in a contiguous foreland-basin system, most likely triggered by thrust stacking and topographic loading in the interior of the plateau from ~17 Ma. The outward N to NE-directed propagation of the deformation fronts (< 10.5 Ma) excised parts of the foreland, incorporating new basin sectors into the orogenic plateau and compartmentalizing the foreland into a contractional basin and range topography. This implies that the IP developed during crustal shortening and thickening processes and that sometime after 10.5 Ma the northern IP had reached a lateral size similar to the modern one.

  12. Effect of cylindrical confinement on the determination of laminar flame speeds using outwardly propagating flames

    SciTech Connect

    Burke, Michael P.; Chen, Zheng; Ju, Yiguang; Dryer, Frederick L.

    2009-04-15

    The effect of nonspherical (i.e. cylindrical) bomb geometry on the evolution of outwardly propagating flames and the determination of laminar flame speeds using the conventional constant-pressure technique is investigated experimentally and theoretically. The cylindrical chamber boundary modifies the propagation rate through the interaction of the wall with the flow induced by thermal expansion across the flame (even with constant pressure), which leads to significant distortion of the flame surface for large flame radii. These departures from the unconfined case, especially the resulting nonzero burned gas velocities, can lead to significant errors in flame speeds calculated using the conventional assumptions, especially for large flame radii. For example, at a flame radius of 0.5 times the wall radius, the flame speed calculated neglecting confinement effects can be low by {proportional_to}15% (even with constant pressure). A methodology to estimate the effect of nonzero burned gas velocities on the measured flame speed in cylindrical chambers is presented. Modeling and experiments indicate that the effect of confinement can be neglected for flame radii less than 0.3 times the wall radius while still achieving acceptable accuracy (within 3%). The methodology is applied to correct the flame speed for nonzero burned gas speeds, in order to extend the range of flame radii useful for flame speed measurements. Under the proposed scaling, the burned gas speed can be well approximated as a function of only flame radius for a given chamber geometry - i.e. the correction function need only be determined once for an apparatus and then it can be used for any mixture. Results indicate that the flow correction can be used to extract flame speeds for flame radii up to 0.5 times the wall radius with somewhat larger, yet still acceptable uncertainties for the cases studied. Flow-corrected burning velocities are measured for hydrogen and syngas mixtures at atmospheric and

  13. Indicial response functions of growth and remodeling of common bile duct postobstruction.

    PubMed

    Dang, Quang; Gregersen, Hans; Duch, Birgitte; Kassab, Ghassan S

    2004-03-01

    Biliary duct obstruction is an important clinical condition that stems from cholelithiasis, the neoplasm in the wall or, most commonly, gallbladder stones. The objective of this study is to understand the structural and mechanical remodeling of the common bile duct (CBD) postobstruction. Porcine CBD was ligated near the duodenum that increased the duct's pressure from 6.4 to 18.3 cmH(2)O in the first 12 h and to 30.7 cmH(2)O after 32 days. The remodeling process was studied after 3 h, 12 h, 2 days, 8 days, and 32 days (n = 5 in each group) after obstruction. One additional animal in each group was sham operated. At each scheduled time, the time course of change of morphometry (diameter, length, wall thickness, etc.) and mechanical properties (stress, strain, etc.) was documented. It was found that the diameter increased by about threefold and the wall thickness of the CBD doubled in the 32-day group compared with the sham group (P < 0.001). The stress and strain increased initially with increase in pressure but recovered to near the control values by day 32 due to the structural and mechanical adaptations. Hence, the net effect of the structural and mechanical remodeling is to restore the stress and strain to their homeostatic values. Furthermore, the strain recovers more rapidly and more completely than stress. Finally, the remodeling data were expressed mathematically in terms of indicial response functions (IRF), i.e., change of a particular feature of a CBD in response to a unit step change of the pressure. The IRF approach provides a quantitative description of the remodeling process in the CBD.

  14. Strain history and TGF-β1 induce urinary bladder wall smooth muscle remodeling and elastogenesis

    PubMed Central

    Heise, Rebecca L.; Parekh, Aron; Joyce, Erinn M.; Chancellor, Michael B.; Sacks, Michael S.

    2011-01-01

    Mechanical cues that trigger pathological remodeling in smooth muscle tissues remain largely unknown and are thought to be pivotal triggers for strain-induced remodeling. Thus, an understanding of the effects mechanical stimulation is important to elucidate underlying mechanisms of disease states and in the development of methods for smooth muscle tissue regeneration. For example, the urinary bladder wall (UBW) adaptation to spinal cord injury (SCI) includes extensive hypertrophy as well as increased collagen and elastin, all of which profoundly alter its mechanical response. In addition, the pro-fibrotic growth factor TGF-β1 is upregulated in pathologies of other smooth muscle tissues and may contribute to pathological remodeling outcomes. In the present study, we utilized an ex vivo organ culture system to investigate the response of UBW tissue under various strain-based mechanical stimuli and exogenous TGF-β1 to assess extracellular matrix (ECM) synthesis, mechanical responses, and bladder smooth muscle cell (BSMC) phenotype. Results indicated that a 0.5-Hz strain frequency triangular waveform stimulation at 15% strain resulted in fibrillar elastin production, collagen turnover, and a more compliant ECM. Further, this stretch regime induced changes in cell phenotype while the addition of TGF-β1 altered this phenotype. This phenotypic shift was further confirmed by passive strip biomechanical testing, whereby the bladder groups treated with TGF-β1 were more compliant than all other groups. TGF-β1 increased soluble collagen production in the cultured bladders. Overall, the 0.5-Hz strain-induced remodeling caused increased compliance due to elastogenesis, similar to that seen in early SCI bladders. Thus, organ culture of bladder strips can be used as an experimental model to examine ECM remodeling and cellular phenotypic shift and potentially elucidate BMSCs ability to produce fibrillar elastin using mechanical stretch either alone or in combination with

  15. Strain history and TGF-β1 induce urinary bladder wall smooth muscle remodeling and elastogenesis.

    PubMed

    Heise, Rebecca L; Parekh, Aron; Joyce, Erinn M; Chancellor, Michael B; Sacks, Michael S

    2012-01-01

    Mechanical cues that trigger pathological remodeling in smooth muscle tissues remain largely unknown and are thought to be pivotal triggers for strain-induced remodeling. Thus, an understanding of the effects mechanical stimulation is important to elucidate underlying mechanisms of disease states and in the development of methods for smooth muscle tissue regeneration. For example, the urinary bladder wall (UBW) adaptation to spinal cord injury (SCI) includes extensive hypertrophy as well as increased collagen and elastin, all of which profoundly alter its mechanical response. In addition, the pro-fibrotic growth factor TGF-β1 is upregulated in pathologies of other smooth muscle tissues and may contribute to pathological remodeling outcomes. In the present study, we utilized an ex vivo organ culture system to investigate the response of UBW tissue under various strain-based mechanical stimuli and exogenous TGF-β1 to assess extracellular matrix (ECM) synthesis, mechanical responses, and bladder smooth muscle cell (BSMC) phenotype. Results indicated that a 0.5-Hz strain frequency triangular waveform stimulation at 15% strain resulted in fibrillar elastin production, collagen turnover, and a more compliant ECM. Further, this stretch regime induced changes in cell phenotype while the addition of TGF-β1 altered this phenotype. This phenotypic shift was further confirmed by passive strip biomechanical testing, whereby the bladder groups treated with TGF-β1 were more compliant than all other groups. TGF-β1 increased soluble collagen production in the cultured bladders. Overall, the 0.5-Hz strain-induced remodeling caused increased compliance due to elastogenesis, similar to that seen in early SCI bladders. Thus, organ culture of bladder strips can be used as an experimental model to examine ECM remodeling and cellular phenotypic shift and potentially elucidate BMSCs ability to produce fibrillar elastin using mechanical stretch either alone or in combination with

  16. Plasma Levels of Transforming Growth Factor-β1 Reflect Left Ventricular Remodeling in Aortic Stenosis

    PubMed Central

    Villar, Ana V.; Cobo, Manuel; Llano, Miguel; Montalvo, Cecilia; González-Vílchez, Francisco; Martín-Durán, Rafael; Hurlé, María A.; Nistal, J. Francisco

    2009-01-01

    Background TGF-β1 is involved in cardiac remodeling through an auto/paracrine mechanism. The contribution of TGF-β1 from plasmatic source to pressure overload myocardial remodeling has not been analyzed. We investigated, in patients with valvular aortic stenosis (AS), and in mice subjected to transverse aortic arch constriction (TAC), whether plasma TGF-β1 relates with myocardial remodeling, reflected by LV transcriptional adaptations of genes linked to myocardial hypertrophy and fibrosis, and by heart morphology and function. Methodology/Principal Findings The subjects of the study were: 39 patients operated of AS; 27 healthy volunteers; 12 mice subjected to TAC; and 6 mice sham-operated. Myocardial samples were subjected to quantitative PCR. Plasma TGF-β1 was determined by ELISA. Under pressure overload, TGF-β1 plasma levels were significantly increased both in AS patients and TAC mice. In AS patients, plasma TGF-β1 correlated directly with aortic transvalvular gradients and LV mass surrogate variables, both preoperatively and 1 year after surgery. Plasma TGF-β1 correlated positively with the myocardial expression of genes encoding extracellular matrix (collagens I and III, fibronectin) and sarcomeric (myosin light chain-2, β-myosin heavy chain) remodelling targets of TGF-β1, in TAC mice and in AS patients. Conclusions/Significance A circulating TGF-β1-mediated mechanism is involved, in both mice and humans, in the excessive deposition of ECM elements and hypertrophic growth of cardiomyocytes under pressure overload. The possible value of plasma TGF-β1 as a marker reflecting preoperative myocardial remodeling status in AS patients deserves further analysis in larger patient cohorts. PMID:20041033

  17. Age-related bone resorption in the normal incus: a case of maladaptive remodelling?

    PubMed Central

    Lannigan, F J; O'Higgins, P; Oxnard, C E; McPhie, P

    1995-01-01

    The changes that occur in the normal human incus with age have been investigated. Evidence for age-related changes in this ossicle, especially in the region of the long process, has been accumulating over the last 30-40 years and yet they have neither been confirmed quantitatively nor explained satisfactorily. In this study the results of a morphometric study of the long processes of a series of normal incudes are presented. These demonstrate that the lenticular and long processes undergo progressive symmetric resorption with advancing age. We consider these findings in the light of previous considerations of incudal remodelling and propose that these remodelling changes may reflect a normal adaptive response to the biomechanical milieu of the human middle ear. PMID:7559138

  18. ATRA mechanically reprograms pancreatic stellate cells to suppress matrix remodelling and inhibit cancer cell invasion

    PubMed Central

    Chronopoulos, Antonios; Robinson, Benjamin; Sarper, Muge; Cortes, Ernesto; Auernheimer, Vera; Lachowski, Dariusz; Attwood, Simon; García, Rebeca; Ghassemi, Saba; Fabry, Ben; del Río Hernández, Armando

    2016-01-01

    Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with a dismal survival rate. Persistent activation of pancreatic stellate cells (PSCs) can perturb the biomechanical homoeostasis of the tumour microenvironment to favour cancer cell invasion. Here we report that ATRA, an active metabolite of vitamin A, restores mechanical quiescence in PSCs via a mechanism involving a retinoic acid receptor beta (RAR-β)-dependent downregulation of actomyosin (MLC-2) contractility. We show that ATRA reduces the ability of PSCs to generate high traction forces and adapt to extracellular mechanical cues (mechanosensing), as well as suppresses force-mediated extracellular matrix remodelling to inhibit local cancer cell invasion in 3D organotypic models. Our findings implicate a RAR-β/MLC-2 pathway in peritumoural stromal remodelling and mechanosensory-driven activation of PSCs, and further suggest that mechanical reprogramming of PSCs with retinoic acid derivatives might be a viable alternative to stromal ablation strategies for the treatment of PDAC. PMID:27600527

  19. ATRA mechanically reprograms pancreatic stellate cells to suppress matrix remodelling and inhibit cancer cell invasion.

    PubMed

    Chronopoulos, Antonios; Robinson, Benjamin; Sarper, Muge; Cortes, Ernesto; Auernheimer, Vera; Lachowski, Dariusz; Attwood, Simon; García, Rebeca; Ghassemi, Saba; Fabry, Ben; Del Río Hernández, Armando

    2016-01-01

    Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with a dismal survival rate. Persistent activation of pancreatic stellate cells (PSCs) can perturb the biomechanical homoeostasis of the tumour microenvironment to favour cancer cell invasion. Here we report that ATRA, an active metabolite of vitamin A, restores mechanical quiescence in PSCs via a mechanism involving a retinoic acid receptor beta (RAR-β)-dependent downregulation of actomyosin (MLC-2) contractility. We show that ATRA reduces the ability of PSCs to generate high traction forces and adapt to extracellular mechanical cues (mechanosensing), as well as suppresses force-mediated extracellular matrix remodelling to inhibit local cancer cell invasion in 3D organotypic models. Our findings implicate a RAR-β/MLC-2 pathway in peritumoural stromal remodelling and mechanosensory-driven activation of PSCs, and further suggest that mechanical reprogramming of PSCs with retinoic acid derivatives might be a viable alternative to stromal ablation strategies for the treatment of PDAC. PMID:27600527

  20. Effect of strontium-containing hydroxyapatite bone cement on bone remodeling following hip replacement.

    PubMed

    Ni, Guo X; Lin, Jian H; Chiu, Peter K Y; Li, Zhao Y; Lu, William W

    2010-01-01

    It is uncertain whether the use of bioactive bone cement has any beneficial effect on local bone adaptation following hip replacement. In this study, twelve goats underwent cemented hip hemiarthroplasty unilaterally, with either PMMA bone cement or strontium-containing hydroxyapatite (Sr-HA) bioactive bone cement. Nine months later, the femoral cortical bones at different levels were analyzed by microhardness testing and micro-CT scanning. Extensive bone remodeling was found at proximal and mid-levels in both PMMA and Sr-HA groups. However, with regard to the differences of bone mineral density, cortical bone area and bone hardness between implanted and non-implanted femur, less decreases were found in Sr-HA group than PMMA group at proximal and mid-levels, and significant differences were shown for bone area and hardness at proximal level. The results suggested that the use of Sr-HA cement might alleviate femoral bone remodeling after hip replacement. PMID:19728042

  1. Growth and Remodeling in Blood Vessels Studied In Vivo With Fractal Analysis

    NASA Technical Reports Server (NTRS)

    Parsons-Wingerter, Patricia A.

    2003-01-01

    Every cell in the human body must reside in close proximity to a blood vessel (within approximately 200 mm) because blood vessels provide the oxygen, metabolite, and fluid exchanges required for cellular existence. The growth and remodeling of blood vessels are required to support the normal physiology of embryonic development, reproductive biology, wound healing and adaptive remodeling to exercise, as well as abnormal tissue change in diseases such as cancer, diabetes, and coronary heart disease. Cardiovascular and hemodynamic (blood flow dynamics) alterations experienced by astronauts during long-term spaceflight, including orthostatic intolerance, fluid shifts in the body, and reduced numbers of red (erythrocyte) and white (immune) blood cells, are identified as risk factors of very high priority in the NASA task force report on risk reduction for human spaceflight, the "Critical Path Roadmap."

  2. Control of the delayed outward potassium currents in bursting pace-maker neurones of the snail, Helix pomatia.

    PubMed Central

    Heyer, C B; Lux, H D

    1976-01-01

    The net outward current in bursting pace-maker neurones of the snail (Helix pomatia) during sustained and repeated voltage clamp pulses was studied. The properties of currents remaining in cobalt-Ringer or after TEA injection were compared with those in untreated cells. 2. With sustained voltage clamp depolarizations the net outward current first increases to a maximum at 150 msec and then declines to 60% or less of its peak intensity. This depression, which is greater during repetition of short pulses (e.g. 100 msec pulses at 0-5 sec intervals), represents a true decrease in the outward flow of K (designated IK) and is not due to a decreased driving force resulting from extracellular K accumulation. The steady-state current-voltage (I-V) relationship for IK is N-shaped (Heyer & Lux, 1976). 3. A component of IK persists when Ca and Mg in the medium are replaced by Co (ICo-res). With voltage clamp depolarizations ICo-res increases rapidly to a maximum and then partially inactivates with voltage dependent time constants of hundredths or tenths of seconds. Repolarization removes the inactivation. Thus, repeated stimulation with short pulses does not increase the depression of ICo-res-ICo-res (e.g. measured during voltage steps from holding potentials of -50 to near 0 mV) is smaller in test pulses preceded by depolarization and larger in pulses preceded by hyperpolarization. The steady state I-V relationship is not N-shaped. ICo-res is blocked by intracellular injection of tetraethylammonium (TEA). 4. Repeated voltage clamp depolarization to near 0 mV with 100 msec pulses for neurones with large Ca currents in normal Ringer produces a long-term depression which is maximal with 300-400 msec repolarizations (to -50 mV) between pulses. This corresponds with stimulus parameters for the maximum Ca current (Heyer & Lux, 1976). Intracellular injection of Ca2+ (also Ba2+ and Co2+) likewise reduces the total net outward current and especially the delayed outward current under

  3. Region-specific vascular remodeling and its prevention by artificial gravity in weightless environment.

    PubMed

    Zhang, Li-Fan

    2013-12-01

    Evidence from recent ground and spaceflight studies with animals and humans supports the notion that microgravity-induced vascular remodeling contributes to postflight orthostatic intolerance. In the vascular beds of lower body, such as in splanchnic and lower limb circulation, resistance vessels would undergo hypotrophy and decrement in myogenic tone and vasoreactivity. Thus, despite the concurrent sympathetic activation, the increase in peripheral vascular resistance would still be compromised while astronauts were re-exposed to Earth's 1-G gravity, since ~75 % of the total vascular conductance lies below the heart. On the contrary, cerebral arteries would undergo hypertrophy and vasoreactivity enhancement due to adaptation to cerebral hypertension, which protects the down-stream microcirculation in the brain during spaceflight. However, the enhanced vasoreactivity of cerebral vessels might also aggravate postflight orthostatic intolerance, particularly after long-duration spaceflight. Animal studies have indicated that the underlying mechanisms may involve ion-channel remodeling in vascular smooth muscle cells and vascular NO-NOS and local renin-angiotensin system (L-RAS). Furthermore, vascular remodeling and associated ion-channel and L-RAS changes can be prevented by a countermeasure of daily short-duration restoring to normal standing posture. These findings substantiate in general the hypothesis that redistribution of transmural pressure along the arterial vasculature due to the removal of gravity might be the primary factor that initiates vascular remodeling in microgravity, and daily short-duration restoring its normal distribution by intermittent artificial gravity (IAG) can effectively prevent the vascular adaptation and hence postflight cardiovascular deconditioning. IAG might also be beneficial in maintaining vascular health during future long-duration space flight.

  4. Control of bone remodelling by applied dynamic loads

    NASA Technical Reports Server (NTRS)

    Lanyon, L. E.; Rubin, C. T.

    1984-01-01

    The data showing the relationship between bone mass and peak strain magnitude prepared and submitted for publication. The data from experiments relating remodelling activity with static or dynamic loads were prepared and submitted for publication. Development of programs to relate the location of remodelling activity with he natural and artificial dynamic strain distributions continued. Experiments on the effect of different strain rates on the remodelling response continued.

  5. Pregnancy-induced remodeling of heart valves.

    PubMed

    Pierlot, Caitlin M; Moeller, Andrew D; Lee, J Michael; Wells, Sarah M

    2015-11-01

    Recent studies have demonstrated remodeling of aortic and mitral valves leaflets under the volume loading and cardiac expansion of pregnancy. Those valves' leaflets enlarge with altered collagen fiber architecture, content, and cross-linking and biphasic changes (decreases, then increases) in extensibility during gestation. This study extends our analyses to right-sided valves, with additional compositional measurements for all valves. Valve leaflets were harvested from nonpregnant heifers and pregnant cows. Leaflet structure was characterized by leaflet dimensions, and ECM composition was determined using standard biochemical assays. Histological studies assessed changes in cellular and ECM components. Leaflet mechanical properties were assessed using equibiaxial mechanical testing. Collagen thermal stability and cross-linking were assessed using denaturation and hydrothermal isometric tension tests. Pulmonary and tricuspid leaflet areas increased during pregnancy by 35 and 55%, respectively. Leaflet thickness increased by 20% only in the pulmonary valve and largely in the fibrosa (30% thickening). Collagen crimp length was reduced in both the tricuspid (61%) and pulmonary (42%) valves, with loss of crimped area in the pulmonary valve. Thermomechanics showed decreased collagen thermal stability with surprisingly maintained cross-link maturity. The pulmonary leaflet exhibited the biphasic change in extensibility seen in left side valves, whereas the tricuspid leaflet mechanics remained largely unchanged throughout pregnancy. The tricuspid valve exhibits a remodeling response during pregnancy that is significantly diminished from the other three valves. All valves of the heart remodel in pregnancy in a manner distinct from cardiac pathology, with much similarity valve to valve, but with interesting valve-specific responses in the aortic and tricuspid valves.

  6. Chromatin remodelling: the industrial revolution of DNA around histones.

    PubMed

    Saha, Anjanabha; Wittmeyer, Jacqueline; Cairns, Bradley R

    2006-06-01

    Chromatin remodellers are specialized multi-protein machines that enable access to nucleosomal DNA by altering the structure, composition and positioning of nucleosomes. All remodellers have a catalytic ATPase subunit that is similar to known DNA-translocating motor proteins, suggesting DNA translocation as a unifying aspect of their mechanism. Here, we explore the diversity and specialization of chromatin remodellers, discuss how nucleosome modifications regulate remodeller activity and consider a model for the exposure of nucleosomal DNA that involves the use of directional DNA translocation to pump 'DNA waves' around the nucleosome.

  7. CHD chromatin remodelers and the transcription cycle.

    PubMed

    Murawska, Magdalena; Brehm, Alexander

    2011-01-01

    It is well established that ATP-dependent chromatin remodelers modulate DNA access of transcription factors and RNA polymerases by "opening" or "closing" chromatin structure. However, this view is far too simplistic. Recent findings have demonstrated that these enzymes not only set the stage for the transcription machinery to act but are actively involved at every step of the transcription process. As a consequence, they affect initiation, elongation, termination and RNA processing. In this review we will use the CHD family as a paradigm to illustrate the progress that has been made in revealing these new concepts.

  8. Bacterial genome remodeling through bacteriophage recombination.

    PubMed

    Menouni, Rachid; Hutinet, Geoffrey; Petit, Marie-Agnès; Ansaldi, Mireille

    2015-01-01

    Bacteriophages co-exist and co-evolve with their hosts in natural environments. Virulent phages lyse infected cells through lytic cycles, whereas temperate phages often remain dormant and can undergo lysogenic or lytic cycles. In their lysogenic state, prophages are actually part of the host genome and replicate passively in rhythm with host division. However, prophages are far from being passive residents: they can modify or bring new properties to their host. In this review, we focus on two important phage-encoded recombination mechanisms, i.e. site-specific recombination and homologous recombination, and how they remodel bacterial genomes. PMID:25790500

  9. Bacterial genome remodeling through bacteriophage recombination.

    PubMed

    Menouni, Rachid; Hutinet, Geoffrey; Petit, Marie-Agnès; Ansaldi, Mireille

    2015-01-01

    Bacteriophages co-exist and co-evolve with their hosts in natural environments. Virulent phages lyse infected cells through lytic cycles, whereas temperate phages often remain dormant and can undergo lysogenic or lytic cycles. In their lysogenic state, prophages are actually part of the host genome and replicate passively in rhythm with host division. However, prophages are far from being passive residents: they can modify or bring new properties to their host. In this review, we focus on two important phage-encoded recombination mechanisms, i.e. site-specific recombination and homologous recombination, and how they remodel bacterial genomes.

  10. A Kv3-like persistent, outwardly rectifying, Cs+-permeable, K+ current in rat subthalamic nucleus neurones

    PubMed Central

    Wigmore, Mark A; Lacey, Michael G

    2000-01-01

    A persistent outward K+ current (IPO), activated by depolarization from resting potential, has been identified and characterized in rat subthalamic nucleus (SThN) neurones using whole-cell voltage-clamp recording in brain slices.IPO both rapidly activated (τ= 8 ms at +5 mV) and deactivated (τ= 2 ms at −68 mV), while showing little inactivation. Tail current reversal potentials varied with extracellular K+ concentration in a Nernstian manner.Intracellular Cs+ did not alter either IPO amplitude or the voltage dependence of activation, but blocked transient (A-like) outward currents activated by depolarization. When extracellular K+ was replaced with Cs+, IPO tail current reversal potentials were dependent upon the extracellular Cs+ concentration, indicating an ability to conduct Cs+, as well as K+.IPO was blocked by Ba2+ (1 mm), 4-aminopyridine (1 mm) and tetraethylammonium (TEA; 20 mm), with an IC50 for TEA of 0.39 mm.The IPO conductance appeared maximal (38 nS) at around +27 mV, half-maximal at −13 mV, with the threshold for activation at around −38 mV.TEA (1 mm) blocked the action potential after-hyperpolarization and permitted accommodation of action potential firing at frequencies greater than around 200 Hz.We conclude that IPO, which shares many characteristics of currents attributable to Kv3.1 K+ channels, enables high-frequency spike trains in SThN neurones. PMID:10990536

  11. ECG manifestations of left ventricular electrical remodeling.

    PubMed

    Estes, E Harvey

    2012-01-01

    Research and thinking about the electrocardiographic manifestations of left ventricular hypertrophy has been constrained by a limited conceptual model of the process: heart disease produces chamber enlargement (increased mass), which in turn produces an altered electrocardiogram. The process is much more complex than can be represented in this simple model. A more robust and intricate model is proposed, in which heart (and vascular) disease causes structural changes, electrical changes, biochemical changes, and others, all of which interact to produce electrical remodeling of ventricular myocardium. This electrical remodeling results in a variety of ECG changes. All of these changes interact, leading to an altered clinical course, and to premature death. It is suggested that research, based on this model, can provide new clues to the processes involved, and improve the prediction of clinical outcomes. New directions in research, in recording equipment, and in organizational activities are suggested to test this new model, and to improve the usefulness of the electrocardiogram as a research and diagnostic tool.

  12. Remodeling of cardiolipin by phospholipid transacylation.

    PubMed

    Xu, Yang; Kelley, Richard I; Blanck, Thomas J J; Schlame, Michael

    2003-12-19

    Mitochondrial cardiolipin (CL) contains unique fatty acid patterns, but it is not known how the characteristic molecular species of CL are formed. We found a novel reaction that transfers acyl groups from phosphatidylcholine or phosphatidylethanolamine to CL in mitochondria of rat liver and human lymphoblasts. Acyl transfer was stimulated by ADP, ATP, and ATP gamma S, but not by other nucleotides. Coenzyme A stimulated the reaction only in the absence of adenine nucleotides. Free fatty acids were not incorporated into CL under the same incubation condition. The transacylation required addition of exogenous CL or monolyso-CL, whereas dilyso-CL was not a substrate. Transacylase activity was decreased in lymphoblasts from patients with Barth syndrome (tafazzin deletion), and this was accompanied by drastic changes in the molecular composition of CL. In rat liver, where linoleic acid was the most abundant residue of CL, only linoleoyl groups were transferred into CL, but not oleoyl or arachidonoyl groups. We demonstrated complete remodeling of tetraoleoyl-CL to tetralinoleoyl-CL in rat liver mitochondria and identified the intermediates linoleoyl-trioleoyl-CL, dilinoleoyl-dioleoyl-CL, and trilinoleoyl-oleoyl-CL by high-performance liquid chromatography. The data suggest that CL is remodeled by acyl specific phospholipid transacylation and that tafazzin is an acyltransferase involved in this mechanism.

  13. PARP inhibition and postinfarction myocardial remodeling.

    PubMed

    Halmosi, Robert; Deres, Laszlo; Gal, Roland; Eros, Krisztian; Sumegi, Balazs; Toth, Kalman

    2016-08-01

    Coronary artery disease accounts for the greatest proportion of cardiovascular diseases therefore it is the major cause of death worldwide. Its therapeutic importance is indicated by still high mortality of myocardial infarction, which is one of the most severe forms of CVDs. Moreover, the risk of developing heart failure is very high among survivors. Heart failure is accompanied by high morbidity and mortality rate, therefore this topic is in the focus of researchers' interest. After a myocardial infarct, at first ventricular hypertrophy develops as a compensatory mechanism to decrease wall stress but finally leads to left ventricular dilation. This phenomenon is termed as myocardial remodeling. The main characteristics of underlying mechanisms involve cardiomyocyte growth, vessel changes and increased collagen production, in all of which several mechanical stress induced neurohumoral agents, oxidative stress and signal transduction pathways are involved. The long term activation of these processes ultimately leads to left ventricular dilation and heart failure with decreased systolic function. Oxidative stress causes DNA breaks producing the activation of nuclear poly(ADP-ribose) polymerase-1 (PARP-1) enzyme that leads to energy depletion and unfavorable modulation of different kinase cascades (Akt-1/GSK-3β, MAPKs, various PKC isoforms) and thus it promotes the development of heart failure. Therefore inhibition of PARP enzyme could offer a promising new therapeutical approach to prevent the onset of heart failure among postinfarction patients. The purpose of this review is to give a comprehensive summary about the most significant experimental results and mechanisms in postinfarction remodeling. PMID:27392900

  14. Distinct right ventricle remodeling in response to pressure overload in the rat.

    PubMed

    Mendes-Ferreira, P; Santos-Ribeiro, D; Adão, R; Maia-Rocha, C; Mendes-Ferreira, M; Sousa-Mendes, C; Leite-Moreira, A F; Brás-Silva, C

    2016-07-01

    Pulmonary arterial hypertension (PAH), the most serious chronic disorder of the pulmonary circulation, is characterized by pulmonary vasoconstriction and remodeling, resulting in increased afterload on the right ventricle (RV). In fact, RV function is the main determinant of prognosis in PAH. The most frequently used experimental models of PAH include monocrotaline- and chronic hypoxia-induced PAH, which primarily affect the pulmonary circulation. Alternatively, pulmonary artery banding (PAB) can be performed to achieve RV overload without affecting the pulmonary vasculature, allowing researchers to determine the RV-specific effects of their drugs/interventions. In this work, using two different degrees of pulmonary artery constriction, we characterize, in full detail, PAB-induced adaptive and maladaptive remodeling of the RV at 3 wk after PAB surgery. Our results show that application of a mild constriction resulted in adaptive hypertrophy of the RV, with preserved systolic and diastolic function, while application of a severe constriction resulted in maladaptive hypertrophy, with chamber dilation and systolic and diastolic dysfunction up to the isolated cardiomyocyte level. By applying two different degrees of constriction, we describe, for the first time, a reliable and short-duration PAB model in which RV adaptation can be distinguished at 3 wk after surgery. We characterize, in full detail, structural and functional changes of the RV in its response to moderate and severe constriction, allowing researchers to better study RV physiology and transition to dysfunction and failure, as well as to determine the effects of new therapies. PMID:27199115

  15. Assessment of Maternal Vascular Remodeling During Pregnancy in the Mouse Uterus.

    PubMed

    Kieckbusch, Jens; Gaynor, Louise M; Colucci, Francesco

    2015-12-05

    The placenta mediates the exchange of factors such as gases and nutrients between mother and fetus and has specific demands for supply of blood from the maternal circulation. The maternal uterine vasculature needs to adapt to this temporary demand and the success of this arterial remodeling process has implications for fetal growth. Cells of the maternal immune system, especially natural killer (NK) cells, play a critical role in this process. Here we describe a method to assess the degree of remodeling of maternal spiral arteries during mouse pregnancy. Hematoxylin and eosin-stained tissue sections are scanned and the size of the vessels analysed. As a complementary validation method, we also present a qualitative assessment for the success of the remodeling process by immunohistochemical detection of smooth muscle actin (SMA), which normally disappears from within the arterial vascular media at mid-gestation. Together, these methods enable determination of an important parameter of the pregnancy phenotype. These results can be combined with other endpoints of mouse pregnancy to provide insight into the mechanisms underlying pregnancy-related complications.

  16. Assessment of Maternal Vascular Remodeling During Pregnancy in the Mouse Uterus

    PubMed Central

    Kieckbusch, Jens; Gaynor, Louise M.; Colucci, Francesco

    2015-01-01

    The placenta mediates the exchange of factors such as gases and nutrients between mother and fetus and has specific demands for supply of blood from the maternal circulation. The maternal uterine vasculature needs to adapt to this temporary demand and the success of this arterial remodeling process has implications for fetal growth. Cells of the maternal immune system, especially natural killer (NK) cells, play a critical role in this process. Here we describe a method to assess the degree of remodeling of maternal spiral arteries during mouse pregnancy. Hematoxylin and eosin-stained tissue sections are scanned and the size of the vessels analysed. As a complementary validation method, we also present a qualitative assessment for the success of the remodeling process by immunohistochemical detection of smooth muscle actin (SMA), which normally disappears from within the arterial vascular media at mid-gestation. Together, these methods enable determination of an important parameter of the pregnancy phenotype. These results can be combined with other endpoints of mouse pregnancy to provide insight into the mechanisms underlying pregnancy-related complications. PMID:26710086

  17. Cell-Envelope Remodeling as a Determinant of Phenotypic Antibacterial Tolerance in Mycobacterium tuberculosis

    PubMed Central

    2016-01-01

    The mechanisms that lead to phenotypic antibacterial tolerance in bacteria remain poorly understood. We investigate whether changes in NaCl concentration toward physiologically higher values affect antibacterial efficacy against Mycobacterium tuberculosis (Mtb), the causal agent of human tuberculosis. Indeed, multiclass phenotypic antibacterial tolerance is observed during Mtb growth in physiologic saline. This includes changes in sensitivity to ethionamide, ethambutol, d-cycloserine, several aminoglycosides, and quinolones. By employing organism-wide metabolomic and lipidomic approaches combined with phenotypic tests, we identified a time-dependent biphasic adaptive response after exposure of Mtb to physiological levels of NaCl. A first rapid, extensive, and reversible phase was associated with changes in core and amino acid metabolism. In a second phase, Mtb responded with a substantial remodelling of plasma membrane and outer lipid membrane composition. We demonstrate that phenotypic tolerance at physiological concentrations of NaCl is the result of changes in plasma and outer membrane lipid remodeling and not changes in core metabolism. Altogether, these results indicate that physiologic saline-induced antibacterial tolerance is kinetically coupled to cell envelope changes and demonstrate that metabolic changes and growth arrest are not the cause of phenotypic tolerance observed in Mtb exposed to physiologic concentrations of NaCl. Importantly, this work uncovers a role for bacterial cell envelope remodeling in antibacterial tolerance, alongside well-documented allterations in respiration, metabolism, and growth rate. PMID:27231718

  18. The skeleton in the closet: actin cytoskeletal remodeling in β-cell function.

    PubMed

    Arous, Caroline; Halban, Philippe A

    2015-10-01

    Over the last few decades, biomedical research has considered not only the function of single cells but also the importance of the physical environment within a whole tissue, including cell-cell and cell-extracellular matrix interactions. Cytoskeleton organization and focal adhesions are crucial sensors for cells that enable them to rapidly communicate with the physical extracellular environment in response to extracellular stimuli, ensuring proper function and adaptation. The involvement of the microtubular-microfilamentous cytoskeleton in secretion mechanisms was proposed almost 50 years ago, since when the evolution of ever more sensitive and sophisticated methods in microscopy and in cell and molecular biology have led us to become aware of the importance of cytoskeleton remodeling for cell shape regulation and its crucial link with signaling pathways leading to β-cell function. Emerging evidence suggests that dysfunction of cytoskeletal components or extracellular matrix modification influences a number of disorders through potential actin cytoskeleton disruption that could be involved in the initiation of multiple cellular functions. Perturbation of β-cell actin cytoskeleton remodeling could arise secondarily to islet inflammation and fibrosis, possibly accounting in part for impaired β-cell function in type 2 diabetes. This review focuses on the role of actin remodeling in insulin secretion mechanisms and its close relationship with focal adhesions and myosin II.

  19. DAF-16 employs the chromatin remodeller SWI/SNF to promote stress resistance and longevity.

    PubMed

    Riedel, Christian G; Dowen, Robert H; Lourenco, Guinevere F; Kirienko, Natalia V; Heimbucher, Thomas; West, Jason A; Bowman, Sarah K; Kingston, Robert E; Dillin, Andrew; Asara, John M; Ruvkun, Gary

    2013-05-01

    Organisms are constantly challenged by stresses and privations and require adaptive responses for their survival. The forkhead box O (FOXO) transcription factor DAF-16 (hereafter referred to as DAF-16/FOXO) is a central nexus in these responses, but despite its importance little is known about how it regulates its target genes. Proteomic identification of DAF-16/FOXO-binding partners in Caenorhabditis elegans and their subsequent functional evaluation by RNA interference revealed several candidate DAF-16/FOXO cofactors, most notably the chromatin remodeller SWI/SNF. DAF-16/FOXO and SWI/SNF form a complex and globally co-localize at DAF-16/FOXO target promoters. We show that specifically for gene activation, DAF-16/FOXO depends on SWI/SNF, facilitating SWI/SNF recruitment to target promoters, to activate transcription by presumed remodelling of local chromatin. For the animal, this translates into an essential role for SWI/SNF in DAF-16/FOXO-mediated processes, in particular dauer formation, stress resistance and the promotion of longevity. Thus, we give insight into the mechanisms of DAF-16/FOXO-mediated transcriptional regulation and establish a critical link between ATP-dependent chromatin remodelling and lifespan regulation.

  20. PREDOMINANCE OF LOCAL OVER SYSTEMIC FACTORS IN UTERINE ARTERIAL REMODELING DURING PREGNANCY

    PubMed Central

    Fuller, Robert; Barron, Carolyn; Mandala, Maurizio; Gokina, Natalia; Osol, George

    2009-01-01

    This study utilized a rat model in which pregnancy was surgically restricted to one uterine horn to differentiate between local (fetoplacental) and systemic (endocrine) influences on uterine vascular remodeling during pregnancy. Sprague-Dawley rats with single horn pregnancies were studied on day 20/22 of gestation and compared to age-matched non-pregnant and late pregnant controls. The morphology (axial length, lumen diameter, wall thickness) of the main uterine artery and of smaller arcuate vessels showed that vascular growth was dramatically increased in the pregnant vs. non-pregnant horn, (p<0.05). Arcuate artery wall thickness increased in the non-pregnant horn (compared to non-pregnant controls, p<0.05), suggesting a limited role for systemic hormonal influences on vascular remodeling. Notably, animals with only one functional horn also compensated by increasing the average number of implantation sites per horn from 7.6 to 12.9, thereby maintaining essentially normal litter size without any reduction in fetal or placental weights. These results demonstrate unequivocally that local rather than systemic influences play the dominant role in uterine vascular gestational remodeling of both large and small uterine arteries, and reveal a significant adaptive process that maintains relatively normal fecundity in spite of surgical restriction of normal bilateral pregnancy. PMID:19164479

  1. Prediction of denosumab effects on bone remodeling: A combined pharmacokinetics and finite element modeling.

    PubMed

    Hambli, Ridha; Boughattas, Mohamed Hafedh; Daniel, Jean-Luc; Kourta, Azeddine

    2016-07-01

    Denosumab is a fully human monoclonal antibody that inhibits receptor activator of nuclearfactor-kappa B ligand (RANKL). This key mediator of osteoclast activities has been shown to inhibit osteoclast differentiation and hence, to increase bone mineral density (BMD) in treated patients. In the current study, we develop a computer model to simulate the effects of denosumab treatments (dose and duration) on the proximal femur bone remodeling process quantified by the variation in proximal femur BMD. The simulation model is based on a coupled pharmacokinetics model of denosumab with a pharmacodynamics model consisting of a mechanobiological finite element remodeling model which describes the activities of osteoclasts and osteoblasts. The mechanical behavior of bone is described by taking into account the bone material fatigue damage accumulation and mineralization. A coupled strain-damage stimulus function is proposed which controls the level of bone cell autocrine and paracrine factors. The cellular behavior is based on Komarova et al.׳s (2003) dynamic law which describes the autocrine and paracrine interactions between osteoblasts and osteoclasts and computes cell population dynamics and changes in bone mass at a discrete site of bone remodeling. Therefore, when an external mechanical stress is applied, bone formation and resorption is governed by cell dynamics rather than by adaptive elasticity approaches. The proposed finite element model was implemented in the finite element code Abaqus (UMAT routine). In order to perform a preliminary validation, in vivo human proximal femurs were selected and scanned at two different time intervals (at baseline and at a 36-month interval). Then, a 3D FE model was generated and the denosumab-remodeling algorithm was applied to the scans at t0 simulating daily walking activities for a duration of 36 months. The predicted results (density variation) were compared to existing published ones performed on a human cohort (FREEDOM

  2. Homeoviscous Adaptation of Membranes in Archaea.

    PubMed

    Oger, Philippe M

    2015-01-01

    Because membranes play a central role in regulating fluxes inward and outward from the cells, maintaining the appropriate structure of the membrane is crucial to maintain cellular integrity and functions. Microbes often face contrasted and fluctuating environmental conditions, to which they need to adapt or die. Membrane adaptation is achieved by a modification of the membrane lipid composition, a strategy termed homeoviscous adaptation. Homeoviscous adaptation in archaea involves strategies similar to that observed in bacteria and eucarya, such as the regulation of lipid chain length or saturation levels, as well as strategies specific to archaea, such as the regulation of the number of cycles along the isoprenoid chains or the regulation of the ratio between mono and bipolar lipids. Although not described yet described in hyperthermophilic bacteria, it is possible that these two strategies also apply to these latter organisms. PMID:26174392

  3. Substrate-bound outward-open state of the betaine transporter BetP provides insights into Na+ coupling

    NASA Astrophysics Data System (ADS)

    Perez, Camilo; Faust, Belinda; Mehdipour, Ahmad Reza; Francesconi, Kevin A.; Forrest, Lucy R.; Ziegler, Christine

    2014-07-01

    The Na+-coupled betaine symporter BetP shares a highly conserved fold with other sequence unrelated secondary transporters, for example, with neurotransmitter symporters. Recently, we obtained atomic structures of BetP in distinct conformational states, which elucidated parts of its alternating-access mechanism. Here, we report a structure of BetP in a new outward-open state in complex with an anomalous scattering substrate, adding a fundamental piece to an unprecedented set of structural snapshots for a secondary transporter. In combination with molecular dynamics simulations these structural data highlight important features of the sequential formation of the substrate and sodium-binding sites, in which coordinating water molecules play a crucial role. We observe a strictly interdependent binding of betaine and sodium ions during the coupling process. All three sites undergo progressive reshaping and dehydration during the alternating-access cycle, with the most optimal coordination of all substrates found in the closed state.

  4. The giant cardiac membrane patch method: stimulation of outward Na(+)-Ca2+ exchange current by MgATP.

    PubMed Central

    Collins, A; Somlyo, A V; Hilgemann, D W

    1992-01-01

    1. A giant patch method was used to study the stimulatory effect of cytoplasmic MgATP on outward Na(+)-Ca2+ exchange current in inside-out cardiac membrane patches (1-10 G omega seals with 14-24 microns pipette tip diameters) excised from guinea-pig, rabbit and mouse myocytes. 2. To establish the validity of the method with respect to structure, bleb formation was examined with electron microscopy and with confocal fluorescence light microscopy. The blebs, which form as the sarcolemma detaches, excluded intracellular organelles and transverse tubules. The blebbed cells contained normal sarcomeres, sarcoplasmic reticulum, triads and diads. 3. To further establish the validity of the method for ion transport studies, measurements of Na(+)-K+ pump currents and charge movements are described briefly which demonstrate (i) free access to the cytoplasmic membrane side, (ii) MgATP dependence comparable to reconstituted pump (Kd, 94 microns), (iii) fast, rigorous concentration control and (iv) Na(+)-K+ pump densities in the range of whole-cell densities. 4. Stimulation of outward Na(+)-Ca2+ exchange current by MgATP attenuated exchange current decay during step increments of cytoplasmic sodium, shifted the secondary activation of outward exchange current by cytoplasmic calcium to lower free calcium concentrations and, particularly in mouse cardiac sarcolemma, induced cytoplasmic calcium-independent current. 5. Upon removal of MgATP the stimulatory effect usually decayed with a t50 (half-time) of about 3 min. However, the reversal took place much more rapidly (t50, 5-20 s) in patches from individual guinea-pig and rabbit myocyte batches. When decay was rapid, secondary activation by cytoplasmic calcium was shifted to higher free cytoplasmic calcium concentrations (Kd, 10-65 microns-free calcium). 6. With repeated applications of MgATP the rate and magnitude of the stimulatory effect progressively decreased. 7. The Kd for MgATP of the initial rate of stimulation of outward

  5. Multimodality Imaging of Myocardial Injury and Remodeling

    PubMed Central

    Kramer, Christopher M.; Sinusas, Albert J.; Sosnovik, David E.; French, Brent A.; Bengel, Frank M.

    2011-01-01

    Advances in cardiovascular molecular imaging have come at a rapid pace over the last several years. Multiple approaches have been taken to better understand the structural, molecular, and cellular events that underlie the progression from myocardial injury to myocardial infarction (MI) and, ultimately, to congestive heart failure. Multimodality molecular imaging including SPECT, PET, cardiac MRI, and optical approaches is offering new insights into the pathophysiology of MI and left ventricular remodeling in small-animal models. Targets that are being probed include, among others, angiotensin receptors, matrix metalloproteinases, integrins, apoptosis, macrophages, and sympathetic innervation. It is only a matter of time before these advances are applied in the clinical setting to improve post-MI prognostication and identify appropriate therapies in patients to prevent the onset of congestive heart failure. PMID:20395347

  6. Cell wall remodeling under abiotic stress

    PubMed Central

    Tenhaken, Raimund

    2015-01-01

    Plants exposed to abiotic stress respond to unfavorable conditions on multiple levels. One challenge under drought stress is to reduce shoot growth while maintaining root growth, a process requiring differential cell wall synthesis and remodeling. Key players in this process are the formation of reactive oxygen species (ROS) and peroxidases, which initially cross-link phenolic compounds and glycoproteins of the cell walls causing stiffening. The function of ROS shifts after having converted all the peroxidase substrates in the cell wall. If ROS-levels remain high during prolonged stress, OH°-radicals are formed which lead to polymer cleavage. In concert with xyloglucan modifying enzymes and expansins, the resulting cell wall loosening allows further growth of stressed organs. PMID:25709610

  7. Organelle remodeling at membrane contact sites.

    PubMed

    Henne, W Mike

    2016-10-01

    Cellular organelles must execute sophisticated biological processes to persist, and often communicate with one another to exchange metabolites and information. Recent studies suggest inter-organelle membrane contact sites (MCSs) are hubs for this cellular cross-talk. MCSs also govern membrane remodeling, thus controlling aspects of organelle shape, identity, and function. Here, we summarize three emerging phenomena that MCSs appear to govern: 1) organelle identity via the non-vesicular exchange of lipids, 2) mitochondrial shape and division, and 3) endosomal migration in response to sterol trafficking. We also discuss the role for ER-endolysosomal contact sites in cholesterol metabolism, and the potential biomedical importance this holds. Indeed, the emerging field inter-organellar cross-talk promises substantial advances in the fields of lipid metabolism and cell signaling.

  8. Molecular mechanisms of synaptic remodeling in alcoholism.

    PubMed

    Kyzar, Evan J; Pandey, Subhash C

    2015-08-01

    Alcohol use and alcohol addiction represent dysfunctional brain circuits resulting from neuroadaptive changes during protracted alcohol exposure and its withdrawal. Alcohol exerts a potent effect on synaptic plasticity and dendritic spine formation in specific brain regions, providing a neuroanatomical substrate for the pathophysiology of alcoholism. Epigenetics has recently emerged as a critical regulator of gene expression and synaptic plasticity-related events in the brain. Alcohol exposure and withdrawal induce changes in crucial epigenetic processes in the emotional brain circuitry (amygdala) that may be relevant to the negative affective state defined as the "dark side" of addiction. Here, we review the literature concerning synaptic plasticity and epigenetics, with a particular focus on molecular events related to dendritic remodeling during alcohol abuse and alcoholism. Targeting epigenetic processes that modulate synaptic plasticity may yield novel treatments for alcoholism.

  9. Myocardial Tissue Remodeling in Adolescent Obesity

    PubMed Central

    Shah, Ravi V.; Abbasi, Siddique A.; Neilan, Tomas G.; Hulten, Edward; Coelho‐Filho, Otavio; Hoppin, Alison; Levitsky, Lynne; de Ferranti, Sarah; Rhodes, Erinn T.; Traum, Avram; Goodman, Elizabeth; Feng, Henry; Heydari, Bobak; Harris, William S.; Hoefner, Daniel M.; McConnell, Joseph P.; Seethamraju, Ravi; Rickers, Carsten; Kwong, Raymond Y.; Jerosch‐Herold, Michael

    2013-01-01

    Background Childhood obesity is a significant risk factor for cardiovascular disease in adulthood. Although ventricular remodeling has been reported in obese youth, early tissue‐level markers within the myocardium that precede organ‐level alterations have not been described. Methods and Results We studied 21 obese adolescents (mean age, 17.7±2.6 years; mean body mass index [BMI], 41.9±9.5 kg/m2, including 11 patients with type 2 diabetes [T2D]) and 12 healthy volunteers (age, 15.1±4.5 years; BMI, 20.1±3.5 kg/m2) using biomarkers of cardiometabolic risk and cardiac magnetic resonance imaging (CMR) to phenotype cardiac structure, function, and interstitial matrix remodeling by standard techniques. Although left ventricular ejection fraction and left atrial volumes were similar in healthy volunteers and obese patients (and within normal body size‐adjusted limits), interstitial matrix expansion by CMR extracellular volume fraction (ECV) was significantly different between healthy volunteers (median, 0.264; interquartile range [IQR], 0.253 to 0.271), obese adolescents without T2D (median, 0.328; IQR, 0.278 to 0.345), and obese adolescents with T2D (median, 0.376; IQR, 0.336 to 0.407; P=0.0001). ECV was associated with BMI for the entire population (r=0.58, P<0.001) and with high‐sensitivity C‐reactive protein (r=0.47, P<0.05), serum triglycerides (r=0.51, P<0.05), and hemoglobin A1c (r=0.76, P<0.0001) in the obese stratum. Conclusions Obese adolescents (particularly those with T2D) have subclinical alterations in myocardial tissue architecture associated with inflammation and insulin resistance. These alterations precede significant left ventricular hypertrophy or decreased cardiac function. PMID:23963758

  10. Progenitor cells in pulmonary vascular remodeling.

    PubMed

    Yeager, Michael E; Frid, Maria G; Stenmark, Kurt R

    2011-01-01

    Pulmonary hypertension is characterized by cellular and structural changes in the walls of pulmonary arteries. Intimal thickening and fibrosis, medial hypertrophy and fibroproliferative changes in the adventitia are commonly observed, as is the extension of smooth muscle into the previously non-muscularized vessels. A majority of these changes are associated with the enhanced presence of α-SM-actin+ cells and inflammatory cells. Atypical abundances of functionally distinct endothelial cells, particularly in the intima (plexiform lesions), and also in the perivascular regions, are also described. At present, neither the origin(s) of these cells nor the molecular mechanisms responsible for their accumulation, in any of the three compartments of the vessel wall, have been fully elucidated. The possibility that they arise from either resident vascular progenitors or bone marrow-derived progenitor cells is now well established. Resident vascular progenitor cells have been demonstrated to exist within the vessel wall, and in response to certain stimuli, to expand and express myofibroblastic, endothelial or even hematopoietic markers. Bone marrow-derived or circulating progenitor cells have also been shown to be recruited to sites of vascular injury and to assume both endothelial and SM-like phenotypes. Here, we review the data supporting the contributory role of vascular progenitors (including endothelial progenitor cells, smooth muscle progenitor cells, pericytes, and fibrocytes) in vascular remodeling. A more complete understanding of the processes by which progenitor cells modulate pulmonary vascular remodeling will undoubtedly herald a renaissance of therapies extending beyond the control of vascular tonicity and reduction of pulmonary artery pressure. PMID:22034593

  11. Nrf2-Mediated Cardiac Maladaptive Remodeling and Dysfunction in a Setting of Autophagy Insufficiency.

    PubMed

    Qin, Qingyun; Qu, Chen; Niu, Ting; Zang, Huimei; Qi, Lei; Lyu, Linmao; Wang, Xuejun; Nagarkatti, Mitzi; Nagarkatti, Prakash; Janicki, Joseph S; Wang, Xing Li; Cui, Taixing

    2016-01-01

    Nuclear factor erythroid-2-related factor 2 (Nrf2) appears to exert either a protective or detrimental effect on the heart; however, the underlying mechanism remains poorly understood. Herein, we uncovered a novel mechanism for turning off the Nrf2-mediated cardioprotection and switching on Nrf2-mediated cardiac dysfunction. In a murine model of pressure overload-induced cardiac remodeling and dysfunction via transverse aortic arch constriction, knockout of Nrf2 enhanced myocardial necrosis and death rate during an initial stage of cardiac adaptation when myocardial autophagy function is intact. However, knockout of Nrf2 turned out to be cardioprotective throughout the later stage of cardiac maladaptive remodeling when myocardial autophagy function became insufficient. Transverse aortic arch constriction -induced activation of Nrf2 was dramatically enhanced in the heart with impaired autophagy, which is induced by cardiomyocyte-specific knockout of autophagy-related gene (Atg)5. Notably, Nrf2 activation coincided with the upregulation of angiotensinogen (Agt) only in the autophagy-impaired heart after transverse aortic arch constriction. Agt5 and Nrf2 gene loss-of-function approaches in combination with Jak2 and Fyn kinase inhibitors revealed that suppression of autophagy inactivated Jak2 and Fyn and nuclear translocation of Fyn, while enhancing nuclear translocation of Nrf2 and Nrf2-driven Agt expression in cardiomyocytes. Taken together, these results indicate that the pathophysiological consequences of Nrf2 activation are closely linked with the functional integrity of myocardial autophagy during cardiac remodeling. When autophagy is intact, Nrf2 is required for cardiac adaptive responses; however, autophagy impairment most likely turns off Fyn-operated Nrf2 nuclear export thus activating Nrf2-driven Agt transcription, which exacerbates cardiac maladaptation leading to dysfunction. PMID:26573705

  12. Remodeling of Endogenous Mammary Epithelium by Breast Cancer Stem Cells

    PubMed Central

    Parashurama, Natesh; Lobo, Neethan A.; Ito, Ken; Mosley, Adriane R.; Habte, Frezghi G.; Zabala, Maider; Smith, Bryan R.; Lam, Jessica; Weissman, Irving L.; Clarke, Michael F.; Gambhir, Sanjiv S.

    2014-01-01

    Poorly regulated tissue remodeling results in increased breast cancer risk, yet how breast cancer stem cells (CSC) participate in remodeling is unknown. We performed in vivo imaging of changes in fluorescent, endogenous duct architecture as a metric for remodeling. First, we quantitatively imaged physiologic remodeling of primary branches of the developing and regenerating mammary tree. To assess CSC-specific remodeling events, we isolated CSC from MMTV-Wnt1 (mouse mammary tumor virus long-term repeat enhancer driving Wnt1 oncogene) breast tumors, a well studied model in which tissue remodeling affects tumorigenesis. We confirm that CSC drive tumorigenesis, suggesting a link between CSC and remodeling. We find that normal, regenerating, and developing gland maintain a specific branching pattern. In contrast, transplantation of CSC results in changes in the branching patterns of endogenous ducts while non-CSC do not. Specifically, in the presence of CSC, we identified an increased number of branches, branch points, ducts which have greater than 40 branches (5/33 for CSC and 0/39 for non-CSC), and histological evidence of increased branching. Moreover, we demonstrate that only CSC implants invade into surrounding stroma with structures similar to developing mammary ducts (nine for CSC and one for non-CSC). Overall, we demonstrate a novel approach for imaging physiologic and pathological remodeling. Furthermore, we identify unique, CSC-specific, remodeling events. Our data suggest that CSC interact with the microenvironment differently than non-CSC, and that this could eventually be a therapeutic approach for targeting CSC. PMID:22899386

  13. Remodeling of endogenous mammary epithelium by breast cancer stem cells.

    PubMed

    Parashurama, Natesh; Lobo, Neethan A; Ito, Ken; Mosley, Adriane R; Habte, Frezghi G; Zabala, Maider; Smith, Bryan R; Lam, Jessica; Weissman, Irving L; Clarke, Michael F; Gambhir, Sanjiv S

    2012-10-01

    Poorly regulated tissue remodeling results in increased breast cancer risk, yet how breast cancer stem cells (CSC) participate in remodeling is unknown. We performed in vivo imaging of changes in fluorescent, endogenous duct architecture as a metric for remodeling. First, we quantitatively imaged physiologic remodeling of primary branches of the developing and regenerating mammary tree. To assess CSC-specific remodeling events, we isolated CSC from MMTV-Wnt1 (mouse mammary tumor virus long-term repeat enhancer driving Wnt1 oncogene) breast tumors, a well studied model in which tissue remodeling affects tumorigenesis. We confirm that CSC drive tumorigenesis, suggesting a link between CSC and remodeling. We find that normal, regenerating, and developing gland maintain a specific branching pattern. In contrast, transplantation of CSC results in changes in the branching patterns of endogenous ducts while non-CSC do not. Specifically, in the presence of CSC, we identified an increased number of branches, branch points, ducts which have greater than 40 branches (5/33 for CSC and 0/39 for non-CSC), and histological evidence of increased branching. Moreover, we demonstrate that only CSC implants invade into surrounding stroma with structures similar to developing mammary ducts (nine for CSC and one for non-CSC). Overall, we demonstrate a novel approach for imaging physiologic and pathological remodeling. Furthermore, we identify unique, CSC-specific, remodeling events. Our data suggest that CSC interact with the microenvironment differently than non-CSC, and that this could eventually be a therapeutic approach for targeting CSC. PMID:22899386

  14. Pathological Ventricular Remodeling: Mechanisms: Part 1 of 2

    PubMed Central

    Xie, Min; Burchfield, Jana S.; Hill, Joseph A.

    2013-01-01

    Despite declines in heart failure morbidity and mortality with current therapies, re-hospitalization rates remain distressingly high, impacting substantially on individuals, society, and the economy. As a result, the need for new therapeutic advances and novel medical devices is urgent. Disease-related left ventricular remodeling is a complex process involving cardiac myocyte growth and death, vascular rarefaction, fibrosis, inflammation, and electrophysiological remodeling. As these events are highly inter-related, targeting one single molecule or process may not be sufficient. Here, we review molecular and cellular mechanisms governing pathological ventricular remodeling. PMID:23877061

  15. Cardiac Remodeling: Concepts, Clinical Impact, Pathophysiological Mechanisms and Pharmacologic Treatment

    PubMed Central

    Azevedo, Paula S.; Polegato, Bertha F.; Minicucci, Marcos F.; Paiva, Sergio A. R.; Zornoff, Leonardo A. M.

    2016-01-01

    Cardiac remodeling is defined as a group of molecular, cellular and interstitial changes that manifest clinically as changes in size, mass, geometry and function of the heart after injury. The process results in poor prognosis because of its association with ventricular dysfunction and malignant arrhythmias. Here, we discuss the concepts and clinical implications of cardiac remodeling, and the pathophysiological role of different factors, including cell death, energy metabolism, oxidative stress, inflammation, collagen, contractile proteins, calcium transport, geometry and neurohormonal activation. Finally, the article describes the pharmacological treatment of cardiac remodeling, which can be divided into three different stages of strategies: consolidated, promising and potential strategies. PMID:26647721

  16. Interactive solution-adaptive grid generation

    NASA Technical Reports Server (NTRS)

    Choo, Yung K.; Henderson, Todd L.

    1992-01-01

    TURBO-AD is an interactive solution-adaptive grid generation program under development. The program combines an interactive algebraic grid generation technique and a solution-adaptive grid generation technique into a single interactive solution-adaptive grid generation package. The control point form uses a sparse collection of control points to algebraically generate a field grid. This technique provides local grid control capability and is well suited to interactive work due to its speed and efficiency. A mapping from the physical domain to a parametric domain was used to improve difficulties that had been encountered near outwardly concave boundaries in the control point technique. Therefore, all grid modifications are performed on a unit square in the parametric domain, and the new adapted grid in the parametric domain is then mapped back to the physical domain. The grid adaptation is achieved by first adapting the control points to a numerical solution in the parametric domain using control sources obtained from flow properties. Then a new modified grid is generated from the adapted control net. This solution-adaptive grid generation process is efficient because the number of control points is much less than the number of grid points and the generation of a new grid from the adapted control net is an efficient algebraic process. TURBO-AD provides the user with both local and global grid controls.

  17. Arabidopsis FORGETTER1 mediates stress-induced chromatin memory through nucleosome remodeling

    PubMed Central

    Brzezinka, Krzysztof; Altmann, Simone; Czesnick, Hjördis; Nicolas, Philippe; Gorka, Michal; Benke, Eileen; Kabelitz, Tina; Jähne, Felix; Graf, Alexander; Kappel, Christian; Bäurle, Isabel

    2016-01-01

    Plants as sessile organisms can adapt to environmental stress to mitigate its adverse effects. As part of such adaptation they maintain an active memory of heat stress for several days that promotes a more efficient response to recurring stress. We show that this heat stress memory requires the activity of the FORGETTER1 (FGT1) locus, with fgt1 mutants displaying reduced maintenance of heat-induced gene expression. FGT1 encodes the Arabidopsis thaliana orthologue of Strawberry notch (Sno), and the protein globally associates with the promoter regions of actively expressed genes in a heat-dependent fashion. FGT1 interacts with chromatin remodelers of the SWI/SNF and ISWI families, which also display reduced heat stress memory. Genomic targets of the BRM remodeler overlap significantly with FGT1 targets. Accordingly, nucleosome dynamics at loci with altered maintenance of heat-induced expression are affected in fgt1. Together, our results suggest that by modulating nucleosome occupancy, FGT1 mediates stress-induced chromatin memory. DOI: http://dx.doi.org/10.7554/eLife.17061.001 PMID:27680998

  18. Role of lymphocytes in myocardial injury, healing, and remodeling after myocardial infarction.

    PubMed

    Hofmann, Ulrich; Frantz, Stefan

    2015-01-16

    A large body of evidence produced during decades of research indicates that myocardial injury activates innate immunity. On the one hand, innate immunity both aggravates ischemic injury and impedes remodeling after myocardial infarction (MI). On the other hand, innate immunity activation contributes to myocardial healing, as exemplified by monocytes' central role in the formation of a stable scar and protection against intraventricular thrombi after acute infarction. Although innate leukocytes can recognize a wide array of self-antigens via pattern recognition receptors, adaptive immunity activation requires highly specific cooperation between antigen-presenting cells and distinct antigen-specific receptors on lymphocytes. We have only recently begun to examine lymphocyte activation's relationship to adaptive immunity and significance in the context of ischemic myocardial injury. There is some experimental evidence that CD4(+) T-cells contribute to ischemia-reperfusion injury. Several studies have shown that CD4(+) T-cells, especially CD4(+) T-regulatory cells, improve wound healing after MI, whereas depleting B-cells is beneficial post MI. That T-cell activation after MI is induced by T-cell receptor signaling implicates autoantigens that have not yet been identified in this context. Also, the significance of lymphocytes in humans post MI remains unclear, primarily as a result of methodology. This review summarizes current experimental evidence of lymphocytes' activation, functional role, and crosstalk with innate leukocytes in myocardial ischemia-reperfusion injury, wound healing, and remodeling after myocardial infarction.

  19. Imaging the outward motions of clumpy dust clouds around the red supergiant Antares with VLT/VISIR

    NASA Astrophysics Data System (ADS)

    Ohnaka, K.

    2014-08-01

    Aims: We present a 0."5-resolution 17.7 μm image of the red supergiant Antares. Our aim is to study the structure of the circumstellar envelope in detail. Methods: Antares was observed at 17.7 μm with the VLT mid-infrared instrument VISIR. Taking advantage of the BURST mode, in which a large number of short exposure frames are taken, we obtained a diffraction-limited image with a spatial resolution of 0."5. Results: The VISIR image shows six clumpy dust clouds located at 0."8-1."8 (43-96 R⋆ = 136-306 AU) away from the star. We also detected compact emission within a radius of 0."5 around the star. Comparison of our VISIR image taken in 2010 and the 20.8 μm image taken in 1998 with the Keck Telescope reveals the outward motions of four dust clumps. The proper motions of these dust clumps (with respect to the central star) amount to 0."2-0."6 in 12 years. This translates into expansion velocities (projected onto the plane of the sky) of 13-40 km s-1 with an uncertainty of ± 7 km s-1. The inner compact emission seen in the 2010 VISIR image is presumably newly formed dust, because it is not detected in the image taken in 1998. If we assume that the dust is ejected in 1998, the expansion velocity is estimated to be 34 km s-1, in agreement with the velocity of the outward motions of the clumpy dust clouds. The mass of the dust clouds is estimated to be (3-6) × 10-9 M⊙. These values are lower by a factor of 3-7 than the amount of dust ejected in one year estimated from the (gas+dust) mass-loss rate of 2 × 10-6 M⊙ yr-1, suggesting that the continuous mass loss is superimposed on the clumpy dust cloud ejection. Conclusions: The clumpy dust envelope detected in the 17.7 μm diffraction-limited image is similar to the clumpy or asymmetric circumstellar environment of other red supergiants. The velocities of the dust clumps cannot be explained by a simple accelerating outflow, implying the possible random nature of the dust cloud ejection mechanism. Based on VISIR

  20. Muscle damage and muscle remodeling: no pain, no gain?

    PubMed

    Flann, Kyle L; LaStayo, Paul C; McClain, Donald A; Hazel, Mark; Lindstedt, Stan L

    2011-02-15

    Skeletal muscle is a dynamic tissue that responds adaptively to both the nature and intensity of muscle use. This phenotypic plasticity ensures that muscle structure is linked to patterns of muscle use throughout the lifetime of an animal. The cascade of events that result in muscle restructuring - for example, in response to resistance exercise training - is often thought to be initiated by muscle damage. We designed this study to test the hypothesis that symptomatic (i.e. detectable) damage is a necessary precursor for muscle remodeling. Subjects were divided into two experimental populations: pre-trained (PT) and naive (NA). Demonstrable muscle damage was avoided in the PT group by a three-week gradual 'ramp-up' protocol. By contrast, the NA group was subjected to an initial damaging bout of exercise. Both groups participated in an eight-week high-force eccentric-cycle ergometry program (20 min, three times per week) designed to equate the total work done during training between the groups. The NA group experienced signs of damage, absent in the PT group, as indicated by greater than five times higher levels of plasma creatine kinase (CK) and self-reporting of initial perceived soreness and exertion, yet muscle size and strength gains were not different for the two groups. RT-PCR analysis revealed similar increases in levels of the growth factor IGF-1Ea mRNA in both groups. Likewise, the significant (P<0.01) increases in mean cross-sectional area (and total muscle volume) were equal in both groups. Finally, strength increases were identical for both groups (PT=25% and NA=26% improvement). The results of this study suggest that muscle rebuilding - for example, hypertrophy - can be initiated independent of any discernible damage to the muscle.

  1. Aggravated Cardiac Remodeling post Aortocaval Fistula in Unilateral Nephrectomized Rats

    PubMed Central

    Gu, Ye; Zou, Wusong; Zhang, Mingjing; Zhu, Pengfei; Hu, Shao

    2015-01-01

    Background Aortocaval fistula (AV) in rat is a unique model of volume-overload congestive heart failure and cardiac hypertrophy. Living donor kidney transplantation is regarded as beneficial to allograft recipients and not particularly detrimental to the donors. Impact of AV on animals with mild renal dysfunction is not fully understood. In this study, we explored the effects of AV in unilateral nephrectomized (UNX) rats. Methods Adult male Sprague-Dawley (SD) rats were divided into Sham (n = 10), UNX (right kidney remove, n = 10), AV (AV established between the levels of renal arteries and iliac bifurcation, n = 18) and UNX+AV (AV at one week after UNX, n = 22), respectively. Renal outcome was measured by glomerular filtration rate, effective renal plasma flow, fractional excretion of sodium, albuminuria, plasma creatinine, and cystatin C. Focal glomerulosclerosis (FGS) incidence was evaluated by renal histology. Cardiac function was measured by echocardiography and hemodynamic measurements. Results UNX alone induced compensatory left kidney enlargement, increased plasma creatinine and cystatin C levels, and slightly reduced glomerular filtration rate and increased FGS. AV induced significant cardiac enlargement and hypertrophy and reduced cardiac function and increased FGS, these changes were aggravated in UNX+AV rats. Conclusions Although UNX only induces minor renal dysfunction, additional chronic volume overload placement during the adaptation phase of the remaining kidney is associated with aggravated cardiac dysfunction and remodeling in UNX rats, suggesting special medical care is required for UNX or congenital monokidney subjects in case of chronic volume overload as in the case of pregnancy and hyperthyroidism to prevent further adverse cardiorenal events in these individuals. PMID:26252578

  2. Molecular Imaging of Angiogenesis and Vascular Remodeling in Cardiovascular Pathology

    PubMed Central

    Golestani, Reza; Jung, Jae-Joon; Sadeghi, Mehran M.

    2016-01-01

    Angiogenesis and vascular remodeling are involved in a wide array of cardiovascular diseases, from myocardial ischemia and peripheral arterial disease, to atherosclerosis and aortic aneurysm. Molecular imaging techniques to detect and quantify key molecular and cellular players in angiogenesis and vascular remodeling (e.g., vascular endothelial growth factor and its receptors, αvβ3 integrin, and matrix metalloproteinases) can advance vascular biology research and serve as clinical tools for early diagnosis, risk stratification, and selection of patients who would benefit most from therapeutic interventions. To target these key mediators, a number of molecular imaging techniques have been developed and evaluated in animal models of angiogenesis and vascular remodeling. This review of the state of the art molecular imaging of angiogenesis and vascular (and valvular) remodeling, will focus mostly on nuclear imaging techniques (positron emission tomography and single photon emission tomography) that offer high potential for clinical translation. PMID:27275836

  3. ATP-dependent chromatin remodeling shapes the DNA replication landscape

    PubMed Central

    Vincent, Jack A.; Kwong, Tracey J.; Tsukiyama, Toshio

    2009-01-01

    Summary The eukaryotic DNA replication machinery must traverse every nucleosome in the genome during S phase. As nucleosomes are generally inhibitory to DNA-dependent processes, chromatin structure must undergo extensive reorganization to facilitate DNA synthesis. However, the identity of chromatin-remodeling factors involved in replication and how they affect DNA synthesis is largely unknown. Here we show that two highly conserved ATP-dependent chromatin-remodeling complexes in Saccharomyces cerevisiae, Isw2 and Ino80, function in parallel to promote replication fork progression. As a result, Isw2 and Ino80 play especially important roles for replication of late-replicating regions during periods of replication stress. Both Isw2 and Ino80 complexes are enriched at sites of replication, suggesting that these complexes act directly to promote fork progression. These findings identify ATP-dependent chromatin-remodeling complexes promoting DNA replication, and define a specific stage of replication that requires remodeling for normal function. PMID:18408730

  4. Postinfarct Left Ventricular Remodelling: A Prevailing Cause of Heart Failure

    PubMed Central

    Galli, Alessio; Lombardi, Federico

    2016-01-01

    Heart failure is a chronic disease with high morbidity and mortality, which represents a growing challenge in medicine. A major risk factor for heart failure with reduced ejection fraction is a history of myocardial infarction. The expansion of a large infarct scar and subsequent regional ventricular dilatation can cause postinfarct remodelling, leading to significant enlargement of the left ventricular chamber. It has a negative prognostic value, because it precedes the clinical manifestations of heart failure. The characteristics of the infarcted myocardium predicting postinfarct remodelling can be studied with cardiac magnetic resonance and experimental imaging modalities such as diffusion tensor imaging can identify the changes in the architecture of myocardial fibers. This review discusses all the aspects related to postinfarct left ventricular remodelling: definition, pathogenesis, diagnosis, consequences, and available therapies, together with experimental interventions that show promising results against postinfarct remodelling and heart failure. PMID:26989555

  5. Tissue remodeling investigation in varicose veins

    PubMed Central

    Ghaderian, Sayyed Mohammad Hossein; Khodaii, Zohreh

    2012-01-01

    Although the etiology of varicose veins remains unknown, recent studies have focused on endothelial cell integrity and function because the endothelium regulates vessel tone and synthesizes many pro- and anti-inflammatory factors. The aim of this study was to investigate the evidence involving the endothelium in the development of varicose vein disease. In addition, tissue remodeling was investigated in varicose veins to determine the expression of different types of collagen. Tissue specimens of superficial varicose veins and control saphenous vein were used for immunohistochemical and transmission electron microscope (TEM). α-smooth muscle actin, and collagen I, III, IV antibodies were applied for immunohistochemical investigation. Findings of this study showed alterations of the intima, such as focal intimal discontinuity and denudation of endothelium; and the media, such as irregular arrangements of smooth muscle cells and collagen fibres in varicose veins. Our findings showed some changes in terms of distribution of types I, III and IV collagen in the intima and media of varicose vein walls compared with controls. These alterations to the media suggest that the pathological abnormality in varicose veins may be due to the loss of muscle tone as a result of the breakup of its regular structure by the collagen fibres. These findings only described some changes in terms of distribution of these types of collagen in the intima and media of varicose vein walls which may result in venous wall dysfunction in varicosis. PMID:24551759

  6. Shape Remodeling Assemblies in Biologically Inspired Materials

    NASA Astrophysics Data System (ADS)

    Safinya, Cyrus

    2013-03-01

    Much of our research is inspired by, and directed at, understanding the formation of novel structures (both relatively static and highly dynamic) with distinct shapes and morphologies observed in charged biological systems. The structures, in turn, often correlate to specific functions. For example, charged nanoscale tubules and rods and their assemblies are of interest in a range of applications, including as templates for hierarchical nanostructures, encapsulation systems, and biosensors. A series of studies will be described on charged biological assemblies exhibiting ``molecularly-triggered'' dynamical shape changes. In particular, we will focus on protein and lipid based nanotubule formation through small molecule stimuli-induced shape remodeling events. The systems include invertible protein nanotubes from two-state tubulin-protein building blocks and lipid nanotubes and nanorods from curvature stabilizing lipids (mimicking membrane curvature generating proteins). Funded by DOE-BES grant number DOE-DE-FG02-06ER46314 (protein and lipid assembly, lipid synthesis, structure-function) and NSF-DMR-1101900 (phase behavior).

  7. Chromatin modifications remodel cardiac gene expression.

    PubMed

    Mathiyalagan, Prabhu; Keating, Samuel T; Du, Xiao-Jun; El-Osta, Assam

    2014-07-01

    Signalling and transcriptional control involve precise programmes of gene activation and suppression necessary for cardiovascular physiology. Deep sequencing of DNA-bound transcription factors reveals a remarkable complexity of co-activators or co-repressors that serve to alter chromatin modification and regulate gene expression. The regulated complexes characterized by genome-wide mapping implicate the recruitment and exchange of proteins with specific enzymatic activities that include roles for histone acetylation and methylation in key developmental programmes of the heart. As for transcriptional changes in response to pathological stress, co-regulatory complexes are also differentially utilized to regulate genes in cardiac disease. Members of the histone deacetylase (HDAC) family catalyse the removal of acetyl groups from proteins whose pharmacological inhibition has profound effects preventing heart failure. HDACs interact with a complex co-regulatory network of transcription factors, chromatin-remodelling complexes, and specific histone modifiers to regulate gene expression in the heart. For example, the histone methyltransferase (HMT), enhancer of zeste homolog 2 (Ezh2), is regulated by HDAC inhibition and associated with pathological cardiac hypertrophy. The challenge now is to target the activity of enzymes involved in protein modification to prevent or reverse the expression of genes implicated with cardiac hypertrophy. In this review, we discuss the role of HDACs and HMTs with a focus on chromatin modification and gene function as well as the clinical treatment of heart failure. PMID:24812277

  8. TOWARDS A NEW SPATIAL REPRESENTATION OF BONE REMODELING

    PubMed Central

    Graham, Jason M.; Ayati, Bruce P.; Ramakrishnan, Prem S.; Martin, James A.

    2013-01-01

    Irregular bone remodeling is associated with a number of bone diseases such as osteoporosis and multiple myeloma. Computational and mathematical modeling can aid in therapy and treatment as well as understanding fundamental biology. Different approaches to modeling give insight into different aspects of a phenomena so it is useful to have an arsenal of various computational and mathematical models. Here we develop a mathematical representation of bone remodeling that can effectively describe many aspects of the complicated geometries and spatial behavior observed. There is a sharp interface between bone and marrow regions. Also the surface of bone moves in and out, i.e. in the normal direction, due to remodeling. Based on these observations we employ the use of a level-set function to represent the spatial behavior of remodeling. We elaborate on a temporal model for osteoclast and osteoblast population dynamics to determine the change in bone mass which influences how the interface between bone and marrow changes. We exhibit simulations based on our computational model that show the motion of the interface between bone and marrow as a consequence of bone remodeling. The simulations show that it is possible to capture spatial behavior of bone remodeling in complicated geometries as they occur in vitro and in vivo. By employing the level set approach it is possible to develop computational and mathematical representations of the spatial behavior of bone remodeling. By including in this formalism further details, such as more complex cytokine interactions and accurate parameter values, it is possible to obtain simulations of phenomena related to bone remodeling with spatial behavior much as in vitro and in vivo. This makes it possible to perform in silica experiments more closely resembling experimental observations. PMID:22901065

  9. X-ray structures of LeuT in substrate-free outward-open and apo inward-open states

    SciTech Connect

    Krishnamurthy, Harini; Gouaux, Eric

    2012-08-09

    Neurotransmitter sodium symporters are integral membrane proteins that remove chemical transmitters from the synapse and terminate neurotransmission mediated by serotonin, dopamine, noradrenaline, glycine and GABA ({gamma}-aminobutyric acid). Crystal structures of the bacterial homologue, LeuT, in substrate-bound outward-occluded and competitive inhibitor-bound outward-facing states have advanced our mechanistic understanding of neurotransmitter sodium symporters but have left fundamental questions unanswered. Here we report crystal structures of LeuT mutants in complexes with conformation-specific antibody fragments in the outward-open and inward-open states. In the absence of substrate but in the presence of sodium the transporter is outward-open, illustrating how the binding of substrate closes the extracellular gate through local conformational changes: hinge-bending movements of the extracellular halves of transmembrane domains 1, 2 and 6, together with translation of extracellular loop 4. The inward-open conformation, by contrast, involves large-scale conformational changes, including a reorientation of transmembrane domains 1, 2, 5, 6 and 7, a marked hinge bending of transmembrane domain 1a and occlusion of the extracellular vestibule by extracellular loop 4. These changes close the extracellular gate, open an intracellular vestibule, and largely disrupt the two sodium sites, thus providing a mechanism by which ions and substrate are released to the cytoplasm. The new structures establish a structural framework for the mechanism of neurotransmitter sodium symporters and their modulation by therapeutic and illicit substances.

  10. The Outward Bound Bridging Course for Low-Achieving High School Males: Effect on Academic Achievement and Multidimensional Self-Concepts.

    ERIC Educational Resources Information Center

    Marsh, Herbert W.; Richards, Garry

    The Outward Bound Bridging Course is a 6-week residential program designed to improve academic achievement and self-concepts in low-achieving high school males. During 1980-1984, five courses were conducted for 66 Australian high school males. Most of them were ninth grade students, chosen on the basis of poor academic performance, an apparent…

  11. Angiotensin II Type 1 Receptor-Mediated Electrical Remodeling in Mouse Cardiac Myocytes.

    PubMed

    Kim, Jeremy; Gao, Junyuan; Cohen, Ira S; Mathias, Richard T

    2015-01-01

    We recently characterized an autocrine renin angiotensin system (RAS) in canine heart. Activation of Angiotensin II Type 1 Receptors (AT1Rs) induced electrical remodeling, including inhibition of the transient outward potassium current Ito, prolongation of the action potential (AP), increased calcium entry and increased contractility. Electrical properties of the mouse heart are very different from those of dog heart, but if a similar system existed in mouse, it could be uniquely studied through genetic manipulations. To investigate the presence of a RAS in mouse, we measured APs and Ito in isolated myocytes. Application of angiotensin II (A2) for 2 or more hours reduced Ito magnitude, without affecting voltage dependence, and prolonged APs in a dose-dependent manner. Based on dose-inhibition curves, the fast and slow components of Ito (Ito,fast and IK,slow) appeared to be coherently regulated by [A2], with 50% inhibition at an A2 concentration of about 400 nM. This very high K0.5 is inconsistent with systemic A2 effects, but is consistent with an autocrine RAS in mouse heart. Pre-application of the microtubule destabilizing agent colchicine eliminated A2 effects on Ito and AP duration, suggesting these effects depend on intracellular trafficking. Application of the biased agonist SII ([Sar1-Ile4-Ile8]A2), which stimulates receptor internalization without G protein activation, caused Ito reduction and AP prolongation similar to A2-induced changes. These data demonstrate AT1R mediated regulation of Ito in mouse heart. Moreover, all measured properties parallel those measured in dog heart, suggesting an autocrine RAS may be a fundamental feedback system that is present across species. PMID:26430746

  12. Modulation of the transient outward current (Ito) in rat cardiac myocytes and human Kv4.3 channels by mefloquine.

    PubMed

    Perez-Cortes, E J; Islas, A A; Arevalo, J P; Mancilla, C; Monjaraz, E; Salinas-Stefanon, E M

    2015-10-15

    The antimalarial drug mefloquine, is known to be a potassium channel blocker, although its mechanism of action has not being elucidated and its effects on the transient outward current (Ito) and the molecular correlate, the Kv4.3 channel has not being studied. Here, we describe the mefloquine-induced inhibition of the rat ventricular Ito and of CHO cells co-transfected with human Kv4.3 and its accessory subunit hKChIP2C by whole-cell voltage-clamp. Mefloquine inhibited rat Ito and hKv4.3+KChIP2C currents in a concentration-dependent manner with a limited voltage dependence and similar potencies (IC50=8.9μM and 10.5μM for cardiac myocytes and Kv4.3 channels, respectively). In addition, mefloquine did not affect the activation of either current but significantly modified the hKv4.3 steady-state inactivation and recovery from inactivation. The effects of this drug was compared with that of 4-aminopyridine (4-AP), a well-known potassium channel blocker and its binding site does not seem to overlap with that of 4-AP.

  13. Internal and near nozzle flow characteristics in an enlarged model of an outwards opening pintle-type gasoline injector

    NASA Astrophysics Data System (ADS)

    Nouri, J. M.; Abo-Serie, E.; Marchi, A.; Mitroglou, N.; Arcoumanis, C.

    2007-10-01

    The internal nozzle and near the nozzle exit flows of an enlarged transparent model of an outwards opening injector were investigated for different flow rates and needle lifts under steady state flow conditions. A high resolution CCD camera, high speed video camera and an LDV system were employed to visualize the nozzle flow and quantify the tangential velocity characteristics. The images of the internal flow between the valve seat and the square cross-section end of the needle guide revealed the presence of four separated jet flows and four pairs of counter-rotating vortices with each pair bounded in-between two adjacent jets. The counter-rotating vortices are highly unstable with a circumferential oscillatory motion which was transmitted to the spray outside the nozzle with almost the same frequency. The dominant circumferential frequencies at the nozzle exit were identified by FFT analysis of the tangential velocities. A linear relationship exists between the dominant frequencies and the flow Reynolds number based on injection velocity and needle lift. Magnified images of the flow just outside the nozzle exit showed formation of interconnecting streamwise strings on the liquid film as soon as it emerges from the annular exit passage. The interspacing between the strings was found to be linearly related to injection velocity and almost independent of the needle lift.

  14. Membrane potential bistability in nonexcitable cells as described by inward and outward voltage-gated ion channels.

    PubMed

    Cervera, Javier; Alcaraz, Antonio; Mafe, Salvador

    2014-10-30

    The membrane potential of nonexcitable cells, defined as the electrical potential difference between the cell cytoplasm and the extracellular environment when the current is zero, is controlled by the individual electrical conductance of different ion channels. In particular, inward- and outward-rectifying voltage-gated channels are crucial for cell hyperpolarization/depolarization processes, being amenable to direct physical study. High (in absolute value) negative membrane potentials are characteristic of terminally differentiated cells, while low membrane potentials are found in relatively depolarized, more plastic cells (e.g., stem, embryonic, and cancer cells). We study theoretically the hyperpolarized and depolarized values of the membrane potential, as well as the possibility to obtain a bistability behavior, using simplified models for the ion channels that regulate this potential. The bistability regions, which are defined in the multidimensional state space determining the cell state, can be relevant for the understanding of the different model cell states and the transitions between them, which are triggered by changes in the external environment.

  15. Characteristics and roles of the volume-sensitive outwardly rectifying (VSOR) anion channel in the central nervous system.

    PubMed

    Akita, T; Okada, Y

    2014-09-01

    Cell volume regulation (CVR) is essential for all types of cells in the central nervous system (CNS) to counteract cell volume changes that may be associated with neuronal activities or diseases and with osmosensing in the hypothalamus, to facilitate morphological changes during cell proliferation, differentiation and migration, and to execute apoptosis of cells. The regulation is attained by regulating the net influx or efflux of solutes and water across the plasma membrane. The volume-sensitive outwardly rectifying (VSOR) anion channel plays a major role in providing a pathway for anion flux during the regulation. The VSOR anion channel is permeable not only to Cl(-) ions but also to amino acids like glutamate and taurine. This property confers a means of intercellular communications through the opening of the channel in the CNS. Thus exploring the roles of VSOR anion channels is crucial to understand the basic principles of cellular functions in the CNS. Here we review biophysical and pharmacological characteristics of the VSOR anion channel in the CNS, discuss its activation mechanisms and roles in the CNS reported so far, and give some perspectives on the next issues to be examined in the near future.

  16. Mechanism for attenuated outward conductance induced by mutations in the cytoplasmic pore of Kir2.1 channels

    NASA Astrophysics Data System (ADS)

    Chang, Hsueh-Kai; Iwamoto, Masayuki; Oiki, Shigetoshi; Shieh, Ru-Chi

    2015-12-01

    Outward currents through Kir2.1 channels regulate the electrical properties of excitable cells. These currents are subject to voltage-dependent attenuation by the binding of polyamines to high- and low-affinity sites, which leads to inward rectification, thereby controlling cell excitability. To examine the effects of positive charges at the low-affinity site in the cytoplasmic pore on inward rectification, we studied a mutant Kir channel (E224K/H226E) and measured single-channel currents and streaming potentials (Vstream), the latter provide the ratio of water to ions queued in a single-file permeation process in the selectivity filter. The water-ion coupling ratio was near one at a high K+ concentration ([K+]) for the wild-type channel and increased substantially as [K+] decreased. On the other hand, fewer ions occupied the selectivity filter in the mutant at all [K+]. A model for the Kir channel involving a K+ binding site in the wide pore was introduced. Model analyses revealed that the rate constants associated with the binding and release to and from the wide-pore K+ binding site was modified in the mutant. These effects lead to the reduced contribution of a conventional two-ion permeation mode to total conductance, especially at positive potentials, thereby inward rectification.

  17. Moving inwards, moving outwards, moving upwards: the role of spirituality during the early stages of breast cancer.

    PubMed

    Swinton, J; Bain, V; Ingram, S; Heys, S D

    2011-09-01

    The paper reflects on a study which explored the role of spirituality in the lives of women during the first year after being diagnosed with breast cancer. The study utilised a qualitative method (hermeneutic phenomenology) designed to provide rich and thick understanding of women's experiences of breast cancer and to explore possible ways in which spirituality may, or may not, be beneficial in enabling coping and enhancing quality of life. The paper draws on the thinking of David Hay and Viktor Frankl to develop a model of spirituality that includes, but is not defined by, religion and that has the possibility to facilitate effective empirical enquiry. It outlines a threefold movement - inwards, outwards and upwards - that emerged from in-depth interviews with women who have breast cancer. This framework captures something of the spiritual movement that women went through on their cancer journeys and offers some pointers and possibilities for better and more person-centred caring approaches that include recognition of the spiritual dimension of women's experiences for the management of those with breast cancer.

  18. Membrane potential bistability in nonexcitable cells as described by inward and outward voltage-gated ion channels.

    PubMed

    Cervera, Javier; Alcaraz, Antonio; Mafe, Salvador

    2014-10-30

    The membrane potential of nonexcitable cells, defined as the electrical potential difference between the cell cytoplasm and the extracellular environment when the current is zero, is controlled by the individual electrical conductance of different ion channels. In particular, inward- and outward-rectifying voltage-gated channels are crucial for cell hyperpolarization/depolarization processes, being amenable to direct physical study. High (in absolute value) negative membrane potentials are characteristic of terminally differentiated cells, while low membrane potentials are found in relatively depolarized, more plastic cells (e.g., stem, embryonic, and cancer cells). We study theoretically the hyperpolarized and depolarized values of the membrane potential, as well as the possibility to obtain a bistability behavior, using simplified models for the ion channels that regulate this potential. The bistability regions, which are defined in the multidimensional state space determining the cell state, can be relevant for the understanding of the different model cell states and the transitions between them, which are triggered by changes in the external environment. PMID:25286866

  19. Outward- and inward-facing structures of a putative bacterial transition-metal transporter with homology to ferroportin

    PubMed Central

    Taniguchi, Reiya; Kato, Hideaki E.; Font, Josep; Deshpande, Chandrika N.; Wada, Miki; Ito, Koichi; Ishitani, Ryuichiro; Jormakka, Mika; Nureki, Osamu

    2015-01-01

    In vertebrates, the iron exporter ferroportin releases Fe2+ from cells into plasma, thereby maintaining iron homeostasis. The transport activity of ferroportin is suppressed by the peptide hormone hepcidin, which exhibits upregulated expression in chronic inflammation, causing iron-restrictive anaemia. However, due to the lack of structural information about ferroportin, the mechanisms of its iron transport and hepcidin-mediated regulation remain largely elusive. Here we report the crystal structures of a putative bacterial homologue of ferroportin, BbFPN, in both the outward- and inward-facing states. Despite undetectable sequence similarity, BbFPN adopts the major facilitator superfamily fold. A comparison of the two structures reveals that BbFPN undergoes an intra-domain conformational rearrangement during the transport cycle. We identify a substrate metal-binding site, based on structural and mutational analyses. Furthermore, the BbFPN structures suggest that a predicted hepcidin-binding site of ferroportin is located within its central cavity. Thus, BbFPN may be a valuable structural model for iron homeostasis regulation by ferroportin. PMID:26461048

  20. Characteristics and roles of the volume-sensitive outwardly rectifying (VSOR) anion channel in the central nervous system.

    PubMed

    Akita, T; Okada, Y

    2014-09-01

    Cell volume regulation (CVR) is essential for all types of cells in the central nervous system (CNS) to counteract cell volume changes that may be associated with neuronal activities or diseases and with osmosensing in the hypothalamus, to facilitate morphological changes during cell proliferation, differentiation and migration, and to execute apoptosis of cells. The regulation is attained by regulating the net influx or efflux of solutes and water across the plasma membrane. The volume-sensitive outwardly rectifying (VSOR) anion channel plays a major role in providing a pathway for anion flux during the regulation. The VSOR anion channel is permeable not only to Cl(-) ions but also to amino acids like glutamate and taurine. This property confers a means of intercellular communications through the opening of the channel in the CNS. Thus exploring the roles of VSOR anion channels is crucial to understand the basic principles of cellular functions in the CNS. Here we review biophysical and pharmacological characteristics of the VSOR anion channel in the CNS, discuss its activation mechanisms and roles in the CNS reported so far, and give some perspectives on the next issues to be examined in the near future. PMID:24937753

  1. Novel concepts in airway inflammation and remodelling in asthma.

    PubMed

    Saglani, Sejal; Lloyd, Clare M

    2015-12-01

    The hallmark pathological features of asthma include airway eosinophilic inflammation and structural changes (remodelling) which are associated with an irreversible loss in lung function that tracks from childhood to adulthood. In parallel with changes in function, pathological abnormalities occur early, during the pre-school years, are established by school age and subsequently remain (even though symptoms may remit for periods during adulthood). Given the equal importance of inflammation and remodelling in asthma pathogenesis, there is a significant disparity in studies undertaken to investigate the contribution of each. The majority focus on the role of inflammation, and although novel therapeutics such as those targeted against T-helper cell type 2 (Th2) mediators have arisen, it is apparent that targeting inflammation alone has not allowed disease modification. Therefore, unless airway remodelling is addressed for future therapeutic strategies, it is unlikely that we will progress towards a cure for asthma. Having acknowledged these limitations, the focus of this review is to highlight the gaps in our current knowledge about the mechanisms underlying airway remodelling, the relationships between remodelling, inflammation and function, remodelling and clinical phenotypes, and the importance of utilising innovative and realistic pre-clinical models to uncover effective, disease-modifying therapeutic strategies. PMID:26541520

  2. Clinical Implications and Pathogenesis of Esophageal Remodeling in Eosinophilic Esophagitis

    PubMed Central

    Hirano, Ikuo; Aceves, Seema S.

    2014-01-01

    In eosinophilic esophagitis (EoE), remodeling changes are manifest histologically in both the epithelium as well as in the subepithelium where lamina propria (LP) fibrosis, expansion of the muscularis propria and increased vascularity occur. The major clinical symptoms and complications of EoE are largely consequences of esophageal remodeling. Important mediators of the process include IL-5, IL-13, TGFβ1, mast cells, fibroblasts and eosinophils. Methods to detect remodeling effects include upper endoscopy, histopathology, barium esophagram, endoscopic ultrasonography, esophageal manometry, and functional luminal imaging. These modalities provide evidence of organ dysfunction that include focal and diffuse esophageal strictures, expansion of the mucosa and subepithelium, esophageal motor abnormalities and reduced esophageal distensibility. Complications of food impaction and perforations of the esophageal wall have been associated with reduction in esophageal caliber and increased esophageal mural stiffness. The therapeutic benefits of topical corticosteroids and elimination diet therapy in resolving mucosal eosinophilic inflammation of the esophagus are evident. Available therapies, however, have demonstrated variable ability to reverse existing remodeling changes of the esophagus. Systemic therapies that include novel, targeted biologic agents have the potential of addressing subepithelial remodeling. Esophageal dilation remains a useful, adjunctive therapeutic maneuver in symptomatic adults with esophageal stricture. As novel treatments emerge, it is essential that therapeutic endpoints account for the fundamental contributions of esophageal remodeling to overall disease activity. PMID:24813517

  3. Alterations in vasomotor control of coronary resistance vessels in remodelled myocardium of swine with a recent myocardial infarction.

    PubMed

    Duncker, Dirk J; de Beer, Vincent J; Merkus, Daphne

    2008-05-01

    The mechanism underlying the progressive deterioration of left ventricular (LV) dysfunction after myocardial infarction (MI) towards overt heart failure remains incompletely understood, but may involve impairments in coronary blood flow regulation within remodelled myocardium leading to intermittent myocardial ischemia. Blood flow to the remodelled myocardium is hampered as the coronary vasculature does not grow commensurate with the increase in LV mass and because extravascular compression of the coronary vasculature is increased. In addition to these factors, an increase in coronary vasomotor tone, secondary to neurohumoral activation and endothelial dysfunction, could also contribute to the impaired myocardial oxygen supply. Consequently, we explored, in a series of studies, the alterations in regulation of coronary resistance vessel tone in remodelled myocardium of swine with a 2 to 3-week-old MI. These studies indicate that myocardial oxygen balance is perturbed in remodelled myocardium, thereby forcing the myocardium to increase its oxygen extraction. These perturbations do not appear to be the result of blunted beta-adrenergic or endothelial NO-mediated coronary vasodilator influences, and are opposed by an increased vasodilator influence through opening of K(ATP) channels. Unexpectedly, we observed that despite increased circulating levels of noradrenaline, angiotensin II and endothelin-1, alpha-adrenergic tone remained negligible, while the coronary vasoconstrictor influences of endogenous endothelin and angiotensin II were virtually abolished. We conclude that, early after MI, perturbations in myocardial oxygen balance are observed in remodelled myocardium. However, adaptive alterations in coronary resistance vessel control, consisting of increased vasodilator influences in conjunction with blunted vasoconstrictor influences, act to minimize the impairments of myocardial oxygen balance.

  4. Metabolic Remodeling in Iron-deficient Fungi

    PubMed Central

    Philpott, Caroline C.; Leidgens, Sebastien; Frey, Avery G.

    2012-01-01

    Eukaryotic cells contain dozens, perhaps hundreds, of iron-dependent proteins, which perform critical functions in nearly every major cellular process. Nutritional iron is frequently available to cells in only limited amounts; thus, unicellular and higher eukaryotes have evolved mechanisms to cope with iron scarcity. These mechanisms have been studied at the molecular level in the model eukaryotes Saccharomyces cerevisiae and Schizosaccharomyces pombe, as well as in some pathogenic fungi. Each of these fungal species exhibits metabolic adaptations to iron deficiency that serve to reduce the cell’s reliance on iron. However, the regulatory mechanisms that accomplish these adaptations differ greatly between fungal species. PMID:22306284

  5. Differentiation potentials of perivascular cells in the bone tissue remodeling zones under microgravity

    NASA Astrophysics Data System (ADS)

    Rodionova, Natalia; Katkova, Olena

    Adaptive remodeling processes in the skeleton bones occur in the close topographical interconnection with blood capillaries followed by perivascular cells. Radioautographic studies with 3Н- thymidine (Kimmel D.B., Fee W.S., 1980; Rodionova N.V., 1989, 2006) has shown that in osteogenesis zones there is sequential differentiation process of the perivascular cells into osteogenic ones. Using electron microscopy and cytochemistry we studied perivsacular cells in metaphysis of the rats femoral bones under conditions of modeling microgravity (28 days duration) and in femoral bonеs metaphyses of rats flown on board of the space laboratory (Spacelab - 2) It was revealed that population of the perivascular cells is not homogeneous in adaptive zones of the remodeling in both control and test groups (lowering support loading). This population comprises adjacent to endothelium little differentiated forms and isolated cells with differentiation features (specific volume of rough endoplasmic reticulum in cytoplasm is increased). Majority of the perivascular cells in the control group reveals reaction to alkaline phosphatase (marker of the osteogenic differentiation). In little differentiated cells this reaction is registered in nucleolus, nucleous and cytoplasm. In differentiating cells activity of the alkaline phosphatase is also detected on the outer surface of the cellular membrane. Unlike the control group in the bones of animals under microgravitaty reaction to the alkaline phosphatase is registered not for all cells of perivascular population. Part of the differentiating perivascular cells does not contain a product of the reaction. There is also visible trend of individual alkaline phosphatase containing perivascular cells amounts decrease (i.e. osteogenic cells-precursors). Under microgravity some little differentiated perivascular cells reveal destruction signs. Found decrease trend of the alkaline phosphatase containing cells (i.e. osteogenic cells) number in

  6. Changes in the population of perivascular cells in the bone tissue remodeling zones under microgravity

    NASA Astrophysics Data System (ADS)

    Katkova, Olena; Rodionova, Natalia; Shevel, Ivan

    2016-07-01

    Microgravity and long-term hypokinesia induce reduction both in bone mass and mineral saturation, which can lead to the development of osteoporosis and osteopenia. (Oganov, 2003). Reorganizations and adaptive remodeling processes in the skeleton bones occur in the topographical interconnection with blood capillaries and perivascular cells. Radioautographic studies with 3H- thymidine (Kimmel, Fee, 1980; Rodionova, 1989, 2006) have shown that in osteogenesis zones there is sequential differentiation process of the perivascular cells into osteogenic. Hence the study of populations of perivascular stromal cells in areas of destructive changes is actual. Perivascular cells from metaphysis of the rat femoral bones under conditions of modeling microgravity were studied using electron microscopy and cytochemistry (hindlimb unloading, 28 days duration) and biosatellite «Bion-M1» (duration of flight from April 19 till May 19, 2013 on C57, black mice). It was revealed that both control and test groups populations of the perivascular cells are not homogeneous in remodeling adaptive zones. These populations comprise of adjacent to endothelium poorly differentiated forms and isolated cells with signs of differentiation (specific increased volume of rough endoplasmic reticulum in cytoplasm). Majority of the perivascular cells in the control group (modeling microgravity) reveals reaction to alkaline phosphatase (marker of the osteogenic differentiation). In poorly differentiated cells this reaction is registered in nucleolus, nucleous and cytoplasm. In differentiating cells activity of the alkaline phosphatase is also detected on the outer surface of the cellular membrane. Unlike the control group in the bones of experimental animals reaction to the alkaline phosphatase is registered not in all cells of perivascular population. Part of the differentiating perivascular cells does not contain a product of the reaction. Under microgravity some poorly differentiated perivascular

  7. Onward, Upward and Outward.

    ERIC Educational Resources Information Center

    Ferguson, Sue; And Others

    The document is intended to provide teachers and parents of preschool or kindergarten aurally handicapped children with a resource of materials and books which can be used to provide and supplement experiences for the child. Play and other manipulative materials are analyzed in chart form according to the skill(s) which they develop. Included are…

  8. OUTWARD MIGRATION OF JUPITER AND SATURN IN 3:2 OR 2:1 RESONANCE IN RADIATIVE DISKS: IMPLICATIONS FOR THE GRAND TACK AND NICE MODELS

    SciTech Connect

    Pierens, Arnaud; Raymond, Sean N.; Nesvorny, David; Morbidelli, Alessandro

    2014-11-01

    Embedded in the gaseous protoplanetary disk, Jupiter and Saturn naturally become trapped in 3:2 resonance and migrate outward. This serves as the basis of the Grand Tack model. However, previous hydrodynamical simulations were restricted to isothermal disks, with moderate aspect ratio and viscosity. Here we simulate the orbital evolution of the gas giants in disks with viscous heating and radiative cooling. We find that Jupiter and Saturn migrate outward in 3:2 resonance in modest-mass (M {sub disk} ≈ M {sub MMSN}, where MMSN is the {sup m}inimum-mass solar nebula{sup )} disks with viscous stress parameter α between 10{sup –3} and 10{sup –2}. In disks with relatively low-mass (M {sub disk} ≲ M {sub MMSN}), Jupiter and Saturn get captured in 2:1 resonance and can even migrate outward in low-viscosity disks (α ≤ 10{sup –4}). Such disks have a very small aspect ratio (h ∼ 0.02-0.03) that favors outward migration after capture in 2:1 resonance, as confirmed by isothermal runs which resulted in a similar outcome for h ∼ 0.02 and α ≤ 10{sup –4}. We also performed N-body runs of the outer solar system starting from the results of our hydrodynamical simulations and including 2-3 ice giants. After dispersal of the gaseous disk, a Nice model instability starting with Jupiter and Saturn in 2:1 resonance results in good solar systems analogs. We conclude that in a cold solar nebula, the 2:1 resonance between Jupiter and Saturn can lead to outward migration of the system, and this may represent an alternative scenario for the evolution of the solar system.

  9. Obstruction-induced pulmonary vascular remodeling.

    PubMed

    Chow, Ming-Jay; Zou, Yu; He, Huamei; McGowan, Francis X; Zurakowski, David; Zhang, Yanhang

    2011-11-01

    Pulmonary obstruction occurs in many common forms of congenital heart disease. In this study, pulmonary artery (PA) banding is used as a model for pulmonary stenosis. Significant remodeling of the vascular bed occurs as a result of a prolonged narrowing of the PAs, and here we quantify the biophysical and molecular changes proximal and distal to the obstruction. Main and branch PAs are harvested from banded and sham rabbits and their mechanical properties are assessed using a biaxial tensile tester. Measurements defined as initial and stiff slopes are taken, assuming a linear region at the start and end of the J-shaped stress-strain curves, along with a transitional knee point. Collagen, elastin assays, Movat's pentachrome staining, and Doppler protocols are used to quantify biochemical, structural, and physiological differences. The banded main PAs have significantly greater initial slopes while banded branch PAs have lower initial slopes; however, this change in mechanical behavior cannot be explained by the assay results as the elastin content in both main and branch PAs is not significantly different. The stiff slopes of the banded main PAs are higher, which is attributed to the significantly greater amounts of insoluble collagen. Shifting of the knee points reveals a decreased toe region in the main PAs but an opposite trend in the branch PAs. The histology results show a loss of integrity of the media, increase in ground substance, and dispersion of collagen in the banded tissue samples. This indicates other structural changes could have led to the mechanical differences in banded and normal tissue. PMID:22168741

  10. Remodeling of alveolar septa after murine pneumonectomy

    PubMed Central

    Ysasi, Alexandra B.; Wagner, Willi L.; Bennett, Robert D.; Ackermann, Maximilian; Valenzuela, Cristian D.; Belle, Janeil; Tsuda, Akira; Konerding, Moritz A.

    2015-01-01

    In most mammals, removing one lung (pneumonectomy) results in the compensatory growth of the remaining lung. In mice, stereological observations have demonstrated an increase in the number of mature alveoli; however, anatomic evidence of the early phases of alveolar growth has remained elusive. To identify changes in the lung microstructure associated with neoalveolarization, we used tissue histology, electron microscopy, and synchrotron imaging to examine the configuration of the alveolar duct after murine pneumonectomy. Systematic histological examination of the cardiac lobe demonstrated no change in the relative frequency of dihedral angle components (Ends, Bends, and Junctions) (P > 0.05), but a significant decrease in the length of a subset of septal ends (“E”). Septal retraction, observed in 20–30% of the alveolar ducts, was maximal on day 3 after pneumonectomy (P < 0.01) and returned to baseline levels within 3 wk. Consistent with septal retraction, the postpneumonectomy alveolar duct diameter ratio (Dout:Din) was significantly lower 3 days after pneumonectomy compared to all controls except for the detergent-treated lung (P < 0.001). To identify clumped capillaries predicted by septal retraction, vascular casting, analyzed by both scanning electron microscopy and synchrotron imaging, demonstrated matted capillaries that were most prominent 3 days after pneumonectomy. Numerical simulations suggested that septal retraction could reflect increased surface tension within the alveolar duct, resulting in a new equilibrium at a higher total energy and lower surface area. The spatial and temporal association of these microstructural changes with postpneumonectomy lung growth suggests that these changes represent an early phase of alveolar duct remodeling. PMID:26078396

  11. Vein graft adaptation and fistula maturation in the arterial environment

    PubMed Central

    Lu, Daniel Y; Chen, Elizabeth Y; Wong, Daniel J; Yamamoto, Kota; Protack, Clinton D; Williams, Willis T; Assi, Roland; Hall, Michael R; Sadaghianloo, Nirvana; Dardik, Alan

    2014-01-01

    Veins are exposed to the arterial environment during two common surgical procedures, creation of vein grafts and arteriovenous fistulae (AVF). In both cases veins adapt to the arterial environment that is characterized by different hemodynamic conditions and increased oxygen tension compared to the venous environment. Successful venous adaptation to the arterial environment is critical for long term success of the vein graft or AVF, and in both cases is generally characterized by venous dilation and wall thickening. However, AVF are exposed to a high flow, high shear stress, low pressure arterial environment, and adapt mainly via outward dilation with less intimal thickening. Vein grafts are exposed to a moderate flow, moderate shear stress, high pressure arterial environment, and adapt mainly via increased wall thickening with less outward dilation. We review the data that describe these differences, as well as the underlying molecular mechanisms that mediate these processes. Despite extensive research, there are few differences in the molecular pathways that regulate cell proliferation and migration or matrix synthesis, secretion, or degradation currently identified between vein graft adaptation and AVF maturation that account for the different types of venous adaptation to arterial environments. PMID:24582063

  12. The contribution of arachidonate 15-lipoxygenase in tissue macrophages to adipose tissue remodeling.

    PubMed

    Kwon, H-J; Kim, S-N; Kim, Y-A; Lee, Y-H

    2016-01-01

    Cellular plasticity in adipose tissue involves adipocyte death, its clearance, and de novo adipogenesis, enabling homeostatic turnover and adaptation to metabolic challenges; however, mechanisms regulating these serial events are not fully understood. The present study investigated the roles of arachidonate 15-lipoxygenase (Alox15) in the clearance of dying adipocytes by adipose tissue macrophages. First, upregulation of Alox15 expression and apoptotic adipocyte death in gonadal white adipose tissue (gWAT) were characterized during adipose tissue remodeling induced by β3-adrenergic receptor stimulation. Next, an in vitro reconstruction of adipose tissue macrophages and apoptotic adipocytes recapitulated adipocyte clearance by macrophages and demonstrated that macrophages co-cultured with apoptotic adipocytes increased the expression of efferocytosis-related genes. Genetic deletion and pharmacological inhibition of Alox15 diminished the levels of adipocyte clearance by macrophages in a co-culture system. Gene expression profiling of macrophages isolated from gWAT of Alox15 knockout (KO) mice demonstrated distinct phenotypes, especially downregulation of genes involved in lipid uptake and metabolism compared to wild-type mice. Finally, in vivo β3-adrenergic stimulation in Alox15 KO mice failed to recruit crown-like structures, a macrophage network clearing dying adipocytes in gWAT. Consequently, in Alox15 KO mice, proliferation/differentiation of adipocyte progenitors and β3-adrenergic remodeling of gWAT were impaired compared to wild-type control mice. Collectively, our data established a pivotal role of Alox15 in the resolution of adipocyte death and in adipose tissue remodeling. PMID:27362803

  13. Outward stabilization of the S4 segments in domains III and IV enhances lidocaine block of sodium channels

    PubMed Central

    Sheets, Michael F; Hanck, Dorothy A

    2007-01-01

    The anti-arrhythmic drug lidocaine has been shown to have a lower affinity for block of voltage-gated sodium channels at hyperpolarized potentials compared to depolarized potentials. Concomitantly, lidocaine reduces maximum gating charge (Qmax) by 40% resulting from the complete stabilization of the S4 in domain III in an outward, depolarized position and partial stabilization of the S4 in domain IV in wild-type Na+ channels (NaV1.5). To investigate whether the pre-positioning of the S4 segments in these two domains in a depolarized conformation increases affinity for lidocaine block, a cysteine residue was substituted for the 3rd outermost charged residue in the S4 of domain III (R3C-DIII) and for the 2nd outermost Arg in S4 of domain IV (R2C-DIV) in NaV1.5. After biotinylation by exposure to extracellular MTSEA-biotin the mutated S4s became stabilized in an outward, depolarized position. For Na+ channels containing both mutations (R3C-DIII + R2C-DIV) the IC50 for rested-state lidocaine block decreased from 194 ± 15 μm in control to 28 ± 2 μm after MTSEA-biotin modification. To determine whether an intact inactivation gate (formed by the linker between domains III and IV) was required for local anaesthetic drugs to modify Na+ channel gating currents, a Cys was substituted for the Phe in the IFM motif of the inactivation gate (ICM) and then modified by intracellular MTSET (WT-ICMMTSET) before exposure to intracellular QX-222, a quarternary amine. Although WT-ICMMTSET required higher concentrations of drug to block INa compared to WT, Qmax decreased by 35% and the V1/2 shifted leftward as previously demonstrated for WT. The effect of stabilization of the S4s in domains III and IV in the absence of an intact inactivation gate on lidocaine block was determined for R3C-DIII + ICM, R2C-DIV + ICM and R3C-DIII + R2C-DIV + ICM, and compared to WT-ICM. IC50 values were 1360 ± 430 μm, 890 ± 70 μm, 670 ± 30 μm and 1920 ± 60 μm, respectively. Thermodynamic mutant

  14. 4-Aminopyridine causes a voltage-dependent block of the transient outward K+ current in rat melanotrophs.

    PubMed Central

    Kehl, S J

    1990-01-01

    1. Whole-cell voltage-clamp recordings were made from acutely dissociated melanotrophs obtained from adult rats. 2. In the presence of external Na+ and Ca2+ channel blockers and 20 mM-tetraethylammonium (TEA) depolarizations to -40 mV or more evoked a fast-activating fast-inactivating outward K+ current (IK(f)). Double-pulse experiments showed that steady-state half-inactivation occurred near -37 mV; half-maximal activation of IK(f) occurred at -15 mV. Recovery from inactivation in most cells fitted a single exponential with a time constant of 40-50 ms. 3. When applied either internally or externally, 1-2.5 mM-4-aminopyridine (4-AP) substantially reduced IK(f) but the degree of block was affected by the intensity, duration and frequency of depolarizing commands. 4. Analysis of the steady-state voltage dependence of the block by 4-AP showed that half-maximal blocking occurred at approximately -31 mV. This implied that 4-AP binds to the resting state of the IK(f) channel. 5. Studies of the time dependence for the blocking or unblocking of IK(f) showed that both processes were exponential with mean time constants of 1942 ms (at -70 mV) and 726 ms (at 20 mV), respectively. Recovery from inactivation was apparently unaffected by 4-AP. 6. A four-state sequential model in which 4-AP reversibly binds to the resting state of the channel replicates the frequency dependence of the 4-AP blockade. PMID:2100315

  15. Transient outward potassium current, ‘Ito’, phenotypes in the mammalian left ventricle: underlying molecular, cellular and biophysical mechanisms

    PubMed Central

    Patel, Sangita P; Campbell, Donald L

    2005-01-01

    At least two functionally distinct transient outward K+ current (Ito) phenotypes can exist across the free wall of the left ventricle (LV). Based upon their voltage-dependent kinetics of recovery from inactivation, these two phenotypes are designated ‘Ito,fast’ (recovery time constants on the order of tens of milliseconds) and ‘Ito,slow’ (recovery time constants on the order of thousands of milliseconds). Depending upon species, either Ito,fast, Ito,slow or both current phenotypes may be expressed in the LV free wall. The expression gradients of these two Ito phenotypes across the LV free wall are typically heterogeneous and, depending upon species, may consist of functional phenotypic gradients of both Ito,fast and Ito,slow and/or density gradients of either phenotype. We review the present evidence (molecular, biophysical, electrophysiological and pharmacological) for Kv4.2/4.3 α subunits underlying LV Ito,fast and Kv1.4 α subunits underlying LV Ito,slow and speculate upon the potential roles of each of these currents in determining frequency-dependent action potential characteristics of LV subepicardial versus subendocardial myocytes in different species. We also review the possible functional implications of (i) ancillary subunits that regulate Kv1.4 and Kv4.2/4.3 (Kvβ subunits, DPPs), (ii) KChIP2 isoforms, (iii) spider toxin-mediated block of Kv4.2/4.3 (Heteropoda toxins, phrixotoxins), and (iv) potential mechanisms of modulation of Ito,fast and Ito,slow by cellular redox state, [Ca2+]i and kinase-mediated phosphorylation. Ito phenotypic activation and state-dependent gating models and molecular structure–function relationships are also discussed. PMID:15831535

  16. Mefenamic acid bi-directionally modulates the transient outward K{sup +} current in rat cerebellar granule cells

    SciTech Connect

    Zhang Man; Shi Wenjie; Fei Xiaowei; Liu Yarong; Zeng Ximin; Mei Yanai

    2008-02-01

    The effect of non-steroidal anti-inflammatory drugs (NSAIDs) on ion channels has been widely studied in several cell models, but less is known about their modulatory mechanisms. In this report, the effect of mefenamic acid on voltage-activated transient outward K{sup +} current (I{sub A}) in cultured rat cerebellar granule cells was investigated. At a concentration of 5 {mu}M to 100 {mu}M, mefenamic acid reversibly inhibited I{sub A} in a dose-dependent manner. However, mefenamic acid at a concentration of 1 {mu}M significantly increased the amplitude of I{sub A} to 113 {+-} 1.5% of the control. At more than 10 {mu}M, mefenamic acid inhibited the amplitude of I{sub A} without any effect on activation or inactivation. In addition, a higher concentration of mefenamic acid induced a significant acceleration of recovery from inactivation with an increase of the peak amplitude elicited by the second test pulse. Intracellular application of mefenamic acid could significantly increase the amplitude of I{sub A}, but had no effect on the inhibition induced by extracellular mefenamic acid, implying that mefenamic acid may exert its effect from both inside and outside the ion channel. Furthermore, the activation of current induced by intracellular application of mefenamic acid was mimicked by other cyclooxygenase inhibitors and arachidonic acid. Our data demonstrate that mefenamic acid is able to bi-directionally modulate I{sub A} channels in neurons at different concentrations and by different methods of application, and two different mechanisms may be involved.

  17. Effects of Sleep Deprivation on Action Potential and Transient Outward Potassium Current in Ventricular Myocytes in Rats

    PubMed Central

    Fang, Zhou; Ren, Yi-Peng; Lu, Cai-Yi; Li, Yang; Xu, Qiang; Peng, Li; Fan, Yong-Yan

    2015-01-01

    Background Sleep deprivation contributes to the development and recurrence of ventricular arrhythmias. However, the electrophysiological changes in ventricular myocytes in sleep deprivation are still unknown. Material/Methods Sleep deprivation was induced by modified multiple platform technique. Fifty rats were assigned to control and sleep deprivation 1, 3, 5, and 7 days groups, and single ventricular myocytes were enzymatically dissociated from rat hearts. Action potential duration (APD) and transient outward current (Ito) were recorded using whole-cell patch clamp technique. Results Compared with the control group, the phases of APD of ventricular myocytes in 3, 5, and 7 days groups were prolonged and APD at 20% and 50% level of repolarization (APD20 and APD50) was significantly elongated (The APD20 values of control, 1, 3, 5, and 7 days groups: 5.66±0.16 ms, 5.77±0.20 ms, 8.28±0.30 ms, 11.56±0.32 ms, 13.24±0.56 ms. The APD50 values: 50.66±2.16 ms, 52.77±3.20 ms, 65.28±5.30 ms, 83.56±7.32 ms, 89.24±5.56 ms. P<0.01, n=18). The current densities of Ito significantly decreased. The current density-voltage (I–V) curve of Ito was vitally suppressed downward. The steady-state inactivation curve and steady-state activation curve of Ito were shifted to left and right, respectively, in sleep deprivation rats. The inactivation recovery time of Ito was markedly retarded and the time of closed-state inactivation was markedly accelerated in 3, 5, and 7 days groups. Conclusions APD of ventricular myocytes in sleep deprivation rats was significantly prolonged, which could be attributed to decreased activation and accelerated inactivation of Ito. PMID:25694200

  18. P2X4 Activation Modulates Volume-sensitive Outwardly Rectifying Chloride Channels in Rat Hepatoma Cells*

    PubMed Central

    Varela, Diego; Penna, Antonello; Simon, Felipe; Eguiguren, Ana Luisa; Leiva-Salcedo, Elías; Cerda, Oscar; Sala, Francisco; Stutzin, Andrés

    2010-01-01

    Volume-sensitive outwardly rectifying (VSOR) Cl− channels are critical for the regulatory volume decrease (RVD) response triggered upon cell swelling. Recent evidence indicates that H2O2 plays an essential role in the activation of these channels and that H2O2 per se activates the channels under isotonic isovolumic conditions. However, a significant difference in the time course for current onset between H2O2-induced and hypotonicity-mediated VSOR Cl− activation is observed. In several cell types, cell swelling induced by hypotonic challenges triggers the release of ATP to the extracellular medium, which in turn, activates purinergic receptors and modulates cell volume regulation. In this study, we have addressed the effect of purinergic receptor activation on H2O2-induced and hypotonicity-mediated VSOR Cl− current activation. Here we show that rat hepatoma cells (HTC) exposed to a 33% hypotonic solution responded by rapidly activating VSOR Cl− current and releasing ATP to the extracellular medium. In contrast, cells exposed to 200 μm H2O2 VSOR Cl− current onset was significantly slower, and ATP release was not detected. In cells exposed to either 11% hypotonicity or 200 μm H2O2, exogenous addition of ATP in the presence of extracellular Ca2+ resulted in a decrease in the half-time for VSOR Cl− current onset. Conversely, in cells that overexpress a dominant-negative mutant of the ionotropic receptor P2X4 challenged with a 33% hypotonic solution, the half-time for VSOR Cl− current onset was significantly slowed down. Our results indicate that, at high hypotonic imbalances, swelling-induced ATP release activates the purinergic receptor P2X4, which in turn modulates the time course of VSOR Cl− current onset in a extracellular Ca2+-dependent manner. PMID:20056605

  19. P2X4 activation modulates volume-sensitive outwardly rectifying chloride channels in rat hepatoma cells.

    PubMed

    Varela, Diego; Penna, Antonello; Simon, Felipe; Eguiguren, Ana Luisa; Leiva-Salcedo, Elías; Cerda, Oscar; Sala, Francisco; Stutzin, Andrés

    2010-03-01

    Volume-sensitive outwardly rectifying (VSOR) Cl(-) channels are critical for the regulatory volume decrease (RVD) response triggered upon cell swelling. Recent evidence indicates that H(2)O(2) plays an essential role in the activation of these channels and that H(2)O(2) per se activates the channels under isotonic isovolumic conditions. However, a significant difference in the time course for current onset between H(2)O(2)-induced and hypotonicity-mediated VSOR Cl(-) activation is observed. In several cell types, cell swelling induced by hypotonic challenges triggers the release of ATP to the extracellular medium, which in turn, activates purinergic receptors and modulates cell volume regulation. In this study, we have addressed the effect of purinergic receptor activation on H(2)O(2)-induced and hypotonicity-mediated VSOR Cl(-) current activation. Here we show that rat hepatoma cells (HTC) exposed to a 33% hypotonic solution responded by rapidly activating VSOR Cl(-) current and releasing ATP to the extracellular medium. In contrast, cells exposed to 200 microm H(2)O(2) VSOR Cl(-) current onset was significantly slower, and ATP release was not detected. In cells exposed to either 11% hypotonicity or 200 microm H(2)O(2), exogenous addition of ATP in the presence of extracellular Ca(2+) resulted in a decrease in the half-time for VSOR Cl(-) current onset. Conversely, in cells that overexpress a dominant-negative mutant of the ionotropic receptor P2X4 challenged with a 33% hypotonic solution, the half-time for VSOR Cl(-) current onset was significantly slowed down. Our results indicate that, at high hypotonic imbalances, swelling-induced ATP release activates the purinergic receptor P2X4, which in turn modulates the time course of VSOR Cl(-) current onset in a extracellular Ca(2+)-dependent manner. PMID:20056605

  20. Decreases in body temperature and body mass constitute pre-hibernation remodelling in the Syrian golden hamster, a facultative mammalian hibernator.

    PubMed

    Chayama, Yuichi; Ando, Lisa; Tamura, Yutaka; Miura, Masayuki; Yamaguchi, Yoshifumi

    2016-04-01

    Hibernation is an adaptive strategy for surviving during periods with little or no food availability, by profoundly reducing the metabolic rate and the core body temperature (T b). Obligate hibernators (e.g. bears, ground squirrels, etc.) hibernate every winter under the strict regulation of endogenous circannual rhythms, and they are assumed to undergo adaptive remodelling in autumn, the pre-hibernation period, prior to hibernation. However, little is known about the nature of pre-hibernation remodelling. Syrian hamsters (Mesocricetus auratus) are facultative hibernators that can hibernate irrespective of seasons when exposed to prolonged short photoperiod and cold ambient temperature (SD-Cold) conditions. Their T b set point reduced by the first deep torpor (DT) and then increased gradually after repeated cycles of DT and periodic arousal (PA), and finally recovered to the level observed before the prolonged SD-Cold in the post-hibernation period. We also found that, before the initiation of hibernation, the body mass of animals decreased below a threshold, indicating that hibernation in this species depends on body condition. These observations suggest that Syrian hamsters undergo pre-hibernation remodelling and that T b and body mass can be useful physiological markers to monitor the remodelling process during the pre-hibernation period.

  1. Decreases in body temperature and body mass constitute pre-hibernation remodelling in the Syrian golden hamster, a facultative mammalian hibernator

    PubMed Central

    Chayama, Yuichi; Ando, Lisa; Tamura, Yutaka; Miura, Masayuki

    2016-01-01

    Hibernation is an adaptive strategy for surviving during periods with little or no food availability, by profoundly reducing the metabolic rate and the core body temperature (Tb). Obligate hibernators (e.g. bears, ground squirrels, etc.) hibernate every winter under the strict regulation of endogenous circannual rhythms, and they are assumed to undergo adaptive remodelling in autumn, the pre-hibernation period, prior to hibernation. However, little is known about the nature of pre-hibernation remodelling. Syrian hamsters (Mesocricetus auratus) are facultative hibernators that can hibernate irrespective of seasons when exposed to prolonged short photoperiod and cold ambient temperature (SD-Cold) conditions. Their Tb set point reduced by the first deep torpor (DT) and then increased gradually after repeated cycles of DT and periodic arousal (PA), and finally recovered to the level observed before the prolonged SD-Cold in the post-hibernation period. We also found that, before the initiation of hibernation, the body mass of animals decreased below a threshold, indicating that hibernation in this species depends on body condition. These observations suggest that Syrian hamsters undergo pre-hibernation remodelling and that Tb and body mass can be useful physiological markers to monitor the remodelling process during the pre-hibernation period. PMID:27152216

  2. Decreases in body temperature and body mass constitute pre-hibernation remodelling in the Syrian golden hamster, a facultative mammalian hibernator.

    PubMed

    Chayama, Yuichi; Ando, Lisa; Tamura, Yutaka; Miura, Masayuki; Yamaguchi, Yoshifumi

    2016-04-01

    Hibernation is an adaptive strategy for surviving during periods with little or no food availability, by profoundly reducing the metabolic rate and the core body temperature (T b). Obligate hibernators (e.g. bears, ground squirrels, etc.) hibernate every winter under the strict regulation of endogenous circannual rhythms, and they are assumed to undergo adaptive remodelling in autumn, the pre-hibernation period, prior to hibernation. However, little is known about the nature of pre-hibernation remodelling. Syrian hamsters (Mesocricetus auratus) are facultative hibernators that can hibernate irrespective of seasons when exposed to prolonged short photoperiod and cold ambient temperature (SD-Cold) conditions. Their T b set point reduced by the first deep torpor (DT) and then increased gradually after repeated cycles of DT and periodic arousal (PA), and finally recovered to the level observed before the prolonged SD-Cold in the post-hibernation period. We also found that, before the initiation of hibernation, the body mass of animals decreased below a threshold, indicating that hibernation in this species depends on body condition. These observations suggest that Syrian hamsters undergo pre-hibernation remodelling and that T b and body mass can be useful physiological markers to monitor the remodelling process during the pre-hibernation period. PMID:27152216

  3. Adaptive Management

    EPA Science Inventory

    Adaptive management is an approach to natural resource management that emphasizes learning through management where knowledge is incomplete, and when, despite inherent uncertainty, managers and policymakers must act. Unlike a traditional trial and error approach, adaptive managem...

  4. IL-17A promotes ventricular remodeling after myocardial infarction.

    PubMed

    Zhou, Su-Feng; Yuan, Jing; Liao, Meng-Yang; Xia, Ni; Tang, Ting-Ting; Li, Jing-Jing; Jiao, Jiao; Dong, Wen-Yong; Nie, Shao-Fang; Zhu, Zheng-Feng; Zhang, Wen-Cai; Lv, Bing-Jie; Xiao, Hong; Wang, Qing; Tu, Xin; Liao, Yu-Hua; Shi, Guo-Ping; Cheng, Xiang

    2014-10-01

    Inflammatory responses play an important role in the pathogenesis of adverse ventricular remodeling after myocardial infarction (MI). We previously demonstrated that interleukin (IL)-17A plays a pathogenic role in myocardial ischemia/reperfusion injury and viral myocarditis. However, the role of IL-17A in post-MI remodeling and the related mechanisms have not been fully elucidated. Acute MI was induced by permanent ligation of the left anterior descending coronary artery in C57BL/6 mice. Repletion of IL-17A significantly aggravated both early- and late-phase ventricular remodeling, as demonstrated by increased infarct size, deteriorated cardiac function, increased myocardial fibrosis, and cardiomyocyte apoptosis. By contrast, genetic IL-17A deficiency had the opposite effect. Additional studies in vitro indicated that IL-17A induces neonatal cardiomyocyte (from C57BL/6 mice) apoptosis through the activation of p38, p53 phosphorylation, and Bax redistribution. These data demonstrate that IL-17A induces cardiomyocyte apoptosis through the p38 mitogen-activated protein kinase (MAPK)-p53-Bax signaling pathway and promotes both early- and late-phase post-MI ventricular remodeling. IL-17A might be an important target in preventing heart failure after MI. Key message: We demonstrated that IL-17A plays a pathogenic role both in the early and late stages of post-MI remodeling. IL-17A induces murine cardiomyocyte apoptosis. IL-17A induces murine cardiomyocyte apoptosis through the p38 MAPK-p53-Bax signaling pathway.

  5. Chromatin remodeling facilitates DNA incision in UV-damaged nucleosomes.

    PubMed

    Lee, Kyungeun; Kim, Deok Ryong; Ahn, Byungchan

    2004-08-31

    The DNA repair machinery must locate and repair DNA damage all over the genome. As nucleosomes inhibit DNA repair in vitro, it has been suggested that chromatin remodeling might be required for efficient repair in vivo. To investigate a possible contribution of nucleosome dynamics and chromatin remodeling to the repair of UV-photoproducts in nucleosomes, we examined the effect of a chromatin remodeling complex on the repair of UV-lesions by Micrococcus luteus UV endonuclease (ML-UV endo) and T4-endonuclease V (T4-endoV) in reconstituted mononucleosomes positioned at one end of a 175-bp long DNA fragment. Repair by ML-UV endo and T4-endoV was inefficient in mononucleosomes compared with naked DNA. However, the human nucleosome remodeling complex, hSWI/SNF, promoted more homogeneous repair by ML-UV endo and T4-endo V in reconstituted nucleosomes. This result suggests that recognition of DNA damage could be facilitated by a fluid state of the chromatin resulting from chromatin remodeling activities. PMID:15359130

  6. Chemistry of bone remodelling preserved in extant and fossil Sirenia.

    PubMed

    Anné, Jennifer; Wogelius, Roy A; Edwards, Nicholas P; van Veelen, Arjen; Ignatyev, Konstantin; Manning, Phillip L

    2016-05-01

    Bone remodelling is a crucial biological process needed to maintain elemental homeostasis. It is important to understand the trace elemental inventories that govern these processes as malfunctions in bone remodelling can have devastating effects on an organism. In this study, we use a combination of X-ray techniques to map, quantify, and characterise the coordination chemistry of trace elements within the highly remodelled bone tissues of extant and extinct Sirenia (manatees and dugongs). The dense bone structure and unique body chemistry of sirenians represent ideal tissues for studying both high remodelling rates as well as unique fossilisation pathways. Here, elemental maps revealed uncorrelated patterning of Ca and Zn within secondary osteons in both extant and fossil sirenians, as well as elevated Sr within the connecting canals of fossil sirenians. Concentrations of these elements are comparable between extant and fossil material indicating geochemical processing of the fossil bone has been minimal. Zn was found to be bound in the same coordination within the apatite structure in both extant and fossil bone. Accurate quantification of trace elements in extant material was only possible when the organic constituents of the bone were included. The comparable distributions, concentrations, and chemical coordination of these physiologically important trace elements indicate the chemistry of bone remodelling has been preserved for 19 million years. This study signifies the powerful potential of merging histological and chemical techniques in the understanding of physiological processes in both extant and extinct vertebrates. PMID:26923825

  7. Role of nucleosome remodeling in neurodevelopmental and intellectual disability disorders.

    PubMed

    López, Alberto J; Wood, Marcelo A

    2015-01-01

    It is becoming increasingly important to understand how epigenetic mechanisms control gene expression during neurodevelopment. Two epigenetic mechanisms that have received considerable attention are DNA methylation and histone acetylation. Human exome sequencing and genome-wide association studies have linked several neurobiological disorders to genes whose products actively regulate DNA methylation and histone acetylation. More recently, a third major epigenetic mechanism, nucleosome remodeling, has been implicated in human developmental and intellectual disability (ID) disorders. Nucleosome remodeling is driven primarily through nucleosome remodeling complexes with specialized ATP-dependent enzymes. These enzymes directly interact with DNA or chromatin structure, as well as histone subunits, to restructure the shape and organization of nucleosome positioning to ultimately regulate gene expression. Of particular interest is the neuron-specific Brg1/hBrm Associated Factor (nBAF) complex. Mutations in nBAF subunit genes have so far been linked to Coffin-Siris syndrome (CSS), Nicolaides-Baraitser syndrome (NBS), schizophrenia, and Autism Spectrum Disorder (ASD). Together, these human developmental and ID disorders are powerful examples of the impact of epigenetic modulation on gene expression. This review focuses on the new and emerging role of nucleosome remodeling in neurodevelopmental and ID disorders and whether nucleosome remodeling affects gene expression required for cognition independently of its role in regulating gene expression required for development. PMID:25954173

  8. Auditory cortex directs the input-specific remodeling of thalamus.

    PubMed

    Nelson, Sultan L; Kong, Lingzhi; Liu, Xiuping; Yan, Jun

    2015-10-01

    Input-specific remodeling is observed both in the primary auditory cortex (AI) and the ventral division of the medial geniculate body of the thalamus (MGBv) through motivation such as learning. Here, we show the role of AI in the MGBv remodeling induced by the electrical stimulation (ES) of the central division of the inferior colliculus (ICc). For the MGBv neurons with frequency tunings different from those of electrically stimulated ICc neurons, their frequency tunings shifted towards the tunings of the ICc neurons. AI neurons also showed this input-specific remodeling after ES of the ICc (ESICc). Interestingly, the input-specific remodeling of MGBv was eliminated when the AI was inactivated using cortical application of muscimol. For the MGBv neurons tuned to the same frequency as the stimulated ICc neurons, their tunings were kept but their responses were facilitated after the ESICc. In contrast to the input-specific tuning shifts, this facilitation was rarely impacted by the AI inactivation. Thus, we conclude that AI directs the input-specific remodeling of MGBv induced by ESICc. It is suggested that the tuning shift in the MGBv primarily takes place in the AI and is relayed to the MGBv through the corticofugal system while the MGBv mainly highlights the frequency information emphasized in ICc.

  9. Lipid remodelling is a widespread strategy in marine heterotrophic bacteria upon phosphorus deficiency

    PubMed Central

    Sebastián, Marta; Smith, Alastair F; González, José M; Fredricks, Helen F; Van Mooy, Benjamin; Koblížek, Michal; Brandsma, Joost; Koster, Grielof; Mestre, Mireia; Mostajir, Behzad; Pitta, Paraskevi; Postle, Anthony D; Sánchez, Pablo; Gasol, Josep M; Scanlan, David J; Chen, Yin

    2016-01-01

    Upon phosphorus (P) deficiency, marine phytoplankton reduce their requirements for P by replacing membrane phospholipids with alternative non-phosphorus lipids. It was very recently demonstrated that a SAR11 isolate also shares this capability when phosphate starved in culture. Yet, the extent to which this process occurs in other marine heterotrophic bacteria and in the natural environment is unknown. Here, we demonstrate that the substitution of membrane phospholipids for a variety of non-phosphorus lipids is a conserved response to P deficiency among phylogenetically diverse marine heterotrophic bacteria, including members of the Alphaproteobacteria and Flavobacteria. By deletion mutagenesis and complementation in the model marine bacterium Phaeobacter sp. MED193 and heterologous expression in recombinant Escherichia coli, we confirm the roles of a phospholipase C (PlcP) and a glycosyltransferase in lipid remodelling. Analyses of the Global Ocean Sampling and Tara Oceans metagenome data sets demonstrate that PlcP is particularly abundant in areas characterized by low phosphate concentrations. Furthermore, we show that lipid remodelling occurs seasonally and responds to changing nutrient conditions in natural microbial communities from the Mediterranean Sea. Together, our results point to the key role of lipid substitution as an adaptive strategy enabling heterotrophic bacteria to thrive in the vast P-depleted areas of the ocean. PMID:26565724

  10. Human miR-221/222 in Physiological and Atherosclerotic Vascular Remodeling

    PubMed Central

    Chistiakov, Dmitry A.; Sobenin, Igor A.; Orekhov, Alexander N.; Bobryshev, Yuri V.

    2015-01-01

    A cluster of miR-221/222 is a key player in vascular biology through exhibiting its effects on vascular smooth muscle cells (VSMCs) and endothelial cells (ECs). These miRNAs contribute to vascular remodeling, an adaptive process involving phenotypic and behavioral changes in vascular cells in response to vascular injury. In proliferative vascular diseases such as atherosclerosis, pathological vascular remodeling plays a prominent role. The miR-221/222 cluster controls development and differentiation of ECs but inhibits their proangiogenic activation, proliferation, and migration. miR-221/222 are primarily implicated in maintaining endothelial integrity and supporting quiescent EC phenotype. Vascular expression of miR-221/222 is upregulated in initial atherogenic stages causing inhibition of angiogenic recruitment of ECs and increasing endothelial dysfunction and EC apoptosis. In contrast, these miRNAs stimulate VSMCs and switching from the VSMC “contractile” phenotype to the “synthetic” phenotype associated with induction of proliferation and motility. In atherosclerotic vessels, miR-221/222 drive neointima formation. Both miRNAs contribute to atherogenic calcification of VSMCs. In advanced plaques, chronic inflammation downregulates miR-221/222 expression in ECs that in turn could activate intralesion neoangiogenesis. In addition, both miRNAs could contribute to cardiovascular pathology through their effects on fat and glucose metabolism in nonvascular tissues such as adipose tissue, liver, and skeletal muscles. PMID:26221589

  11. TRIP13 is a protein-remodeling AAA+ ATPase that catalyzes MAD2 conformation switching

    PubMed Central

    Ye, Qiaozhen; Rosenberg, Scott C; Moeller, Arne; Speir, Jeffrey A; Su, Tiffany Y; Corbett, Kevin D

    2015-01-01

    The AAA+ family ATPase TRIP13 is a key regulator of meiotic recombination and the spindle assembly checkpoint, acting on signaling proteins of the conserved HORMA domain family. Here we present the structure of the Caenorhabditis elegans TRIP13 ortholog PCH-2, revealing a new family of AAA+ ATPase protein remodelers. PCH-2 possesses a substrate-recognition domain related to those of the protein remodelers NSF and p97, while its overall hexameric architecture and likely structural mechanism bear close similarities to the bacterial protein unfoldase ClpX. We find that TRIP13, aided by the adapter protein p31(comet), converts the HORMA-family spindle checkpoint protein MAD2 from a signaling-active ‘closed’ conformer to an inactive ‘open’ conformer. We propose that TRIP13 and p31(comet) collaborate to inactivate the spindle assembly checkpoint through MAD2 conformational conversion and disassembly of mitotic checkpoint complexes. A parallel HORMA protein disassembly activity likely underlies TRIP13's critical regulatory functions in meiotic chromosome structure and recombination. DOI: http://dx.doi.org/10.7554/eLife.07367.001 PMID:25918846

  12. Activation of common signaling pathways during remodeling of the heart and the bladder.

    PubMed

    Koeck, Ivonne; Burkhard, Fiona C; Monastyrskaya, Katia

    2016-02-15

    The heart and the urinary bladder are hollow muscular organs, which can be afflicted by pressure overload injury due to pathological conditions such as hypertension and bladder outlet obstruction. This increased outflow resistance induces hypertrophy, marked by dramatic changes in the organs' phenotype and function. The end result in both the heart and the bladder can be acute organ failure due to advanced fibrosis and the subsequent loss of contractility. There is emerging evidence that microRNAs (miRNAs) play an important role in the pathogenesis of heart failure and bladder dysfunction. MiRNAs are endogenous non-coding single-stranded RNAs, which regulate gene expression and control adaptive and maladaptive organ remodeling processes. This Review summarizes the current knowledge of molecular alterations in the heart and the bladder and highlights common signaling pathways and regulatory events. The miRNA expression analysis and experimental target validation done in the heart provide a valuable source of information for investigators working on the bladder and other organs undergoing the process of fibrotic remodeling. Aberrantly expressed miRNA are amendable to pharmacological manipulation, offering an opportunity for development of new therapies for cardiac and bladder hypertrophy and failure.

  13. Remodeling of the Streptococcus agalactiae Transcriptome in Response to Growth Temperature

    PubMed Central

    Mereghetti, Laurent; Sitkiewicz, Izabela; Green, Nicole M.; Musser, James M.

    2008-01-01

    Background To act as a commensal bacterium and a pathogen in humans and animals, Streptococcus agalactiae (group B streptococcus, GBS) must be able to monitor and adapt to different environmental conditions. Temperature variation is a one of the most commonly encountered variables. Methodology/Principal Findings To understand the extent to which GBS modify gene expression in response to temperatures encountered in the various hosts, we conducted a whole genome transcriptome analysis of organisms grown at 30°C and 40°C. We identified extensive transcriptome remodeling at various stages of growth, especially in the stationary phase (significant transcript changes occurred for 25% of the genes). A large proportion of genes involved in metabolism was up-regulated at 30°C in stationary phase. Conversely, genes up-regulated at 40°C relative to 30°C include those encoding virulence factors such as hemolysins and extracellular secreted proteins with LPXTG motifs. Over-expression of hemolysins was linked to larger zones of hemolysis and enhanced hemolytic activity at 40°C. A key theme identified by our study was that genes involved in purine metabolism and iron acquisition were significantly up-regulated at 40°C. Conclusion/Significance Growth of GBS in vitro at different temperatures resulted in extensive remodeling of the transcriptome, including genes encoding proven and putative virulence genes. The data provide extensive new leads for molecular pathogenesis research. PMID:18665215

  14. The SWI/SNF chromatin remodeling complex regulates germinal center formation by repressing Blimp-1 expression.

    PubMed

    Choi, Jinwook; Jeon, Shin; Choi, Seungjin; Park, Kyungsoo; Seong, Rho Hyun

    2015-02-17

    Germinal center (GC) reaction is crucial in adaptive immune responses. The formation of GC is coordinated by the expression of specific genes including Blimp-1 and Bcl-6. Although gene expression is critically influenced by the status of chromatin structure, little is known about the role of chromatin remodeling factors for regulation of GC formation. Here, we show that the SWI/SNF chromatin remodeling complex is required for GC reactions. Mice lacking Srg3/mBaf155, a core component of the SWI/SNF complex, showed impaired differentiation of GC B and follicular helper T cells in response to T cell-dependent antigen challenge. The SWI/SNF complex regulates chromatin structure at the Blimp-1 locus and represses its expression by interacting cooperatively with Bcl-6 and corepressors. The defect in GC reactions in mice lacking Srg3 was due to the derepression of Blimp-1 as supported by genetic studies with Blimp-1-ablated mice. Hence, our study identifies the SWI/SNF complex as a key mediator in GC reactions by modulating Bcl-6-dependent Blimp-1 repression.

  15. Focal myocardial infarction induces global remodeling of cardiac sympathetic innervation: neural remodeling in a spatial context

    PubMed Central

    Ajijola, Olujimi A.; Yagishita, Daigo; Patel, Krishan J.; Vaseghi, Marmar; Zhou, Wei; Yamakawa, Kentaro; So, Eileen; Lux, Robert L.; Mahajan, Aman

    2013-01-01

    Myocardial infarction (MI) induces neural and electrical remodeling at scar border zones. The impact of focal MI on global functional neural remodeling is not well understood. Sympathetic stimulation was performed in swine with anteroapical infarcts (MI; n = 9) and control swine (n = 9). A 56-electrode sock was placed over both ventricles to record electrograms at baseline and during left, right, and bilateral stellate ganglion stimulation. Activation recovery intervals (ARIs) were measured from electrograms. Global and regional ARI shortening, dispersion of repolarization, and activation propagation were assessed before and during sympathetic stimulation. At baseline, mean ARI was shorter in MI hearts than control hearts (365 ± 8 vs. 436 ± 9 ms, P < 0.0001), dispersion of repolarization was greater in MI versus control hearts (734 ± 123 vs. 362 ± 32 ms2, P = 0.02), and the infarcted region in MI hearts showed longer ARIs than noninfarcted regions (406 ± 14 vs. 365 ± 8 ms, P = 0.027). In control animals, percent ARI shortening was greater on anterior than posterior walls during right stellate ganglion stimulation (P = 0.0001), whereas left stellate ganglion stimulation showed the reverse (P = 0.0003). In infarcted animals, this pattern was completely lost. In 50% of the animals studied, sympathetic stimulation, compared with baseline, significantly altered the direction of activation propagation emanating from the intramyocardial scar during pacing. In conclusion, focal distal anterior MI alters regional and global pattern of sympathetic innervation, resulting in shorter ARIs in infarcted hearts, greater repolarization dispersion, and altered activation propagation. These conditions may underlie the mechanisms by which arrhythmias are initiated when sympathetic tone is enhanced. PMID:23893167

  16. Chromatin Remodeling by Imitation Switch (ISWI) Class ATP-dependent Remodelers Is Stimulated by Histone Variant H2A.Z

    PubMed Central

    Goldman, Joseph A.; Garlick, Joseph D.; Kingston, Robert E.

    2010-01-01

    ATP-dependent chromatin remodeling complexes rearrange nucleosomes by altering the position of DNA around the histone octamer. Although chromatin remodelers and the histone variant H2A.Z colocalize on transcriptional control regions, whether H2A.Z directly affects remodeler association or activity is unclear. We determined the relative association of remodelers with H2A.Z chromatin and tested whether replacement of H2A.Z in a nucleosome altered the activity of remodeling enzymes. Many families of remodelers showed increased association with H2A.Z chromatin, but only the ISWI family of chromatin remodelers showed stimulated activity in vitro. An acidic patch on the nucleosome surface, extended by inclusion of H2A.Z in nucleosomes and essential for viability, is required for ISWI stimulation. We conclude that H2A.Z incorporation increases nucleosome remodeling activity of the largest class of mammalian remodelers (ISWI) and that it correlates with increased association of other remodelers to chromatin. This reveals two possible modes for regulation of a remodeler by a histone variant. PMID:19940112

  17. Transient Mesenteric Ischemia Leads to Remodeling of Rat Mesenteric Resistance Arteries

    PubMed Central

    Caracuel, Laura; Jiménez-Altayó, Francesc; Romo, Mónica; Márquez-Martín, Ana; Dantas, Ana P.; Vila, Elisabet

    2012-01-01

    Mesenteric ischemia/reperfusion (I/R) is associated with high rates of morbidity and mortality. We studied the effect of mesenteric I/R on structural and mechanical properties of rat mesenteric resistance artery (MRA) that, once disrupted, might impact the outcome of this devastating clinical condition. Superior mesenteric artery from Wistar–Kyoto rats was occluded (90 min) and reperfused (24 h). The effect of tezosentan, a dual endothelin (ET)-receptor antagonist, was studied in ischemic (IO) and sham-operated (SO) animals. MRA structure and mechanics were assessed by pressure myography. Nuclei distribution, elastin content and organization, collagen I/III and ET-1 expression, ET-1 plasma levels, superoxide anion (O2⋅−) production, and mRNA levels of NAD(P)H-oxidase subunits were measured. To assess ET-1 effects on O2⋅− production, MRA from non-operated rats were incubated in culture medium with ET-1. Mesenteric I/R increased MRA wall thickness (P < 0.05) and cross-sectional area (P < 0.05) but decreased wall stiffness (P < 0.05). Arterial remodeling was paralleled by enhancement of: (i) collagen I/III expression (P < 0.01), ET-1 expression (P < 0.05), and O2⋅− formation (P < 0.01) in the vessel wall; (ii) number of internal elastic lamina (IEL) fenestrae (P < 0.05); and (iii) plasma levels of ET-1 (P < 0.05). Moreover, ET-1 increased O2⋅− (P < 0.05) production in cultured MRA. Tezosentan prevented hypertrophic remodeling and collagen I/III deposition, and enhanced O2⋅− production, but it did not affect the decreased wall stiffness after mesenteric I/R. These results indicate that 90 min occlusion/24 h reperfusion induces hypertrophic remodeling of MRA linked to ET-1-mediated increase of collagen and O2⋅−. Decreased stiffness may be associated with increased number of IEL fenestrae. The resulting MRA remodeling, initially adaptive, might become maladaptive contributing to the pathology and poor

  18. Regulation of the Golgi Complex by Phospholipid Remodeling Enzymes

    PubMed Central

    Ha, Kevin D.; Clarke, Benjamin A.; Brown, William J.

    2012-01-01

    The mammalian Golgi complex is a highly dynamic organelle consisting of stacks of flattened cisternae with associated coated vesicles and membrane tubules that contribute to cargo import and export, intra-cisternal trafficking, and overall Golgi architecture. At the morphological level, all of these structures are continuously remodeled to carry out these trafficking functions. Recent advances have shown that continual phospholipid remodeling by phospholipase A (PLA) and lysophospholipid acyltransferase (LPAT) enzymes, which deacylate and reacylate Golgi phospholipids, respectively, contributes to this morphological remodeling. Here we review the identification and characterization of four cytoplasmic PLA enzymes and one integral membrane LPAT that participate in the dynamic functional organization of the Golgi complex, and how some of these enzymes are integrated to determine the relative abundance of COPI vesicle and membrane tubule formation. PMID:22562055

  19. Remodeling of legacy systems in health care using UML.

    PubMed

    Garde, Sebastian; Knaup, Petra; Herold, Ralf

    2002-01-01

    Research projects in the field of Medical Informatics often involve the development of application systems. Usually they are developed over a longer period of time, so that at a certain point of time a systematically planned reimplementation is necessary. The first step of reimplementation should be a systematic and comprehensive remodeling. When using UML for this task a systematic approach for remodeling activities is missing. Therefore, we developed a method for remodeling of legacy systems (Qumquad) and applied it to DOSPO, a documentation and therapy planning system for pediatric oncology. Qumquad helps to systematically carry out three steps: the modeling of the current actual state of the application system, the systematic identification of weak points and the development of a target concept for reimplementation considering the identified weak points. Results show that this approach is valuable and feasible and could be applied to various application systems in health care.

  20. Remodelling the extracellular matrix in development and disease

    PubMed Central

    Bonnans, Caroline; Chou, Jonathan; Werb, Zena

    2015-01-01

    The extracellular matrix (ECM) is a highly dynamic structure that is present in all tissues and continuously undergoes controlled remodelling. This process involves quantitative and qualitative changes in the ECM, mediated by specific enzymes that are responsible for ECM degradation, such as metalloproteinases. The ECM interacts with cells to regulate diverse functions, including proliferation, migration and differentiation. ECM remodelling is crucial for regulating the morphogenesis of the intestine and lungs, as well as of the mammary and submandibular glands. Dysregulation of ECM composition, structure, stiffness and abundance contributes to several pathological conditions, such as fibrosis and invasive cancer. A better understanding of how the ECM regulates organ structure and function and of how ECM remodelling affects disease progression will contribute to the development of new therapeutics. PMID:25415508

  1. Computational Study of Growth and Remodeling in the Aortic Arch

    PubMed Central

    Alford, Patrick W.; Taber, Larry A.

    2009-01-01

    Opening angles (OAs) are associated with growth and remodeling in arteries. One curiosity has been the relatively large OAs found in the aortic arch of some animals. Here, we use computational models to explore the reasons behind this phenomenon. The artery is assumed to contain a smooth muscle/collagen phase and an elastin phase. In the models, growth and remodeling of smooth muscle/collagen depends on wall stress and fluid shear stress. Remodeling of elastin, which normally turns over very slowly, is neglected. The results indicate that OAs generally increase with longitudinal curvature (torus model), earlier elastin production during development, and decreased wall stiffness. Correlating these results with available experimental data suggests that all of these effects may contribute to the large OAs in the aortic arch. The models also suggest that the slow turnover rate of elastin limits longitudinal growth. These results should promote increased understanding of the causes of residual stress in arteries. PMID:18792831

  2. Remodeling of legacy systems in health care using UML.

    PubMed

    Garde, Sebastian; Knaup, Petra; Herold, Ralf

    2002-01-01

    Research projects in the field of Medical Informatics often involve the development of application systems. Usually they are developed over a longer period of time, so that at a certain point of time a systematically planned reimplementation is necessary. The first step of reimplementation should be a systematic and comprehensive remodeling. When using UML for this task a systematic approach for remodeling activities is missing. Therefore, we developed a method for remodeling of legacy systems (Qumquad) and applied it to DOSPO, a documentation and therapy planning system for pediatric oncology. Qumquad helps to systematically carry out three steps: the modeling of the current actual state of the application system, the systematic identification of weak points and the development of a target concept for reimplementation considering the identified weak points. Results show that this approach is valuable and feasible and could be applied to various application systems in health care. PMID:15460740

  3. Iron chelation inhibits the development of pulmonary vascular remodeling.

    PubMed

    Wong, Chi-Ming; Preston, Ioana R; Hill, Nicholas S; Suzuki, Yuichiro J

    2012-11-01

    Reactive oxygen species (ROS) have been implicated in the pathogenesis of pulmonary hypertension. Because iron is an important regulator of ROS biology, this study examined the effects of iron chelation on the development of pulmonary vascular remodeling. The administration of an iron chelator, deferoxamine, to rats prevented chronic hypoxia-induced pulmonary hypertension and pulmonary vascular remodeling. Various iron chelators inhibited the growth of cultured pulmonary artery smooth muscle cells. Protein carbonylation, an important iron-dependent biological event, was promoted in association with pulmonary vascular remodeling and cell growth. A proteomic approach identified that Rho GDP-dissociation inhibitor (a negative regulator of RhoA) is carbonylated. In human plasma, the protein carbonyl content was significantly higher in patients with idiopathic pulmonary arterial hypertension than in healthy controls. These results suggest that iron plays an important role in the ROS-dependent mechanism underlying the development of pulmonary hypertension.

  4. Iron chelation inhibits the development of pulmonary vascular remodeling

    PubMed Central

    Wong, Chi-Ming; Preston, Ioana R.; Hill, Nicholas S.; Suzuki, Yuichiro J.

    2012-01-01

    Reactive oxygen species (ROS) have been implicated in the pathogenesis of pulmonary hypertension. Since iron is an important regulator of ROS biology, the present study examined the effect of iron chelation on the development of pulmonary vascular remodeling. The administration of an iron chelator, deferoxamine, to rats prevented chronic hypoxia-induced pulmonary hypertension and pulmonary vascular remodeling. Various iron chelators inhibited growth of cultured pulmonary artery smooth muscle cells. Protein carbonylation, an important iron-dependent biological event, was promoted in association with pulmonary vascular remodeling and cell growth. A proteomic approach identified that Rho GDP-dissociation inhibitor (a negative regulator of RhoA) is carbonylated. In human plasma, the protein carbonyl content was significantly higher in patients with idiopathic pulmonary arterial hypertension than in healthy controls. These results suggest that iron plays an important role in the ROS-dependent mechanism underlying the development of pulmonary hypertension. PMID:22974762

  5. Dynamic regulation of transcription factors by nucleosome remodeling.

    PubMed

    Li, Ming; Hada, Arjan; Sen, Payel; Olufemi, Lola; Hall, Michael A; Smith, Benjamin Y; Forth, Scott; McKnight, Jeffrey N; Patel, Ashok; Bowman, Gregory D; Bartholomew, Blaine; Wang, Michelle D

    2015-06-05

    The chromatin landscape and promoter architecture are dominated by the interplay of nucleosome and transcription factor (TF) binding to crucial DNA sequence elements. However, it remains unclear whether nucleosomes mobilized by chromatin remodelers can influence TFs that are already present on the DNA template. In this study, we investigated the interplay between nucleosome remodeling, by either yeast ISW1a or SWI/SNF, and a bound TF. We found that a TF serves as a major barrier to ISW1a remodeling, and acts as a boundary for nucleosome repositioning. In contrast, SWI/SNF was able to slide a nucleosome past a TF, with concurrent eviction of the TF from the DNA, and the TF did not significantly impact the nucleosome positioning. Our results provide direct evidence for a novel mechanism for both nucleosome positioning regulation by bound TFs and TF regulation via dynamic repositioning of nucleosomes.

  6. Dynamical DNA accessibility induced by chromatin remodeling and protein binding

    NASA Astrophysics Data System (ADS)

    Montel, F.; Faivre-Moskalenko, C.; Castelnovo, M.

    2014-11-01

    Chromatin remodeling factors are enzymes being able to alter locally chromatin structure at the nucleosomal level and they actively participate in the regulation of gene expression. Using simple rules for individual nucleosome motion induced by a remodeling factor, we designed simulations of the remodeling of oligomeric chromatin, in order to address quantitatively collective effects in DNA accessibility upon nucleosome mobilization. Our results suggest that accessibility profiles are inhomogeneous thanks to borders effects like protein binding. Remarkably, we show that the accessibility lifetime of DNA sequence is roughly doubled in the vicinity of borders as compared to its value in bulk regions far from the borders. These results are quantitatively interpreted as resulting from the confined diffusion of a large nucleosome depleted region.

  7. Anisotropic stress orients remodelling of mammalian limb bud ectoderm

    PubMed Central

    Lau, Kimberly; Tao, Hirotaka; Liu, Haijiao; Wen, Jun; Sturgeon, Kendra; Sorfazlian, Natalie; Lazic, Savo; Burrows, Jeffrey T. A.; Wong, Michael D.; Li, Danyi; Deimling, Steven; Ciruna, Brian; Scott, Ian; Simmons, Craig; Henkelman, R. Mark; Williams, Trevor; Hadjantonakis, Anna-Katerina; Fernandez-Gonzalez, Rodrigo; Sun, Yu; Hopyan, Sevan

    2016-01-01

    The physical forces that drive morphogenesis are not well characterized in vivo, especially among vertebrates. In the early limb bud, dorsal and ventral ectoderm converge to form the apical ectodermal ridge (AER), although the underlying mechanisms are unclear. By live imaging mouse embryos, we show that prospective AER progenitors intercalate at the dorsoventral boundary and that ectoderm remodels by concomitant cell division and neighbour exchange. Mesodermal expansion and ectodermal tension together generate a dorsoventrally biased stress pattern that orients ectodermal remodelling. Polarized distribution of cortical actin reflects this stress pattern in a β-catenin- and Fgfr2-dependent manner. Intercalation of AER progenitors generates a tensile gradient that reorients resolution of multicellular rosettes on adjacent surfaces, a process facilitated by β-catenin-dependent attachment of cortex to membrane. Therefore, feedback between tissue stress pattern and cell intercalations remodels mammalian ectoderm. PMID:25893915

  8. [Determinants of bone quality and strength independent of bone remodeling].

    PubMed

    Saito, Mitsuru; Marumo, Keishi

    2016-01-01

    Bone mineral density(BMD)and bone microstructure are regulated mainly by bone remodeling. In contrast, bone collagen enzymatic immature and mature cross-links and advanced glycation end products such as pentosidine and carboxyl methyl lysine are affected by various factors. Aging bone tissue is repaired in the process of bone remodeling. However, deterioration of bone material properties markedly advances due to increases in oxidative stress, glycation stress, reactive oxygen species, carbonyl stress associated with aging and reduced sex hormone levels, and glucocorticoid use. To improve bone material properties in osteoporosis, we should use different drug (Saito M, Calcif Tissue Int, REVIEW, 97;242-261, 2015). In this review, we summarized determinants of bone quality and strength independent of bone remodeling. PMID:26728528

  9. Parallel mechanisms suppress cochlear bone remodeling to protect hearing.

    PubMed

    Jáuregui, Emmanuel J; Akil, Omar; Acevedo, Claire; Hall-Glenn, Faith; Tsai, Betty S; Bale, Hrishikesh A; Liebenberg, Ellen; Humphrey, Mary Beth; Ritchie, Robert O; Lustig, Lawrence R; Alliston, Tamara

    2016-08-01

    Bone remodeling, a combination of bone resorption and formation, requires precise regulation of cellular and molecular signaling to maintain proper bone quality. Whereas osteoblasts deposit and osteoclasts resorb bone matrix, osteocytes both dynamically resorb and replace perilacunar bone matrix. Osteocytes secrete proteases like matrix metalloproteinase-13 (MMP13) to maintain the material quality of bone matrix through perilacunar remodeling (PLR). Deregulated bone remodeling impairs bone quality and can compromise hearing since the auditory transduction mechanism is within bone. Understanding the mechanisms regulating cochlear bone provides unique ways to assess bone quality independent of other aspects that contribute to bone mechanical behavior. Cochlear bone is singular in its regulation of remodeling by expressing high levels of osteoprotegerin. Since cochlear bone expresses a key PLR enzyme, MMP13, we examined whether cochlear bone relies on, or is protected from, osteocyte-mediated PLR to maintain hearing and bone quality using a mouse model lacking MMP13 (MMP13(-/-)). We investigated the canalicular network, collagen organization, lacunar volume via micro-computed tomography, and dynamic histomorphometry. Despite finding defects in these hallmarks of PLR in MMP13(-/-) long bones, cochlear bone revealed no differences in these markers, nor hearing loss as measured by auditory brainstem response (ABR) or distortion product oto-acoustic emissions (DPOAEs), between wild type and MMP13(-/-) mice. Dynamic histomorphometry revealed abundant PLR by tibial osteocytes, but near absence in cochlear bone. Cochlear suppression of PLR corresponds to repression of several key PLR genes in the cochlea relative to long bones. These data suggest that cochlear bone uniquely maintains bone quality and hearing independent of MMP13-mediated osteocytic PLR. Furthermore, the cochlea employs parallel mechanisms to inhibit remodeling by osteoclasts and osteoblasts, and by

  10. Synaptic activity and connective tissue remodeling in denervated frog muscle

    PubMed Central

    1994-01-01

    Denervation of skeletal muscle results in dramatic remodeling of the cellular and molecular composition of the muscle connective tissue. This remodeling is concentrated in muscle near neuromuscular junctions and involves the accumulation of interstitial cells and several extracellular matrix molecules. Given the role of extracellular matrix in neurite outgrowth and synaptogenesis, we predict that this remodeling of the junctional connective tissue directly influences the regeneration of the neuromuscular junction. As one step toward understanding the role of this denervation-induced remodeling in synapse formation, we have begun to look for the signals that are involved in initiating the junctional accumulations of interstitial cells and matrix molecules. Here, the role of muscle inactivity as a signal was examined. The distributions of interstitial cells, fibronectin, and tenascin were determined in muscles inactivated by presynaptic blockade of muscle activity with tetrodotoxin. We found that blockade of muscle activity for up to 4 wk produced neither the junctional accumulation of interstitial cells nor the junctional concentrations of tenascin and fibronectin normally present in denervated frog muscle. In contrast, the muscle inactivity induced the extrajunctional appearance of two synapse-specific molecules, the acetylcholine receptor and a muscle fiber antigen, mAb 3B6. These results demonstrate that the remodeling of the junctional connective tissue in response to nerve injury is a unique response of muscle to denervation in that it is initiated by a mechanism that is independent of muscle activity. Thus connective tissue remodeling in denervated skeletal muscle may be induced by signals released from or associated with the nerve other than the evoked release of neurotransmitter. PMID:7525607

  11. The calcium-independent transient outward potassium current in isolated ferret right ventricular myocytes. I. Basic characterization and kinetic analysis

    PubMed Central

    1993-01-01

    Enzymatically isolated myocytes from ferret right ventricles (12-16 wk, male) were studied using the whole cell patch clamp technique. The macroscopic properties of a transient outward K+ current I(to) were quantified. I(to) is selective for K+, with a PNa/PK of 0.082. Activation of I(to) is a voltage-dependent process, with both activation and inactivation being independent of Na+ or Ca2+ influx. Steady-state inactivation is well described by a single Boltzmann relationship (V1/2 = -13.5 mV; k = 5.6 mV). Substantial inactivation can occur during a subthreshold depolarization without any measurable macroscopic current. Both development of and recovery from inactivation are well described by single exponential processes. Ensemble averages of single I(to) channel currents recorded in cell-attached patches reproduce macroscopic I(to) and indicate that inactivation is complete at depolarized potentials. The overall inactivation/recovery time constant curve has a bell-shaped potential dependence that peaks between -10 and -20 mV, with time constants (22 degrees C) ranging from 23 ms (-90 mV) to 304 ms (-10 mV). Steady-state activation displays a sigmoidal dependence on membrane potential, with a net aggregate half- activation potential of +22.5 mV. Activation kinetics (0 to +70 mV, 22 degrees C) are rapid, with I(to) peaking in approximately 5-15 ms at +50 mV. Experiments conducted at reduced temperatures (12 degrees C) demonstrate that activation occurs with a time delay. A nonlinear least- squares analysis indicates that three closed kinetic states are necessary and sufficient to model activation. Derived time constants of activation (22 degrees C) ranged from 10 ms (+10 mV) to 2 ms (+70 mV). Within the framework of Hodgkin-Huxley formalism, Ito gating can be described using an a3i formulation. PMID:8505627

  12. New insight into the ZnO sulfidation reaction: mechanism and kinetics modeling of the ZnS outward growth.

    PubMed

    Neveux, Laure; Chiche, David; Pérez-Pellitero, Javier; Favergeon, Loïc; Gay, Anne-Sophie; Pijolat, Michèle

    2013-02-01

    Zinc oxide based materials are commonly used for the final desulfurization of synthesis gas in Fischer-Tropsch based XTL processes. Although the ZnO sulfidation reaction has been widely studied, little is known about the transformation at the crystal scale, its detailed mechanism and kinetics. A model ZnO material with well-determined characteristics (particle size and shape) has been synthesized to perform this study. Characterizations of sulfided samples (using XRD, TEM and electron diffraction) have shown the formation of oriented polycrystalline ZnS nanoparticles with a predominant hexagonal form (wurtzite phase). TEM observations also have evidenced an outward development of the ZnS phase, showing zinc and oxygen diffusion from the ZnO-ZnS internal interface to the surface of the ZnS particle. The kinetics of ZnO sulfidation by H(2)S has been investigated using isothermal and isobaric thermogravimetry. Kinetic tests have been performed that show that nucleation of ZnS is instantaneous compared to the growth process. A reaction mechanism composed of eight elementary steps has been proposed to account for these results, and various possible rate laws have been determined upon approximation of the rate-determining step. Thermogravimetry experiments performed in a wide range of H(2)S and H(2)O partial pressures have shown that the ZnO sulfidation reaction rate has a nonlinear variation with H(2)S partial pressure at the same time no significant influence of water vapor on reaction kinetics has been observed. From these observations, a mixed kinetics of external interface reaction with water desorption and oxygen diffusion has been determined to control the reaction kinetics and the proposed mechanism has been validated. However, the formation of voids at the ZnO-ZnS internal interface, characterized by TEM and electron tomography, strongly slows down the reaction rate. Therefore, the impact of the decreasing ZnO-ZnS internal interface on reaction kinetics has been

  13. Mechanisms contributing to myocardial potassium channel diversity, regulation and remodeling.

    PubMed

    Yang, Kai-Chien; Nerbonne, Jeanne M

    2016-04-01

    In the mammalian heart, multiple types of K(+) channels contribute to the control of cardiac electrical and mechanical functioning through the regulation of resting membrane potentials, action potential waveforms and refractoriness. There are similarly vast arrays of K(+) channel pore-forming and accessory subunits that contribute to the generation of functional myocardial K(+) channel diversity. Maladaptive remodeling of K(+) channels associated with cardiac and systemic diseases results in impaired repolarization and increased propensity for arrhythmias. Here, we review the diverse transcriptional, post-transcriptional, post-translational, and epigenetic mechanisms contributing to regulating the expression, distribution, and remodeling of cardiac K(+) channels under physiological and pathological conditions. PMID:26391345

  14. Efficient computational simulation of actin stress fiber remodeling.

    PubMed

    Ristori, T; Obbink-Huizer, C; Oomens, C W J; Baaijens, F P T; Loerakker, S

    2016-09-01

    Understanding collagen and stress fiber remodeling is essential for the development of engineered tissues with good functionality. These processes are complex, highly interrelated, and occur over different time scales. As a result, excessive computational costs are required to computationally predict the final organization of these fibers in response to dynamic mechanical conditions. In this study, an analytical approximation of a stress fiber remodeling evolution law was derived. A comparison of the developed technique with the direct numerical integration of the evolution law showed relatively small differences in results, and the proposed method is one to two orders of magnitude faster.

  15. Mechanisms of ATP-Dependent Chromatin Remodeling Motors.

    PubMed

    Zhou, Coral Y; Johnson, Stephanie L; Gamarra, Nathan I; Narlikar, Geeta J

    2016-07-01

    Chromatin remodeling motors play essential roles in all DNA-based processes. These motors catalyze diverse outcomes ranging from sliding the smallest units of chromatin, known as nucleosomes, to completely disassembling chromatin. The broad range of actions carried out by these motors on the complex template presented by chromatin raises many stimulating mechanistic questions. Other well-studied nucleic acid motors provide examples of the depth of mechanistic understanding that is achievable from detailed biophysical studies. We use these studies as a guiding framework to discuss the current state of knowledge of chromatin remodeling mechanisms and highlight exciting open questions that would continue to benefit from biophysical analyses. PMID:27391925

  16. Remodeling of Cell-Cell Junctions in Arrhythmogenic Cardiomyopathy

    PubMed Central

    Asimaki, Angeliki; Saffitz, Jeffrey E.

    2015-01-01

    Arrhythmogenic cardiomyopathy (AC) is a primary myocardial disorder characterized by a high incidence of ventricular arrhythmias often preceding the onset of ventricular remodeling and dysfunction. Approximately 50% of patients diagnosed with AC have one or more mutations in genes encoding desmosomal proteins, although non-desmosomal genes have also been associated with the disease. Increasing evidence implicates remodeling of intercalated disk proteins reflecting abnormal responses to mechanical load and aberrant cell signaling pathways in the pathogenesis of AC. This review summarizes recent advances in understanding disease mechanisms in AC that have come from studies of human myocardium and experimental models. PMID:24460198

  17. [Bone quality and strength relating with bone remodeling].

    PubMed

    Mori, Satoshi

    2016-01-01

    The bone has the functions of mineral reservoir and mechanical support as skeleton. Bone remodeling is the adult mode of bone metabolism, replacing old bone tissue to new one. Bone strength is determined by bone volume, structure and quality such as micro damage, degree of mineralization and collagen cross linkage, which are all controlled by bone remodeling. Bone strength decreases under high turn-over condition by decreasing bone volume and deterioration of bone structure, which also decreases under low turn-over condition by increased micro damage, increasing mineralization and AGE collagen cross linkage.

  18. Efficient computational simulation of actin stress fiber remodeling.

    PubMed

    Ristori, T; Obbink-Huizer, C; Oomens, C W J; Baaijens, F P T; Loerakker, S

    2016-09-01

    Understanding collagen and stress fiber remodeling is essential for the development of engineered tissues with good functionality. These processes are complex, highly interrelated, and occur over different time scales. As a result, excessive computational costs are required to computationally predict the final organization of these fibers in response to dynamic mechanical conditions. In this study, an analytical approximation of a stress fiber remodeling evolution law was derived. A comparison of the developed technique with the direct numerical integration of the evolution law showed relatively small differences in results, and the proposed method is one to two orders of magnitude faster. PMID:26823159

  19. Silent Synapse-Based Circuitry Remodeling in Drug Addiction

    PubMed Central

    2016-01-01

    Exposure to cocaine, and likely other drugs of abuse, generates α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor-silent glutamatergic synapses in the nucleus accumbens. These immature synaptic contacts evolve after drug withdrawal to redefine the neurocircuital properties. These results raise at least three critical questions: (1) what are the molecular and cellular mechanisms that mediate drug-induced generation of silent synapses; (2) how are neurocircuits remodeled upon generation and evolution of drug-generated silent synapses; and (3) what behavioral consequences are produced by silent synapse-based circuitry remodeling? This short review analyzes related experimental results, and extends them to some speculations. PMID:26721952

  20. Autophagy and mitochondrial remodelling in mouse mesenchymal stromal cells challenged with Staphylococcus epidermidis.

    PubMed

    Gorbunov, Nikolai V; McDaniel, Dennis P; Zhai, Min; Liao, Pei-Jyun; Garrison, Bradley R; Kiang, Juliann G

    2015-05-01

    The bone marrow stroma constitutes the marrow-blood barrier, which sustains immunochemical homoeostasis and protection of the haematopoietic tissue in sequelae of systemic bacterial infections. Under these conditions, the bone marrow stromal cells affected by circulating bacterial pathogens shall elicit the adaptive stress-response mechanisms to maintain integrity of the barrier. The objective of this communication was to demonstrate (i) that in vitro challenge of mesenchymal stromal cells, i.e. colony-forming unit fibroblasts (CFU-F), with Staphylococcus epidermidis can activate the autophagy pathway to execute antibacterial defence response, and (ii) that homoeostatic shift because of the bacteria-induced stress includes the mitochondrial remodelling and sequestration of compromised organelles via mitophagy. Implication of Drp1 and PINK1-PARK2-dependent mechanisms in the mitophagy turnover of the aberrant mitochondria in mesenchymal stromal cells is investigated and discussed.

  1. Titin, a Central Mediator for Hypertrophic Signaling, Exercise-Induced Mechanosignaling and Skeletal Muscle Remodeling

    PubMed Central

    Krüger, Martina; Kötter, Sebastian

    2016-01-01

    Titin is a giant scaffold protein with multiple functions in striated muscle physiology. Due to the elastic I-band domains and the filament-like integration in the half-sarcomere titin is an important factor for sarcomere assembly and serves as an adaptable molecular spring that determines myofilament distensibility. Protein-interactions e.g., with muscle ankyrin repeat proteins or muscle LIM-protein link titin to hypertrophic signaling and via p62 and Muscle Ring Finger proteins to mechanisms that control protein quality control. This review summarizes our current knowledge on titin as a central node for exercise-induced mechanosignaling and remodeling and further highlights the pathophysiological implications. PMID:26973541

  2. Dilation and Hypertrophy: A Cell-Based Continuum Mechanics Approach Towards Ventricular Growth and Remodeling

    NASA Astrophysics Data System (ADS)

    Ulerich, J.; Göktepe, S.; Kuhl, E.

    This manuscript presents a continuum approach towards cardiac growth and remodeling that is capable to predict chronic maladaptation of the heart in response to changes in mechanical loading. It is based on the multiplicative decomposition of the deformation gradient into and elastic and a growth part. Motivated by morphological changes in cardiomyocyte geometry, we introduce an anisotropic growth tensor that can capture both hypertrophic wall thickening and ventricular dilation within one generic concept. In agreement with clinical observations, we propose wall thickening to be a stress-driven phenomenon whereas dilation is introduced as a strain-driven process. The features of the proposed approach are illustrated in terms of the adaptation of thin heart slices and in terms overload-induced dilation in a generic bi-ventricular heart model.

  3. Autophagy and mitochondrial remodelling in mouse mesenchymal stromal cells challenged with Staphylococcus epidermidis.

    PubMed

    Gorbunov, Nikolai V; McDaniel, Dennis P; Zhai, Min; Liao, Pei-Jyun; Garrison, Bradley R; Kiang, Juliann G

    2015-05-01

    The bone marrow stroma constitutes the marrow-blood barrier, which sustains immunochemical homoeostasis and protection of the haematopoietic tissue in sequelae of systemic bacterial infections. Under these conditions, the bone marrow stromal cells affected by circulating bacterial pathogens shall elicit the adaptive stress-response mechanisms to maintain integrity of the barrier. The objective of this communication was to demonstrate (i) that in vitro challenge of mesenchymal stromal cells, i.e. colony-forming unit fibroblasts (CFU-F), with Staphylococcus epidermidis can activate the autophagy pathway to execute antibacterial defence response, and (ii) that homoeostatic shift because of the bacteria-induced stress includes the mitochondrial remodelling and sequestration of compromised organelles via mitophagy. Implication of Drp1 and PINK1-PARK2-dependent mechanisms in the mitophagy turnover of the aberrant mitochondria in mesenchymal stromal cells is investigated and discussed. PMID:25721260

  4. Biochemical assay for histone H2A.Z replacement by the yeast SWR1 chromatin remodeling complex.

    PubMed

    Mizuguchi, Gaku; Wu, Wei-Hua; Alami, Samar; Luk, Ed

    2012-01-01

    The evolutionarily conserved histone variant H2A.Z has an important role in the regulation of gene expression and the establishment of a buffer to the spread of silent heterochromatin. Saccharomyces cerevisiae Swr1, a Swi2/Snf2-related ATPase, is the catalytic core of a multisubunit chromatin remodeling enzyme, called the SWR1 complex, that efficiently replaces conventional histone H2A in nucleosomes with histone H2A.Z. Swr1 is required for the deposition of histone H2A.Z at stereotypical promoter locations in vivo, and Swr1 and H2A.Z commonly regulate a subset of yeast genes. Here, we describe an integrated nucleosome assembly-histone replacement system whereby histone exchange by chromatin remodeling activities may be analyzed in vitro. The system demonstrates ATP- and SWR1-complex-dependent replacement of histone H2A for histone H2A.Z on a preassembled nucleosome array. This system may also be adapted to analyze dynamic interactions between chromatin remodeling and modifying enzymes, histone chaperones, and nucleosome substrates containing canonical, variant, or covalently modified histones. PMID:22910211

  5. Interactive solution-adaptive grid generation procedure

    NASA Technical Reports Server (NTRS)

    Henderson, Todd L.; Choo, Yung K.; Lee, Ki D.

    1992-01-01

    TURBO-AD is an interactive solution adaptive grid generation program under development. The program combines an interactive algebraic grid generation technique and a solution adaptive grid generation technique into a single interactive package. The control point form uses a sparse collection of control points to algebraically generate a field grid. This technique provides local grid control capability and is well suited to interactive work due to its speed and efficiency. A mapping from the physical domain to a parametric domain was used to improve difficulties encountered near outwardly concave boundaries in the control point technique. Therefore, all grid modifications are performed on the unit square in the parametric domain, and the new adapted grid is then mapped back to the physical domain. The grid adaption is achieved by adapting the control points to a numerical solution in the parametric domain using control sources obtained from the flow properties. Then a new modified grid is generated from the adapted control net. This process is efficient because the number of control points is much less than the number of grid points and the generation of the grid is an efficient algebraic process. TURBO-AD provides the user with both local and global controls.

  6. Myonuclear domains in muscle adaptation and disease

    NASA Technical Reports Server (NTRS)

    Allen, D. L.; Roy, R. R.; Edgerton, V. R.

    1999-01-01

    Adult skeletal muscle fibers are among the few cell types that are truly multinucleated. Recently, evidence has accumulated supporting a role for the modulation of myonuclear number during muscle remodeling in response to injury, adaptation, and disease. These studies have demonstrated that muscle hypertrophy is associated with, and is dependent on, the addition of newly formed myonuclei via the fusion of myogenic cells to the adult myofiber, whereas muscle atrophy and disease appear to be associated with the loss of myonuclei, possibly through apoptotic-like mechanisms. Moreover, these studies also have demonstrated that myonuclear domain size, i. e., the amount of cytoplasm per myonucleus, is unchanged following the acute phase of hypertrophy but is reduced following atrophy. Together these data demonstrate that modulation of myonuclear number or myonuclear domain size (or both) is a mechanism contributing to the remodeling of adult skeletal muscle in response to alterations in the level of normal neuromuscular activity. Copyright 1999 John Wiley & Sons, Inc.

  7. A model for fatigue crack propagation and remodelling in compact bone.

    PubMed

    Taylor, D; Prendergast, P J

    1997-01-01

    The process of fatigue in bone is of interest for a number of reasons. Fatigue damage in vivo can eventually lead to stress fracture, and may also act as a stimulus for bone remodelling and adaptation. The aim of this paper is to develop a theoretical model which describes the growth of fatigue cracks, especially of microcracks. The growth behaviour of microcracks is complicated by their interactions with the surrounding microstructure. This problem has been identified by researchers working on fatigue in engineering materials. Their work can be adapted to develop an equation in which the growth rate of cracks is related to applied stress conditions and also to a microstructural parameter, d, which is defined as the spacing of barriers to crack growth. The model can be used to generate stress/life data for comparison with in vitro fatigue experiments. It can also be used to investigate two hypotheses: that microcracking stimulates repair and that the level of fatigue damage can act as a signal to initiate adaptation processes of deposition or resorption.

  8. Adaptive SPECT

    PubMed Central

    Barrett, Harrison H.; Furenlid, Lars R.; Freed, Melanie; Hesterman, Jacob Y.; Kupinski, Matthew A.; Clarkson, Eric; Whitaker, Meredith K.

    2008-01-01

    Adaptive imaging systems alter their data-acquisition configuration or protocol in response to the image information received. An adaptive pinhole single-photon emission computed tomography (SPECT) system might acquire an initial scout image to obtain preliminary information about the radiotracer distribution and then adjust the configuration or sizes of the pinholes, the magnifications, or the projection angles in order to improve performance. This paper briefly describes two small-animal SPECT systems that allow this flexibility and then presents a framework for evaluating adaptive systems in general, and adaptive SPECT systems in particular. The evaluation is in terms of the performance of linear observers on detection or estimation tasks. Expressions are derived for the ideal linear (Hotelling) observer and the ideal linear (Wiener) estimator with adaptive imaging. Detailed expressions for the performance figures of merit are given, and possible adaptation rules are discussed. PMID:18541485

  9. Postexercise Dietary Protein Strategies to Maximize Skeletal Muscle Repair and Remodeling in Masters Endurance Athletes: A Review.

    PubMed

    Doering, Thomas M; Reaburn, Peter R; Phillips, Stuart M; Jenkins, David G

    2016-04-01

    Participation rates of masters athletes in endurance events such as long-distance triathlon and running continue to increase. Given the physical and metabolic demands of endurance training, recovery practices influence the quality of successive training sessions and, consequently, adaptations to training. Research has suggested that, after muscle-damaging endurance exercise, masters athletes experience slower recovery rates in comparison with younger, similarly trained athletes. Given that these discrepancies in recovery rates are not observed after non-muscle-damaging exercise, it is suggested that masters athletes have impairments of the protein remodeling mechanisms within skeletal muscle. The importance of postexercise protein feeding for endurance athletes is increasingly being acknowledged, and its role in creating a positive net muscle protein balance postexercise is well known. The potential benefits of postexercise protein feeding include elevating muscle protein synthesis and satellite cell activity for muscle repair and remodeling, as well as facilitating muscle glycogen resynthesis. Despite extensive investigation into age-related anabolic resistance in sedentary aging populations, little is known about how anabolic resistance affects postexercise muscle protein synthesis and thus muscle remodeling in aging athletes. Despite evidence suggesting that physical training can attenuate but not eliminate age-related anabolic resistance, masters athletes are currently recommended to consume the same postexercise dietary protein dose (approximately 20 g or 0.25 g/kg/meal) as younger athletes. Given the slower recovery rates of masters athletes after muscle-damaging exercise, which may be due to impaired muscle remodeling mechanisms, masters athletes may benefit from higher doses of postexercise dietary protein, with particular attention directed to the leucine content of the postexercise bolus.

  10. Adaptive Computing.

    ERIC Educational Resources Information Center

    Harrell, William

    1999-01-01

    Provides information on various adaptive technology resources available to people with disabilities. (Contains 19 references, an annotated list of 129 websites, and 12 additional print resources.) (JOW)

  11. Contour adaptation.

    PubMed

    Anstis, Stuart

    2013-01-01

    It is known that adaptation to a disk that flickers between black and white at 3-8 Hz on a gray surround renders invisible a congruent gray test disk viewed afterwards. This is contrast adaptation. We now report that adapting simply to the flickering circular outline of the disk can have the same effect. We call this "contour adaptation." This adaptation does not transfer interocularly, and apparently applies only to luminance, not color. One can adapt selectively to only some of the contours in a display, making only these contours temporarily invisible. For instance, a plaid comprises a vertical grating superimposed on a horizontal grating. If one first adapts to appropriate flickering vertical lines, the vertical components of the plaid disappears and it looks like a horizontal grating. Also, we simulated a Cornsweet (1970) edge, and we selectively adapted out the subjective and objective contours of a Kanisza (1976) subjective square. By temporarily removing edges, contour adaptation offers a new technique to study the role of visual edges, and it demonstrates how brightness information is concentrated in edges and propagates from them as it fills in surfaces.

  12. School Buildings: Remodeling; Rehabilitation; Modernization; Repair. Bulletin, 1950, No. 17

    ERIC Educational Resources Information Center

    Yiles, Nelson E.

    1950-01-01

    Adequate school plants are essential to a modern educational program. The school plant that is not properly maintained soon fails to provide the service for which it was intended. The total program of maintenance, including repairs, renovation, remodeling, rehabilitation, and modernization should be carefully planned. Some tasks will recur at…

  13. Remodelling the School Workforce in England: A Study in Tyranny

    ERIC Educational Resources Information Center

    Gunter, Helen

    2007-01-01

    Remodelling the school workforce is being rolled out across England with official purposes articulated around work-life balance, improving standards, and the need to efficiently and effectively deploy staffing. This is not new and can be related to ongoing policy thrusts designed to restructure the state as manifest in the haphazard construction…

  14. Regulator of calcineurin 1 mediates pathological vascular wall remodeling

    PubMed Central

    Esteban, Vanesa; Méndez-Barbero, Nerea; Jesús Jiménez-Borreguero, Luis; Roqué, Mercè; Novensá, Laura; Belén García-Redondo, Ana; Salaices, Mercedes; Vila, Luis; Arbonés, María L.

    2011-01-01

    Artery wall remodeling, a major feature of diseases such as hypertension, restenosis, atherosclerosis, and aneurysm, involves changes in the tunica media mass that reduce or increase the vessel lumen. The identification of molecules involved in vessel remodeling could aid the development of improved treatments for these pathologies. Angiotensin II (AngII) is a key effector of aortic wall remodeling that contributes to aneurysm formation and restenosis through incompletely defined signaling pathways. We show that AngII induces vascular smooth muscle cell (VSMC) migration and vessel remodeling in mouse models of restenosis and aneurysm. These effects were prevented by pharmacological inhibition of calcineurin (CN) or lentiviral delivery of CN-inhibitory peptides. Whole-genome analysis revealed >1,500 AngII-regulated genes in VSMCs, with just 11 of them requiring CN activation. Of these, the most sensitive to CN activation was regulator of CN 1 (Rcan1). Rcan1 was strongly activated by AngII in vitro and in vivo and was required for AngII-induced VSMC migration. Remarkably, Rcan1−/− mice were resistant to AngII-induced aneurysm and restenosis. Our results indicate that aneurysm formation and restenosis share mechanistic elements and identify Rcan1 as a potential therapeutic target for prevention of aneurysm and restenosis progression. PMID:21930771

  15. CREB Selectively Controls Learning-Induced Structural Remodeling of Neurons

    ERIC Educational Resources Information Center

    Middei, Silvia; Spalloni, Alida; Longone, Patrizia; Pittenger, Christopher; O'Mara, Shane M.; Marie, Helene; Ammassari-Teule, Martine

    2012-01-01

    The modulation of synaptic strength associated with learning is post-synaptically regulated by changes in density and shape of dendritic spines. The transcription factor CREB (cAMP response element binding protein) is required for memory formation and in vitro dendritic spine rearrangements, but its role in learning-induced remodeling of neurons…

  16. Minor Groove Binder Distamycin Remodels Chromatin but Inhibits Transcription

    PubMed Central

    Majumder, Parijat; Banerjee, Amrita; Shandilya, Jayasha; Senapati, Parijat; Chatterjee, Snehajyoti; Kundu, Tapas K.; Dasgupta, Dipak

    2013-01-01

    The condensed structure of chromatin limits access of cellular machinery towards template DNA. This in turn represses essential processes like transcription, replication, repair and recombination. The repression is alleviated by a variety of energy dependent processes, collectively known as “chromatin remodeling”. In a eukaryotic cell, a fine balance between condensed and de-condensed states of chromatin helps to maintain an optimum level of gene expression. DNA binding small molecules have the potential to perturb such equilibrium. We present herein the study of an oligopeptide antibiotic distamycin, which binds to the minor groove of B-DNA. Chromatin mobility assays and circular dichroism spectroscopy have been employed to study the effect of distamycin on chromatosomes, isolated from the liver of Sprague-Dawley rats. Our results show that distamycin is capable of remodeling both chromatosomes and reconstituted nucleosomes, and the remodeling takes place in an ATP-independent manner. Binding of distamycin to the linker and nucleosomal DNA culminates in eviction of the linker histone and the formation of a population of off-centered nucleosomes. This hints at a possible corkscrew type motion of the DNA with respect to the histone octamer. Our results indicate that distamycin in spite of remodeling chromatin, inhibits transcription from both DNA and chromatin templates. Therefore, the DNA that is made accessible due to remodeling is either structurally incompetent for transcription, or bound distamycin poses a roadblock for the transcription machinery to advance. PMID:23460895

  17. Molecular Mechanisms of Pulmonary Vascular Remodeling in Pulmonary Arterial Hypertension

    PubMed Central

    Leopold, Jane A.; Maron, Bradley A.

    2016-01-01

    Pulmonary arterial hypertension (PAH) is a devastating disease that is precipitated by hypertrophic pulmonary vascular remodeling of distal arterioles to increase pulmonary artery pressure and pulmonary vascular resistance in the absence of left heart, lung parenchymal, or thromboembolic disease. Despite available medical therapy, pulmonary artery remodeling and its attendant hemodynamic consequences result in right ventricular dysfunction, failure, and early death. To limit morbidity and mortality, attention has focused on identifying the cellular and molecular mechanisms underlying aberrant pulmonary artery remodeling to identify pathways for intervention. While there is a well-recognized heritable genetic component to PAH, there is also evidence of other genetic perturbations, including pulmonary vascular cell DNA damage, activation of the DNA damage response, and variations in microRNA expression. These findings likely contribute, in part, to dysregulation of proliferation and apoptosis signaling pathways akin to what is observed in cancer; changes in cellular metabolism, metabolic flux, and mitochondrial function; and endothelial-to-mesenchymal transition as key signaling pathways that promote pulmonary vascular remodeling. This review will highlight recent advances in the field with an emphasis on the aforementioned molecular mechanisms as contributors to the pulmonary vascular disease pathophenotype. PMID:27213345

  18. The Remodeling Conjecture and the Faber-Pandharipande Formula

    NASA Astrophysics Data System (ADS)

    Bouchard, Vincent; Catuneanu, Andrei; Marchal, Olivier; Sułkowski, Piotr

    2013-01-01

    In this note, we prove that the free energies F g constructed from the Eynard-Orantin topological recursion applied to the curve mirror to {{C}^3} reproduce the Faber-Pandharipande formula for genus g Gromov-Witten invariants of {{C}^3} . This completes the proof of the remodeling conjecture for {{C}^3}.

  19. Analgesic Drugs Alter Connective Tissue Remodeling and Mechanical Properties.

    PubMed

    Carroll, Chad C

    2016-01-01

    Exercising individuals commonly consume analgesics, but these medications alter tendon and skeletal muscle connective tissue properties, possibly limiting a person from realizing the full benefits of exercise training. I detail the novel hypothesis that analgesic medications alter connective tissue structure and mechanical properties by modifying fibroblast production of growth factors and matrix enzymes, which are responsible for extracellular matrix remodeling.

  20. Energy Efficiency Measures to Incorporate into Remodeling Projects

    SciTech Connect

    Liaukus, C.

    2014-12-01

    Energy improvements in a home are often approached as one concerted effort, beginning with a simple walk-through assessment or more in-depth energy audit and followed by the installation of recommended energy measures. While this approach allows for systems thinking to guide the efforts, comprehensive energy improvements of this nature are undertaken by a relatively small number of U.S. households compared to piecemeal remodeling efforts. In this report, the U.S Department of Energy Building America Retrofit Alliance research team examines the improvement of a home’s energy performance in an opportunistic way by examining what can be done to incorporate energy efficiency measures into general remodeling work and home repair projects. This allows for energy efficiency upgrades to occur at the same time as remodeling proejcts. There are challenges to this approach, not the least of which being that the work will take place over time in potentially many separate projects. The opportunity to improve a home’s energy efficiency at one time expands or contracts with the scope of the remodel. As such, guidance on how to do each piece thoughtfully and with consideration for potential future projects, is critical.

  1. Energy Efficiency Measures to Incorporate into Remodeling Projects

    SciTech Connect

    Liaukus, C.

    2014-12-01

    Energy improvements in a home are often approached as one concerted effort, beginning with a simple walk-through assessment or more in-depth energy audit and followed by the installation of recommended energy measures. While this approach allows for systems thinking to guide the efforts, comprehensive energy improvements of this nature are undertaken by a relatively small number of the households in our nation compared to more piecemeal remodeling efforts. Even when programs like the Weatherization Assistance Program and Home Performance with ENERGY STAR are considered, homes that have had a comprehensive energy makeover still represent a small fraction of the 111.1 million households. In this report, the U.S Department of Energy Building America Retrofit Alliance research team looks at the improvement of a home's energy performance in an opportunistic way: it examines what can be done to incorporate energy efficiency measures into general remodeling work and home repair projects. This allows for the possibility for people who would not normally pursue energy efficiency but will remodel their kitchen or re-side their home to improve their home's performance at the same time. There are challenges to this approach, not the least of which being that the work will take place over time in potentially many separate projects. The opportunity to improve a home's energy efficiency at one time expands or contracts with the scope of the remodel. As such, guidance on how to do each piece thoughtfully and with consideration for potential future projects, is critical.

  2. 19. 'Southern Pacific Company, Pacific Lines, Remodeling of Piers For ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    19. 'Southern Pacific Company, Pacific Lines, Remodeling of Piers For Renewal of Br. 210-C Near Tehama, Sac. Division, Scale 1' = 40' & 1/4' = 1'-0', Sept. 1927, M.W.D., Drawing 5935, Sheet 2.' - Southern Pacific Railroad Shasta Route, Bridge No. 210.52, Milepost 210.52, Tehama, Tehama County, CA

  3. "New Professionalism," Workforce Remodeling and the Restructuring of Teachers' Work

    ERIC Educational Resources Information Center

    Stevenson, Howard; Carter, Bob; Passy, Rowena

    2007-01-01

    Since its election in 1997 the Labour government's policy has sought to promote a "new professionalism" amongst teachers. First mooted at the time when new performance management arrangements were introduced, the discourse of new professionalism has now become closely associated with the "workforce remodeling" agenda in which teachers' work is…

  4. Pentoxifylline Attenuates Cardiac Remodeling Induced by Tobacco Smoke Exposure

    PubMed Central

    Minicucci, Marcos; Oliveira, Fernando; Santos, Priscila; Polegato, Bertha; Roscani, Meliza; Fernandes, Ana Angelica; Lustosa, Beatriz; Paiva, Sergio; Zornoff, Leonardo; Azevedo, Paula

    2016-01-01

    Background Tobacco smoke exposure is an important risk factor for cardiac remodeling. Under this condition, inflammation, oxidative stress, energy metabolism abnormalities, apoptosis, and hypertrophy are present. Pentoxifylline has anti‑inflammatory, anti-apoptotic, anti-thrombotic and anti-proliferative properties. Objective The present study tested the hypothesis that pentoxifylline would attenuate cardiac remodeling induced by smoking. Methods Wistar rats were distributed in four groups: Control (C), Pentoxifylline (PX), Tobacco Smoke (TS), and PX-TS. After two months, echocardiography, invasive blood pressure measurement, biochemical, and histological studies were performed. The groups were compared by two-way ANOVA with a significance level of 5%. Results TS increased left atrium diameter and area, which was attenuated by PX. In the isolated heart study, TS lowered the positive derivate (+dp/dt), and this was attenuated by PX. The antioxidants enzyme superoxide dismutase and glutathione peroxidase were decreased in the TS group; PX recovered these activities. TS increased lactate dehydrogenase (LDH) and decreased 3-hydroxyacyl Coenzyme A dehydrogenases (OH-DHA) and citrate synthase (CS). PX attenuated LDH, 3-OH-DHA and CS alterations in TS-PX group. TS increased IL-10, ICAM-1, and caspase-3. PX did not influence these variables. Conclusion TS induced cardiac remodeling, associated with increased inflammation, oxidative stress, apoptosis, and changed energy metabolism. PX attenuated cardiac remodeling by reducing oxidative stress and improving cardiac bioenergetics, but did not act upon cardiac cytokines and apoptosis. PMID:27096523

  5. Remodeling of University of Minnesota President's House and Office.

    ERIC Educational Resources Information Center

    Minnesota State Office of the Legislative Auditor, St. Paul. Program Evaluation Div.

    A report on the remodeling projects at the University of Minnesota president's house and office is presented, noting significant shortcomings in the way the projects were managed and in the reporting relationship that existed between the Board of Regents and the university's administration. Recommendations are offered to the university on how…

  6. 17. Photographic copy of original remodeling drawings dated July 8, ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    17. Photographic copy of original remodeling drawings dated July 8, 1988 (original sepia in plan room of Base Civil Engineer, Scott AFB) First and second floor plans - Scott Air Force Base, General Officer Quarters, 229 Birchard Street, O'Fallon, St. Clair County, IL

  7. 18. Photographic copy of original remodeling drawings dated July 8, ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    18. Photographic copy of original remodeling drawings dated July 8, 1988 (original sepia in plan room of Base Civil Engineer, Scott AFB) First and second floor demolition and framing plan - Scott Air Force Base, General Officer Quarters, 229 Birchard Street, O'Fallon, St. Clair County, IL

  8. Effects of Electrical and Structural Remodeling on Atrial Fibrillation Maintenance: A Simulation Study

    PubMed Central

    Krogh-Madsen, Trine; Abbott, Geoffrey W.; Christini, David J.

    2012-01-01

    Atrial fibrillation, a common cardiac arrhythmia, often progresses unfavourably: in patients with long-term atrial fibrillation, fibrillatory episodes are typically of increased duration and frequency of occurrence relative to healthy controls. This is due to electrical, structural, and contractile remodeling processes. We investigated mechanisms of how electrical and structural remodeling contribute to perpetuation of simulated atrial fibrillation, using a mathematical model of the human atrial action potential incorporated into an anatomically realistic three-dimensional structural model of the human atria. Electrical and structural remodeling both shortened the atrial wavelength - electrical remodeling primarily through a decrease in action potential duration, while structural remodeling primarily slowed conduction. The decrease in wavelength correlates with an increase in the average duration of atrial fibrillation/flutter episodes. The dependence of reentry duration on wavelength was the same for electrical vs. structural remodeling. However, the dynamics during atrial reentry varied between electrical, structural, and combined electrical and structural remodeling in several ways, including: (i) with structural remodeling there were more occurrences of fragmented wavefronts and hence more filaments than during electrical remodeling; (ii) dominant waves anchored around different anatomical obstacles in electrical vs. structural remodeling; (iii) dominant waves were often not anchored in combined electrical and structural remodeling. We conclude that, in simulated atrial fibrillation, the wavelength dependence of reentry duration is similar for electrical and structural remodeling, despite major differences in overall dynamics, including maximal number of filaments, wave fragmentation, restitution properties, and whether dominant waves are anchored to anatomical obstacles or spiralling freely. PMID:22383869

  9. Protective role of heme oxygenase-1 in atrial remodeling.

    PubMed

    Yeh, Yung-Hsin; Hsu, Lung-An; Chen, Ying-Hwa; Kuo, Chi-Tai; Chang, Gwo-Jyh; Chen, Wei-Jan

    2016-09-01

    Structural and electrical remodeling in the atrium constitutes the main feature of atrial fibrillation (AF), which is characterized by increased oxidative stress. Heme oxygenase-1 (HO-1) is a potent anti-oxidant system that may provide protection against various oxidative stress-related diseases. The aim of this study is to investigate whether HO-1 has a protective effect on AF-related remodeling. Cultured atrium-derived myocytes (HL-1 cell line) were used to evaluate tachypacing-induced oxidative stress, structural, and electrical remodeling. Transforming growth factor-β (TGF-β) was utilized to assess collagen (a main fibrosis-related protein) expression in atrial fibroblasts. Tachypacing in HL-1 myocytes and treatment of atrial fibroblasts with TGF-β enhanced the expression of HO-1, both of which were mediated by the activation of nuclear factor erythroid-2-related factor 2. Over-expression of HO-1 in HL-1 cells attenuated tachypacing-induced oxidative stress, myofibril degradation, down-regulation of L-type calcium channel, and shortening of action potential duration. Furthermore, HO-1 over-expression in atrial fibroblasts blocked the up-regulation of collagen by TGF-β, implicating a protective role of HO-1 in structural and electrical remodeling in the atrium. In vivo, HO-1(-/-) mice exhibited a higher degree of oxidative stress, myofibril degradation, and collagen deposit in their atria than wild-type mice. Moreover, burst atrial pacing induced a greater susceptibility to AF in HO-1(-/-) mice than in wild-type mice. In conclusion, a negative-feedback regulation of HO-1 in activated atrial myocytes and fibroblasts may provide protection against AF-related remodeling and AF development. PMID:27562817

  10. Remodeling of Super-hydrophobic Surfaces.

    PubMed

    Extrand, C W

    2016-08-30

    An experimental study on the underlying mechanisms of structured super-hydrophobic surfaces was recently published [ Butt, H.-J.; et al. How Water Advances on Superhydrophobic Surfaces. Phys. Rev. Lett. 2016, 116, 096101 . DOI: 10.1103/PhysRevLett.116.096101 ]. After depositing small drops of water, Butt's group inclined their surfaces to initiate movement. They examined the contact between the water and structured surfaces with confocal microscopy. They observed that drops were suspended atop the protruding features and movement of water was different at the advancing and receding edges. At the advancing edge, the water interface descended downward and draped itself across the features. At the receding edge, water jumped from one feature to the next. As Butt and co-workers did not test their data against any existing model, that is done in this paper. Here, a previously proposed model that employs linear averaging at the contact line was adapted to their surfaces in an attempt to estimate their contact and sliding angles. Predictions from the model generally agreed with their experimental measurements. PMID:27541362

  11. Climate adaptation

    NASA Astrophysics Data System (ADS)

    Kinzig, Ann P.

    2015-03-01

    This paper is intended as a brief introduction to climate adaptation in a conference devoted otherwise to the physics of sustainable energy. Whereas mitigation involves measures to reduce the probability of a potential event, such as climate change, adaptation refers to actions that lessen the impact of climate change. Mitigation and adaptation differ in other ways as well. Adaptation does not necessarily have to be implemented immediately to be effective; it only needs to be in place before the threat arrives. Also, adaptation does not necessarily require global, coordinated action; many effective adaptation actions can be local. Some urban communities, because of land-use change and the urban heat-island effect, currently face changes similar to some expected under climate change, such as changes in water availability, heat-related morbidity, or changes in disease patterns. Concern over those impacts might motivate the implementation of measures that would also help in climate adaptation, despite skepticism among some policy makers about anthropogenic global warming. Studies of ancient civilizations in the southwestern US lends some insight into factors that may or may not be important to successful adaptation.

  12. Length adaptation of smooth muscle contractile filaments in response to sustained activation.

    PubMed

    Stålhand, Jonas; Holzapfel, Gerhard A

    2016-05-21

    Airway and bladder smooth muscles are known to undergo length adaptation under sustained contraction. This adaptation process entails a remodelling of the intracellular actin and myosin filaments which shifts the peak of the active force-length curve towards the current length. Smooth muscles are therefore able to generate the maximum force over a wide range of lengths. In contrast, length adaptation of vascular smooth muscle has attracted very little attention and only a handful of studies have been reported. Although their results are conflicting on the existence of a length adaptation process in vascular smooth muscle, it seems that, at least, peripheral arteries and arterioles undergo such adaptation. This is of interest since peripheral vessels are responsible for pressure regulation, and a length adaptation will affect the function of the cardiovascular system. It has, e.g., been suggested that the inward remodelling of resistance vessels associated with hypertension disorders may be related to smooth muscle adaptation. In this study we develop a continuum mechanical model for vascular smooth muscle length adaptation by assuming that the muscle cells remodel the actomyosin network such that the peak of the active stress-stretch curve is shifted towards the operating point. The model is specialised to hamster cheek pouch arterioles and the simulated response to stepwise length changes under contraction. The results show that the model is able to recover the salient features of length adaptation reported in the literature.

  13. Effective chromosome pairing requires chromatin remodeling at the onset of meiosis

    PubMed Central

    Colas, Isabelle; Shaw, Peter; Prieto, Pilar; Wanous, Michael; Spielmeyer, Wolfgang; Mago, Rohit; Moore, Graham

    2008-01-01

    During meiosis, homologous chromosomes (homologues) recognize each other and then intimately associate. Studies exploiting species with large chromosomes reveal that chromatin is remodeled at the onset of meiosis before this intimate association. However, little is known about the effect the remodeling has on pairing. We show here in wheat that chromatin remodeling of homologues can only occur if they are identical or nearly identical. Moreover, a failure to undergo remodeling results in reduced pairing between the homologues. Thus, chromatin remodeling at the onset of meiosis enables the chromosomes to become competent to pair and recombine efficiently. PMID:18417451

  14. Computational simulation of the bone remodeling using the finite element method: an elastic-damage theory for small displacements

    PubMed Central

    2013-01-01

    Background The resistance of the bone against damage by repairing itself and adapting to environmental conditions is its most important property. These adaptive changes are regulated by physiological process commonly called the bone remodeling. Better understanding this process requires that we apply the theory of elastic-damage under the hypothesis of small displacements to a bone structure and see its mechanical behavior. Results The purpose of the present study is to simulate a two dimensional model of a proximal femur by taking into consideration elastic-damage and mechanical stimulus. Here, we present a mathematical model based on a system of nonlinear ordinary differential equations and we develop the variational formulation for the mechanical problem. Then, we implement our mathematical model into the finite element method algorithm to investigate the effect of the damage. Conclusion The results are consistent with the existing literature which shows that the bone stiffness drops in damaged bone structure under mechanical loading. PMID:23663260

  15. CT-1-CP-induced ventricular electrical remodeling in mice.

    PubMed

    Chen, Shu-fen; Wei, Tao-zhi; Rao, Li-ya; Xu, Ming-guang; Dong, Zhan-ling

    2015-02-01

    The chronic effects of carboxyl-terminal polypeptide of Cardiotrophin-1 (CT-1-CP) on ventricular electrical remodeling were investigated. CT-1-CP, which contains 16 amino acids in sequence of the C-terminal of Cardiotrophin-1, was selected and synthesized, and then administered to Kunming mice (aged 5 weeks) by intraperitoneal injection (500 ng·g⁻¹·day⁻¹) (4 groups, n=10 and female: male=1:1 in each group) for 1, 2, 3 and 4 weeks, respectively. The control group (n=10, female: male=1:1) was injected by physiological saline for 4 weeks. The epicardial monophasic action potential (MAP) was recorded by using a contact-type MAP electrode placed vertically on the left ventricular (LV) epicardium surface, and the electrocardiogram (ECG) signal in lead II was monitored synchronously. ECG intervals (RR, PR, QRS and QT) and the amplitude of MAP (Am), the maximum upstroke velocity (Vmax), as well as action potential durations (APDs) at different repolarization levels (APD30, APD50, APD70, and APD90) of MAP were determined and analyzed in detail. There were no significant differences in RR and P intervals between CT-1-CP-treated groups and control group, but the PR segment and the QRS complex were greater in the former than in the latter (F=2.681 and 5.462 respectively, P<0.05). Though QT interval and the corrected QT interval (QTc) were shorter in CT-1-CP-treated groups than in control group, the QT dispersion (QTd) of them was greater in the latter than in the former (F=3.090, P<0.05) and increased with the time. The ECG monitoring synchronously with the MAP showed that the compression of MAP electrode on the left ventricular epicardium induced performance similar to myocardium ischemia. As compared with those before chest-opening, the PR segment and QT intervals remained basically unchanged in control group, but prolonged significantly in all CT-1-CP-treated groups and the prolongation of QT intervals increased gradually along with the time of exposure to CT-1-CP

  16. Toothbrush Adaptations.

    ERIC Educational Resources Information Center

    Exceptional Parent, 1987

    1987-01-01

    Suggestions are presented for helping disabled individuals learn to use or adapt toothbrushes for proper dental care. A directory lists dental health instructional materials available from various organizations. (CB)

  17. Physical principles of membrane remodelling during cell mechanoadaptation

    PubMed Central

    Kosmalska, Anita Joanna; Casares, Laura; Elosegui-Artola, Alberto; Thottacherry, Joseph Jose; Moreno-Vicente, Roberto; González-Tarragó, Víctor; del Pozo, Miguel Ángel; Mayor, Satyajit; Arroyo, Marino; Navajas, Daniel; Trepat, Xavier; Gauthier, Nils C.; Roca-Cusachs, Pere

    2015-01-01

    Biological processes in any physiological environment involve changes in cell shape, which must be accommodated by their physical envelope—the bilayer membrane. However, the fundamental biophysical principles by which the cell membrane allows for and responds to shape changes remain unclear. Here we show that the 3D remodelling of the membrane in response to a broad diversity of physiological perturbations can be explained by a purely mechanical process. This process is passive, local, almost instantaneous, before any active remodelling and generates different types of membrane invaginations that can repeatedly store and release large fractions of the cell membrane. We further demonstrate that the shape of those invaginations is determined by the minimum elastic and adhesive energy required to store both membrane area and liquid volume at the cell–substrate interface. Once formed, cells reabsorb the invaginations through an active process with duration of the order of minutes. PMID:26073653

  18. ATP Dependent Chromatin Remodeling Enzymes in Embryonic Stem Cells

    PubMed Central

    Saladi, Srinivas Vinod

    2010-01-01

    Embryonic stem (ES) cells are pluripotent cells that can self renew or be induced to differentiate into multiple cell lineages, and thus have the potential to be utilized in regenerative medicine. Key pluripotency specific factors (Oct 4/Sox2/Nanog/Klf4) maintain the pluripotent state by activating expression of pluripotency specific genes and by inhibiting the expression of developmental regulators. Pluripotent ES cells are distinguished from differentiated cells by a specialized chromatin state that is required to epigenetically regulate the ES cell phenotype. Recent studies show that in addition to pluripotency specific factors, chromatin remodeling enzymes play an important role in regulating ES cell chromatin and the capacity to self-renew and to differentiate. Here we review recent studies that delineate the role of ATP dependent chromatin remodeling enzymes in regulating ES cell chromatin structure. PMID:20148317

  19. The role of microRNAs in bone remodeling

    PubMed Central

    Jing, Dian; Hao, Jin; Shen, Yu; Tang, Ge; Li, Mei-Le; Huang, Shi-Hu; Zhao, Zhi-He

    2015-01-01

    Bone remodeling is balanced by bone formation and bone resorption as well as by alterations in the quantities and functions of seed cells, leading to either the maintenance or deterioration of bone status. The existing evidence indicates that microRNAs (miRNAs), known as a family of short non-coding RNAs, are the key post-transcriptional repressors of gene expression, and growing numbers of novel miRNAs have been verified to play vital roles in the regulation of osteogenesis, osteoclastogenesis, and adipogenesis, revealing how they interact with signaling molecules to control these processes. This review summarizes the current knowledge of the roles of miRNAs in regulating bone remodeling as well as novel applications for miRNAs in biomaterials for therapeutic purposes. PMID:26208037

  20. Dental implant design--effect on bone remodeling.

    PubMed

    Pilliar, R M; Deporter, D A; Watson, P A; Valiquette, N

    1991-04-01

    Bone remodeling around three different endosseous dental implant designs placed in dog mandibles was studied using radiography during lengthy periods of function and by histology after animal sacrifice. The three designs investigated were (a) threaded (c.p. titanium), (b) fully porous-coated (titanium alloy), and (c) partially porous-coated (titanium alloy). The implants were kept in function for either 32 weeks (fully porous-coated) or 73 to 77 weeks (partially porous-coated and threaded). The studies indicated that some crestal bone loss occurred for both the threaded and partially porous-coated implants while no significant bone loss was seen with fully porous-coated implants in the absence of plaque-associated infection. It is suggested that these observed differences are a result of the different stress states that develop in bone surrounding the three designs underlying the importance of implant design on bone remodeling.

  1. The solid state environment orchestrates embryonic development and tissue remodeling

    NASA Technical Reports Server (NTRS)

    Damsky, C. H.; Moursi, A.; Zhou, Y.; Fisher, S. J.; Globus, R. K.

    1997-01-01

    Cell interactions with extracellular matrix and with other cells play critical roles in morphogenesis during development and in tissue homeostasis and remodeling throughout life. Extracellular matrix is information-rich, not only because it is comprised of multifunctional structural ligands for cell surface adhesion receptors, but also because it contains peptide signaling factors, and proteinases and their inhibitors. The functions of these groups of molecules are extensively interrelated. In this review, three primary cell culture models are described that focus on adhesion receptors and their roles in complex aspects of morphogenesis and remodeling: the regulation of proteinase expression by fibronectin and integrins in synovial fibroblasts; the regulation of osteoblast differentiation and survival by fibronectin, and the regulation of trophoblast differentiation and invasion by integrins, cadherins and immunoglobulin family adhesion receptors.

  2. Design stars: how small DNA viruses remodel the host nucleus.

    PubMed

    Jiang, Mengxi; Imperiale, Michael J

    2012-05-01

    Numerous host components are encountered by viruses during the infection process. While some of these host structures are left unchanged, others may go through dramatic remodeling processes. In this review, we summarize these host changes that occur during small DNA virus infections, with a focus on host nuclear components and pathways. Although these viruses differ significantly in their genome structures and infectious pathways, there are common nuclear targets that are altered by various viral factors. Accumulating evidence suggests that these nuclear remodeling processes are often essential for productive viral infections and/or viral-induced transformation. Understanding the complex interactions between viruses and these host structures and pathways will help to build a more integrated network of how the virus completes its life cycle and point toward the design of novel therapeutic regimens that either prevent harmful viral infections or employ viruses as nontraditional treatment options or molecular tools.

  3. Frequent mutations in chromatin-remodeling genes in pulmonary carcinoids

    PubMed Central

    Lu, Xin; Sun, Ruping; Ozretić, Luka; Seidal, Danila; Zander, Thomas; Leenders, Frauke; George, Julie; Müller, Christian; Dahmen, Ilona; Pinther, Berit; Bosco, Graziella; Konrad, Kathryn; Altmüller, Janine; Nürnberg, Peter; Achter, Viktor; Lang, Ulrich; Schneider, Peter M; Bogus, Magdalena; Soltermann, Alex; Brustugun, Odd Terje; Helland, Åslaug; Solberg, Steinar; Lund-Iversen, Marius; Ansén, Sascha; Stoelben, Erich; Wright, Gavin M.; Russell, Prudence; Wainer, Zoe; Solomon, Benjamin; Field, John K; Hyde, Russell; Davies, Michael PA.; Heukamp, Lukas C; Petersen, Iver; Perner, Sven; Lovly, Christine; Cappuzzo, Federico; Travis, William D; Wolf, Jürgen; Vingron, Martin; Brambilla, Elisabeth; Haas, Stefan A.; Buettner, Reinhard; Thomas, Roman K

    2014-01-01

    Pulmonary carcinoids are rare neuroendocrine tumors of the lung. The molecular alterations underlying the pathogenesis of these tumors have not been systematically studied so far. Here we perform gene copy number analysis (n=54), genome/exome (n=44) and transcriptome (n=69) sequencing of pulmonary carcinoids and observe frequent mutations in chromatin-remodeling genes. Covalent histone modifiers and subunits of the SWI/SNF complex are mutated in 40% and 22.2% of the cases respectively, with MEN1, PSIP1 and ARID1A being recurrently affected. In contrast to small-cell lung cancer and large-cell neuroendocrine tumors, TP53 and RB1 mutations are rare events, suggesting that pulmonary carcinoids are not early progenitor lesions of the highly aggressive lung neuroendocrine tumors but arise through independent cellular mechanisms. These data also suggest that inactivation of chromatin remodeling genes is sufficient to drive transformation in pulmonary carcinoids. PMID:24670920

  4. Probabilistic Study of Bone Remodeling Using Finite Element Analysis

    NASA Astrophysics Data System (ADS)

    Werner, C.; Gorla, R. S. R.

    2013-08-01

    The dynamic bone remodeling process is a computationally challenging research area that struggles to understand the actual mechanisms. It has been observed that a mechanical stimulus in the bone greatly affects the remodeling process. A 3D finite element model of a femur is created and a probabilistic analysis is performed on the model. The probabilistic analysis measures the sensitivities of various parameters related to the material properties, geometric properties, and the three load cases defined as Single Leg Stance, Abduction, and Adduction. The sensitivity of each parameter is based on the calculated maximum mechanical stimulus and analyzed at various values of probabilities ranging from 0.001 to 0.999. The analysis showed that the parameters associated with the Single Leg Stance load case had the highest sensitivity with a probability of 0.99 and the angle of the force applied to the joint of the proximal femur had the overall highest sensitivity

  5. The population model of bone remodelling employed the optimal control.

    PubMed

    Moroz, Adam

    2012-11-01

    Several models have been developed in recent years which apply population dynamics methods to describe the mechanisms of bone remodelling. This study incorporates the population kinetics model of bone turnover (including the osteocyte loop regulation) with the optimal control technique. Model simulations have been performed with a wide range of rate parameters using the Monte Carlo method. The regression method has also been used to investigate the interdependence of the location of equilibrium and the characteristics of the equilibrium/relaxation time on the rate parameters employed. The dynamic optimal control outlook for the regulation of bone remodelling processes, in the context of the osteocyte-control population model, has been discussed. Optimisation criteria have been formulated from the perspective of the energetic and metabolic losses in the tissue, with respect to the performance of the bone multicellular unit.

  6. Remodeling myelination: implications for mechanisms of neural plasticity.

    PubMed

    Chang, Kae-Jiun; Redmond, Stephanie A; Chan, Jonah R

    2016-02-01

    One of the most significant paradigm shifts in membrane remodeling is the emerging view that membrane transformation is not exclusively controlled by cytoskeletal rearrangement, but also by biophysical constraints, adhesive forces, membrane curvature and compaction. One of the most exquisite examples of membrane remodeling is myelination. The advent of myelin was instrumental in advancing the nervous system during vertebrate evolution. With more rapid and efficient communication between neurons, faster and more complex computations could be performed in a given time and space. Our knowledge of how myelin-forming oligodendrocytes select and wrap axons has been limited by insufficient spatial and temporal resolution. By virtue of recent technological advances, progress has clarified longstanding controversies in the field. Here we review insights into myelination, from target selection to axon wrapping and membrane compaction, and discuss how understanding these processes has unexpectedly opened new avenues of insight into myelination-centered mechanisms of neural plasticity.

  7. Osteocyte Remodeling of the Perilacunar and Pericanalicular Matrix

    PubMed Central

    Qing, Hai; Bonewald, Lynda F

    2009-01-01

    With additional functions of osteocytes being identified, the concept that osteocytes are just “static lacunar-dwelling cells” is no longer accepted. We reviewed most of the relevant literature on osteocyte's function in the direct remodeling of the perilucunar matrix, discussing the advantages and disadvantages. Special attention was paid to how the negative researchers argue about the “osteocytic osteolysis” principle, and how the positive side addressed the arguments. We also discussed the newly found data of osteocytic remodeling function from our group. With more biotechnology in hand, there is increased excitement in the prospect of now being able to answer the two important questions: do osteocytes have the capability to remove mineral from the perilacunar matrix and if so what are the molecular and cellular mechanisms? do osteocytes have the capability to deposit new mineral on the perilacunar matrix and if so what are the cellular and molecular mechanisms? PMID:20687297

  8. ISWI chromatin remodeling complexes in the DNA damage response

    PubMed Central

    Aydin, Özge Z; Vermeulen, Wim; Lans, Hannes

    2014-01-01

    Regulation of chromatin structure is an essential component of the DNA damage response (DDR), which effectively preserves the integrity of DNA by a network of multiple DNA repair and associated signaling pathways. Within the DDR, chromatin is modified and remodeled to facilitate efficient DNA access, to control the activity of repair proteins and to mediate signaling. The mammalian ISWI family has recently emerged as one of the major ATP-dependent chromatin remodeling complex families that function in the DDR, as it is implicated in at least 3 major DNA repair pathways: homologous recombination, non-homologous end-joining and nucleotide excision repair. In this review, we discuss the various manners through which different ISWI complexes regulate DNA repair and how they are targeted to chromatin containing damaged DNA. PMID:25486562

  9. SUN4 is essential for nuclear remodeling during mammalian spermiogenesis.

    PubMed

    Calvi, Alessandra; Wong, Arnette Shi Wei; Wright, Graham; Wong, Esther Sook Miin; Loo, Tsui Han; Stewart, Colin L; Burke, Brian

    2015-11-15

    One of the more dramatic examples of cellular reorganization occurs during spermiogenesis in which a roughly spherical spermatid is transformed into a mature sperm cell. A highlight of this process involves nuclear remodeling whereby the round spermatid nucleus is sculpted into an elongated and polar structure. This transformation in nuclear architecture features chromatin condensation, changes in the composition and organization of the nuclear lamina and redistribution and elimination of nuclear pore complexes. The manchette, a cytoplasmic microtubule-based structure is thought to play a crucial role in the remodeling process. Here we show that SUN4, a spermatid nuclear membrane protein has an essential function in coupling the manchette to the nuclear periphery. In the absence of SUN4, manchette microtubules appear highly disorganized and the nucleus itself fails to elongate. Consequently, mice deficient in SUN4 display globozoospermia with associated infertility.

  10. ISWI chromatin remodeling complexes in the DNA damage response.

    PubMed

    Aydin, Özge Z; Vermeulen, Wim; Lans, Hannes

    2014-01-01

    Regulation of chromatin structure is an essential component of the DNA damage response (DDR), which effectively preserves the integrity of DNA by a network of multiple DNA repair and associated signaling pathways. Within the DDR, chromatin is modified and remodeled to facilitate efficient DNA access, to control the activity of repair proteins and to mediate signaling. The mammalian ISWI family has recently emerged as one of the major ATP-dependent chromatin remodeling complex families that function in the DDR, as it is implicated in at least 3 major DNA repair pathways: homologous recombination, non-homologous end-joining and nucleotide excision repair. In this review, we discuss the various manners through which different ISWI complexes regulate DNA repair and how they are targeted to chromatin containing damaged DNA.

  11. Nucleosome breathing and remodeling constrain CRISPR-Cas9 function.

    PubMed

    Isaac, R Stefan; Jiang, Fuguo; Doudna, Jennifer A; Lim, Wendell A; Narlikar, Geeta J; Almeida, Ricardo

    2016-04-28

    The CRISPR-Cas9 bacterial surveillance system has become a versatile tool for genome editing and gene regulation in eukaryotic cells, yet how CRISPR-Cas9 contends with the barriers presented by eukaryotic chromatin is poorly understood. Here we investigate how the smallest unit of chromatin, a nucleosome, constrains the activity of the CRISPR-Cas9 system. We find that nucleosomes assembled on native DNA sequences are permissive to Cas9 action. However, the accessibility of nucleosomal DNA to Cas9 is variable over several orders of magnitude depending on dynamic properties of the DNA sequence and the distance of the PAM site from the nucleosome dyad. We further find that chromatin remodeling enzymes stimulate Cas9 activity on nucleosomal templates. Our findings imply that the spontaneous breathing of nucleosomal DNA together with the action of chromatin remodelers allow Cas9 to effectively act on chromatin in vivo.

  12. Nascent chain-monitored remodeling of the Sec machinery for salinity adaptation of marine bacteria

    PubMed Central

    Ishii, Eiji; Chiba, Shinobu; Hashimoto, Narimasa; Kojima, Seiji; Homma, Michio; Ito, Koreaki; Akiyama, Yoshinori; Mori, Hiroyuki

    2015-01-01

    SecDF interacts with the SecYEG translocon in bacteria and enhances protein export in a proton-motive-force-dependent manner. Vibrio alginolyticus, a marine-estuarine bacterium, contains two SecDF paralogs, V.SecDF1 and V.SecDF2. Here, we show that the export-enhancing function of V.SecDF1 requires Na+ instead of H+, whereas V.SecDF2 is Na+-independent, presumably requiring H+. In accord with the cation-preference difference, V.SecDF2 was only expressed under limited Na+ concentrations whereas V.SecDF1 was constitutive. However, it is not the decreased concentration of Na+ per se that the bacterium senses to up-regulate the V.SecDF2 expression, because marked up-regulation of the V.SecDF2 synthesis was observed irrespective of Na+ concentrations under certain genetic/physiological conditions: (i) when the secDF1VA gene was deleted and (ii) whenever the Sec export machinery was inhibited. VemP (Vibrio export monitoring polypeptide), a secretory polypeptide encoded by the upstream ORF of secDF2VA, plays the primary role in this regulation by undergoing regulated translational elongation arrest, which leads to unfolding of the Shine–Dalgarno sequence for translation of secDF2VA. Genetic analysis of V. alginolyticus established that the VemP-mediated regulation of SecDF2 is essential for the survival of this marine bacterium in low-salinity environments. These results reveal that a class of marine bacteria exploits nascent-chain ribosome interactions to optimize their protein export pathways to propagate efficiently under different ionic environments that they face in their life cycles. PMID:26392525

  13. A muscle-liver-fat signalling axis is essential for central control of adaptive adipose remodelling

    PubMed Central

    Shimizu, Noriaki; Maruyama, Takako; Yoshikawa, Noritada; Matsumiya, Ryo; Ma, Yanxia; Ito, Naoki; Tasaka, Yuki; Kuribara-Souta, Akiko; Miyata, Keishi; Oike, Yuichi; Berger, Stefan; Schütz, Günther; Takeda, Shin’ichi; Tanaka, Hirotoshi

    2015-01-01

    Skeletal muscle has a pleiotropic role in organismal energy metabolism, for example, by storing protein as an energy source, or by excreting endocrine hormones. Muscle proteolysis is tightly controlled by the hypothalamus-pituitary-adrenal signalling axis via a glucocorticoid-driven transcriptional programme. Here we unravel the physiological significance of this catabolic process using skeletal muscle-specific glucocorticoid receptor (GR) knockout (GRmKO) mice. These mice have increased muscle mass but smaller adipose tissues. Metabolically, GRmKO mice show a drastic shift of energy utilization and storage in muscle, liver and adipose tissues. We demonstrate that the resulting depletion of plasma alanine serves as a cue to increase plasma levels of fibroblast growth factor 21 (FGF21) and activates liver-fat communication, leading to the activation of lipolytic genes in adipose tissues. We propose that this skeletal muscle-liver-fat signalling axis may serve as a target for the development of therapies against various metabolic diseases, including obesity. PMID:25827749

  14. Mast cells: Versatile regulators of inflammation, tissue remodeling, host defense and homeostasis

    PubMed Central

    Galli, Stephen J.; Tsai, Mindy

    2009-01-01

    Summary The possible roles of mast cells in heath and disease have been a topic of interest for over one hundred and twenty five years. Many adaptive or pathological processes affecting the skin or other anatomical sites have been associated with morphological evidence of mast cell activation, and/or with changes in mast cell numbers or phenotype. Such observations, taken together with the known functions of the diverse mediators, cytokines and growth factors which can be secreted by mast cells, have suggested many potential functions for mast cells in health and disease. Definitively identifying the importance of mast cells in biological responses in humans is difficult. However, mutant mice which are profoundly mast cell-deficient, especially those which can undergo engraftment with wild type or genetically-altered mast cells, provide an opportunity to investigate the importance of mast cells, and specific mast cell functions or products, in various adaptive or pathological responses in mice. Such work has shown that mast cells can significantly influence multiple features of inflammatory or immune responses, through diverse effects that can either promote or, surprisingly, suppress, aspects of these responses. Through such functions, mast cells can significantly influence inflammation, tissue remodeling, host defense and homeostasis. PMID:18024086

  15. Morphological and functional remodeling of the neuromuscular junction by skeletal muscle PGC-1α

    PubMed Central

    Arnold, Anne-Sophie; Gill, Jonathan; Christe, Martine; Ruiz, Rocío; McGuirk, Shawn; St-Pierre, Julie; Tabares, Lucía; Handschin, Christoph

    2014-01-01

    The neuromuscular junction (NMJ) exhibits high morphological and functional plasticity. In the mature muscle, the relative levels of physical activity are major determinants of NMJ function. Classically, motor neuron-mediated activation patterns of skeletal muscle have been thought of as the major drivers of NMJ plasticity and the ensuing fiber-type determination in muscle. Here we use muscle-specific transgenic animals for the peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α) as a genetic model for trained mice to elucidate the contribution of skeletal muscle to activity-induced adaptation of the NMJ. We find that muscle-specific expression of PGC-1α promotes a remodeling of the NMJ, even in the absence of increased physical activity. Importantly, these plastic changes are not restricted to post-synaptic structures, but extended to modulation of pre-synaptic cell morphology and function. Therefore, our data indicate that skeletal muscle significantly contributes to the adaptation of the NMJ subsequent to physical activity. PMID:24686533

  16. Rigid and remodelled: cerebrovascular structure and function after experimental high-thoracic spinal cord transection.

    PubMed

    Phillips, A A; Matin, N; Frias, B; Zheng, M M Z; Jia, M; West, C; Dorrance, A M; Laher, I; Krassioukov, A V

    2016-03-15

    High-thoracic or cervical spinal cord injury (SCI) is associated with several critical clinical conditions related to impaired cerebrovascular health, including: 300-400% increased risk of stroke, cognitive decline and diminished cerebral blood flow regulation. The purpose of this study was to examine the influence of high-thoracic (T3 spinal segment) SCI on cerebrovascular structure and function, as well as molecular markers of profibrosis. Seven weeks after complete T3 spinal cord transection (T3-SCI, n = 15) or sham injury (Sham, n = 10), rats were sacrificed for either middle cerebral artery (MCA) structure and function assessments via ex vivo pressure myography, or immunohistochemical analyses. Myogenic tone was unchanged, but over a range of transmural pressures, inward remodelling occurred after T3-SCI with a 40% reduction in distensibility (both P < 0.05), and a 33% reduction in vasoconstrictive reactivity to 5-HT trending toward significance (P = 0.09). After T3-SCI, the MCA had more collagen I (42%), collagen III (24%), transforming growth factor β (47%) and angiotensin II receptor type 2 (132%), 27% less elastin as well as concurrent increased wall thickness and reduced lumen diameter (all P < 0.05). Sympathetic innervation (tyrosine hydroxylase-positive axon density) and endothelium-dependent dilatation (carbachol) of the MCA were not different between groups. This study demonstrates profibrosis and hypertrophic inward remodelling within the largest cerebral artery after high-thoracic SCI, leading to increased stiffness and possibly impaired reactivity. These deleterious adaptations would substantially undermine the capacity for regulation of cerebral blood flow and probably underlie several cerebrovascular clinical conditions in the SCI population.

  17. Extensive gene remodeling in the viral world: new evidence for nongradual evolution in the mobilome network.

    PubMed

    Jachiet, Pierre-Alain; Colson, Philippe; Lopez, Philippe; Bapteste, Eric

    2014-08-07

    Complex nongradual evolutionary processes such as gene remodeling are difficult to model, to visualize, and to investigate systematically. Despite these challenges, the creation of composite (or mosaic) genes by combination of genetic segments from unrelated gene families was established as an important adaptive phenomena in eukaryotic genomes. In contrast, almost no general studies have been conducted to quantify composite genes in viruses. Although viral genome mosaicism has been well-described, the extent of gene mosaicism and its rules of emergence remain largely unexplored. Applying methods from graph theory to inclusive similarity networks, and using data from more than 3,000 complete viral genomes, we provide the first demonstration that composite genes in viruses are 1) functionally biased, 2) involved in key aspects of the arm race between cells and viruses, and 3) can be classified into two distinct types of composite genes in all viral classes. Beyond the quantification of the widespread recombination of genes among different viruses of the same class, we also report a striking sharing of genetic information between viruses of different classes and with different nucleic acid types. This latter discovery provides novel evidence for the existence of a large and complex mobilome network, which appears partly bound by the sharing of genetic information and by the formation of composite genes between mobile entities with different genetic material. Considering that there are around 10E31 viruses on the planet, gene remodeling appears as a hugely significant way of generating and moving novel sequences between different kinds of organisms on Earth.

  18. Remodelling the vascular microenvironment of glioblastoma with alpha-particles

    PubMed Central

    Behling, Katja; Maguire, William F.; Di Gialleonardo, Valentina; Heeb, Lukas E.M.; Hassan, Iman F.; Veach, Darren R.; Keshari, Kayvan R.; Gutin, Philip H.; Scheinberg, David A.; McDevitt, Michael R.

    2016-01-01

    Rationale Tumors escape anti-angiogenic therapy by activation of pro-angiogenic signaling pathways. Bevacizumab is approved for the treatment of recurrent glioblastoma, but patients inevitably develop resistance to this angiogenic inhibitor. We investigated targeted α-particle therapy with 225Ac-E4G10 as an anti-vascular approach and previously showed increased survival and tumor control in a high-grade transgenic orthotopic glioblastoma model. Here we investigate changes in tumor-vascular morphology and functionality caused by 225Ac-E4G10. Methods We investigated remodeling of tumor microenvironment in transgenic Ntva glioblastoma mice using a therapeutic 7.4 kBq dose of 225Ac-E4G10. Immunofluorescence and immunohistochemical analyses imaged morphological changes in the tumor blood brain barrier microenvironment. Multi-color flow cytometry quantified the endothelial progenitor cell population in the bone marrow. Diffusion-weighted magnetic resonance imaged functional changes of the tumor vascular network. Results The mechanism of drug action is a combination of glioblastoma vascular microenvironment remodeling, edema relief, and depletion of regulatory T and endothelial progenitor cells. The primary remodeling event is the reduction of both endothelial and perivascular cell populations. Tumor-associated edema and necrosis was lessened and resulted in increased perfusion and reduced diffusion. Pharmacological uptake of dasatinib into tumor was enhanced following α-particle therapy. Conclusion Targeted anti-vascular α-particle radiation remodels the glioblastoma vascular microenvironment via a multimodal mechanism of action and provides insight into the vascular architecture of Platelet-derived growth factor driven glioblastoma. PMID:27261519

  19. Carrier-Mediated Transport of Nicotine Across the Inner Blood-Retinal Barrier: Involvement of a Novel Organic Cation Transporter Driven by an Outward H(+) Gradient.

    PubMed

    Tega, Yuma; Kubo, Yoshiyuki; Yuzurihara, Chihiro; Akanuma, Shin-Ichi; Hosoya, Ken-Ichi

    2015-09-01

    The present study was carried out to investigate the blood-to-retina transport of nicotine across the inner blood-retinal barrier (BRB). Using the in vivo vascular injection method, the blood-to-retina influx clearance of nicotine across the BRB was determined as 131 μL/(min?g retina), which is much higher than that of a nonpermeable paracellular marker, and blood-to-retina transport of nicotine was inhibited by organic cations such as pyrilamine and verapamil. The nicotine uptake by a conditionally immortalized rat retinal capillary endothelial cell line (TR-iBRB2 cells), an in vitro model of the inner BRB, exhibited time, temperature, and concentration dependence with a Km of 492 μM. These results suggest the involvement of a carrier-mediated transport process in nicotine transport in the inner BRB. The nicotine uptake by TR-iBRB2 cells was stimulated by an outwardly directed H(+) gradient, and the uptake was significantly inhibited by bulky and hydrophobic cationic drugs, whereas inhibitors of organic cation transporters did not show inhibitory effect. These results suggest that the novel organic cation transport system driven by an outwardly directed H(+) gradient is involved in the blood-to-retina transport of nicotine across the inner BRB.

  20. Failure mechanism for flexible dye-sensitized solar cells under repeated outward bending: Cracking and spalling off of nano-porous titanium dioxide film

    NASA Astrophysics Data System (ADS)

    He, Xue-Long; Yang, Guan-Jun; Li, Chang-Jiu; Liu, Mei; Fan, Sheng-Qiang

    2015-04-01

    Flexibility, as well as efficiency, of flexible dye-sensitized solar cells (DSCs) is of significant importance to their applications. In this study, quantitative bending test, carried out with a lab-developed solar cell bending tester, is used to simulate the flexible service condition. The photovoltaic performance, morphology of the photoanode and electrochemical property evolution during bending service are examined to aim at understanding the bending failure mechanism for the flexible DSCs under repeated outward bending (the TiO2 film in the photoanode is in tension). Results show that when the bending radius is 12 mm, the efficiency of the plastic DSCs keeps unchanged with increasing the bending cycle. When the bending radius is smaller than 12 mm, the efficiency of the flexible DSCs decreases with increasing the bending cycle. The electrochemical impedance spectroscopy results show that the increase of the electron transport resistance (Rt) in TiO2 network is responsible for the degradation of efficiency. Furthermore, the photoanodes after repeated bending is cracking and spalling off from the ITO surface. Finally, a failure model for the flexible DSCs under repeated outward bending is proposed.

  1. Force and pressure-recovery characteristics at supersonic speeds of a conical nose inlet with bypasses discharging outward from the body axis

    NASA Technical Reports Server (NTRS)

    Beke, Andrew; Allen, J L

    1953-01-01

    Aerodynamic and performance characteristics of a conical spike nacelle-type inlet with two bypasses are presented at Mach numbers of 1.6, 1.8, and 2.0 for angles of attach up to 90 degrees. The bypasses were located 6 inlet diameters downstream of the inlet and were designed to discharge the bypass mass flow outward from the body axis. The inlet was designed to attain a mass-flow ratio of unity at a Mach number of 2.0. It is shown that discharging the bypass mass flow outward from the body nearly doubles the critical drag of a similar configuration but with bypass discharge in an axial direction. As a result of this greater drag, the net force on the model in the flight direction is reduced when comparison is made with the axial discharge case. The lift and pitching-moment coefficients are slightly higher than those for a configuration without bypasses. Approximately 25 % of the maximum inlet mass flow was discharged through the bypasses, and the pressure-recovery and mass-flow characteristics were in qualitative and quantitative agreement with the results of an investigation of a similar configuration with axial discharge.

  2. Endocrine remodelling of the adult intestine sustains reproduction in Drosophila.

    PubMed

    Reiff, Tobias; Jacobson, Jake; Cognigni, Paola; Antonello, Zeus; Ballesta, Esther; Tan, Kah Junn; Yew, Joanne Y; Dominguez, Maria; Miguel-Aliaga, Irene

    2015-01-01

    The production of offspring is energetically costly and relies on incompletely understood mechanisms that generate a positive energy balance. In mothers of many species, changes in key energy-associated internal organs are common yet poorly characterised functionally and mechanistically. In this study, we show that, in adult Drosophila females, the midgut is dramatically remodelled to enhance reproductive output. In contrast to extant models, organ remodelling does not occur in response to increased nutrient intake and/or offspring demands, but rather precedes them. With spatially and temporally directed manipulations, we identify juvenile hormone (JH) as an anticipatory endocrine signal released after mating. Acting through intestinal bHLH-PAS domain proteins Methoprene-tolerant (Met) and Germ cell-expressed (Gce), JH signals directly to intestinal progenitors to yield a larger organ, and adjusts gene expression and sterol regulatory element-binding protein (SREBP) activity in enterocytes to support increased lipid metabolism. Our findings identify a metabolically significant paradigm of adult somatic organ remodelling linking hormonal signals, epithelial plasticity, and reproductive output.

  3. PDGFRα plays a crucial role in connective tissue remodeling.

    PubMed

    Horikawa, Shinjiro; Ishii, Yoko; Hamashima, Takeru; Yamamoto, Seiji; Mori, Hisashi; Fujimori, Toshihiko; Shen, Jie; Inoue, Ran; Nishizono, Hirofumi; Itoh, Hiroshi; Majima, Masataka; Abraham, David; Miyawaki, Toshio; Sasahara, Masakiyo

    2015-12-07

    Platelet derived growth factor (PDGF) plays a pivotal role in the remodeling of connective tissues. Emerging data indicate the distinctive role of PDGF receptor-α (PDGFRα) in this process. In the present study, the Pdgfra gene was systemically inactivated in adult mouse (α-KO mouse), and the role of PDGFRα was examined in the subcutaneously implanted sponge matrices. PDGFRα expressed in the fibroblasts of Pdgfra-preserving control mice (Flox mice), was significantly reduced in the sponges in α-KO mice. Neovascularized areas were largely suppressed in the α-KO mice than in the Flox mice, whereas the other parameters related to the blood vessels and endothelial cells were similar. The deposition of collagen and fibronectin and the expression of collagen 1a1 and 3a1 genes were significantly reduced in α-KO mice. There was a significantly decrease in the number and dividing fibroblasts in the α-KO mice, and those of macrophages were similar between the two genotypes. Hepatocyte growth factor (Hgf) gene expression was suppressed in Pdgfra-inactivated fibroblasts and connective tissue. The findings implicate the role of PDGFRα-dependent ECM and HGF production in fibroblasts that promotes the remodeling of connective tissue and suggest that PDGFRα may be a relevant target to regulate connective tissue remodeling.

  4. Pulmonary arterial remodeling revealed by microfocal x-ray tomography

    NASA Astrophysics Data System (ADS)

    Karau, Kelly L.; Molthen, Robert C.; Johnson, Roger H.; Dhyani, Anita H.; Haworth, Steven T.; Dawson, Christopher A.

    2001-05-01

    Animal models and micro-CT imaging are useful for understanding the functional consequences of, and identifying the genes involved in, the remodeling of vascular structures that accompanies pulmonary vascular disease. Using a micro-CT scanner to image contrast-enhanced arteries in excised lungs from fawn hooded rats (a strain genetically susceptible to hypoxia induced pulmonary hypertension), we found that portions of the pulmonary arterial tree downstream from a given diameter were morphometrically indistinguishable. This 'self-consistency' property provided a means for summarizing the pulmonary arterial tree architecture and mechanical properties using a parameter vector obtained from measurements of the contiguous set of vessel segments comprising the longest (principal) pathway and its branches over a range of vascular pressures. This parameter vector was used to characterize the pulmonary vascular remodeling that occurred in rats exposed to a hypoxic (11.5% oxygen) environment and provided the input to a hemodynamic model relating structure to function. The major effect of the remodeling was a longitudinally (pulmonary artery to arterioles) uniform decrease in vessel distensibility that resulted in a 90% increase in arterial resistance. Despite the almost uniform change in vessel distensibility, over 50% of the resistance increase was attributable to vessels with unstressed diameters less than 125 microns.

  5. Senataxin controls meiotic silencing through ATR activation and chromatin remodeling.

    PubMed

    Yeo, Abrey J; Becherel, Olivier J; Luff, John E; Graham, Mark E; Richard, Derek; Lavin, Martin F

    2015-01-01

    Senataxin, defective in ataxia oculomotor apraxia type 2, protects the genome by facilitating the resolution of RNA-DNA hybrids (R-loops) and other aspects of RNA processing. Disruption of this gene in mice causes failure of meiotic recombination and defective meiotic sex chromosome inactivation, leading to male infertility. Here we provide evidence that the disruption of Setx leads to reduced SUMOylation and disruption of protein localization across the XY body during meiosis. We demonstrate that senataxin and other DNA damage repair proteins, including ataxia telangiectasia and Rad3-related protein-interacting partner, are SUMOylated, and a marked downregulation of both ataxia telangiectasia and Rad3-related protein-interacting partner and TopBP1 leading to defective activation and signaling through ataxia telangiectasia and Rad3-related protein occurs in the absence of senataxin. Furthermore, chromodomain helicase DNA-binding protein 4, a component of the nucleosome remodeling and deacetylase chromatin remodeler that interacts with both ataxia telangiectasia and Rad3-related protein and senataxin was not recruited efficiently to the XY body, triggering altered histone acetylation and chromatin conformation in Setx (-/-) pachytene-staged spermatocytes. These results demonstrate that senataxin has a critical role in ataxia telangiectasia and Rad3-related protein- and chromodomain helicase DNA-binding protein 4-mediated transcriptional silencing and chromatin remodeling during meiosis providing greater insight into its critical role in gene regulation to protect against neurodegeneration. PMID:27462424

  6. Senataxin controls meiotic silencing through ATR activation and chromatin remodeling

    PubMed Central

    Yeo, Abrey J; Becherel, Olivier J; Luff, John E; Graham, Mark E; Richard, Derek; Lavin, Martin F

    2015-01-01

    Senataxin, defective in ataxia oculomotor apraxia type 2, protects the genome by facilitating the resolution of RNA–DNA hybrids (R-loops) and other aspects of RNA processing. Disruption of this gene in mice causes failure of meiotic recombination and defective meiotic sex chromosome inactivation, leading to male infertility. Here we provide evidence that the disruption of Setx leads to reduced SUMOylation and disruption of protein localization across the XY body during meiosis. We demonstrate that senataxin and other DNA damage repair proteins, including ataxia telangiectasia and Rad3-related protein-interacting partner, are SUMOylated, and a marked downregulation of both ataxia telangiectasia and Rad3-related protein-interacting partner and TopBP1 leading to defective activation and signaling through ataxia telangiectasia and Rad3-related protein occurs in the absence of senataxin. Furthermore, chromodomain helicase DNA-binding protein 4, a component of the nucleosome remodeling and deacetylase chromatin remodeler that interacts with both ataxia telangiectasia and Rad3-related protein and senataxin was not recruited efficiently to the XY body, triggering altered histone acetylation and chromatin conformation in Setx−/− pachytene-staged spermatocytes. These results demonstrate that senataxin has a critical role in ataxia telangiectasia and Rad3-related protein- and chromodomain helicase DNA-binding protein 4-mediated transcriptional silencing and chromatin remodeling during meiosis providing greater insight into its critical role in gene regulation to protect against neurodegeneration. PMID:27462424

  7. A Computational Model for Simulating Spaceflight Induced Bone Remodeling

    NASA Technical Reports Server (NTRS)

    Pennline, James A.; Mulugeta, Lealem

    2014-01-01

    An overview of an initial development of a model of bone loss due to skeletal unloading in weight bearing sites is presented. The skeletal site chosen for the initial application of the model is the femoral neck region because hip fractures can be debilitating to the overall performance health of astronauts. The paper begins with the motivation for developing such a model of the time course of change in bone in order to understand the mechanism of bone demineralization experienced by astronauts in microgravity, to quantify the health risk, and to establish countermeasures. Following this, a general description of a mathematical formulation of the process of bone remodeling is discussed. Equations governing the rate of change of mineralized bone volume fraction and active osteoclast and osteoblast are illustrated. Some of the physiology of bone remodeling, the theory of how imbalance in remodeling can cause bone loss, and how the model attempts to capture this is discussed. The results of a preliminary validation analysis that was carried out are presented. The analysis compares a set of simulation results against bone loss data from control subjects who participated in two different bed rest studies. Finally, the paper concludes with outlining the current limitations and caveats of the model, and planned future work to enhance the state of the model.

  8. Cerebral salt wasting syndrome after calvarial remodeling in craniosynostosis.

    PubMed

    Byeon, Jun-Hee; Yoo, Gyeol

    2005-10-01

    Hyponatremia and increased urine output after calvarial remodeling have been noted in pediatric patients with craniosynostosis. If not treated properly, patients develop hypoosmotic conditions that can lead to cerebral edema, increased intracranial pressure, and collapsed circulation. Postoperative hyponatremia after central nervous system surgery is considered as the syndrome of inappropriate antidiuretic hormone (SIADH) secretion. Recently, however, cerebral salt wasting syndrome (CSWS) instead of SIADH has been reported frequently. CSWS is associated with a decreased serum sodium level, increased urinary sodium level, increased urine output, decreased ECF volume, increased atrial natriuretic peptide (ANP) level, and increased brain natriuretic peptide (BNP) level. We experienced nine patients with craniosynostosis who underwent calvarial remodeling. By postoperative day 1, the ANP and BNP levels increased by 3-6 folds compared with the preoperative levels. They returned to the normal levels by postoperative day 5. The ADH level was within the normal range even after operation. The urinary sodium level increased in all patients by postoperative day 1 and 3. But the serum sodium level, and serum and urine osmolarity were normal due to appropriate replacement of sodium and fluid. After calvarial remodeling, the potential development of CSWS should be considered and distinguished from SIADH. The patients with CSWS require normal saline resuscitation and should prophylactically receive normal saline.

  9. Age-dependent motor unit remodelling in human limb muscles.

    PubMed

    Piasecki, Mathew; Ireland, Alex; Jones, David A; McPhee, Jamie S

    2016-06-01

    Voluntary control of skeletal muscle enables humans to interact with and manipulate the environment. Lower muscle mass, weakness and poor coordination are common complaints in older age and reduce physical capabilities. Attention has focused on ways of maintaining muscle size and strength by exercise, diet or hormone replacement. Without appropriate neural innervation, however, muscle cannot function. Emerging evidence points to a neural basis of muscle loss. Motor unit number estimates indicate that by age around 71 years, healthy older people have around 40 % fewer motor units. The surviving low- and moderate-threshold motor units recruited for moderate intensity contractions are enlarged by around 50 % and show increased fibre density, presumably due to collateral reinnervation of denervated fibres. Motor unit potentials show increased complexity and the stability of neuromuscular junction transmissions is decreased. The available evidence is limited by a lack of longitudinal studies, relatively small sample sizes, a tendency to examine the small peripheral muscles and relatively few investigations into the consequences of motor unit remodelling for muscle size and control of movements in older age. Loss of motor neurons and remodelling of surviving motor units constitutes the major change in ageing muscles and probably contributes to muscle loss and functional impairments. The deterioration and remodelling of motor units likely imposes constraints on the way in which the central nervous system controls movements. PMID:26667009

  10. Remodeling sensory cortical maps implants specific behavioral memory.

    PubMed

    Bieszczad, K M; Miasnikov, A A; Weinberger, N M

    2013-08-29

    Neural mechanisms underlying the capacity of memory to be rich in sensory detail are largely unknown. A candidate mechanism is learning-induced plasticity that remodels the adult sensory cortex. Here, expansion in the primary auditory cortical (A1) tonotopic map of rats was induced by pairing a 3.66-kHz tone with activation of the nucleus basalis, mimicking the effects of natural associative learning. Remodeling of A1 produced de novo specific behavioral memory, but neither memory nor plasticity was consistently at the frequency of the paired tone, which typically decreased in A1 representation. Rather, there was a specific match between individual subjects' area of expansion and the tone that was strongest in each animal's memory, as determined by post-training frequency generalization gradients. These findings provide the first demonstration of a match between the artificial induction of specific neural representational plasticity and artificial induction of behavioral memory. As such, together with prior and present findings for detection, correlation and mimicry of plasticity with the acquisition of memory, they satisfy a key criterion for neural substrates of memory. This demonstrates that directly remodeling sensory cortical maps is sufficient for the specificity of memory formation.

  11. Mechanisms underlying heterologous skin scaffold-mediated tissue remodeling

    PubMed Central

    Mimura, Kallyne K. O.; Moraes, Andréia R.; Miranda, Aline C.; Greco, Rebecca; Ansari, Tahera; Sibbons, Paul; Greco, Karin V.; Oliani, Sonia M.

    2016-01-01

    Biocompatibility of two newly developed porcine skin scaffolds was assessed after 3, 14, 21 and 90 days of implantation in rats. Both scaffolds showed absence of cells, preservation of ECM and mechanical properties comparable to non-decellularised skin before implantation. Host cell infiltration was much prominent on both scaffolds when compared to Permacol (surgical control). At day 3, the grafts were surrounded by polymorphonuclear cells, which were replaced by a notable number of IL-6-positive cells at day 14. Simultaneously, the number of pro-inflammatory M1-macrophage was enhanced. Interestingly, a predominant pro-remodeling M2 response, with newly formed vessels, myofibroblasts activation and a shift on the type of collagen expression was sequentially delayed (around 21 days). The gene expression of some trophic factors involved in tissue remodeling was congruent with the cellular events. Our findings suggested that the responsiveness of macrophages after non-crosslinked skin scaffolds implantation seemed to intimately affect various cell responses and molecular events; and this range of mutually reinforcing actions was predictive of a positive tissue remodeling that was essential for the long-standing success of the implants. Furthermore, our study indicates that non-crosslinked biologic scaffold implantation is biocompatible to the host tissue and somehow underlying molecular events involved in tissue repair. PMID:27725772

  12. Atrial Electrophysiological Remodeling and Fibrillation in Heart Failure

    PubMed Central

    Pandit, Sandeep V.; Workman, Antony J.

    2016-01-01

    Heart failure (HF) causes complex, chronic changes in atrial structure and function, which can cause substantial electrophysiological remodeling and predispose the individual to atrial fibrillation (AF). Pharmacological treatments for preventing AF in patients with HF are limited. Improved understanding of the atrial electrical and ionic/molecular mechanisms that promote AF in these patients could lead to the identification of novel therapeutic targets. Animal models of HF have identified numerous changes in atrial ion currents, intracellular calcium handling, action potential waveform and conduction, as well as expression and signaling of associated proteins. These studies have shown that the pattern of electrophysiological remodeling likely depends on the duration of HF, the underlying cardiac pathology, and the species studied. In atrial myocytes and tissues obtained from patients with HF or left ventricular systolic dysfunction, the data on changes in ion currents and action potentials are largely equivocal, probably owing mainly to difficulties in controlling for the confounding influences of multiple variables, such as patient’s age, sex, disease history, and drug treatments, as well as the technical challenges in obtaining such data. In this review, we provide a summary and comparison of the main animal and human electrophysiological studies to date, with the aim of highlighting the consistencies in some of the remodeling patterns, as well as identifying areas of contention and gaps in the knowledge, which warrant further investigation. PMID:27812293

  13. Ventricular restoration--a surgical approach to reverse ventricular remodeling.

    PubMed

    Buckberg, Gerald D

    2004-10-01

    Congestive heart failure is most often caused by scar from coronary occlusion. The transition from occluded vessel to scar to dilation results in a remodeled ventricle that changes shape from ellipse to sphere. This shape change following an index event is called remodeling and a surgical approach for restoration (bring back to normal) will be described that uses the patient's own tissue, rather than employing heart replacement by mechanical devices or transplantation. The surgical restoration approach was taken by the RESTORE group that comprises an international medical and surgical team that will report (a) the remodeling infrastructure, role of compensatory remote muscle, and factors underlying surgical restoration decisions, (b) structural basis for ventricular geometric changes and surgical background for restoration, (c) individual rebuilding experience in 1150 patients over 20 years from one center, (d) integrated 5 year results from the RESTORE team in 1198 patients, (e) electrical aspects of restoration in 382 patients with only one AICD used, (f) how restoration improves mechanical synchrony without electrical devices, (g) geometric reasons for secondary mitral insufficiency and impact of adding mitral repair during SVR procedures, and (h) importance of defining site specific scar in no ischemic disease to identify a similar trigger lesion in non ischemic cardiomyopathy. The importance of a team approach by the RESTORE group may set the benchmark for collaborative world wide groups, and thereby depart from traditional focal approaches by individual disciplines. PMID:15886970

  14. Circadian rhythms and memory formation: regulation by chromatin remodeling.

    PubMed

    Sahar, Saurabh; Sassone-Corsi, Paolo

    2012-01-01

    Epigenetic changes, such as DNA methylation or histone modification, can remodel the chromatin and regulate gene expression. Remodeling of chromatin provides an efficient mechanism of transducing signals, such as light or nutrient availability, to regulate gene expression. CLOCK:BMAL1 mediated activation of clock-controlled genes (CCGs) is coupled to circadian changes in histone modification at their promoters. Several chromatin modifiers, such as the deacetylases SIRT1 and HDAC3 or methyltransferase MLL1, have been shown to be recruited to the promoters of the CCGs in a circadian manner. Interestingly, the central element of the core clock machinery, the transcription factor CLOCK, also possesses histone acetyltransferase activity. Rhythmic expression of the CCGs is abolished in the absence of these chromatin modifiers. Recent research has demonstrated that chromatin remodeling is at the cross-roads of circadian rhythms and regulation of metabolism and aging. It would be of interest to identify if similar pathways exist in the epigenetic regulation of memory formation. PMID:22470318

  15. Remodeling of the Methylation Landscape in Breast Cancer Metastasis

    PubMed Central

    Reyngold, Marsha; Turcan, Sevin; Giri, Dilip; Kannan, Kasthuri; Walsh, Logan A.; Viale, Agnes; Drobnjak, Marija; Vahdat, Linda T.; Lee, William; Chan, Timothy A.

    2014-01-01

    The development of breast cancer metastasis is accompanied by dynamic transcriptome changes and dramatic alterations in nuclear and chromatin structure. The basis of these changes is incompletely understood. The DNA methylome of primary breast cancers contribute to transcriptomic heterogeneity and different metastatic behavior. Therefore we sought to characterize methylome remodeling during regional metastasis. We profiled the DNA methylome and transcriptome of 44 matched primary breast tumors and regional metastases. Striking subtype-specific patterns of metastasis-associated methylome remodeling were observed, which reflected the molecular heterogeneity of breast cancers. These divergent changes occurred primarily in CpG island (CGI)-poor areas. Regions of methylome reorganization shared by the subtypes were also observed, and we were able to identify a metastasis-specific methylation signature that was present across the breast cancer subclasses. These alterations also occurred outside of CGIs and promoters, including sequences flanking CGIs and intergenic sequences. Integrated analysis of methylation and gene expression identified genes whose expression correlated with metastasis-specific methylation. Together, these findings significantly enhance our understanding of the epigenetic reorganization that occurs during regional breast cancer metastasis across the major breast cancer subtypes and reveal the nature of methylome remodeling during this process. PMID:25083786

  16. Endocrine remodelling of the adult intestine sustains reproduction in Drosophila

    PubMed Central

    Reiff, Tobias; Jacobson, Jake; Cognigni, Paola; Antonello, Zeus; Ballesta, Esther; Tan, Kah Junn; Yew, Joanne Y; Dominguez, Maria; Miguel-Aliaga, Irene

    2015-01-01

    The production of offspring is energetically costly and relies on incompletely understood mechanisms that generate a positive energy balance. In mothers of many species, changes in key energy-associated internal organs are common yet poorly characterised functionally and mechanistically. In this study, we show that, in adult Drosophila females, the midgut is dramatically remodelled to enhance reproductive output. In contrast to extant models, organ remodelling does not occur in response to increased nutrient intake and/or offspring demands, but rather precedes them. With spatially and temporally directed manipulations, we identify juvenile hormone (JH) as an anticipatory endocrine signal released after mating. Acting through intestinal bHLH-PAS domain proteins Methoprene-tolerant (Met) and Germ cell-expressed (Gce), JH signals directly to intestinal progenitors to yield a larger organ, and adjusts gene expression and sterol regulatory element-binding protein (SREBP) activity in enterocytes to support increased lipid metabolism. Our findings identify a metabolically significant paradigm of adult somatic organ remodelling linking hormonal signals, epithelial plasticity, and reproductive output. DOI: http://dx.doi.org/10.7554/eLife.06930.001 PMID:26216039

  17. Remodeling of bovine endometrium throughout the estrous cycle.

    PubMed

    Arai, Miki; Yoshioka, Shin; Tasaki, Yukari; Okuda, Kiyoshi

    2013-11-01

    The mammalian endometrium changes morphologically and functionally throughout the estrous cycle. In some species, endometrial cells also undergo periodic proliferation and degeneration. However, the remodeling of bovine endometrium throughout the estrous cycle remains unclear. In the present study, we examined how the remodeling of bovine endometrium varied through the estrous cycle by measuring the relative rates of cell proliferation and apoptosis. Cells positive for both KI-67 (a proliferation marker) and cleaved caspase-3 (CCP3: an apoptotic cell marker) were immunohistochemically evaluated throughout the estrous cycle in the luminal and glandular epithelia, and the stroma of bovine endometrium. Percentages of KI-67-positive cells tended to be higher at the early luteal and follicular stages than at the mid and late luteal stages in all cell types. Similarly, percentages of CCP3-positive cells were higher at the early luteal stage than at the mid and late luteal stages in the luminal epithelium and stroma. Furthermore, CCP3 expression levels by Western blot analysis agreed with these immunohistological observations. On the other hand, DNA fragmentation was detected in the bovine endometrium without significant differences during the estrous cycle by the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) method. Together, these results show that cell proliferation and apoptosis undergo cyclic patterns in the bovine endometrium, and suggest that the bovine endometrium is remodeled in each estrous cycle. PMID:24051170

  18. The human tri-peptide GHK and tissue remodeling.

    PubMed

    Pickart, Loren

    2008-01-01

    Tissue remodeling follows the initial phase of wound healing and stops inflammatory and scar-forming processes, then restores the normal tissue morphology. The human peptide Gly-(L-His)-(L-Lys) or GHK, has a copper 2+ (Cu(2+)) affinity similar to the copper transport site on albumin and forms GHK-Cu, a complex with Cu(2+). These two molecules activate a plethora of remodeling related processes: (1) chemoattraction of repair cells such as macrophages, mast cells, capillary cells; (2) anti-inflammatory actions (suppression of free radicals, thromboxane formation, release of oxidizing iron, transforming growth factor beta-1, tumor necrosis factor alpha and protein glycation while increasing superoxide dismutase, vessel vasodilation, blocking ultraviolet damage to skin keratinocytes and improving fibroblast recovery after X-ray treatments); (3) increases protein synthesis of collagen, elastin, metalloproteinases, anti-proteases, vascular endothelial growth factor, fibroblast growth factor 2, nerve growth factor, neutrotropins 3 and 4, and erythropoietin; (4) increases the proliferation of fibroblasts and keratinocytes; nerve outgrowth, angiogenesis, and hair follicle size. GHK-Cu stimulates wound healing in numerous models and in humans. Controlled studies on aged skin demonstrated that it tightens skin, improves elasticity and firmness, reduces fine lines, wrinkles, photodamage and hyperpigmentation. GHK-Cu also improves hair transplant success, protects hepatic tissue from tetrachloromethane poisoning, blocks stomach ulcer development, and heals intestinal ulcers and bone tissue. These results are beginning to define the complex biochemical processes that regulate tissue remodeling. PMID:18644225

  19. Response and adaptation of bone cells to simulated microgravity

    NASA Astrophysics Data System (ADS)

    Hu, Lifang; Li, Runzhi; Su, Peihong; Arfat, Yasir; Zhang, Ge; Shang, Peng; Qian, Airong

    2014-11-01

    Bone loss induced by microgravity during space flight is one of the most deleterious factors on astronaut's health and is mainly attributed to an unbalance in the process of bone remodeling. Studies from the space microgravity have demonstrated that the disruption of bone remodeling is associated with the changes of four main functional bone cells, including osteoblast, osteoclast, osteocyte, and mesenchymal stem cells. For the limited availability, expensive costs and confined experiment conditions for conducting space microgravity studies, the mechanism of bone cells response and adaptation to microgravity is still unclear. Therefore, some ground-based simulated microgravity methods have been developed to investigate the bioeffects of microgravity and the mechanisms. Here, based on our studies and others, we review how bone cells (osteoblasts, osteoclasts, osteocytes and mesenchymal stem cells) respond and adapt to simulated microgravity.

  20. Osteocyte control of bone remodeling: is sclerostin a key molecular coordinator of the balanced bone resorption-formation cycles?

    PubMed

    Sapir-Koren, R; Livshits, G

    2014-12-01

    Osteocytes, entrapped within a newly mineralized bone matrix, possess a unique cellular identity due to a specialized morphology and a molecular signature. These features endow them to serve as a bone response mechanism for mechanical stress in their microenvironment. Sclerostin, a primarily osteocyte product, is widely considered as a mechanotranduction key molecule whose expression is suppressed by mechanical loading, or it is induced by unloading. This review presents a model suggesting that sclerostin is major mediator for integrating mechanical, local, and hormonal signals, sensed by the osteocytes, in controlling the remodeling apparatus. This central role is achieved through interplay between two opposing mechanisms: (1) unloading-induced high sclerostin levels, which antagonize Wnt-canonical-β-catenin signaling in osteocytes and osteoblasts, permitting simultaneously Wnt-noncanonical and/or other pathways in osteocytes and osteoclasts, directed at bone resorption; (2) mechanical loading results in low sclerostin levels, activation of Wnt-canonical signaling, and bone formation. Therefore, adaptive bone remodeling occurring at a distinct bone compartment is orchestrated by altered sclerostin levels, which regulate the expression of the other osteocyte-specific proteins, such as RANKL, OPG, and proteins encoded by "mineralization-related genes" (DMP1, PHEX, and probably FGF23). For example, under specific terms, sclerostin regulates differential RANKL and OPG production, and creates a dynamic RANKL/OPG ratio, leading either to bone formation or resorption. It also controls the expression of PHEX, DMP1, and most likely FGF23, leading to either bone matrix mineralization or its inhibition. Such opposing up- or down-regulation of remodeling phases allows osteocytes to function as an "external unit", ensuring transition from bone resorption to bone formation.Mini Abstract: The osteocyte network plays a central role in directing bone response either to mechanical

  1. A gene-centric study of common carotid artery remodelling

    PubMed Central

    Harrison, Seamus C.; Zabaneh, Delilah; Asselbergs, Folkert W.; Drenos, Fotios; Jones, Gregory T.; Shah, Sonia; Gertow, Karl; Sennblad, Bengt; Strawbridge, Rona J.; Gigante, Bruna; Holewijn, Suzanne; De Graaf, Jacqueline; Vermeulen, Sita; Folkersen, Lasse; van Rij, Andre M.; Baldassarre, Damiano; Veglia, Fabrizio; Talmud, Philippa J.; Deanfield, John E.; Agu, Obi; Kivimaki, Mika; Kumari, Meena; Bown, Matthew J.; Nyyssönen, Kristiina; Rauramaa, Rainer; Smit, Andries J.; Franco-Cereceda, Anders; Giral, Philippe; Mannarino, Elmo; Silveira, Angela; Syvänen, Ann-Christine; de Borst, Gert J.; van der Graaf, Yolanda; de Faire, Ulf; Baas, Annette F.; Blankensteijn, Jan D.; Wareham, Nicholas J.; Fowkes, Gerry; Tzoulaki, Ionna; Price, Jacqueline F.; Tremoli, Elena; Hingorani, Aroon D.; Eriksson, Per; Hamsten, Anders; Humphries, Steve E.

    2013-01-01

    Background Expansive remodelling is the process of compensatory arterial enlargement in response to atherosclerotic stimuli. The genetic determinants of this process are poorly characterized. Methods Genetic association analyses of inter-adventitial common carotid artery diameter (ICCAD) in the IMPROVE study (n = 3427) using the Illumina 200k Metabochip was performed. Single nucleotide polymorphisms (SNPs) that met array-wide significance were taken forward for analysis in three further studies (n = 5704), and tested for association with Abdominal Aortic Aneurysm (AAA). Results rs3768445 on Chromosome 1q24.3, in a cluster of protein coding genes (DNM3, PIGC, C1orf105) was associated with larger ICCAD in the IMPROVE study. For each copy of the rare allele carried, ICCAD was on average 0.13 mm greater (95% CI 0.08–0.18 mm, P = 8.2 × 10−8). A proxy SNP (rs4916251, R2 = 0.99) did not, however, show association with ICCAD in three follow-up studies (P for replication = 0.29). There was evidence of interaction between carotid intima-media thickness (CIMT) and rs4916251 on ICCAD in two of the cohorts studies suggesting that it plays a role in the remodelling response to atherosclerosis. In meta-analysis of 5 case–control studies pooling data from 5007 cases and 43,630 controls, rs4916251 was associated with presence of AAA 1.10, 95% CI 1.03–1.17, p = 2.8 × 10−3, I2 = 18.8, Q = 0.30). A proxy SNP, rs4916251 was also associated with increased expression of PIGC in aortic tissue, suggesting that this may the mechanism by which this locus affects vascular remodelling. Conclusions Common variation at 1q24.3 is associated with expansive vascular remodelling and risk of AAA. These findings support a hypothesis that pathways involved in systemic vascular remodelling play a role in AAA development. PMID:23246012

  2. Central Role of Cellular Senescence in TSLP-Induced Airway Remodeling in Asthma

    PubMed Central

    Wu, Jinxiang; Dong, Fangzheng; Wang, Rui-An; Wang, Junfei; Zhao, Jiping; Yang, Mengmeng; Gong, Wenbin; Cui, Rutao; Dong, Liang

    2013-01-01

    Background Airway remodeling is a repair process that occurs after injury resulting in increased airway hyper-responsiveness in asthma. Thymic stromal lymphopoietin (TSLP), a vital cytokine, plays a critical role in orchestrating, perpetuating and amplifying the inflammatory response in asthma. TSLP is also a critical factor in airway remodeling in asthma. Objectives To examine the role of TSLP-induced cellular senescence in airway remodeling of asthma in vitro and in vivo. Methods Cellular senescence and airway remodeling were examined in lung specimens from patients with asthma using immunohischemical analysis. Both small molecule and shRNA approaches that target the senescent signaling pathways were used to explore the role of cellular senescence in TSLP-induced airway remodeling in vitro. Senescence-Associated β-galactosidase (SA-β-Gal) staining, and BrdU assays were used to detect cellular senescence. In addition, the Stat3-targeted inhibitor, WP1066, was evaluated in an asthma mouse model to determine if inhibiting cellular senescence influences airway remodeling in asthma. Results Activation of cellular senescence as evidenced by checkpoint activation and cell cycle arrest was detected in airway epithelia samples from patients with asthma. Furthermore, TSLP-induced cellular senescence was required for airway remodeling in vitro. In addition, a mouse asthma model indicates that inhibiting cellular senescence blocks airway remodeling and relieves airway resistance. Conclusion TSLP stimulation can induce cellular senescence during airway remodeling in asthma. Inhibiting the signaling pathways of cellular senescence overcomes TSLP-induced airway remodeling. PMID:24167583

  3. Genome-wide nucleosome specificity and function of chromatin remodellers in ES cells.

    PubMed

    de Dieuleveult, Maud; Yen, Kuangyu; Hmitou, Isabelle; Depaux, Arnaud; Boussouar, Fayçal; Bou Dargham, Daria; Jounier, Sylvie; Humbertclaude, Hélène; Ribierre, Florence; Baulard, Céline; Farrell, Nina P; Park, Bongsoo; Keime, Céline; Carrière, Lucie; Berlivet, Soizick; Gut, Marta; Gut, Ivo; Werner, Michel; Deleuze, Jean-François; Olaso, Robert; Aude, Jean-Christophe; Chantalat, Sophie; Pugh, B Franklin; Gérard, Matthieu

    2016-02-01

    ATP-dependent chromatin remodellers allow access to DNA for transcription factors and the general transcription machinery, but whether mammalian chromatin remodellers target specific nucleosomes to regulate transcription is unclear. Here we present genome-wide remodeller-nucleosome interaction profiles for the chromatin remodellers Chd1, Chd2, Chd4, Chd6, Chd8, Chd9, Brg1 and Ep400 in mouse embryonic stem (ES) cells. These remodellers bind one or both full nucleosomes that flank micrococcal nuclease (MNase)-defined nucleosome-free promoter regions (NFRs), where they separate divergent transcription. Surprisingly, large CpG-rich NFRs that extend downstream of annotated transcriptional start sites are nevertheless bound by non-nucleosomal or subnucleosomal histone variants (H3.3 and H2A.Z) and marked by H3K4me3 and H3K27ac modifications. RNA polymerase II therefore navigates hundreds of base pairs of altered chromatin in the sense direction before encountering an MNase-resistant nucleosome at the 3' end of the NFR. Transcriptome analysis after remodeller depletion reveals reciprocal mechanisms of transcriptional regulation by remodellers. Whereas at active genes individual remodellers have either positive or negative roles via altering nucleosome stability, at polycomb-enriched bivalent genes the same remodellers act in an opposite manner. These findings indicate that remodellers target specific nucleosomes at the edge of NFRs, where they regulate ES cell transcriptional programs.

  4. Adaptive Development

    NASA Technical Reports Server (NTRS)

    2005-01-01

    The goal of this research is to develop and demonstrate innovative adaptive seal technologies that can lead to dramatic improvements in engine performance, life, range, and emissions, and enhance operability for next generation gas turbine engines. This work is concentrated on the development of self-adaptive clearance control systems for gas turbine engines. Researchers have targeted the high-pressure turbine (HPT) blade tip seal location for following reasons: Current active clearance control (ACC) systems (e.g., thermal case-cooling schemes) cannot respond to blade tip clearance changes due to mechanical, thermal, and aerodynamic loads. As such they are prone to wear due to the required tight running clearances during operation. Blade tip seal wear (increased clearances) reduces engine efficiency, performance, and service life. Adaptive sealing technology research has inherent impact on all envisioned 21st century propulsion systems (e.g. distributed vectored, hybrid and electric drive propulsion concepts).

  5. Adaptive management

    USGS Publications Warehouse

    Allen, Craig R.; Garmestani, Ahjond S.

    2015-01-01

    Adaptive management is an approach to natural resource management that emphasizes learning through management where knowledge is incomplete, and when, despite inherent uncertainty, managers and policymakers must act. Unlike a traditional trial and error approach, adaptive management has explicit structure, including a careful elucidation of goals, identification of alternative management objectives and hypotheses of causation, and procedures for the collection of data followed by evaluation and reiteration. The process is iterative, and serves to reduce uncertainty, build knowledge and improve management over time in a goal-oriented and structured process.

  6. Computational simulations of hemodynamic changes within thoracic, coronary, and cerebral arteries following early wall remodeling in response to distal aortic coarctation

    PubMed Central

    Coogan, Jessica S.; Humphrey, Jay D.; Figueroa, C. Alberto

    2012-01-01

    Mounting evidence suggests that the pulsatile character of blood pressure and flow within large arteries plays a particularly important role as a mechano-biological stimulus for wall growth and remodeling. Nevertheless, understanding better the highly coupled interactions between evolving wall geometry, structure, and properties and the hemodynamics will require significantly more experimental data. Computational fluid–solid-growth models promise to aid in the design and interpretation of such experiments and to identify candidate mechanobiological mechanisms for the observed arterial adaptations. Motivated by recent aortic coarctation models in animals, we used a computational fluid–solid interaction model to study possible local and systemic effects on the hemodynamics within the thoracic aorta and coronary, carotid, and cerebral arteries due to a distal aortic coarctation and subsequent spatial variations in wall adaptation. In particular, we studied an initial stage of acute cardiac compensation (i.e., maintenance of cardiac output) followed by early arterial wall remodeling (i.e., spatially varying wall thickening and stiffening). Results suggested, for example, that while coarctation increased both the mean and pulse pressure in the proximal vessels, the locations nearest to the coarctation experienced the greatest changes in pulse pressure. In addition, after introducing a spatially varying wall adaptation, pressure, left ventricular work, and wave speed all increased. Finally, vessel wall strain similarly experienced spatial variations consistent with the degree of vascular wall adaptation. PMID:22415052

  7. Radio-Adaptive Responses of Mouse Myocardiocytes

    NASA Technical Reports Server (NTRS)

    Seawright, John W.; Westby, Christian M.

    2011-01-01

    One of the most significant occupational hazards to an astronaut is the frequent exposure to radiation. Commonly associated with increased risk for cancer related morbidity and mortality, radiation is also known to increase the risk for cardiovascular related disorders including: pericarditis, hypertension, and heart failure. It is believed that these radiation-induced disorders are a result of abnormal tissue remodeling. It is unknown whether radiation exposure promotes remodeling through fibrotic changes alone or in combination with programmed cell death. Furthermore, it is not known whether it is possible to mitigate the hazardous effects of radiation exposure. As such, we assessed the expression and mechanisms of radiation-induced tissue remodeling and potential radio-adaptive responses of p53-mediated apoptosis and fibrosis pathways along with markers for oxidative stress and inflammation in mice myocardium. 7 week old, male, C57Bl/6 mice were exposed to 6Gy (H) or 5cGy followed 24hr later with 6Gy (LH) Cs-137 gamma radiation. Mice were sacrificed and their hearts extirpated 4, 24, or 72hr after final irradiation. Real Time - Polymerase Chain Reaction was used to evaluate target genes. Pro-apoptotic genes Bad and Bax, pro-cell survival genes Bcl2 and Bcl2l2, fibrosis gene Vegfa, and oxidative stress genes Sod2 and GPx4 showed a reduced fold regulation change (Bad,-6.18; Bax,-6.94; Bcl2,-5.09; Bcl2l2,-4.03; Vegfa, -11.84; Sod2,-5.97; GPx4*,-28.72; * = Bonferroni adjusted p-value . 0.003) 4hr after H, but not after 4hr LH when compared to control. Other p53-mediated apoptosis genes Casp3, Casp9, Trp53, and Myc exhibited down-regulation but did not achieve a notable level of significance 4hr after H. 24hr after H, genetic down-regulation was no longer present compared to 24hr control. These data suggest a general reduction in genetic expression 4hrs after a high dose of gamma radiation. However, pre-exposure to 5cGy gamma radiation appears to facilitate a radio-adaptive

  8. Adaptive Thresholds

    SciTech Connect

    Bremer, P. -T.

    2014-08-26

    ADAPT is a topological analysis code that allow to compute local threshold, in particular relevance based thresholds for features defined in scalar fields. The initial target application is vortex detection but the software is more generally applicable to all threshold based feature definitions.

  9. Soft skills turned into hard facts: nucleosome remodelling at developmental switches.

    PubMed

    Chioda, M; Becker, P B

    2010-07-01

    Nucleosome remodelling factors are regulators of DNA accessibility in chromatin and lubricators of all major functions of eukaryotic genomes. Their action is transient and reversible, yet can be decisive for irreversible cell-fate decisions during development. In addition to the well-known local actions of nucleosome remodelling factors during transcription initiation, more global and fundamental roles for remodelling complexes in shaping the epigenome during development are emerging.

  10. Soft skills turned into hard facts: nucleosome remodelling at developmental switches.

    PubMed

    Chioda, M; Becker, P B

    2010-07-01

    Nucleosome remodelling factors are regulators of DNA accessibility in chromatin and lubricators of all major functions of eukaryotic genomes. Their action is transient and reversible, yet can be decisive for irreversible cell-fate decisions during development. In addition to the well-known local actions of nucleosome remodelling factors during transcription initiation, more global and fundamental roles for remodelling complexes in shaping the epigenome during development are emerging. PMID:20372184

  11. Detection of postischemic regional left ventricular delayed outward wall motion or diastolic stunning after exercise-induced ischemia in patients with stable effort angina by using color kinesis.

    PubMed

    Ishii, Katsuhisa; Miwa, Kunihisa; Sakurai, Takahiro; Kataoka, Kazuaki; Imai, Makoto; Kintaka, Aya; Aoyama, Takeshi; Kawanami, Masaki

    2008-04-01

    To determine whether postischemic diastolic stunning could be detected using color kinesis, we evaluated regional left ventricular (LV) diastolic wall motion in 36 patients with stable effort angina and a coronary stenosis (> or = 70% of luminal diameter), and in 30 control subjects. Regional LV filling fraction in the short-axis view during the first 30% of the LV filling time (color kinesis diastolic index) was determined before, 20 minutes, 1 hour, and 24 hours after the treadmill exercise test. In 33 of the 36 patients (92%), new regional LV delayed outward motion during early diastole (color kinesis diastolic index < or = 40%) was detected at 20 minutes after exercise. The regional LV delayed diastolic wall motion showed significant improvement but persisted 1 hour afterward in 20 of 36 patients (56%), and disappeared 24 hours after exercise. Detection of regional stunned myocardium with impaired diastolic function may be a useful tool for the diagnosis of coronary artery disease.

  12. Extracellular Ubiquitin: Role in Myocyte Apoptosis and Myocardial Remodeling.

    PubMed

    Scofield, Stephanie L C; Amin, Parthiv; Singh, Mahipal; Singh, Krishna

    2015-01-01

    Ubiquitin (UB) is a highly conserved low molecular weight (8.5 kDa) protein. It consists of 76 amino acid residues and is found in all eukaryotic cells. The covalent linkage of UB to a variety of cellular proteins (ubiquitination) is one of the most common posttranslational modifications in eukaryotic cells. This modification generally regulates protein turnover and protects the cells from damaged or misfolded proteins. The polyubiquitination of proteins serves as a signal for degradation via the 26S proteasome pathway. UB is present in trace amounts in body fluids. Elevated levels of UB are described in the serum or plasma of patients under a variety of conditions. Extracellular UB is proposed to have pleiotropic roles including regulation of immune response, anti-inflammatory, and neuroprotective activities. CXCR4 is identified as receptor for extracellular UB in hematopoietic cells. Heart failure represents a major cause of morbidity and mortality in western society. Cardiac remodeling is a determinant of the clinical course of heart failure. The components involved in myocardial remodeling include-myocytes, fibroblasts, interstitium, and coronary vasculature. Increased sympathetic nerve activity in the form of norepinephrine is a common feature during heart failure. Acting via β-adrenergic receptor (β-AR), norepinephrine is shown to induce myocyte apoptosis and myocardial fibrosis. β-AR stimulation increases extracellular levels of UB in myocytes, and UB inhibits β-AR-stimulated increases in myocyte apoptosis and myocardial fibrosis. This review summarizes intracellular and extracellular functions of UB with particular emphasis on the role of extracellular UB in cardiac myocyte apoptosis and myocardial remodeling. PMID:26756642

  13. [Effects of aldosterone receptor blocker therapy on cardiac remodeling].

    PubMed

    Boccanelli, A; Battagliese, A

    2006-01-01

    Cardiac remodeling is a physiologic or pathologic condition that occurs after myocardial infarction, pressure overload, myocardial inflammatory diseases, idiopathic dilated cardiomyopathy or volume overload. In spite of different etiologies, molecular, biochemical and mechanical processes are the same. The change in left ventricular function brings about a complex neuro-hormonal disorder, and disease progression is due to the combined action of several biological factors with toxic effects on the heart and vessels. The renin-angiotensin-aldosterone system (RAAS) is very important in this process, through the effects on hydro-saline balance or through direct processes on myocardium. A direct effect of aldosterone in myocardial fibrosis after the detection of heart tissue aldosterone production has been demonstrated. In the past, the attention of physicians and researchers was focused on angiotensin II inhibition; and therefore, on angiotensin-converting enzyme (ACE) inhibitors, considering them sufficient to antagonize the effects of aldosterone. Nevertheless, this theory has been confuted in recent studies, with the evidence of elevated plasmatic aldosterone levels in patients treated with ACE-inhibitors and angiotensin receptor blockers. This phenomenon probably is due to the activation of secondary ACTH mediated pathways of trial aldosterone production. It has been demonstrated that aldosterone receptor inhibition is effective in reducing cardiac remodeling and mortality. AREA-IN CHF is the first multicentric, double blind, randomized, placebo control study to compare canrenone, an aldosterone receptor blocker, with placebo. The primary end point is the echocardiographic evaluation of left ventricular remodeling. Secondary end points are left ventricular end-systolic volume, ejection fraction, diastolic filling patterns, NYHA functional class, and mortality and hospitalizations of cardiac origin. In addition, bio-humoral effects of aldosterone receptor blocker

  14. Monocyte interaction accelerates HCl-induced lung epithelial remodeling

    PubMed Central

    2014-01-01

    Background Acute respiratory distress syndrome (ARDS) is characterized by overwhelming inflammatory responses and lung remodeling. We hypothesized that leukocyte infiltration during the inflammatory response modulates epithelial remodeling through a mechanism of epithelial-mesenchymal transition (EMT). Methods Human lung epithelial cells were treated for 30 min with hydrochloric acid (HCl). Human monocytes were then cocultured with the epithelial cells for up to 48 h, in the presence or absence of blocking peptides against lymphocyte function-associated antigen-1 (LFA-1), or tyrphostin A9, a specific inhibitor for platelet-derived growth factor (PDGF) receptor tyrosine kinase. Results Exposure of lung epithelial cells to HCl resulted in increased expression of intercellular adhesion molecule-1 (ICAM-1) and production of interleukin (IL)-8 at 24 h. The expression of the epithelial markers E-cadherin decreased while the mesenchymal markers vimentin and α-smooth muscle actin (α-SMA) increased at 24 h and remained high at 48 h. The addition of monocytes augmented the profiles of lower expression of epithelial markers and higher mesenchymal markers accompanied by increased collagen deposition. This EMT profile was associated with an enhanced production of IL-8 and PDGF. Treatment of the lung epithelial cells with the LAF-1 blocking peptides CD11a237–246 or/and CD18112–122 suppressed monocyte adhesion, production of IL-8, PDGF and hydroxyproline as well as EMT markers. Treatment with tyrphostin A9 prevented the EMT profile shift induced by HCl stimulation. Conclusions The interaction between epithelial cells and monocytes enhanced epithelial remodelling after initial injury through EMT signalling that is associated with the release of soluble mediators, including IL-8 and PDGF. PMID:25108547

  15. Oleanolic acid alleviated pressure overload-induced cardiac remodeling.

    PubMed

    Liao, Hai-Han; Zhang, Nan; Feng, Hong; Zhang, Ning; Ma, Zhen-Guo; Yang, Zheng; Yuan, Yuan; Bian, Zhou-Yan; Tang, Qi-Zhu

    2015-11-01

    Previous study has demonstrated that oleanolic acid (OA) possessing the anti-inflammatory and anti-oxidant properties blunted high-glucose-induced diabetic cardiomyopathy and ameliorated experimental autoimmune myocarditis in mice. However, little is known about its effects on pressure overload-induced cardiac remodeling. Herein, we investigated the effect of OA on cardiac remodeling and underlying mechanism. Mice, subjected to aortic banding (AB), were randomly assigned into control group and experimental group. OA premixed in diets was administered to mice after 3 days of AB. Echocardiography and catheter-based measurements of hemodynamic parameters were performed after 8 weeks' treatment of OA. Histologic examination and molecular analyses were used to assess cardiac hypertrophy and tissue fibrosis. In addition, the inhibitory effects of OA on H9c2 cardiomyocytes and cardiac primary fibroblast responded to the stimulation of AngII were also investigated. OA ameliorated the systolic and diastolic dysfunction induced by pressure overload evidenced by echocardiography and catheter-based measurements. OA also decreased the mRNA expression of cardiac hypertrophy and fibrosis markers evidenced by RT-PCR. It has been shown in our study that pressure overload activated the phosphorylations of Akt, mTOR, p70s6k, S6, GSK3β, and FoxO3a, and treatment of OA attenuated the phosphorylation of these proteins. In addition, hypertrophy of cardiomyocytes and fibrosis markers induced by AngII was inhibited by OA in vitro. Our findings uncover that OA suppressed AB-induced cardiac hypertrophy, partly by inhibiting the activity of Akt/mTOR pathway, and suggest that treatment of OA may have a benefit on retarding the progress of cardiac remodeling under long terms of pressure overload. PMID:26215454

  16. Galectin-3 Participates in Cardiovascular Remodeling Associated With Obesity.

    PubMed

    Martínez-Martínez, Ernesto; López-Ándres, Natalia; Jurado-López, Raquel; Rousseau, Elodie; Bartolomé, Mará Visitación; Fernández-Celis, Amaya; Rossignol, Patrick; Islas, Fabian; Antequera, Alfonso; Prieto, Santiago; Luaces, María; Cachofeiro, Victoria

    2015-11-01

    Remodeling, diastolic dysfunction, and arterial stiffness are some of the alterations through which obesity affects the cardiovascular system. Fibrosis and inflammation are important mechanisms underlying cardiovascular remodeling, although the precise promoters involved in these processes are still unclear. Galectin-3 (Gal-3) induces inflammation and fibrosis in the cardiovascular system. We have investigated the potential role of Gal-3 in cardiac damage in morbidly obese patients, and we have evaluated the protective effect of the Gal-3 inhibition in the occurrence of cardiovascular fibrosis and inflammation in an experimental model of obesity. Morbid obesity is associated with alterations in cardiac remodeling, mainly left ventricular hypertrophy and diastolic dysfunction. Obesity and hypertension are the main determinants of left ventricular hypertrophy. Insulin resistance, left ventricular hypertrophy, and circulating levels of C-reactive protein and Gal-3 are associated with a worsening of diastolic function in morbidly obese patients. Obesity upregulates Gal-3 production in the cardiovascular system in a normotensive animal model of diet-induced obesity by feeding for 6 weeks a high-fat diet (33.5% fat). Gal-3 inhibition with modified citrus pectin (100 mg/kg per day) reduced cardiovascular levels of Gal-3, total collagen, collagen I, transforming and connective growth factors, osteopontin, and monocyte chemoattractant protein-1 in the heart and aorta of obese animals without changes in body weight or blood pressure. In morbidly obese patients, Gal-3 levels are associated with diastolic dysfunction. In obese animals, Gal-3 blockade decreases cardiovascular fibrosis and inflammation. These data suggest that Gal-3 could be a novel therapeutic target in cardiac fibrosis and inflammation associated with obesity.

  17. Reversibility of Adverse, Calcineurin-Dependent Cardiac Remodeling

    PubMed Central

    Berry, Jeff M.; Le, Vien; Rotter, David; Battiprolu, Pavan K.; Grinsfelder, Bennett; Tannous, Paul; Burchfield, Jana S.; Czubryt, Michael; Backs, Johannes; Olson, Eric N.; Rothermel, Beverly A.; Hill, Joseph A.

    2011-01-01

    Background Studies to dissect the role of calcineurin in pathological cardiac remodeling have relied heavily on murine models, where genetic gain- and loss-of-function manipulations are initiated at or before birth. However, the great majority of clinical cardiac pathology occurs in adults. Yet, nothing is known about the effects of calcineurin when its activation commences in adulthood. Further, despite the fact that ventricular hypertrophy is a well established risk factor for heart failure, the relative pace and progression of these two major phenotypic features of heart disease are unknown. Methods and Results We engineered mice harboring in cardiomyocytes a constitutively active calcineurin transgene driven by a tetracycline-responsive promoter element. Expression of the mutant calcineurin transgene was initiated for variable lengths of time to determine the natural history of disease pathogenesis, and to determine when, if ever, these events are reversible. Activation of the calcineurin transgene in adult mice triggered rapid and robust cardiac growth with features characteristic of pathological hypertrophy. Concentric hypertrophy preceded the development of systolic dysfunction, fetal gene activation, fibrosis, and clinical heart failure. Further, cardiac hypertrophy reversed spontaneously when calcineurin activity was turned off, and expression of fetal genes reverted to baseline. Fibrosis, a prominent feature of pathological cardiac remodeling, manifested partial reversibility. Conclusions Together, these data establish and define the deleterious effects of calcineurin signaling in adult heart and reveal that calcineurin-dependent hypertrophy with concentric geometry precedes systolic dysfunction and heart failure. Furthermore, these findings demonstrate that during much of the disease process, calcineurin-dependent remodeling remains reversible. PMID:21700928

  18. Benign prostatic hyperplasia: age-related tissue-remodeling.

    PubMed

    Untergasser, Gerold; Madersbacher, Stephan; Berger, Peter

    2005-03-01

    Aging and androgens are the two established risk factors for the development of benign prostatic hyperplasia (BPH) and benign prostatic enlargement (BPE), which can lead to lower urinary tract symptoms (LUTS) in elderly men. BPH, consisting of a nodular overgrowth of the epithelium and fibromuscular tissue within transition zone and periurethral areas, is first detectable around the fourth decade of life and affects nearly all men by the ninth decade. The pathogenesis of BPH is still largely unresolved, but multiple partially overlapping and complementary theories have been proposed, all of which seem to be operative at least to some extent. In addition to nerve-, endocrine- and immune system, local para- and luminocrine pleiotrope mechanisms/factors are implicated in the prostatic tissue-remodeling process. Prostate tissue-remodeling in the transition zone is characterized by: (i) hypertrophic basal cells, (ii) altered secretions of luminal cells leading to calcification, clogged ducts and inflammation, (iii) lymphocytic infiltration with production of proinflammatory cytokines, (iv) increased radical oxygen species (ROS) production that damages epithelial and stromal cells, (v) increased basic fibroblast (bFGF) and transforming growth factor beta (TGF-beta 1) production leading to stromal proliferation, transdifferentiation and extracellular matrix production, (vi) altered autonomous innervation that decreases relaxation and leads to a high adrenergic tonus, (vii) and altered neuroendocine cell function and release of neuroendocrine peptides (NEP). This review summarizes the multifactorial nature of prostate tissue remodeling in elderly men with symptomatic BPH with a particular focus on changes of cell-cell interactions and cell functions in the human aging prostate.

  19. Systemic and Pulmonary Vascular Remodelling in Chronic Obstructive Pulmonary Disease

    PubMed Central

    Muñoz-Esquerre, Mariana; López-Sánchez, Marta; Escobar, Ignacio; Huertas, Daniel; Penín, Rosa; Molina-Molina, María; Manresa, Frederic; Dorca, Jordi; Santos, Salud

    2016-01-01

    Background Chronic Obstructive Pulmonary Disease (COPD) is associated with subclinical systemic atherosclerosis and pulmonary vascular remodelling characterized by intimal hyperplasia and luminal narrowing. We aimed to determine differences in the intimal thickening of systemic and pulmonary arteries in COPD subjects and smokers. Secondary aims include comparisons with a non-smokers group; determining the clinical variables associated with systemic and pulmonary intimal thickening, and the correlations between systemic and pulmonary remodelling changes. Methods All consecutive subjects undergoing lung resection were included and divided into 3 groups: 1) COPD, 2) smokers, and 3) non-smokers. Sections of the 5th intercostal artery and muscular pulmonary arteries were measured by histo-morphometry. Four parameters of intimal thickening were evaluated: 1) percentage of intimal area (%IA), 2) percentage of luminal narrowing, 3) intimal thickness index, and 4) intima-to-media ratio. Results In the adjusted analysis, the systemic arteries of COPD subjects showed greater intimal thickening (%IA) than those of smokers (15.6±1.5% vs. 14.2±1.6%, p = 0.038). In the pulmonary arteries, significant differences were observed for %IA between the 2 groups (37.3±2.2% vs. 29.3±2.3%, p = 0.016). Among clinical factors, metabolic syndrome, gender and COPD status were associated with the systemic intimal thickening, while only COPD status was associated with pulmonary intimal thickening. A correlation between the %IA of the systemic and pulmonary arteries was observed (Spearman’s rho = 0.46, p = 0.008). Conclusions Greater intimal thickening in systemic and pulmonary arteries is observed in COPD patients than in smokers. There is a correlation between systemic and pulmonary vascular remodelling in the overall population. PMID:27046203

  20. Hypothyroidism and Its Rapid Correction Alter Cardiac Remodeling

    PubMed Central

    Itani, Tarek; Moubarak, Majed; Aftimos, Georges; Farès, Nassim

    2014-01-01

    The cardiovascular effects of mild and overt thyroid disease include a vast array of pathological changes. As well, thyroid replacement therapy has been suggested for preserving cardiac function. However, the influence of thyroid hormones on cardiac remodeling has not been thoroughly investigated at the molecular and cellular levels. The purpose of this paper is to study the effect of hypothyroidism and thyroid replacement therapy on cardiac alterations. Thirty Wistar rats were divided into 2 groups: a control (n = 10) group and a group treated with 6-propyl-2-thiouracil (PTU) (n = 20) to induce hypothyroidism. Ten of the 20 rats in the PTU group were then treated with L-thyroxine to quickly re-establish euthyroidism. The serum levels of inflammatory markers, such as C-reactive protein (CRP), tumor necrosis factor alpha (TNF-α), interleukin 6 (IL6) and pro-fibrotic transforming growth factor beta 1 (TGF-β1), were significantly increased in hypothyroid rats; elevations in cardiac stress markers, brain natriuretic peptide (BNP) and cardiac troponin T (cTnT) were also noted. The expressions of cardiac remodeling genes were induced in hypothyroid rats in parallel with the development of fibrosis, and a decline in cardiac function with chamber dilation was measured by echocardiography. Rapidly reversing the hypothyroidism and restoring the euthyroid state improved cardiac function with a decrease in the levels of cardiac remodeling markers. However, this change further increased the levels of inflammatory and fibrotic markers in the plasma and heart and led to myocardial cellular infiltration. In conclusion, we showed that hypothyroidism is related to cardiac function decline, fibrosis and inflammation; most importantly, the rapid correction of hypothyroidism led to cardiac injuries. Our results might offer new insights for the management of hypothyroidism-induced heart disease. PMID:25333636

  1. VEGF receptors mediate hypoxic remodeling of adult ovine carotid arteries.

    PubMed

    Adeoye, Olayemi O; Bouthors, Vincent; Hubbell, Margaret C; Williams, James M; Pearce, William J

    2014-10-01

    Recent studies suggest that VEGF contributes to hypoxic remodeling of arterial smooth muscle, although hypoxia produces only transient increases in VEGF that return to normoxic levels despite sustained changes in arterial structure and function. To explore how VEGF might contribute to long-term hypoxic vascular remodeling, this study explores the hypothesis that chronic hypoxia produces sustained increases in smooth muscle VEGF receptor density that mediate long-term vascular effects of hypoxia. Carotid arteries from adult sheep maintained at sea level or altitude (3,820 m) for 110 days were harvested and denuded of endothelium. VEGF levels were similar in chronically hypoxic and normoxic arteries, as determined by immunoblotting. In contrast, VEGF receptor levels were significantly increased by 107% (VEGF-R1) and 156% (VEGF-R2) in hypoxic compared with normoxic arteries. In arteries that were organ cultured 24 h with 3 nM VEGF, VEGF replicated effects of hypoxia on abundances of smooth muscle α actin (SMαA), myosin light chain kinase (MLCK), and MLC20 and the effects of hypoxia on colocalization of MLC20 with SMαA, as measured via confocal microscopy. VEGF did not replicate the effects of chronic hypoxia on colocalization of MLCK with SMαA or MLCK with MLC20, suggesting that VEGF's role in hypoxic remodeling is highly protein specific, particularly for contractile protein organization. VEGF effects in organ culture were inhibited by VEGF receptor blockers vatalinib (240 nM) and dasatinib (6.3 nM). These findings support the hypothesis that long-term upregulation of VEGF receptors help mediate sustained effects of hypoxia on the abundance and colocalization of contractile proteins in arterial smooth muscle. PMID:25038104

  2. Maladaptive dendritic spine remodeling contributes to diabetic neuropathic pain.

    PubMed

    Tan, Andrew M; Samad, Omar A; Fischer, Tanya Z; Zhao, Peng; Persson, Anna-Karin; Waxman, Stephen G

    2012-05-16

    Diabetic neuropathic pain imposes a huge burden on individuals and society, and represents a major public health problem. Despite aggressive efforts, diabetic neuropathic pain is generally refractory to available clinical treatments. A structure-function link between maladaptive dendritic spine plasticity and pain has been demonstrated previously in CNS and PNS injury models of neuropathic pain. Here, we reasoned that if dendritic spine remodeling contributes to diabetic neuropathic pain, then (1) the presence of malformed spines should coincide with the development of pain, and (2) disrupting maladaptive spine structure should reduce chronic pain. To determine whether dendritic spine remodeling contributes to neuropathic pain in streptozotocin (STZ)-induced diabetic rats, we analyzed dendritic spine morphology and electrophysiological and behavioral signs of neuropathic pain. Our results show changes in dendritic spine shape, distribution, and shape on wide-dynamic-range (WDR) neurons within lamina IV-V of the dorsal horn in diabetes. These diabetes-induced changes were accompanied by WDR neuron hyperexcitability and decreased pain thresholds at 4 weeks. Treatment with NSC23766 (N(6)-[2-[[4-(diethylamino)-1-methylbutyl]amino]-6-methyl-4-pyrimidinyl]-2-methyl-4,6-quinolinediamine trihydrochloride), a Rac1-specific inhibitor known to interfere with spine plasticity, decreased the presence of malformed spines in diabetes, attenuated neuronal hyperresponsiveness to peripheral stimuli, reduced spontaneous firing activity from WDR neurons, and improved nociceptive mechanical pain thresholds. At 1 week after STZ injection, animals with hyperglycemia with no evidence of pain had few or no changes in spine morphology. These results demonstrate that diabetes-induced maladaptive dendritic spine remodeling has a mechanistic role in neuropathic pain. Molecular pathways that control spine morphogenesis and plasticity may be promising future targets for treatment.

  3. Genome-wide nucleosome specificity and function of chromatin remodellers in ES cells

    PubMed Central

    de Dieuleveult, Maud; Yen, Kuangyu; Hmitou, Isabelle; Depaux, Arnaud; Boussouar, Fayçal; Dargham, Daria Bou; Jounier, Sylvie; Humbertclaude, Hélène; Ribierre, Florence; Baulard, Céline; Farrell, Nina P.; Park, Bongsoo; Keime, Céline; Carrière, Lucie; Berlivet, Soizick; Gut, Marta; Gut, Ivo; Werner, Michel; Deleuze, Jean-François; Olaso, Robert; Aude, Jean-Christophe; Chantalat, Sophie; Pugh, B. Franklin; Gérard, Matthieu

    2015-01-01

    Summary ATP-dependent chromatin remodellers allow access to DNA for transcription factors and the general transcription machinery, but whether mammalian chromatin remodellers1–3 target specific nucleosomes to regulate transcription is unclear. Here, we present genome-wide remodeller-nucleosome interaction profiles for Chd1, Chd2, Chd4, Chd6, Chd8, Chd9, Brg1 and Ep400 in mouse embryonic stem (ES) cells. These remodellers bind one or both full nucleosomes that flank MNase-defined nucleosome-free promoter regions (NFRs), where they separate divergent transcription. Surprisingly, large CpG-rich NFRs that extend downstream of annotated transcriptional start sites (TSSs) are nevertheless chromatinized with non-nucleosomal or subnucleosomal histone variants (H3.3 and H2A.Z) and modifications (H3K4me3 and H3K27ac). RNA polymerase (pol) II therefore navigates hundreds of bp of altered chromatin in the sense direction before encountering an MNase-resistant nucleosome at the 3′ end of the NFR. Transcriptome analysis upon remodeller depletion reveals reciprocal mechanisms of transcriptional regulation by remodellers. Whereas at active genes individual remodellers play either positive or negative roles via altering nucleosome stability, at polycomb-enriched bivalent genes the same remodellers act in an opposite manner. These findings indicate that remodellers target specific nucleosomes at the edge of NFRs, where they regulate ES cell transcriptional programs. PMID:26814966

  4. Integrated remodeling-to-fracture finite element model of human proximal femur behavior.

    PubMed

    Hambli, Ridha; Lespessailles, Eric; Benhamou, Claude-Laurent

    2013-01-01

    The purpose of this work was to develop an integrated remodeling-to-fracture finite element model allowing for the combined simulation of (i) simulation of a human proximal femur remodeling under a given boundary conditions, (ii) followed by the simulation of its fracture behavior (force-displacement curve and fracture pattern) under quasi-static load. The combination of remodeling and fracture simulation into one unified model consists in considering that the femur properties resulting from the remodeling simulation correspond to the initial state for the fracture prediction. The remodeling model is based on phenomenological one based on a coupled strain and fatigue damage stimulus. The fracture model is based on continuum damage mechanics in order to predict the progressive fracturing process which allows to predict the fracture pattern and the complete force-displacement curve under quasi-static load. To prevent mesh-dependence that generally affects the damage propagation rate, regularization technique was applied in the current work. To investigate the potential of the proposed unified remodeling-to-fracture model, we performed remodeling simulations on a 3D proximal femur model for a duration of 365 days under five different daily loading conditions followed by a side fall fracture simulation reproducing previously published experimental tests (de Bakker et al. (2009), case C, male, 72 years old). We show here that the implementation of an integrated remodeling-to-fracture model provides more realistic prediction strategy to assess the bone remodeling effects on the fracture risk of bone.

  5. Airway and lung remodelling in chronic pulmonary obstructive disease: a role for muscarinic receptor antagonists?

    PubMed

    Roth, Michael

    2015-01-01

    Lung tissue remodelling in chronic inflammatory lung diseases has long been regarded as a follow-up event to inflammation. Recent studies have indicated that, although airway and lung tissue remodelling is often independent of inflammation, it precedes or causes inflammation. None of the available therapies has a significant effect on airway and lung tissue remodelling in asthma, bronchiectasis, fibrosis and chronic obstructive pulmonary disease (COPD). The goal of stopping or reversing lung tissue remodelling is difficult, as the term summarizes the net effect of independent events, including (1) cell proliferation, (2) cell volume increase, (3) cell migration, (4) modified deposition and metabolism of specific extracellular matrix components, and (5) local action of infiltrated inflammatory cells. The extracellular matrix of the lung has a very high turnover, and thus small changes may accumulate to significant structural pathologies, which seem to be irreversible. The most important question is 'why are pathological changes of the lung structure irreversible and resistant to drugs?' Many drugs have the potential to reduce remodelling mechanisms in vitro but fail in clinical trials. New evidence suggests that muscarinic receptor inhibitors have the potential to improve lung function through modifying tissue remodelling. However, the role of muscarinic receptors in lung remodelling, especially their supportive role for other remodelling driving factors, needs to be further investigated. The focus of this review is the role of muscarinic receptors in lung tissue remodelling as it has been reported in the human lung.

  6. Functional Insights into Chromatin Remodelling from Studies on CHARGE Syndrome

    PubMed Central

    Basson, M. Albert; van Ravenswaaij-Arts, Conny

    2015-01-01

    CHARGE syndrome is a rare genetic syndrome characterised by a unique combination of multiple organ anomalies. Dominant loss-of-function mutations in the gene encoding chromodomain helicase DNA binding protein 7 (CHD7), which is an ATP-dependent chromatin remodeller, have been identified as the cause of CHARGE syndrome. Here, we review recent work aimed at understanding the mechanism of CHD7 function in normal and pathological states, highlighting results from biochemical and in vivo studies. The emerging picture from this work suggests that the mechanisms by which CHD7 fine-tunes gene expression are context specific, consistent with the pleiotropic nature of CHARGE syndrome. PMID:26411921

  7. Expression of RANKL/OPG during bone remodeling in vivo

    SciTech Connect

    Tanaka, H.; Mine, T.; Ogasa, H.; Taguchi, T.; Liang, C.T.

    2011-08-12

    Highlights: {yields} This is the first study to determine the relationship between osteogenic differentiation and RANKL/OPG expression during bone remodeling in vivo. {yields} The OPG expression peak occurred during the bone formation phase, whereas the marked elevation of RANKL expression was observed during the bone resorption phase. {yields} Histological analysis showed that RANKL/OPG immunoreactivity was predominantly associated with bone marrow cells in the marrow cavity. {yields} The present study confirmed that RANKL/OPG are key factors linking bone formation to resorption during the bone remodeling process. -- Abstract: The interaction between receptor activator of nuclear factor {kappa}B ligand (RANKL) and osteoprotegerin (OPG) plays a dominant role in osteoclastogenesis. As both proteins are produced by osteoblast lineage cells, they are considered to represent a key link between bone formation and resorption. In this study, we investigated the expression of RANKL and OPG during bone remodeling in vivo to determine the relationship between osteoclastogenic stimulation and osteoblastic differentiation. Total RNA was prepared from rat femurs after marrow ablation on days 0, 3, 6, and 9. The temporal activation patterns of osteoblast-related genes (procollagen {alpha}1 (I), alkaline phosphatase, osteopontin, and osteocalcin) were examined by Northern blot analysis. An appreciable increase in the expression of these osteoblast markers was observed on day 3. The peak increase in gene expression was observed on day 6 followed by a slight reduction by day 9. Real-time PCR analysis showed that the OPG mRNA expression was markedly upregulated on day 6 and slightly decreased on day 9. In contrast, RANKL mRNA expression was increased by more than 20-fold on day 9. The RANKL/OPG ratio, an index of osteoclastogenic stimulation, peaked on day 9. Histological analysis showed that RANKL and OPG immunoreactivity were predominantly associated with bone marrow cells. The

  8. Optimization of a Cemented Femoral Prosthesis Considering Bone Remodeling.

    PubMed

    Corso, Leandro Luis; Spinelli, Leandro de Freitas; Schnaid, Fernando; Zanrosso, Crisley Dossin; Marczak, Rogério José

    2016-01-01

    The study presents a numerical methodology for minimizing the bone loss in human femur submitted to total hip replacement (THR) procedure with focus on cemented femoral stem. Three-dimensional computational models were used to describe the femoral bone behavior. An optimization procedure using the genetic algorithm (GA) method was applied in order to minimize the bone loss, considering the geometry and the material of the prosthesis as well as the design of the stem. Internal and external bone remodeling were analyzed numerically. The numerical method proposed here showed that the bone mass loss could be reduced by 24%, changing the design parameters. PMID:26540616

  9. Mechanoelectrical remodeling and arrhythmias during progression of hypertrophy

    PubMed Central

    Jin, Hongwei; Chemaly, Elie R.; Lee, Ahyoung; Kho, Changwon; Hadri, Lahouaria; Hajjar, Roger J.; Akar, Fadi G.

    2010-01-01

    Despite a clear association between left ventricular (LV) mechanical dysfunction in end-stage heart failure and the incidence of arrhythmias, the majority of sudden cardiac deaths occur at earlier stages of disease development. The mechanisms by which structural, mechanical, and molecular alterations predispose to arrhythmias at the tissue level before the onset of LV dysfunction remain unclear. In a rat model of pressure overload hypertrophy (PoH) produced by ascending aortic banding, we correlated mechanical and structural changes measured in vivo with key electrophysiological changes measured ex vivo in the same animals. We found that action potential prolongation, a hallmark of electrical remodeling at the tissue level, is highly correlated with changes in LV wall thickness but not mechanical function. In contrast, conduction delays are not predicted by either mechanical or structural changes during disease development. Moreover, disrupted Cx43 phosphorylation at intermediate (increased) and late (decreased) stages of PoH are associated with moderate and severe conduction delays, respectively. Interestingly, the level of interaction between Cx43 and the cytoskeletal protein ZO-1 is exclusively decreased at the late stage of PoH. Closely coupled action potentials consistent with afterdepolarization-mediated triggered beats were readily observed in 6 of 15 PoH hearts but never in controls. Similarly, PoH (8/15) but not control hearts exhibited sustained episodes of ventricular tachycardia after rapid stimulation. The initiation and early maintenance of arrhythmias in PoH were formed by rapid and highly uniform activation wavefronts emanating from sites distal to the former site of stimulation. In conclusion, repolarization but not conduction delays are predicted by structural remodeling in PoH. Cx43 phosphorylation is disrupted at intermediate (increased) and late (decreased) stages, which are associated with conduction delays. Dephosphorylation of Cx43 is

  10. Functional Insights into Chromatin Remodelling from Studies on CHARGE Syndrome.

    PubMed

    Basson, M Albert; van Ravenswaaij-Arts, Conny

    2015-10-01

    CHARGE syndrome is a rare genetic syndrome characterised by a unique combination of multiple organ anomalies. Dominant loss-of-function mutations in the gene encoding chromodomain helicase DNA binding protein 7 (CHD7), which is an ATP-dependent chromatin remodeller, have been identified as the cause of CHARGE syndrome. Here, we review recent work aimed at understanding the mechanism of CHD7 function in normal and pathological states, highlighting results from biochemical and in vivo studies. The emerging picture from this work suggests that the mechanisms by which CHD7 fine-tunes gene expression are context specific, consistent with the pleiotropic nature of CHARGE syndrome. PMID:26411921

  11. Altered thermogenesis and impaired bone remodeling in Misty mice.

    PubMed

    Motyl, Katherine J; Bishop, Kathleen A; DeMambro, Victoria E; Bornstein, Sheila A; Le, Phuong; Kawai, Masanobu; Lotinun, Sutada; Horowitz, Mark C; Baron, Roland; Bouxsein, Mary L; Rosen, Clifford J

    2013-09-01

    Fat mass may be modulated by the number of brown-like adipocytes in white adipose tissue (WAT) in humans and rodents. Bone remodeling is dependent on systemic energy metabolism and, with age, bone remodeling becomes uncoupled and brown adipose tissue (BAT) function declines. To test the interaction between BAT and bone, we employed Misty (m/m) mice, which were reported be deficient in BAT. We found that Misty mice have accelerated age-related trabecular bone loss and impaired brown fat function (including reduced temperature, lower expression of Pgc1a, and less sympathetic innervation compared to wild-type (+/ +)). Despite reduced BAT function, Misty mice had normal core body temperature, suggesting heat is produced from other sources. Indeed, upon acute cold exposure (4°C for 6 hours), inguinal WAT from Misty mice compensated for BAT dysfunction by increasing expression of Acadl, Pgc1a, Dio2, and other thermogenic genes. Interestingly, acute cold exposure also decreased Runx2 and increased Rankl expression in Misty bone, but only Runx2 was decreased in wild-type. Browning of WAT is under the control of the sympathetic nervous system (SNS) and, if present at room temperature, could impact bone metabolism. To test whether SNS activity could be responsible for accelerated trabecular bone loss, we treated wild-type and Misty mice with the β-blocker, propranolol. As predicted, propranolol slowed trabecular bone volume/total volume (BV/TV) loss in the distal femur of Misty mice without affecting wild-type. Finally, the Misty mutation (a truncation of DOCK7) also has a significant cell-autonomous role. We found DOCK7 expression in whole bone and osteoblasts. Primary osteoblast differentiation from Misty calvaria was impaired, demonstrating a novel role for DOCK7 in bone remodeling. Despite the multifaceted effects of the Misty mutation, we have shown that impaired brown fat function leads to altered SNS activity and bone loss, and for the first time that cold

  12. Development of Bone Remodeling Model for Spaceflight Bone Physiology Analysis

    NASA Technical Reports Server (NTRS)

    Pennline, James A.; Werner, Christopher R.; Lewandowski, Beth; Thompson, Bill; Sibonga, Jean; Mulugeta, Lealem

    2015-01-01

    Current spaceflight exercise countermeasures do not eliminate bone loss. Astronauts lose bone mass at a rate of 1-2% a month (Lang et al. 2004, Buckey 2006, LeBlanc et al. 2007). This may lead to early onset osteoporosis and place the astronauts at greater risk of fracture later in their lives. NASA seeks to improve understanding of the mechanisms of bone remodeling and demineralization in 1g in order to appropriately quantify long term risks to astronauts and improve countermeasures. NASA's Digital Astronaut Project (DAP) is working with NASA's bone discipline to develop a validated computational model to augment research efforts aimed at achieving this goal.

  13. Selection on a Subunit of the NURF Chromatin Remodeler Modifies Life History Traits in a Domesticated Strain of Caenorhabditis elegans.

    PubMed

    Large, Edward E; Xu, Wen; Zhao, Yuehui; Brady, Shannon C; Long, Lijiang; Butcher, Rebecca A; Andersen, Erik C; McGrath, Patrick T

    2016-07-01

    Evolutionary life history theory seeks to explain how reproductive and survival traits are shaped by selection through allocations of an individual's resources to competing life functions. Although life-history traits evolve rapidly, little is known about the genetic and cellular mechanisms that control and couple these tradeoffs. Here, we find that two laboratory-adapted strains of C. elegans descended from a single common ancestor that lived in the 1950s have differences in a number of life-history traits, including reproductive timing, lifespan, dauer formation, growth rate, and offspring number. We identified a quantitative trait locus (QTL) of large effect that controls 24%-75% of the total trait variance in reproductive timing at various timepoints. Using CRISPR/Cas9-induced genome editing, we show this QTL is due in part to a 60 bp deletion in the 3' end of the nurf-1 gene, which is orthologous to the human gene encoding the BPTF component of the NURF chromatin remodeling complex. Besides reproduction, nurf-1 also regulates growth rate, lifespan, and dauer formation. The fitness consequences of this deletion are environment specific-it increases fitness in the growth conditions where it was fixed but decreases fitness in alternative laboratory growth conditions. We propose that chromatin remodeling, acting through nurf-1, is a pleiotropic regulator of life history trade-offs underlying the evolution of multiple traits across different species. PMID:27467070

  14. Selection on a Subunit of the NURF Chromatin Remodeler Modifies Life History Traits in a Domesticated Strain of Caenorhabditis elegans

    PubMed Central

    Large, Edward E.; Zhao, Yuehui; Long, Lijiang; Butcher, Rebecca A.; Andersen, Erik C.; McGrath, Patrick T.

    2016-01-01

    Evolutionary life history theory seeks to explain how reproductive and survival traits are shaped by selection through allocations of an individual’s resources to competing life functions. Although life-history traits evolve rapidly, little is known about the genetic and cellular mechanisms that control and couple these tradeoffs. Here, we find that two laboratory-adapted strains of C. elegans descended from a single common ancestor that lived in the 1950s have differences in a number of life-history traits, including reproductive timing, lifespan, dauer formation, growth rate, and offspring number. We identified a quantitative trait locus (QTL) of large effect that controls 24%–75% of the total trait variance in reproductive timing at various timepoints. Using CRISPR/Cas9-induced genome editing, we show this QTL is due in part to a 60 bp deletion in the 3’ end of the nurf-1 gene, which is orthologous to the human gene encoding the BPTF component of the NURF chromatin remodeling complex. Besides reproduction, nurf-1 also regulates growth rate, lifespan, and dauer formation. The fitness consequences of this deletion are environment specific—it increases fitness in the growth conditions where it was fixed but decreases fitness in alternative laboratory growth conditions. We propose that chromatin remodeling, acting through nurf-1, is a pleiotropic regulator of life history trade-offs underlying the evolution of multiple traits across different species. PMID:27467070

  15. The transcription factor PHR1 regulates lipid remodeling and triacylglycerol accumulation in Arabidopsis thaliana during phosphorus starvation

    PubMed Central

    Pant, Bikram Datt; Burgos, Asdrubal; Pant, Pooja; Cuadros-Inostroza, Alvaro; Willmitzer, Lothar; Scheible, Wolf-Rüdiger

    2015-01-01

    Lipid remodeling is one of the most dramatic metabolic responses to phosphorus (P) starvation. It consists of the degradation of phospholipids to release the phosphate needed by the cell and the accumulation of glycolipids to replace phospholipids in the membranes. It is shown that PHR1, a well-described transcriptional regulator of P starvation of the MYB family, largely controls this response. Glycerolipid composition and the expression of most lipid-remodeling gene transcripts analysed were altered in the phr1 mutant under phosphate starvation in comparison to wild-type plants. In addition to these results, the lipidomic characterization of wild-type plants showed two novel features of the lipid response to P starvation for Arabidopsis. Triacylglycerol (TAG) accumulates dramatically under P starvation (by as much as ~20-fold in shoots and ~13-fold in roots), a response known to occur in green algae but hardly known in plants. Surprisingly, there was an increase in phosphatidylglycerol (PG) in P-starved roots, a response that may be adaptive as it was suppressed in the phr1 mutant. PMID:25680792

  16. Imprinting of idiosyncratic experience in cortical sensory maps: neural substrates of representational remodeling and correlative perceptual changes.

    PubMed

    Xerri, Christian

    2008-09-01

    Over the past 30 years, extensive research has been conducted in the field of cortical plasticity, under the impetus of seminal studies showing that the mature brain retains a capacity to reorganize the morphological and functional architecture of its neural circuits in order to adapt to environmental changes and mediate functional recovery following injury. Much effort has been focused on determining how idiosyncratic experience translates into molecular, structural and physiological changes in the sensory and motor representations embedded within cortical networks. The wealth of data generated by a broad spectrum of experimental manipulations has allowed unprecedented progress in our understanding of the physiological processes and neuroplasticity mechanisms underlying cortical representational remodeling. The objective of the present review is to put various facets of cortical map plasticity into perspective so as to examine possible links between changes occurring at multiple scales of the neural organization of the mature brain. The main focus is on neural substrates that mediate the instructive influence of experience and behavioral context on cortical reorganization, and perceptual correlates of representational remodeling. PMID:18423904

  17. Connector adapter

    NASA Technical Reports Server (NTRS)

    Hacker, Scott C. (Inventor); Dean, Richard J. (Inventor); Burge, Scott W. (Inventor); Dartez, Toby W. (Inventor)

    2007-01-01

    An adapter for installing a connector to a terminal post, wherein the connector is attached to a cable, is presented. In an embodiment, the adapter is comprised of an elongated collet member having a longitudinal axis comprised of a first collet member end, a second collet member end, an outer collet member surface, and an inner collet member surface. The inner collet member surface at the first collet member end is used to engage the connector. The outer collet member surface at the first collet member end is tapered for a predetermined first length at a predetermined taper angle. The collet includes a longitudinal slot that extends along the longitudinal axis initiating at the first collet member end for a predetermined second length. The first collet member end is formed of a predetermined number of sections segregated by a predetermined number of channels and the longitudinal slot.

  18. Adaptive VFH

    NASA Astrophysics Data System (ADS)

    Odriozola, Iñigo; Lazkano, Elena; Sierra, Basi

    2011-10-01

    This paper investigates the improvement of the Vector Field Histogram (VFH) local planning algorithm for mobile robot systems. The Adaptive Vector Field Histogram (AVFH) algorithm has been developed to improve the effectiveness of the traditional VFH path planning algorithm overcoming the side effects of using static parameters. This new algorithm permits the adaptation of planning parameters for the different type of areas in an environment. Genetic Algorithms are used to fit the best VFH parameters to each type of sector and, afterwards, every section in the map is labelled with the sector-type which best represents it. The Player/Stage simulation platform has been chosen for making all sort of tests and to prove the new algorithm's adequateness. Even though there is still much work to be carried out, the developed algorithm showed good navigation properties and turned out to be softer and more effective than the traditional VFH algorithm.

  19. Adaptive sampler

    DOEpatents

    Watson, B.L.; Aeby, I.

    1980-08-26

    An adaptive data compression device for compressing data is described. The device has a frequency content, including a plurality of digital filters for analyzing the content of the data over a plurality of frequency regions, a memory, and a control logic circuit for generating a variable rate memory clock corresponding to the analyzed frequency content of the data in the frequency region and for clocking the data into the memory in response to the variable rate memory clock.

  20. Adaptive sampler

    DOEpatents

    Watson, Bobby L.; Aeby, Ian

    1982-01-01

    An adaptive data compression device for compressing data having variable frequency content, including a plurality of digital filters for analyzing the content of the data over a plurality of frequency regions, a memory, and a control logic circuit for generating a variable rate memory clock corresponding to the analyzed frequency content of the data in the frequency region and for clocking the data into the memory in response to the variable rate memory clock.

  1. Adaptive antennas

    NASA Astrophysics Data System (ADS)

    Barton, P.

    1987-04-01

    The basic principles of adaptive antennas are outlined in terms of the Wiener-Hopf expression for maximizing signal to noise ratio in an arbitrary noise environment; the analogy with generalized matched filter theory provides a useful aid to understanding. For many applications, there is insufficient information to achieve the above solution and thus non-optimum constrained null steering algorithms are also described, together with a summary of methods for preventing wanted signals being nulled by the adaptive system. The three generic approaches to adaptive weight control are discussed; correlation steepest descent, weight perturbation and direct solutions based on sample matrix conversion. The tradeoffs between hardware complexity and performance in terms of null depth and convergence rate are outlined. The sidelobe cancellor technique is described. Performance variation with jammer power and angular distribution is summarized and the key performance limitations identified. The configuration and performance characteristics of both multiple beam and phase scan array antennas are covered, with a brief discussion of performance factors.

  2. Aortic pulse pressure homeostasis emerges from physiological adaptation of systemic arteries to local mechanical stresses.

    PubMed

    Nguyen, Phuc H; Tuzun, Egemen; Quick, Christopher M

    2016-09-01

    Aortic pulse pressure arises from the interaction of the heart, the systemic arterial system, and peripheral microcirculations. The complex interaction between hemodynamics and arterial remodeling precludes the ability to experimentally ascribe changes in aortic pulse pressure to particular adaptive responses. Therefore, the purpose of the present work was to use a human systemic arterial system model to test the hypothesis that pulse pressure homeostasis can emerge from physiological adaptation of systemic arteries to local mechanical stresses. First, we assumed a systemic arterial system that had a realistic topology consisting of 121 arterial segments. Then the relationships of pulsatile blood pressures and flows in arterial segments were characterized by standard pulse transmission equations. Finally, each arterial segment was assumed to remodel to local stresses following three simple rules: 1) increases in endothelial shear stress increases radius, 2) increases in wall circumferential stress increases wall thickness, and 3) increases in wall circumferential stress decreases wall stiffness. Simulation of adaptation by iteratively calculating pulsatile hemodynamics, mechanical stresses, and vascular remodeling led to a general behavior in response to mechanical perturbations: initial increases in pulse pressure led to increased arterial compliances, and decreases in pulse pressure led to decreased compliances. Consequently, vascular adaptation returned pulse pressures back toward baseline conditions. This behavior manifested when modeling physiological adaptive responses to changes in cardiac output, changes in peripheral resistances, and changes in local arterial radii. The present work, thus, revealed that pulse pressure homeostasis emerges from physiological adaptation of systemic arteries to local mechanical stresses.

  3. Signalling from dead cells drives inflammation and vessel remodelling.

    PubMed

    Bennett, Martin; Yu, Haixiang; Clarke, Murray

    2012-01-01

    Death of vascular smooth muscle cells (VSMCs) has been demonstrated in vessel development and in disease, most notably in atherosclerosis, but also after injury and remodelling. VSMC death promotes multiple features of vulnerable plaques, but also induces features of normal vessel ageing and cystic medial necrosis, including loss of VSMCs, elastin fragmentation and loss, increased glycosaminoglycans and speckled calcification. VSMC apoptosis in the absence of efficient phagocytosis also produces inflammation due to secondary necrosis; in contrast, VSMC apoptosis in normal vessels can be silent. We have investigated the consequences of VSMC apoptosis in both disease and during vessel remodelling. We find that VSMCs release specific cytokines dependent upon the mode of cell death; IL-1β predominates during apoptosis, whilst IL-1α predominates during necrosis. Both IL-1α and β promote release of further cytokines from adjacent live cells, in particular IL-6 and MCP-1. The balance of cytokines results in pathology with differing compositions, including inflammation or neointima formation/vascular repair, via direct promotion of VSMC proliferation and migration. Thus, VSMC death can promote either pathology or repair, depending upon the context and cytokine signalling.

  4. LPS Remodeling Triggers Formation of Outer Membrane Vesicles in Salmonella

    PubMed Central

    Elhenawy, Wael; Bording-Jorgensen, Michael; Valguarnera, Ezequiel; Haurat, M. Florencia; Wine, Eytan

    2016-01-01

    ABSTRACT Outer membrane vesicles (OMV) are proposed to mediate multiple functions during pathogenesis and symbiosis. However, the mechanisms responsible for OMV formation remain poorly understood. It has been shown in eukaryotic membranes that lipids with an inverted-cone shape favor the formation of positive membrane curvatures. Based on these studies, we formulated the hypothesis that lipid A deacylation might impose shape modifications that result in the curvature of the outer membrane (OM) and subsequent OMV formation. We tested the effect of lipid A remodeling on OMV biogenesis employing Salmonella enterica serovar Typhimurium as a model organism. Expression of the lipid A deacylase PagL resulted in increased vesiculation, without inducing an envelope stress response. Mass spectrometry analysis revealed profound differences in the patterns of lipid A in OM and OMV, with accumulation of deacylated lipid A forms exclusively in OMV. OMV biogenesis by intracellular bacteria upon macrophage infection was drastically reduced in a pagL mutant strain. We propose a novel mechanism for OMV biogenesis requiring lipid A deacylation in the context of a multifactorial process that involves the orchestrated remodeling of the outer membrane. PMID:27406567

  5. Nucleosome breathing and remodeling constrain CRISPR-Cas9 function

    PubMed Central

    Isaac, R Stefan; Jiang, Fuguo; Doudna, Jennifer A; Lim, Wendell A; Narlikar, Geeta J; Almeida, Ricardo

    2016-01-01

    The CRISPR-Cas9 bacterial surveillance system has become a versatile tool for genome editing and gene regulation in eukaryotic cells, yet how CRISPR-Cas9 contends with the barriers presented by eukaryotic chromatin is poorly understood. Here we investigate how the smallest unit of chromatin, a nucleosome, constrains the activity of the CRISPR-Cas9 system. We find that nucleosomes assembled on native DNA sequences are permissive to Cas9 action. However, the accessibility of nucleosomal DNA to Cas9 is variable over several orders of magnitude depending on dynamic properties of the DNA sequence and the distance of the PAM site from the nucleosome dyad. We further find that chromatin remodeling enzymes stimulate Cas9 activity on nucleosomal templates. Our findings imply that the spontaneous breathing of nucleosomal DNA together with the action of chromatin remodelers allow Cas9 to effectively act on chromatin in vivo. DOI: http://dx.doi.org/10.7554/eLife.13450.001 PMID:27130520

  6. Integrative models of vascular remodeling during tumor growth

    PubMed Central

    Rieger, Heiko; Welter, Michael

    2015-01-01

    Malignant solid tumors recruit the blood vessel network of the host tissue for nutrient supply, continuous growth, and gain of metastatic potential. Angiogenesis (the formation of new blood vessels), vessel cooption (the integration of existing blood vessels into the tumor vasculature), and vessel regression remodel the healthy vascular network into a tumor-specific vasculature that is in many respects different from the hierarchically organized arterio-venous blood vessel network of the host tissues. Integrative models based on detailed experimental data and physical laws implement in silico the complex interplay of molecular pathways, cell proliferation, migration, and death, tissue microenvironment, mechanical and hydrodynamic forces, and the fine structure of the host tissue vasculature. With the help of computer simulations high-precision information about blood flow patterns, interstitial fluid flow, drug distribution, oxygen and nutrient distribution can be obtained and a plethora of therapeutic protocols can be tested before clinical trials. In this review, we give an overview over the current status of integrative models describing tumor growth, vascular remodeling, blood and interstitial fluid flow, drug delivery, and concomitant transformations of the microenvironment. © 2015 The Authors. WIREs Systems Biology and Medicine published by Wiley Periodicals, Inc. PMID:25808551

  7. Antenatal Hypoxia and Pulmonary Vascular Function and Remodeling

    PubMed Central

    Papamatheakis, Demosthenes G.; Blood, Arlin B.; Kim, Joon H.; Wilson, Sean M.

    2015-01-01

    This review provides evidence that antenatal hypoxia, which represents a significant and worldwide problem, causes prenatal programming of the lung. A general overview of lung development is provided along with some background regarding transcriptional and signaling systems of the lung. The review illustrates that antenatal hypoxic stress can induce a continuum of responses depending on the species examined. Fetuses and newborns of certain species and specific human populations are well acclimated to antenatal hypoxia. However, antenatal hypoxia causes pulmonary vascular disease in fetuses and newborns of most mammalian species and humans. Disease can range from mild pulmonary hypertension, to severe vascular remodeling and dangerous elevations in pressure. The timing, length, and magnitude of the intrauterine hypoxic stress are important to disease development, however there is also a genetic-environmental relationship that is not yet completely understood. Determining the origins of pulmonary vascular remodeling and pulmonary hypertension and their associated effects is a challenging task, but is necessary in order to develop targeted therapies for pulmonary hypertension in the newborn due to antenatal hypoxia that can both treat the symptoms and curtail or reverse disease progression. PMID:24063380

  8. Vascular Remodelling and Mesenchymal Transition in Systemic Sclerosis

    PubMed Central

    Nicolosi, Pier Andrea; Tombetti, Enrico; Maugeri, Norma; Rovere-Querini, Patrizia; Brunelli, Silvia; Manfredi, Angelo A.

    2016-01-01

    Fibrosis of the skin and of internal organs, autoimmunity, and vascular inflammation are hallmarks of Systemic Sclerosis (SSc). The injury and activation of endothelial cells, with hyperplasia of the intima and eventual obliteration of the vascular lumen, are early features of SSc. Reduced capillary blood flow coupled with deficient angiogenesis leads to chronic hypoxia and tissue ischemia, enforcing a positive feed-forward loop sustaining vascular remodelling, further exacerbated by extracellular matrix accumulation due to fibrosis. Despite numerous developments and a growing number of controlled clinical trials no treatment has been shown so far to alter SSc natural history, outlining the need of further investigation in the molecular pathways involved in the pathogenesis of the disease. We review some processes potentially involved in SSc vasculopathy, with attention to the possible effect of sustained vascular inflammation on the plasticity of vascular cells. Specifically we focus on mesenchymal transition, a key phenomenon in the cardiac and vascular development as well as in the remodelling of injured vessels. Recent work supports the role of transforming growth factor-beta, Wnt, and Notch signaling in these processes. Importantly, endothelial-mesenchymal transition may be reversible, possibly offering novel cues for treatment. PMID:27069480

  9. Antenatal hypoxia and pulmonary vascular function and remodeling.

    PubMed

    Papamatheakis, Demosthenes G; Blood, Arlin B; Kim, Joon H; Wilson, Sean M

    2013-09-01

    This review provides evidence that antenatal hypoxia, which represents a significant and worldwide problem, causes prenatal programming of the lung. A general overview of lung development is provided along with some background regarding transcriptional and signaling systems of the lung. The review illustrates that antenatal hypoxic stress can induce a continuum of responses depending on the species examined. Fetuses and newborns of certain species and specific human populations are well acclimated to antenatal hypoxia. However, antenatal hypoxia causes pulmonary vascular disease in fetuses and newborns of most mammalian species and humans. Disease can range from mild pulmonary hypertension, to severe vascular remodeling and dangerous elevations in pressure. The timing, length, and magnitude of the intrauterine hypoxic stress are important to disease development, however there is also a genetic-environmental relationship that is not yet completely understood. Determining the origins of pulmonary vascular remodeling and pulmonary hypertension and their associated effects is a challenging task, but is necessary in order to develop targeted therapies for pulmonary hypertension in the newborn due to antenatal hypoxia that can both treat the symptoms and curtail or reverse disease progression.

  10. Mechanisms of bone remodeling: implications for clinical practice.

    PubMed

    Kenny, Anne M; Raisz, Lawrence G

    2002-01-01

    The adult skeleton undergoes continuous remodeling. The remodeling cycle involves the interaction of cells of osteoblastic and osteoclastic lineage and is regulated by both systemic hormones and local factors. In addition to the systemic calcium-regulating hormones, parathyroid hormone, 1,25-dihydroxy vitamin D and calcitonin, sex hormones play an important role. Estrogen has been identified as the major inhibitor of bone resorption in both men and women. Androgen is important not only as a source of estrogen, through the action of aromatase, but also for its direct effect in stimulating bone formation. The effects of sex hormones may be mediated by their ability to alter the secretion of local cytokines, prostaglandins and growth factors. Sex hormone action is also modulated by the level of sex hormone-binding globulin in the circulation. A more precise analysis of these effects has been made possible by the development of new methods of measuring not only bone mineral density, but also relative rates of bone formation and resorption using biochemical markers. These new approaches have allowed us to define more precisely the specific roles of androgens, estrogens and other regulatory hormones in human skeletal physiology and pathophysiology. PMID:11829079

  11. Circadian Epigenomic Remodeling and Hepatic Lipogenesis: Lessons from HDAC3

    PubMed Central

    Sun, Zheng; Feng, Dan; Everett, Logan J.; Bugge, Anne; Lazar, Mitchell A.

    2013-01-01

    Circadian rhythms have evolved to anticipate metabolic needs across the 24-hour light/dark cycle. This is accomplished by circadian expression of metabolic genes orchestrated by transcription factors through chromatin remodeling and histone modifications. Our recent genome-wide study on histone deacetylase 3 (HDAC3) in mouse liver provides novel insights into the molecular link between circadian rhythm and hepatic de novo lipogenesis. We found that liver-specific knockout of HDAC3 in adult mouse display severe hepatic steatosis associated with enhanced de novo lipogenesis and increased expression of lipogenic genes. Genome-wide analysis (ChIP-seq) revealed a pronounced circadian pattern of HDAC3 occupancy on genes involved in lipid metabolism, which is inversely related to histone acetylation and RNA polymerase II recruitment at these sites. The cistromes of HDAC3 and its binding partner, nuclear receptor co-repressor (NCoR), significantly overlap with that of Rev-erbα, a nuclear receptor directly involved in the core circadian machinery. Knockout of Rev-erbα in mouse also leads to hepatic steatosis and enhanced de novo lipogenesis. Collectively, these data suggest that the circadian epigenomic remodeling controlled by HDAC3, and largely directed by Rev-erbα, is essential for homeostasis of the lipogenic process in liver. PMID:21900149

  12. Early remodeling of the neocortex upon episodic memory encoding.

    PubMed

    Bero, Adam W; Meng, Jia; Cho, Sukhee; Shen, Abra H; Canter, Rebecca G; Ericsson, Maria; Tsai, Li-Huei

    2014-08-12

    Understanding the mechanisms by which long-term memories are formed and stored in the brain represents a central aim of neuroscience. Prevailing theory suggests that long-term memory encoding involves early plasticity within hippocampal circuits, whereas reorganization of the neocortex is thought to occur weeks to months later to subserve remote memory storage. Here we report that long-term memory encoding can elicit early transcriptional, structural, and functional remodeling of the neocortex. Parallel studies using genome-wide RNA sequencing, ultrastructural imaging, and whole-cell recording in wild-type mice suggest that contextual fear conditioning initiates a transcriptional program in the medial prefrontal cortex (mPFC) that is accompanied by rapid expansion of the synaptic active zone and postsynaptic density, enhanced dendritic spine plasticity, and increased synaptic efficacy. To address the real-time contribution of the mPFC to long-term memory encoding, we performed temporally precise optogenetic inhibition of excitatory mPFC neurons during contextual fear conditioning. Using this approach, we found that real-time inhibition of the mPFC inhibited activation of the entorhinal-hippocampal circuit and impaired the formation of long-term associative memory. These findings suggest that encoding of long-term episodic memory is associated with early remodeling of neocortical circuits, identify the prefrontal cortex as a critical regulator of encoding-induced hippocampal activation and long-term memory formation, and have important implications for understanding memory processing in healthy and diseased brain states.

  13. Fibroblast cytoskeletal remodeling contributes to connective tissue tension.

    PubMed

    Langevin, Helene M; Bouffard, Nicole A; Fox, James R; Palmer, Bradley M; Wu, Junru; Iatridis, James C; Barnes, William D; Badger, Gary J; Howe, Alan K

    2011-05-01

    The visco-elastic behavior of connective tissue is generally attributed to the material properties of the extracellular matrix rather than cellular activity. We have previously shown that fibroblasts within areolar connective tissue exhibit dynamic cytoskeletal remodeling within minutes in response to tissue stretch ex vivo and in vivo. Here, we tested the hypothesis that fibroblasts, through this cytoskeletal remodeling, actively contribute to the visco-elastic behavior of the whole tissue. We measured significantly increased tissue tension when cellular function was broadly inhibited by sodium azide and when cytoskeletal dynamics were compromised by disrupting microtubules (with colchicine) or actomyosin contractility (via Rho kinase inhibition). These treatments led to a decrease in cell body cross-sectional area and cell field perimeter (obtained by joining the end of all of a fibroblast's processes). Suppressing lamellipodia formation by inhibiting Rac-1 decreased cell body cross-sectional area but did not affect cell field perimeter or tissue tension. Thus, by changing shape, fibroblasts can dynamically modulate the visco-elastic behavior of areolar connective tissue through Rho-dependent cytoskeletal mechanisms. These results have broad implications for our understanding of the dynamic interplay of forces between fibroblasts and their surrounding matrix, as well as for the neural, vascular, and immune cell populations residing within connective tissue.

  14. Remodeling of tissue-engineered bone structures in vivo.

    PubMed

    Hofmann, Sandra; Hilbe, Monika; Fajardo, Robert J; Hagenmüller, Henri; Nuss, Katja; Arras, Margarete; Müller, Ralph; von Rechenberg, Brigitte; Kaplan, David L; Merkle, Hans P; Meinel, Lorenz

    2013-09-01

    Implant design for bone regeneration is expected to be optimized when implant structures resemble the anatomical situation of the defect site. We tested the validity of this hypothesis by exploring the feasibility of generating different in vitro engineered bone-like structures originating from porous silk fibroin scaffolds decorated with RGD sequences (SF-RGD), seeded with human mesenchymal stem cells (hMSC). Scaffolds with small (106-212 μm), medium (212-300 μm), and large pore diameter ranges (300-425 μm) were seeded with hMSC and subsequently differentiated in vitro into bone-like tissue resembling initial scaffold geometries and featuring bone-like structures. Eight weeks after implantation into calvarial defects in mice, the in vitro engineered bone-like tissues had remodeled into bone featuring different proportions of woven/lamellar bone bridging the defects. Regardless of pore diameter, all implants integrated well, vascularization was advanced, and bone marrow ingrowth had started. Ultimately, in this defect model, the geometry of the in vitro generated tissue-engineered bone structure, trabecular- or plate-like, had no significant impact on the healing of the defect, owing to an efficient remodeling of its structure after implantation. PMID:23958323

  15. Danger Control Programs Cause Tissue Injury and Remodeling

    PubMed Central

    Hagemann, Jan H.; Haegele, Holger; Müller, Susanna; Anders, Hans-Joachim

    2013-01-01

    Are there common pathways underlying the broad spectrum of tissue pathologies that develop upon injuries and from subsequent tissue remodeling? Here, we explain the pathophysiological impact of a set of evolutionary conserved danger control programs for tissue pathology. These programs date back to the survival benefits of the first multicellular organisms upon traumatic injuries by launching a series of danger control responses, i.e., 1. Haemostasis, or clotting to control bleeding; 2. Host defense, to control pathogen entry and spreading; 3. Re-epithelialisation, to recover barrier functions; and 4. Mesenchymal, to repair to regain tissue stability. Taking kidney pathology as an example, we discuss how clotting, inflammation, epithelial healing, and fibrosis/sclerosis determine the spectrum of kidney pathology, especially when they are insufficiently activated or present in an overshooting and deregulated manner. Understanding the evolutionary benefits of these response programs may refine the search for novel therapeutic targets to limit organ dysfunction in acute injuries and in progressive chronic tissue remodeling. PMID:23759985

  16. Cell Wall Composition, Biosynthesis and Remodeling during Pollen Tube Growth

    PubMed Central

    Mollet, Jean-Claude; Leroux, Christelle; Dardelle, Flavien; Lehner, Arnaud

    2013-01-01

    The pollen tube is a fast tip-growing cell carrying the two sperm cells to the ovule allowing the double fertilization process and seed setting. To succeed in this process, the spatial and temporal controls of pollen tube growth within the female organ are critical. It requires a massive cell wall deposition to promote fast pollen tube elongation and a tight control of the cell wall remodeling to modify the mechanical properties. In addition, during its journey, the pollen tube interacts with the pistil, which plays key roles in pollen tube nutrition, guidance and in the rejection of the self-incompatible pollen. This review focuses on our current knowledge in the biochemistry and localization of the main cell wall polymers including pectin, hemicellulose, cellulose and callose from several pollen tube species. Moreover, based on transcriptomic data and functional genomic studies, the possible enzymes involved in the cell wall remodeling during pollen tube growth and their impact on the cell wall mechanics are also described. Finally, mutant analyses have permitted to gain insight in the function of several genes involved in the pollen tube cell wall biosynthesis and their roles in pollen tube growth are further discussed. PMID:27137369

  17. Extracellular Matrix Molecular Remodeling in Human Liver Fibrosis Evolution

    PubMed Central

    Baiocchini, Andrea; Montaldo, Claudia; Conigliaro, Alice; Grimaldi, Alessio; Correani, Virginia; Mura, Francesco; Ciccosanti, Fabiola; Rotiroti, Nicolina; Brenna, Alessia; Montalbano, Marzia; D’Offizi, Gianpiero; Capobianchi, Maria Rosaria; Alessandro, Riccardo; Piacentini, Mauro; Schininà, Maria Eugenia; Maras, Bruno; Del Nonno, Franca; Tripodi, Marco; Mancone, Carmine

    2016-01-01

    Chronic liver damage leads to pathological accumulation of ECM proteins (liver fibrosis). Comprehensive characterization of the human ECM molecular composition is essential for gaining insights into the mechanisms of liver disease. To date, studies of ECM remodeling in human liver diseases have been hampered by the unavailability of purified ECM. Here, we developed a decellularization method to purify ECM scaffolds from human liver tissues. Histological and electron microscopy analyses demonstrated that the ECM scaffolds, devoid of plasma and cellular components, preserved the three-dimensional ECM structure and zonal distribution of ECM components. This method has been then applied on 57 liver biopsies of HCV-infected patients at different stages of liver fibrosis according to METAVIR classification. Label-free nLC-MS/MS proteomics and computation biology were performed to analyze the ECM molecular composition in liver fibrosis progression, thus unveiling protein expression signatures specific for the HCV-related liver fibrotic stages. In particular, the ECM molecular composition of liver fibrosis was found to involve dynamic changes in matrix stiffness, flexibility and density related to the dysregulation of predominant collagen, elastic fibers and minor components with both structural and signaling properties. This study contributes to the understanding of the molecular bases underlying ECM remodeling in liver fibrosis and suggests new molecular targets for fibrolytic strategies. PMID:26998606

  18. Energy Excess, Glucose Utilization, and Skeletal Remodeling: New Insights.

    PubMed

    Lecka-Czernik, Beata; Rosen, Clifford J

    2015-08-01

    Skeletal complications have recently been recognized as another of the several comorbidities associated with diabetes. Clinical studies suggest that disordered glucose and lipid metabolism have a profound effect on bone. Diabetes-related changes in skeletal homeostasis result in a significant increased risk of fractures, although the pathophysiology may differ from postmenopausal osteoporosis. Efforts to understand the underlying mechanisms of diabetic bone disease have focused on the direct interaction of adipose tissue with skeletal remodeling and the potential influence of glucose utilization and energy uptake on these processes. One aspect that has emerged recently is the major role of the central nervous system in whole-body metabolism, bone turnover, adipose tissue remodeling, and beta cell secretion of insulin. Importantly, the skeleton contributes to the metabolic balance inherent in physiologic states. New animal models have provided the insights necessary to begin to dissect the effects of obesity and insulin resistance on the acquisition and maintenance of bone mass. In this Perspective, we focus on potential mechanisms that underlie the complex interactions between adipose tissue and skeletal turnover by focusing on the clinical evidence and on preclinical studies indicating that glucose intolerance may have a significant impact on the skeleton. In addition, we raise fundamental questions that need to be addressed in future studies to resolve the conundrum associated with glucose intolerance, obesity, and osteoporosis.

  19. Evidence of structural remodeling in the dyssynchronous failing heart.

    PubMed

    Helm, Patrick A; Younes, Laurent; Beg, Mirza F; Ennis, Daniel B; Leclercq, Christophe; Faris, Owen P; McVeigh, Elliot; Kass, David; Miller, Michael I; Winslow, Raimond L

    2006-01-01

    Ventricular remodeling of both geometry and fiber structure is a prominent feature of several cardiac pathologies. Advances in MRI and analytical methods now make it possible to measure changes of cardiac geometry, fiber, and sheet orientation at high spatial resolution. In this report, we use diffusion tensor imaging to measure the geometry, fiber, and sheet architecture of eight normal and five dyssynchronous failing canine hearts, which were explanted and fixed in an unloaded state. We apply novel computational methods to identify statistically significant changes of cardiac anatomic structure in the failing and control heart populations. The results demonstrate significant regional differences in geometric remodeling in the dyssynchronous failing heart versus control. Ventricular chamber dilatation and reduction in wall thickness in septal and some posterior and anterior regions are observed. Primary fiber orientation showed no significant change. However, this result coupled with the local wall thinning in the septum implies an altered transmural fiber gradient. Further, we observe that orientation of laminar sheets become more vertical in the early-activated septum, with no significant change of sheet orientation in the late-activated lateral wall. Measured changes in both fiber gradient and sheet structure will affect both the heterogeneity of passive myocardial properties as well as electrical activation of the ventricles.

  20. FIBROBLAST CYTOSKELETAL REMODELING CONTRIBUTES TO CONNECTIVE TISSUE TENSION

    PubMed Central

    Langevin, Helene M.; Bouffard, Nicole A.; Fox, James R.; Palmer, Bradley M.; Wu, Junru; Iatridis, James C.; Barnes, William D.; Badger, Gary J.; Howe, Alan K.

    2011-01-01

    The viscoelastic behavior of connective tissue is generally attributed to the material properties of the extracellular matrix rather than cellular activity. We have previously shown that fibroblasts within areolar connective tissue exhibit dynamic cytoskeletal remodeling within minutes in response to tissue stretch ex vivo and in vivo. Here, we tested the hypothesis that fibroblasts, through this cytoskeletal remodeling, actively contribute to the viscoelastic behavior of the whole tissue. We measured significantly increased tissue tension when cellular function was broadly inhibited by sodium azide and when cytoskeletal dynamics were compromised by disrupting microtubules (with colchicine) or actomyosin contractility (via Rho kinase inhibition). These treatments led to a decrease in cell body cross-sectional area and cell field perimeter (obtained by joining the end of all of a fibroblast’s processes). Suppressing lamellipodia formation by inhibiting Rac-1 decreased cell body cross-sectional area but did not affect cell field perimeter or tissue tension. Thus, by changing shape, fibroblasts can dynamically modulate the viscoelastic behavior of areolar connective tissue through Rho-dependent cytoskeletal mechanisms. These results have broad implications for our understanding of the dynamic interplay of forces between fibroblasts and their surrounding matrix, as well as for the neural, vascular and immune cell populations residing within connective tissue. PMID:20945345