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Sample records for adaptive outward remodeling

  1. Mesenteric Resistance Arteries in Type 2 Diabetic db/db Mice Undergo Outward Remodeling

    PubMed Central

    Souza-Smith, Flavia M.; Katz, Paige S.; Trask, Aaron J.; Stewart, James A.; Lord, Kevin C.; Varner, Kurt J.; Vassallo, Dalton V.; Lucchesi, Pamela A.

    2011-01-01

    Objective Resistance vessel remodeling is controlled by myriad of hemodynamic and neurohormonal factors. This study characterized structural and molecular remodeling in mesenteric resistance arteries (MRAs) in diabetic (db/db) and control (Db/db) mice. Methods Structural properties were assessed in isolated MRAs from 12 and 16 wk-old db/db and Db/db mice by pressure myography. Matrix regulatory proteins were measured by Western blot analysis. Mean arterial pressure and superior mesenteric blood flow were measured in 12 wk-old mice by telemetry and a Doppler flow nanoprobe, respectively. Results Blood pressure was similar between groups. Lumen diameter and medial cross-sectional area were significantly increased in 16 wk-old db/db MRA compared to control, indicating outward hypertrophic remodeling. Moreover, wall stress and cross-sectional compliance were significantly larger in diabetic arteries. These remodeling indices were associated with increased expression of matrix regulatory proteins matrix metalloproteinase (MMP)-9, MMP-12, tissue inhibitors of matrix metalloproteinase (TIMP)-1, TIMP-2, and plasminogen activator inhibitor-1 (PAI-1) in db/db arteries. Finally, superior mesenteric artery blood flow was increased by 46% in 12 wk-old db/db mice, a finding that preceded mesenteric resistance artery remodeling. Conclusions These data suggest that flow-induced hemodynamic changes may supersede the local neurohormonal and metabolic milieu to culminate in hypertrophic outward remodeling of type 2 DM mesenteric resistance arteries. PMID:21829729

  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. The role of transient outward K+ current in electrical remodelling induced by voluntary exercise in female rat hearts.

    PubMed

    Stones, Rachel; Billeter, Rudolf; Zhang, Henggui; Harrison, Simon; White, Ed

    2009-11-01

    Regular exercise can lead to electrical remodelling of the heart. The cellular mechanisms associated with these changes are not well understood, and are difficult to study in human tissue but are important given that exercise is recommended to the general population. We have investigated the role played by the transient outward K+ current (I(to)) in the changes in electrical activity seen in response to voluntary exercise training in rats. Female rats undertook 6 weeks of voluntary wheel running exercise (TRN) or were sedentary controls (SED). Monophasic action potentials (MAPs) were recorded from the surface of whole hearts. Whole cell patch clamp recordings of I(to); mRNA and protein levels of selected targets in sub-epicardial (EPI) and sub-endocardial myocardium of SED and TRN hearts were compared. In TRN rats, heart weight:body weight was significantly increased and epicardial MAPs significantly prolonged. I(to) density was reduced in TRN EPI myocytes, such that the transmural gradient of I(to) was significantly reduced (P < 0.05). Computer modelling of these changes in I(to) predicted the observed changes in action potential profile. However, transmural gradients in mRNA and protein expression for Kv4.2 or mRNA levels of the Kv4.2 regulators; KChIP2 and Irx-5 were not significantly altered by voluntary exercise. We conclude that voluntary exercise electrical remodelling is caused, at least in part, by a decrease in EPI I(to), possibly because of fewer functional channels in the membrane, which results in a fall in the transmural action potential duration gradient.

  4. 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

  5. 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

  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. Respiratory muscle fiber remodeling in chronic hyperinflation: dysfunction or adaptation?

    PubMed

    Clanton, Thomas L; Levine, Sanford

    2009-07-01

    The diaphragm and other respiratory muscles undergo extensive remodeling in both animal models of emphysema and in human chronic obstructive pulmonary disease, but the nature of the remodeling is different in many respects. One common feature is a shift toward improved endurance characteristics and increased oxidative capacity. Furthermore, both animals and humans respond to chronic hyperinflation by diaphragm shortening. Although in rodent models this clearly arises by deletion of sarcomeres in series, the mechanism has not been proven conclusively in human chronic obstructive pulmonary disease. Unique characteristics of the adaptation in human diaphragms include shifts to more predominant slow, type I fibers, expressing slower myosin heavy chain isoforms, and type I and type II fiber atrophy. Although some laboratories report reductions in specific force, this may be accounted for by decreases in myosin heavy chain content as the muscles become more oxidative and more efficient. More recent findings have reported reductions in Ca(2+) sensitivity and reduced myofibrillar elastic recoil. In contrast, in rodent models of disease, there is no consistent evidence for loss of specific force, no consistent shift in fiber populations, and atrophy is predominantly seen only in fast, type IIX fibers. This review challenges the hypothesis that the adaptations in human diaphragm represent a form of dysfunction, secondary to systemic disease, and suggest that most findings can as well be attributed to adaptive processes of a complex muscle responding to unique alterations in its working environment.

  8. Effects of mechanical stimuli on adaptive remodeling of condylar cartilage.

    PubMed

    Sriram, D; Jones, A; Alatli-Burt, I; Darendeliler, M A

    2009-05-01

    Trabecular bone has been shown to be responsive to low-magnitude, high-frequency mechanical stimuli. This study aimed to assess the effects of these stimuli on condylar cartilage and its endochondral bone. Forty female 12-week-old C3H mice were divided into 3 groups: baseline control (killed at day 0), sham (killed at day 28 without exposure to mechanical stimuli), and experimental (killed following 28 days of exposure to mechanical stimuli). The experimental group was subjected to mechanical vibration of 30 Hz, for 20 minutes per day, 5 days per week, for 28 days. The specimens were analyzed by micro-computed tomography. The experimental group demonstrated a significant decrease in the volume of condylar cartilage and also a significant increase in bone histomorphometric parameters. The results suggest that the low-magnitude, high-frequency mechanical stimuli enhance adaptive remodeling of condylar cartilage, evidenced by the advent of endochondral bone replacing the hypertrophic cartilage.

  9. 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.

  10. 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

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

    PubMed

    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

    2015-06-23

    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.

  12. Mechanism for adaptive remodeling of the bacterial flagellar switch

    PubMed Central

    Lele, Pushkar P.; Branch, Richard W.; Nathan, Vedhavalli S. J.; Berg, Howard C.

    2012-01-01

    The bacterial flagellar motor has been shown in previous work to adapt to changes in the steady-state concentration of the chemotaxis signaling molecule, CheY-P, by changing the FliM content. We show here that the number of FliM molecules in the motor and the fraction of FliM molecules that exchange depend on the direction of flagellar rotation, not on CheY-P binding per se. Our results are consistent with a model in which the structural differences associated with the direction of rotation modulate the strength of FliM binding. When the motor spins counterclockwise, FliM binding strengthens, the fraction of FliM molecules that exchanges decreases, and the ring content increases. The larger number of CheY-P binding sites enhances the motor’s sensitivity, i.e., the motor adapts. An interesting unresolved question is how additional copies of FliM might be accommodated. PMID:23169659

  13. Halofuginone Stimulates Adaptive Remodeling and Preserves Re-Endothelialization in Balloon-Injured Rat Carotid Arteries

    PubMed Central

    Guo, Lian-Wang; Wang, Bowen; Goel, Shakti A.; Little, Christopher; Takayama, Toshio; Shi, Xu Dong; Roenneburg, Drew; DiRenzo, Daniel; Kent, K. Craig

    2014-01-01

    Background Three major processes, constrictive vessel remodeling, intimal hyperplasia and retarded re-endothelialization, contribute to restenosis after vascular reconstructions. Clinically used drugs inhibit intimal hyperplasia but delay re-endothelialization and also cause constrictive remodeling. Here we have examined halofuginone (HF), a herbal derivative, for its beneficial effects on vessel remodeling and differential inhibition of intimal hyperplasia versus re-endothelialization. Methods and Results Two weeks after perivascular application to balloon-injured rat common carotid arteries, HF versus vehicle (n=6 animals) enlarged luminal area 2.14 fold by increasing vessel size (adaptive remodeling, 123%), reducing intimal hyperplasia (74.3%) without inhibiting re-endothelialization. Consistent with its positive effect on vessel expansion, HF reduced collagen type-1 (but not type-3) production in injured arteries as well as that from adventitial fibroblasts in vitro. In support of its differential effects on intimal hyperplasia versus re-endothelialization, HF produced greater inhibition of vascular smooth muscle cell versus endothelial cell proliferation at concentrations around 50 nM. Furthermore, HF at 50 nM effectively blocked Smad3 phosphorylation in smooth muscle cells which is known to promote smooth muscle cell proliferation, migration, and intimal hyperplasia, but HF had no effect on phospho-Smad3 in endothelial cells. Conclusions Periadventitial delivery of HF dramatically increased lumen patency via adaptive remodeling and selective inhibition of intimal hyperplasia without affecting endothelium recovery. HF is the first reported small molecule that has favorable effects on all three major processes involved in restenosis. PMID:25074254

  14. Rationale of platelet gel to augment adaptive remodeling of the injured heart.

    PubMed

    Mogan, Christopher; Larson, Douglas F

    2004-06-01

    Cardiac pathologic events including; myocardial infarction, viral infection and hypertrophy, and aging, may trigger maladaptive remodeling of the myocardium. Maladaptive remodeling results in diastolic and systolic dysfunction, myocyte loss, and malformation of the extracellular matrix. It is proposed that platelet gel applied to the site of myocardial injury may provide the proper cytokines, growth factors, and chemokines to promote adaptive remodeling. The hypothesis is that platelet gel concentrates may provide a temporary and local hyperphysiologic concentration of platelet secretory factors that may initiate adaptive myocardial healing. Autologous platelet gel can be derived from concentrated platelets activated and induced to secrete cytokines, growth factors, and chemokines with an array of stimulating agents. This report discusses selected platelet secretory factors, including; IL-1beta, TGF-beta, TGF-alpha, FGF, EGF, PDGF, and IGF, which support the concept that platelet concentrates can mediate cardiac wound healing. In conclusion, application of platelet gel to areas of cardiac injury may offer a therapeutic means to stimulate myocyte regeneration, angiogenesis, and restoration of a normal extracellular matrix composition.

  15. 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

  16. 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

  17. Chromatin remodeling regulates catalase expression during cancer cells adaptation to chronic oxidative stress.

    PubMed

    Glorieux, Christophe; Sandoval, Juan Marcelo; Fattaccioli, Antoine; Dejeans, Nicolas; Garbe, James C; Dieu, Marc; Verrax, Julien; Renard, Patricia; Huang, Peng; Calderon, Pedro Buc

    2016-10-01

    Regulation of ROS metabolism plays a major role in cellular adaptation to oxidative stress in cancer cells, but the molecular mechanism that regulates catalase, a key antioxidant enzyme responsible for conversion of hydrogen peroxide to water and oxygen, remains to be elucidated. Therefore, we investigated the transcriptional regulatory mechanism controlling catalase expression in three human mammary cell lines: the normal mammary epithelial 250MK primary cells, the breast adenocarcinoma MCF-7 cells and an experimental model of MCF-7 cells resistant against oxidative stress resulting from chronic exposure to H2O2 (Resox), in which catalase was overexpressed. Here we identify a novel promoter region responsible for the regulation of catalase expression at -1518/-1226 locus and the key molecules that interact with this promoter and affect catalase transcription. We show that the AP-1 family member JunB and retinoic acid receptor alpha (RARα) mediate catalase transcriptional activation and repression, respectively, by controlling chromatin remodeling through a histone deacetylases-dependent mechanism. This regulatory mechanism plays an important role in redox adaptation to chronic exposure to H2O2 in breast cancer cells. Our study suggests that cancer adaptation to oxidative stress may be regulated by transcriptional factors through chromatin remodeling, and reveals a potential new mechanism to target cancer cells.

  18. Adaptive remodelling by FliN in the bacterial rotary motor

    PubMed Central

    Branch, Richard W.; Sayegh, Michael N.; Shen, Chong; Nathan, Vedavalli S.J.; Berg, Howard C.

    2014-01-01

    Sensory adaptation in the E. coli chemosensory pathway has been the subject of interest for decades, with investigation focusing on the receptors that process extracellular inputs. Recent studies demonstrate that the flagellar motors responsible for cell locomotion also play a role, adding or subtracting FliM subunits to maximise sensitivity to pathway signals. It is difficult to reconcile this FliM remodelling with the observation that partner FliN subunits are relatively static fixtures in the motor. By fusing a fluorescent protein internally to FliN, we show that there is in fact significant FliN remodelling. The kinetics and stoichiometry of FliN in steady-state and in adapting motors are investigated and found to match the behaviour of FliM in all respects except for timescale, where FliN rates are about four times slower. We notice that motor adaptation is slower in the presence of the fluorescent protein, indicating a possible source for the difference. The behaviour of FliM and FliN is consistent with a kinetic and stoichiometric model that contradicts the traditional view of a packed, rigid motor architecture. PMID:25046382

  19. OUTWARD BOUND IN THE MAINSTREAM OF AMERICAN EDUCATION, A SYNOPSIS OF SIX OUTWARD BOUND MAINSTREAM PROJECTS.

    ERIC Educational Resources Information Center

    Outward Bound, Inc., Andover, MA.

    A SYNOPSIS IS OFFERED OF SIX DIFFERENT OUTWARD-BOUND PROGRAMS, EACH OF WHICH IS AN ADAPTATION OF THE BASIC OUTWARD-BOUND PHILOSOPHY OF HAVING YOUNG PEOPLE RECOGNIZE FOR THEMSELVES THEIR PHYSICAL, EMOTIONAL, AND SPIRITUAL CAPABILITIES SO THAT THEY WILL DEVELOP A STRONG SENSE OF SELF-RELIANCE AND INNER STRENGTH. THE ADAMS COUNTY, COLORADO,…

  20. Modulation of gene expression in bone cells during strain-adapted bone remodeling

    NASA Astrophysics Data System (ADS)

    Klein-Nulend, J.; Bacabac, R. G.; Vatsa, A.; Tan, S. D.; Smit, Th. H.; van Loon, J. J. W. A.

    2005-08-01

    Bone tissue can adapt to changing mechanical demands. The osteocytes are believed to play a role as the "professional" mechanosensory cells of bone, and the lacuno-canalicular network as the structure that mediates mechanosensing. Loading on bone produces flow of interstitial fluid in the lacunar-canalicular network along the surface of osteocytes, which is likely the physiological signal for bone cell adaptive responses in vivo. The alignment of secondary osteons along the dominant loading direction suggests that bone remodeling is guided by mechanical strain. We propose that alignment during remodeling occurs as a result of different canalicular flow patterns around cutting cone and reversal zone during loading.The response of osteocytes to fluid flow includes prostaglandin synthesis and expression of inducible cyclooxygenase-2, an enzyme that mediates mechanical loading-induced bone formation in vivo. The response of osteocytes to fluid flow also includes nitric oxide production, and expression of endothelial nitric oxide synthase. Nitric oxide has been shown to mediate the mechanical effects in bone, leading to enhanced prostaglandin E2 release. These studies have increased our understanding of the cell biology underlying Wolff's Law. This may lead to new strategies for combating disuse-related osteoporosis, such as occurs during long- mission spaceflights.

  1. Senescent Remodeling of the Innate and Adaptive Immune System in the Elderly Men with Prostate Cancer

    PubMed Central

    Taverna, Gianluigi; Seveso, Mauro; Giusti, Guido; Hurle, Rodolfo; Graziotti, Pierpaolo; Štifter, Sanja; Chiriva-Internati, Maurizio; Grizzi, Fabio

    2014-01-01

    Despite years of intensive investigation that has been made in understanding prostate cancer, it remains a major cause of death in men worldwide. Prostate cancer emerges from multiple alterations that induce changes in expression patterns of genes and proteins that function in networks controlling critical cellular events. Based on the exponential aging of the population and the increasing life expectancy in industrialized Western countries, prostate cancer in the elderly men is becoming a disease of increasing significance. Aging is a progressive degenerative process strictly integrated with inflammation. Several theories have been proposed that attempt to define the role of chronic inflammation in aging including redox stress, mitochondrial damage, immunosenescence, and epigenetic modifications. Here, we review the innate and adaptive immune systems and their senescent remodeling in elderly men with prostate cancer. PMID:24772169

  2. Exercise-Induced Skeletal Muscle Remodeling and Metabolic Adaptation: Redox Signaling and Role of Autophagy

    PubMed Central

    Giammarioli, Anna Maria; Chiandotto, Sergio; Spoletini, Ilaria

    2014-01-01

    Abstract Significance: Skeletal muscle is a highly plastic tissue. Exercise evokes signaling pathways that strongly modify myofiber metabolism and physiological and contractile properties of skeletal muscle. Regular physical activity is beneficial for health and is highly recommended for the prevention of several chronic conditions. In this review, we have focused our attention on the pathways that are known to mediate physical training-induced plasticity. Recent Advances: An important role for redox signaling has recently been proposed in exercise-mediated muscle remodeling and peroxisome proliferator-activated receptor γ (PPARγ) coactivator-1α (PGC-1α) activation. Still more currently, autophagy has also been found to be involved in metabolic adaptation to exercise. Critical Issues: Both redox signaling and autophagy are processes with ambivalent effects; they can be detrimental and beneficial, depending on their delicate balance. As such, understanding their role in the chain of events induced by exercise and leading to skeletal muscle remodeling is a very complicated matter. Moreover, the study of the signaling induced by exercise is made even more difficult by the fact that exercise can be performed with several different modalities, with this having different repercussions on adaptation. Future Directions: Unraveling the complexity of the molecular signaling triggered by exercise on skeletal muscle is crucial in order to define the therapeutic potentiality of physical training and to identify new pharmacological compounds that are able to reproduce some beneficial effects of exercise. In evaluating the effect of new “exercise mimetics,” it will also be necessary to take into account the involvement of reactive oxygen species, reactive nitrogen species, and autophagy and their controversial effects. Antioxid. Redox Signal. 21, 154–176. PMID:24450966

  3. 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…

  4. Towards a New Generation of Outward Bound.

    ERIC Educational Resources Information Center

    Martin, Andrew

    2000-01-01

    Outward Bound Czech Republic developed a course for international participants in which everybody is simultaneously an actor and viewer in a 2-week theater play. A five-stage process of developing "dramaturgy" allows instructors to adapt the scenario to participant needs and thus enhance the likelihood of challenge and transfer of…

  5. Effects of loading frequency on the functional adaptation of trabeculae predicted by bone remodeling simulation.

    PubMed

    Kameo, Yoshitaka; Adachi, Taiji; Hojo, Masaki

    2011-08-01

    The process of bone remodeling is regulated by metabolic activities of many bone cells. While osteoclasts and osteoblasts are responsible for bone resorption and formation, respectively, activities of these cells are believed to be controlled by a mechanosensory system of osteocytes embedded in the extracellular bone matrix. Several experimental and theoretical studies have suggested that the strain-derived interstitial fluid flow in lacuno-canalicular porosity serves as the prime mover for bone remodeling. Previously, we constructed a mathematical model for trabecular bone remodeling that interconnects the microscopic cellular activities with the macroscopic morphological changes in trabeculae through the mechanical hierarchy. This model assumes that fluid-induced shear stress acting on osteocyte processes is a driving force for bone remodeling. The validity of this model has been demonstrated with a remodeling simulation using a two-dimensional trabecular model. In this study, to investigate the effects of loading frequency, which is thought to be a significant mechanical factor in bone remodeling, we simulated morphological changes of a three-dimensional single trabecula under cyclic uniaxial loading with various frequencies. The results of the simulation show the trabecula reoriented to the loading direction with the progress of bone remodeling. Furthermore, as the imposed loading frequency increased, the diameter of the trabecula in the equilibrium state was enlarged by remodeling. These results indicate that our simulation model can successfully evaluate the relationship between loading frequency and trabecular bone remodeling.

  6. 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

  7. Adaptive Redox Response of Mesenchymal Stromal Cells to Stimulation with Lipopolysaccharide Inflammagen: Mechanisms of Remodeling of Tissue Barriers in Sepsis

    DTIC Science & Technology

    2013-03-08

    Mechanisms of Remodeling of Tissue Barriers in Sepsis Nikolai V. Gorbunov1*, Bradley R. Garrison1, Dennis P. McDaniel2, Min Zhai1, Pei-Jyun Liao1... sepsis [2, 5]. This problem leads to the searching for other potential mechanisms that could produce adverse effects on host metabolome resulting...understanding of the basic cellular mechanisms implicated in redox adaptive responses in 16 tissue barriers. This particular area of the molecular

  8. 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

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

    PubMed

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

    2016-02-01

    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.

  10. A finite element-based constrained mixture implementation for arterial growth, remodeling, and adaptation: theory and numerical verification.

    PubMed

    Valentín, A; Humphrey, J D; Holzapfel, G A

    2013-08-01

    We implemented a constrained mixture model of arterial growth and remodeling in a nonlinear finite element framework to facilitate numerical analyses of diverse cases of arterial adaptation and maladaptation, including disease progression, resulting in complex evolving geometries and compositions. This model enables hypothesis testing by predicting consequences of postulated characteristics of cell and matrix turnover, including evolving quantities and orientations of fibrillar constituents and nonhomogenous degradation of elastin or loss of smooth muscle function. The nonlinear finite element formulation is general within the context of arterial mechanics, but we restricted our present numerical verification to cylindrical geometries to allow comparisons with prior results for two special cases: uniform transmural changes in mass and differential growth and remodeling within a two-layered cylindrical model of the human aorta. The present finite element model recovers the results of these simplified semi-inverse analyses with good agreement.

  11. 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

  12. 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…

  13. 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.

  14. Coronary artery compliance and adaptive vessel remodelling in patients with stable and unstable coronary artery disease

    PubMed Central

    Jeremias, A; Spies, C; Herity, N; Pomerantsev, E; Yock, P; Fitzgerald, P; Yeung, A

    2000-01-01

    OBJECTIVE—To test the hypothesis that patients with unstable coronary syndromes show accentuated compensatory vessel enlargement compared with patients with stable angina, and that this may in part be related to increased coronary artery distensibility.
DESIGN AND PATIENTS—In 23 patients with unstable coronary syndromes (10 with non-Q wave myocardial infarction and 13 with unstable angina), the culprit lesion was investigated by intravascular ultrasound before intervention. The vessel cross sectional area (VA), lumen area (LA), and plaque area (VA minus LA) were measured at end diastole and end systole at the lesion site and at the proximal and distal reference segments. Similar measurements were made in 23 patients with stable angina admitted during the same period and matched for age, sex, and target vessel. Calculations were made of remodelling index (VA at lesion site ÷ VA at reference site), distensibility index ([(ΔA/A)/ΔP] × 103, where ΔA is the luminal area change in systole and diastole and ΔP the difference in systolic and diastolic blood pressure measured at the tip of the guiding catheter during a cardiac cycle), and stiffness index β ([ln(Psys/Pdias)]/(ΔD/D), where Psys is systolic pressure, Pdias is diastolic pressure, and ΔD is the difference between systolic and diastolic lumen diameters). Positive remodelling was defined as when the VA at the lesion was > 1.05 times larger than at the proximal reference site, and negative remodelling when the VA at the lesion was < 0.95 of the reference site.
RESULTS—Mean (SD) LA at the lesion site was similar in both groups (4.03 (1.8) v 4.01 (1.93) mm2), while plaque area was larger in the unstable group (13.29 (4.04) v 8.34 (3.6) mm2, p < 0.001). Remodelling index was greater in the unstable group (1.14 (0.18) v 0.83 (0.15), p < 0.001). Positive remodelling was observed in 15 patients in the unstable group (65%) but in only two (9%) in the stable group (p < 0

  15. Bone Microenvironment Specific Roles of ITAM Adapter Signaling during Bone Remodeling Induced by Acute Estrogen-Deficiency

    PubMed Central

    Wu, Yalei; Torchia, James; Yao, Wei; Lane, Nancy E.; Lanier, Lewis L.; Nakamura, Mary C.; Humphrey, Mary Beth

    2007-01-01

    Immunoreceptor tyrosine-based activation motif (ITAM) signaling mediated by DAP12 or Fcε receptor Iγ chain (FcRγ) have been shown to be critical for osteoclast differentiation and maturation under normal physiological conditions. Their function in pathological conditions is unknown. We studied the role of ITAM signaling during rapid bone remodeling induced by acute estrogen-deficiency in wild-type (WT), DAP12-deficient (DAP12-/-), FcRγ-deficient (FcRγ-/-) and double-deficient (DAP12-/-FcRγ-/-) mice. Six weeks after ovariectomy (OVX), DAP12-/-FcRγ-/- mice showed resistance to lumbar vertebral body (LVB) trabecular bone loss, while WT, DAP12-/- and FcRγ-/- mice had significant LVB bone loss. In contrast, all ITAM adapter-deficient mice responded to OVX with bone loss in both femur and tibia of approximately 40%, relative to basal bone volumes. Only WT mice developed significant cortical bone loss after OVX. In vitro studies showed microenvironmental changes induced by OVX are indispensable for enhanced osteoclast formation and function. Cytokine changes, including TGFβ and TNFα, were able to induce osteoclastogenesis independent of RANKL in BMMs from WT but not DAP12-/- and DAP12-/-FcRγ-/- mice. FSH stimulated RANKL-induced osteoclast differentiation from BMMs in WT, but not DAP12-/- and DAP12-/-FcRγ-/- mice. Our study demonstrates that although ITAM adapter signaling is critical for normal bone remodeling, estrogen-deficiency induces an ITAM adapter-independent bypass mechanism allowing for enhanced osteoclastogenesis and activation in specific bony microenvironments. PMID:17611621

  16. A Finite Element Based Constrained Mixture Implementation for Arterial Growth, Remodeling, and Adaptation: Theory and Numerical Verification

    PubMed Central

    Valentín, A.; Humphrey, J. D.; Holzapfel, G. A.

    2013-01-01

    We implemented a constrained mixture model of arterial growth and remodeling (G&R) in a nonlinear finite element framework to facilitate numerical analyses of diverse cases of arterial adaptation and maladaptation, including disease progression, resulting in complex evolving geometries and compositions. This model enables hypothesis testing by predicting consequences of postulated characteristics of cell and matrix turnover, including evolving quantities and orientations of fibrillar constituents and non-homogenous degradation of elastin or loss of smooth muscle function. The non-linear finite element formulation is general within the context of arterial mechanics, but we restricted our present numerical verification to cylindrical geometries to allow comparisons to prior results for two special cases: uniform transmural changes in mass and differential G&R within a two-layered cylindrical model of the human aorta. The present finite element model recovers the results of these simplified semi-inverse analyses with good agreement. PMID:23713058

  17. Myocardial β2-adrenoceptor gene delivery promotes coordinated cardiac adaptive remodelling and angiogenesis in heart failure

    PubMed Central

    Rengo, G; Zincarelli, C; Femminella, GD; Liccardo, D; Pagano, G; de Lucia, C; Altobelli, GG; Cimini, V; Ruggiero, D; Perrone-Filardi, P; Gao, E; Ferrara, N; Lymperopoulos, A; Koch, WJ; Leosco, D

    2012-01-01

    BACKGROUND AND PURPOSE We investigated whether β2-adrenoceptor overexpression could promote angiogenesis and improve blood perfusion and left ventricular (LV) remodeling of the failing heart. EXPERIMENTAL APPROACH We explored the angiogenic effects of β2-adrenoceptor overexpression in a rat model of post-myocardial infarction (MI) heart failure (HF). Cardiac adenoviral-mediated β2-adrenoceptor overexpression was obtained via direct intramyocardial injection 4-weeks post-MI. Adenovirus(Ad)-GFP and saline injected rats served as controls. Furthermore, we extended our observation to β2-adrenoceptor −/− mice undergoing MI. KEY RESULTS Transgenes were robustly expressed in the LV at 2 weeks post-gene therapy, whereas their expression was minimal at 4-weeks post-gene delivery. In HF rats, cardiac β2-adrenoceptor overexpression resulted in enhanced basal and isoprenaline-stimulated cardiac contractility at 2-weeks post-gene delivery. At 4 weeks post-gene transfer, Ad-β2-adrenoceptor HF rats showed improved LV remodeling and cardiac function. Importantly, β2-adrenoceptor overexpression was associated with a markedly increased capillary and arteriolar length density and enhanced in vivo myocardial blood flow and coronary reserve. At the molecular level, cardiac β2-adrenoceptor gene transfer induced the activation of the VEGF/PKB/eNOS pro-angiogenic pathway. In β2-adrenoceptor−/− mice, we found a ∼25% reduction in cardiac capillary density compared with β2-adrenoceptor+/+ mice. The lack of β2-adrenoceptors was associated with a higher mortality rate at 30 days and LV dilatation, and a worse global cardiac contractility compared with controls. CONCLUSIONS AND IMPLICATION β2-Adrenoceptors play an important role in the regulation of the angiogenic response in HF. The activation of VEGF/PKB/eNOS pathway seems to be strongly involved in this mechanism. PMID:22452704

  18. Teacher Education in Outward Bound.

    ERIC Educational Resources Information Center

    Robinson, Richard A.

    A series of Outward Bound programs and experiences was planned for El Paso County, Colorado, school teachers to increase their awareness of their personal characteristics, especially those that might enhance learning on the part of their students. Part of the planning for the program involved a survey of county high school teachers, counselors,…

  19. 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

  20. Some Educational Implications & Contributions of Outward Bound.

    ERIC Educational Resources Information Center

    Australian Outward Bound School, Sydney.

    The development of Outward Bound, from the early beginnings in Britain through expansion in over 30 locations throughout the world, is outlined, and Outward Bound educational aspects are analyzed in terms of the Australian Outward Bound School. The concepts of experiential education, lifelong education, and the broader Australian educational scene…

  1. Adaptive Chromatin Remodeling Drives Glioblastoma Stem Cell Plasticity and Drug Tolerance.

    PubMed

    Liau, Brian B; Sievers, Cem; Donohue, Laura K; Gillespie, Shawn M; Flavahan, William A; Miller, Tyler E; Venteicher, Andrew S; Hebert, Christine H; Carey, Christopher D; Rodig, Scott J; Shareef, Sarah J; Najm, Fadi J; van Galen, Peter; Wakimoto, Hiroaki; Cahill, Daniel P; Rich, Jeremy N; Aster, Jon C; Suvà, Mario L; Patel, Anoop P; Bernstein, Bradley E

    2017-02-02

    Glioblastoma, the most common and aggressive malignant brain tumor, is propagated by stem-like cancer cells refractory to existing therapies. Understanding the molecular mechanisms that control glioblastoma stem cell (GSC) proliferation and drug resistance may reveal opportunities for therapeutic interventions. Here we show that GSCs can reversibly transition to a slow-cycling, persistent state in response to targeted kinase inhibitors. In this state, GSCs upregulate primitive developmental programs and are dependent upon Notch signaling. This transition is accompanied by widespread redistribution of repressive histone methylation. Accordingly, persister GSCs upregulate, and are dependent on, the histone demethylases KDM6A/B. Slow-cycling cells with high Notch activity and histone demethylase expression are present in primary glioblastomas before treatment, potentially contributing to relapse. Our findings illustrate how cancer cells may hijack aspects of native developmental programs for deranged proliferation, adaptation, and tolerance. They also suggest strategies for eliminating refractory tumor cells by targeting epigenetic and developmental pathways.

  2. Are uniform regional safety factors an objective of adaptive modeling/remodeling in cortical bone?

    PubMed

    Skedros, John G; Dayton, Michael R; Sybrowsky, Christian L; Bloebaum, Roy D; Bachus, Kent N

    2003-07-01

    It has been hypothesized that a major objective of morphological adaptation in limb-bone diaphyses is the achievement of uniform regional safety factors between discrete cortical locations (e.g. between cranial and caudal cortices at mid-diaphysis). This hypothesis has been tested, and appears to be supported in the diaphyses of ovine and equine radii. The present study more rigorously examined this question using the equine third metacarpal (MC3), which has had functionally generated intracortical strains estimated by a sophisticated finite element model. Mechanical properties of multiple mid-diaphyseal specimens were evaluated in both tension and compression, allowing for testing of habitually tensed or compressed regions in their respective habitual loading mode ("strain-mode-specific" loading). Elastic modulus, and yield and ultimate strength and strain, were correlated with in vivo strain data from a previously published finite element model. Mechanical tests revealed minor variations in elastic modulus, and yield and ultimate strength in both tension and compression loading, while physiological strains varied significantly between the cortices. Contrary to the hypothesis of uniform safety factors, the MC3 has a broad range of tension (caudo-medial, 4.0; cranio-lateral, 37.7) and compression (caudo-medial, 5.7; cranio-lateral, 68.9) safety factors.

  3. Durum Wheat Roots Adapt to Salinity Remodeling the Cellular Content of Nitrogen Metabolites and Sucrose

    PubMed Central

    Annunziata, Maria Grazia; Ciarmiello, Loredana F.; Woodrow, Pasqualina; Maximova, Eugenia; Fuggi, Amodio; Carillo, Petronia

    2017-01-01

    Plants are currently experiencing increasing salinity problems due to irrigation with brackish water. Moreover, in fields, roots can grow in soils which show spatial variation in water content and salt concentration, also because of the type of irrigation. Salinity impairs crop growth and productivity by inhibiting many physiological and metabolic processes, in particular nitrate uptake, translocation, and assimilation. Salinity determines an increase of sap osmolality from about 305 mOsmol kg−1 in control roots to about 530 mOsmol kg−1 in roots under salinity. Root cells adapt to salinity by sequestering sodium in the vacuole, as a cheap osmoticum, and showing a rearrangement of few nitrogen-containing metabolites and sucrose in the cytosol, both for osmotic adjustment and oxidative stress protection, thus providing plant viability even at low nitrate levels. Mainly glycine betaine and sucrose at low nitrate concentration, and glycine betaine, asparagine and proline at high nitrate levels can be assumed responsible for the osmotic adjustment of the cytosol, the assimilation of the excess of ammonium and the scavenging of ROS under salinity. High nitrate plants with half of the root system under salinity accumulate proline and glutamine in both control and salt stressed split roots, revealing that osmotic adjustment is not a regional effect in plants. The expression level and enzymatic activities of asparagine synthetase and Δ1-pyrroline-5-carboxylate synthetase, as well as other enzymatic activities of nitrogen and carbon metabolism, are analyzed. PMID:28119716

  4. Determination of remodeling parameters for a strain-adaptive finite element model of the distal ulna.

    PubMed

    Neuert, Mark A C; Dunning, Cynthia E

    2013-09-01

    Strain energy-based adaptive material models are used to predict bone resorption resulting from stress shielding induced by prosthetic joint implants. Generally, such models are governed by two key parameters: a homeostatic strain-energy state (K) and a threshold deviation from this state required to initiate bone reformation (s). A refinement procedure has been performed to estimate these parameters in the femur and glenoid; this study investigates the specific influences of these parameters on resulting density distributions in the distal ulna. A finite element model of a human ulna was created using micro-computed tomography (µCT) data, initialized to a homogeneous density distribution, and subjected to approximate in vivo loading. Values for K and s were tested, and the resulting steady-state density distribution compared with values derived from µCT images. The sensitivity of these parameters to initial conditions was examined by altering the initial homogeneous density value. The refined model parameters selected were then applied to six additional human ulnae to determine their performance across individuals. Model accuracy using the refined parameters was found to be comparable with that found in previous studies of the glenoid and femur, and gross bone structures, such as the cortical shell and medullary canal, were reproduced. The model was found to be insensitive to initial conditions; however, a fair degree of variation was observed between the six specimens. This work represents an important contribution to the study of changes in load transfer in the distal ulna following the implementation of commercial orthopedic implants.

  5. Architecture of the Flagellar Switch Complex of Escherichia coli: Conformational Plasticity of FliG and Implications for Adaptive Remodeling.

    PubMed

    Kim, Eun A; Panushka, Joseph; Meyer, Trevor; Carlisle, Ryan; Baker, Samantha; Ide, Nicholas; Lynch, Michael; Crane, Brian R; Blair, David F

    2017-03-01

    Structural models of the complex that regulates the direction of flagellar rotation assume either ~34 or ~25 copies of the protein FliG. Support for ~34 came from cross-linking experiments identifying an inter-subunit contact most consistent with that number; support for ~25 came from the observation that flagella can assemble and rotate when FliG is genetically fused to FliF, for which the accepted number is ~25. Here, we have undertaken cross-linking and other experiments to address more fully the question of FliG number. The results indicate a copy number of ~25 for FliG. An interaction between the C-terminal and middle domains, which has been taken to support a model with ~34 copies, is also supported. To reconcile the interaction with a FliG number of ~25, we hypothesize conformational plasticity in an inter-domain segment of FliG that allows some subunits to bridge gaps created by the number mismatch. This proposal is supported by mutant phenotypes and other results indicating that the normally helical segment adopts a more extended conformation in some subunits. The FliG amino-terminal domain is organized in a regular array with dimensions matching a ring in the upper part of the complex. The model predicts that FliG copy number should be tied to that of FliF, whereas FliM copy number can increase or decrease according to the number of FliG subunits that adopt the extended conformation. This has implications for the phenomenon of adaptive switch remodeling, in which FliM the copy number varies to adjust the bias of the switch.

  6. 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

  7. 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,…

  8. Outward Bound: an Experience in Human Development

    ERIC Educational Resources Information Center

    Danenburg, William; Gaggi, Silvio

    1974-01-01

    Two authors describe how their participation in an outward bound program has helped them develop a greater degree of general self confidence, greater ease in dealing with complex and frustrating problems, and a greater appreciation of man's place in the natural environment. They also describe Outward Bound courses that have been especially…

  9. Molecular Aspects of Exercise-induced Cardiac Remodeling.

    PubMed

    Bernardo, Bianca C; McMullen, Julie R

    2016-11-01

    Exercise-induced cardiac remodeling is typically an adaptive response associated with cardiac myocyte hypertrophy and renewal, increased cardiac myocyte contractility, sarcomeric remodeling, cell survival, metabolic and mitochondrial adaptations, electrical remodeling, and angiogenesis. Initiating stimuli/triggers of cardiac remodeling include increased hemodynamic load, increased sympathetic activity, and the release of hormones and growth factors. Prolonged and strenuous exercise may lead to maladaptive exercise-induced cardiac remodeling including cardiac dysfunction and arrhythmia. In addition, this article describes novel therapeutic approaches for the treatment of heart failure that target mechanisms responsible for adaptive exercise-induced cardiac remodeling, which are being developed and tested in preclinical models.

  10. 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…

  11. 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…

  12. Colorado Outward Bound School Rafting Manual.

    ERIC Educational Resources Information Center

    Brown, Al

    River rafting trips at the Colorado Outward Bound School (COBS) present participants with an opportunity for developing self-confidence, self-awareness, and concern for others through challenging and adventuresome group effort, combined with a program of instruction in rafting skills, safety consciousness, and awareness of the natural environment.…

  13. Retinal remodeling.

    PubMed

    Jones, B W; Kondo, M; Terasaki, H; Lin, Y; McCall, M; Marc, R E

    2012-07-01

    Retinal photoreceptor degeneration takes many forms. Mutations in rhodopsin genes or disorders of the retinal pigment epithelium, defects in the adenosine triphosphate binding cassette transporter, ABCR gene defects, receptor tyrosine kinase defects, ciliopathies and transport defects, defects in both transducin and arrestin, defects in rod cyclic guanosine 3',5'-monophosphate phosphodiesterase, peripherin defects, defects in metabotropic glutamate receptors, synthetic enzymatic defects, defects in genes associated with signaling, and many more can all result in retinal degenerative disease like retinitis pigmentosa (RP) or RP-like disorders. Age-related macular degeneration (AMD) and AMD-like disorders are possibly due to a constellation of potential gene targets and gene/gene interactions, while other defects result in diabetic retinopathy or glaucoma. However, all of these insults as well as traumatic insults to the retina result in retinal remodeling. Retinal remodeling is a universal finding subsequent to retinal degenerative disease that results in deafferentation of the neural retina from photoreceptor input as downstream neuronal elements respond to loss of input with negative plasticity. This negative plasticity is not passive in the face of photoreceptor degeneration, with a phased revision of retinal structure and function found at the molecular, synaptic, cell, and tissue levels involving all cell classes in the retina, including neurons and glia. Retinal remodeling has direct implications for the rescue of vision loss through bionic or biological approaches, as circuit revision in the retina corrupts any potential surrogate photoreceptor input to a remnant neural retina. However, there are a number of potential opportunities for intervention that are revealed through the study of retinal remodeling, including therapies that are designed to slow down photoreceptor loss, interventions that are designed to limit or arrest remodeling events, and

  14. 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

  15. 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.

  16. Molecular mechanisms of regulation of fast-inactivating voltage-dependent transient outward K+ current in mouse heart by cell volume changes

    PubMed Central

    Wang, Guan-Lei; Wang, Ge-Xin; Yamamoto, Shintaro; Ye, Linda; Baxter, Heather; Hume, Joseph R; Duan, Dayue

    2005-01-01

    The Kv4.2/4.3 channels are the primary subunits that contribute to the fast-inactivating, voltage-dependent transient outward K+ current (Ito,fast) in the heart. Ito,fast is the critical determinant of the early repolarization of the cardiac action potential and plays an important role in the adaptive remodelling of cardiac myocytes, which usually causes cell volume changes, during myocardial ischaemia, hypertrophy and heart failure. It is not known, however, whether Ito,fast is regulated by cell volume changes. In this study we investigated the molecular mechanism for cell volume regulation of Ito,fast in native mouse left ventricular myocytes. Hyposmotic cell swelling caused a marked increase in densities of the peak Ito,fast and a significant shortening in phase 1 repolarization of the action potential duration. The voltage-dependent gating properties of Ito,fast were, however, not altered by changes in cell volume. In the presence of either protein kinase C (PKC) activator (12,13-dibutyrate) or phosphatase inhibitors (calyculin A and okadaic acid), hyposmotic cell swelling failed to further up-regulate Ito,fast. When expressed in NIH/3T3 cells, both Kv4.2 and Kv4.3 channels were also strongly regulated by cell volume in the same voltage-independent but PKC- and phosphatase-dependent manner as seen in Ito,fast in the native cardiac myocytes. We conclude that Kv4.2/4.3 channels in the heart are regulated by cell volume through a phosphorylation/dephosphorylation pathway mediated by PKC and serine/threonine phosphatase(s). These findings suggest a novel role of Kv4.2/4.3 channels in the adaptive electrical and structural remodelling of cardiac myocytes in response to myocardial hypertrophy, ischaemia and reperfusion. PMID:16081489

  17. Outward Bound Outcome Model Validation and Multilevel Modeling

    ERIC Educational Resources Information Center

    Luo, Yuan-Chun

    2011-01-01

    This study was intended to measure construct validity for the Outward Bound Outcomes Instrument (OBOI) and to predict outcome achievement from individual characteristics and course attributes using multilevel modeling. A sample of 2,340 participants was collected by Outward Bound USA between May and September 2009 using the OBOI. Two phases of…

  18. Outward Bound: The Congruence of Principles and Practice.

    ERIC Educational Resources Information Center

    Estes, Cheryl A.

    Since its inception in 1941, Outward Bound has retained certain core values, but some instructors and administrators have been concerned that these principles are no longer being conveyed in practice. With the collaboration of 13 experts, the 11 principles of Outward Bound programs in the United States were identified and defined. These principles…

  19. 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

  20. Teaching resources. Chromatin remodeling.

    PubMed

    Lue, Neal F

    2005-07-26

    This Teaching Resource provides lecture notes and slides for a class covering chromatin remodeling mechanisms and is part of the course "Cell Signaling Systems: a Course for Graduate Students." The lecture begins with a discussion of chromatin organization and then proceeds to describe the process of chromatin remodeling through a review of chromatin remodeling complexes and methods used to study their function.

  1. Activation of outward K+ currents: effect of VIP in oesophagus

    PubMed Central

    Jury, Jennifer; Daniel, Edwin E

    1999-01-01

    Electrical field stimulations (EFS) of the opossum and canine lower oesophageal sphincters (OLOS and CLOS respectively) and opossum oesophageal body circular muscle (OOBCM) induce non-adrenergic, non-cholinergic (NANC) relaxations of any active tension and NO-mediated hyperpolarization. VIP relaxes the OLOS and CLOS and any tone in OOBCM without major electrophysiological effects. These relaxations are not blocked by NOS inhibitors. Using isolated smooth muscle cells, we tested whether VIP acted through myogenic NO production.Outward currents were similar in OOBCM and OLOS and NO increased them regardless of pipette Ca2+i, from 50–8000 nM. L-NAME or L-NOARG did not block outward currents in OLOS at 200 nM pipette Ca2+.Outward currents in CLOS cells decreased at 200 nM pipette Ca2+ or less but NO donors still increased them. VIP had no effect on outward currents in cells from OOBCM, OLOS or CLOS under conditions of pipette Ca2+ at which NO donors increased outward K+ currents.We conclude, VIP does not mimic electrophysiological effects of NO donors on isolated cells of OOBCM, OLOS or CLOS. VIP relaxes the OLOS and CLOS and inhibits contraction of OOBCM by a mechanism unrelated to release of myogenic NO or an increase in outward current.Also, the different dependence of outward currents of OOBCM and OLOS on pipette Ca2+ from those of CLOS suggests that different K+ channels are involved and that myogenic NO production contributes to K+ channel activity in CLOS but not in OLOS or OOBCM. PMID:10385258

  2. Outward currents in Drosophila larval neurons: dunce lacks a maintained outward current component downregulated by cAMP.

    PubMed

    Delgado, R; Davis, R; Bono, M R; Latorre, R; Labarca, P

    1998-02-15

    Outward current modulation by cAMP was investigated in wild type (wt) and dunce (dnc) Drosophila larval neurons. dnc is deficient in a cAMP phosphodiesterase and has altered memory. Outward current modulation by cAMP was investigated by acute or chronic exposure to cAMP analogs. The analysis included a scrutiny of outward current modulation by cAMP in neurons from the mushroom bodies (mrb). In Drosophila, the mrb are the centers of olfactory acquisition and retention. Based on outward current patterns, neurons were classified into four types. Downmodulation of outward currents induced by acute application of cAMP analogs was reversible and found only in type I and type IV neurons. In the general wt neuron population, approximately half of neurons exhibited cAMP-modulated, 4-aminopyridine (4-AP)-sensitive currents. On the other hand, a significantly larger fraction of mrb neurons in wt (70%) was endowed with cAMP-modulated, 4-AP-sensitive currents. Only 30% of the dnc neurons displayed outward currents modulated by cAMP. The deficit of cAMP-modulated outward currents was most severe in neurons derived from the mrb of dnc individuals. Only 4% of the mrb neurons of dnc were cAMP-modulated. The dnc defect can be induced by chronic exposure of wt neurons to cAMP analogs. These results document for the first time a well defined electrophysiological neuron phenotype in correlation with the dnc defect. Moreover, this study demonstrates that in dnc mutants such a deficiency affects most severely neurons in brain centers of acquisition and retention.

  3. 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…

  4. Outward Motions of SiO Masers around VX Sgr

    NASA Astrophysics Data System (ADS)

    Su, J. B.; Shen, Z.-Q.; Chen, X.; Jiang, D. R.

    2014-09-01

    We report the proper motions of SiO maser features around VX Sgr from the two-epoch VLBA observations (2006 December 15 and 2007 August 19). The majority of maser feature activities show a trend of outward motions. It is consistent with our previous finding that the outflow may play an important role for SiO maser pumping.

  5. The Instructor's Handbook: North Carolina Outward Bound School.

    ERIC Educational Resources Information Center

    Outward Bound, Morganton, NC.

    To assist North Carolina Outward Bound School instructors in their responsibilities of ensuring that each student is able to achieve safely the objectives of developing self-confidence, concern for others, and self-awareness when confronted by 21 to 28 days of challenging, shared experience involving service and adventure, this revised fourth…

  6. Instructor's Manual, Revised 1976. Colorado Outward Bound School.

    ERIC Educational Resources Information Center

    Colorado Outward Bound School, Denver.

    Providing traditional knowledge and skills, the Colorado Outward Bound School (COBS) program has developed its program around a training phase, an expedition, solo, final expedition, and concluding phase. Intended to be an experiential learning experience that encourages students to become involved in exploring new or unusual areas of their lives,…

  7. The Conscious Use of Metaphor in Outward Bound.

    ERIC Educational Resources Information Center

    Bacon, Stephen Barcia

    Learning is a metaphoric function in which the individual confirms or reorders his sense of reality by relating previous experiences with present ones. Outward Bound, an experiential learning approach, incorporates this insight in its theoretical foundations. The effectiveness of the metaphor is dependent on the extent to which the experience is…

  8. 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…

  9. An Investigation of the Outward Bound Final Expedition

    ERIC Educational Resources Information Center

    Bobilya, Andrew J.; Kalisch, Ken; Daniel, Brad

    2011-01-01

    Research of wilderness programs indicates a clear need for additional investigation of specific program components and their influence on participant outcomes. This study examines one component of the Outward Bound wilderness program--the Final Expedition. The Final Expedition is a student-led wilderness expedition and is also referred to as an…

  10. Comparing Outward Bound and National Outdoor Leadership School Participant Experiences

    ERIC Educational Resources Information Center

    Goldenberg, Marni; Russell, Keith C.; Soule, Katherine

    2011-01-01

    This study explores differences between Outward Bound (OB) and National Outdoor Leadership School (NOLS) participant perspectives on programmatic factors and their relation to outcomes. Although OB and NOLS are assumed to be similar in many ways, as each program offers wilderness expeditions for students in backcountry environments, the mission…

  11. Research on the Outward Bound Process: Implications for Practice.

    ERIC Educational Resources Information Center

    McKenzie, Marcia

    2002-01-01

    Interviews and surveys of 98 students and 7 instructors in Outward Bound Canada found that specific aspects of course activities, the physical environment, instructors, and participants influenced course outcomes. As role models, instructors made a greater contribution to student interpersonal skills than most other course components. Implications…

  12. Beyond "The Outward Bound Process": Rethinking Student Learning.

    ERIC Educational Resources Information Center

    McKenzie, Marcia

    2003-01-01

    A study examined how 28 components of Outward Bound Western Canada (OBWC) courses affected student self-concept, motivation, and interpersonal skills. Data from questionnaires, interviews, and observations of 92 OBWC students generally supported previous research, but also indicated that the objectives of compassion and service received less…

  13. 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…

  14. Adaptation.

    PubMed

    Broom, Donald M

    2006-01-01

    The term adaptation is used in biology in three different ways. It may refer to changes which occur at the cell and organ level, or at the individual level, or at the level of gene action and evolutionary processes. Adaptation by cells, especially nerve cells helps in: communication within the body, the distinguishing of stimuli, the avoidance of overload and the conservation of energy. The time course and complexity of these mechanisms varies. Adaptive characters of organisms, including adaptive behaviours, increase fitness so this adaptation is evolutionary. The major part of this paper concerns adaptation by individuals and its relationships to welfare. In complex animals, feed forward control is widely used. Individuals predict problems and adapt by acting before the environmental effect is substantial. Much of adaptation involves brain control and animals have a set of needs, located in the brain and acting largely via motivational mechanisms, to regulate life. Needs may be for resources but are also for actions and stimuli which are part of the mechanism which has evolved to obtain the resources. Hence pigs do not just need food but need to be able to carry out actions like rooting in earth or manipulating materials which are part of foraging behaviour. The welfare of an individual is its state as regards its attempts to cope with its environment. This state includes various adaptive mechanisms including feelings and those which cope with disease. The part of welfare which is concerned with coping with pathology is health. Disease, which implies some significant effect of pathology, always results in poor welfare. Welfare varies over a range from very good, when adaptation is effective and there are feelings of pleasure or contentment, to very poor. A key point concerning the concept of individual adaptation in relation to welfare is that welfare may be good or poor while adaptation is occurring. Some adaptation is very easy and energetically cheap and

  15. Remodeling A School Shop?

    ERIC Educational Resources Information Center

    Baker, G. E.

    1970-01-01

    Presents guidelines for remodeling a school shop combining major considerations of funds, program changes, class management, and flexibility, with the needs of wiring, painting, and placement of equipment. (Author)

  16. 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

  17. Acid-sensitive outwardly rectifying anion channels in human erythrocytes.

    PubMed

    Kucherenko, Yuliya V; Mörsdorf, Daniel; Lang, Florian

    2009-07-01

    Acid-sensitive outwardly rectifying anion channels (ASOR) have been described in several mammalian cell types. The present whole-cell patch-clamp study elucidated whether those channels are expressed in erythrocytes. To this end whole-cell recordings were made in human erythrocytes from healthy donors treated with low pH and high osmotic pressure. When the pipette solution had a reduced Cl(-) concentration, treatment of the cells with Cl(-)-containing normal and hyperosmotic (addition of sucrose and polyethelene glycol 1000 [PEG-1000] to the Ringer) media with low pH significantly increased the conductance of the cells at positive voltages. Channel activity was highest in the PEG-1000 media (95 and 300 mM PEG-1000, pH 4.5 and 4.3, respectively) where the current-voltage curves demonstrated strong outward rectification and reversed at -40 mV. Substitution of the Cl(-)-containing medium with Cl(-)-free medium resulted in a decrease of the conductance at hyperpolarizing voltages, a shift in reversal potential (to 0 mV) and loss of outward rectification. The chloride currents were inhibited by chloride channels blockers DIDS and NPPB (IC(50) for both was approximately 1 mM) but not with niflumic acid and amiloride. The observations reveal expression of ASOR in erythrocytes.

  18. Effects of allitridum on the transient outward potassium current in rats with heart failure

    PubMed Central

    Zhao, Xiao-Jing; Lin, Kun; Zhang, Yu; Xu, Bin; Liu, Li; Fu, Yi-Cheng; Chen, Xi; Cai, Zhong-Qi; Wu, Zhi-Juan; Huang, Yun; Li, Yang

    2016-01-01

    Objective To study the effect of allitridum on the transient outward potassium current (Ito) of ventricular myocytes in heart failure (HF). Methods The dual enzymatic method was used to separate single ventricular myocytes from Sprague Dawley rats. Patch-clamping was used to record Ito and analyze the effect of allitridum on the current. Results The Ito current had a significant decrease in the HF group, compared with the control group. The density of Ito in the HF group was increased after treatment of allitridum (30 µmol/L). The peak current densities of Ito were enhanced in the HF group from 6.01 ± 0.30 pA/pF to 8.41 ± 0.54 pA/pF (P < 0.01) at +50 mV after treatment with allitridum (30 µmol/L). We also determined the effect of allitridum on the gating mechanism of the Ito in the HF group. Conclusions We found that allitridum increased the Ito by accelerating the activation of channels and shortened the time constants of inactivation, and allitridum decreased the remodeling of Ito in ventricular myocytes of rats with HF. PMID:27899943

  19. 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

  20. Considerations on the Outward Migration of Jupiter and Saturn

    NASA Astrophysics Data System (ADS)

    D'Angelo, G.; Marzari, F.

    2011-12-01

    It has been proposed that the outward orbital migration of Jupiter and Saturn, driven by a gas-dominated protosolar disk, may help explain why they did not move much closer to the Sun. It has also been suggested that some properties of the inner Solar System may be interpreted by invoking an inward migration of Jupiter and Saturn followed by outward migration, once they get caught in the 2:3 mean motion resonance. Hydrodynamical calculations indicate that outward migration of a compact Jupiter-Saturn system may arise from an imbalance between positive and negative Lindblad torques exerted on Jupiter by the disk. The torque density distribution acting on Jupiter extends over ~3 Hill radii on either side of the planet's orbit. The negative part of the distribution samples outer disk portions, partially depleted by the tidal perturbations of both planets. The positive part of the distribution samples inner disk portions, depleted only by the action of Jupiter. The net result may be a positive torque exerted on Jupiter. Saturn, trapped in resonance with Jupiter, migrates outward as well. This mechanism requires the exterior planet's mass not to exceed the interior planet's mass. Thus, it is assumed that neither planet accretes gas from the disk. Yet, models of giant planet formation indicate that these planets would accrete gas at whatever rate the disk provides (Lissauer et al., 2009, Icarus, 199, 338). We performed 2D and 3D hydrodynamical calculations of a Jupiter-Saturn system tidally interacting with a protoplanetary disk and investigated how gas accretion affects their migration history. We assumed initial conditions shown to result in the outward migration of non-accreting planets and recovered such scenario. We then allowed the planets to accrete gas at a disk-limited rate. In agreement with estimates derived for single planets, the assumed disk conditions lead to a mass-doubling time scale of the exterior planet that is 6-9 times as short as that of interior

  1. An Investigation of the Interface between Corporate Leadership Needs and the Outward Bound Experience.

    ERIC Educational Resources Information Center

    Isenhart, Myra W.

    1983-01-01

    Relates leadership needs in corporate organizations with the experiential learning in Outward Bound courses. Explores the value of Outward Bound inductive learning in developing management and leadership potential on three organizational levels--supervisory, middle management, and executive. (PD)

  2. 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

  3. 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.

  4. Three Examples of Service Learning: The Changing Role of Service in Outward Bound.

    ERIC Educational Resources Information Center

    MacArthur, Robert S.

    1982-01-01

    Addresses Outward Bound's redirection and rededication of service by taking a closer look at Hahn's philosophy of service and the models provided by various service-learning programs outside of Outward Bound. Examples which highlight major issues involved are Outward Bound Living/Learning Term and Tucker Foundation at Dartmouth College. (ERB)

  5. 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

  6. 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

  7. Remodeling the Media Center.

    ERIC Educational Resources Information Center

    Baule, Steven M.

    1998-01-01

    Discusses items that need to be considered when remodeling a school media center. Highlights include space and location for various functions, including projections of print versus electronic media; electrical and data wiring needs; lighting; security and supervision; and reuse of existing furniture and equipment. (LRW)

  8. Immune modulation of resistance artery remodelling.

    PubMed

    Schiffrin, Ernesto L

    2012-01-01

    Low-grade inflammation plays a role in cardiovascular disease. The innate and the adaptive immune responses participate in mechanisms that contribute to inflammatory responses. It has been increasingly appreciated that different subsets of lymphocytes and the cytokines they produce modulate the vascular remodelling that occurs in cardiovascular disease. Effector T cells such as T-helper (Th) 1 (interferon-γ-producing) and Th2 lymphocytes (that produce interleukin-4), as well as Th17 (that produce interleukin-17), and T suppressor lymphocytes including regulatory T cells (Treg), which express the transcription factor forkhead box P3 (Foxp3), are involved in the remodelling of small arteries that occurs under the action of angiotensin II, deoxycorticosterone-salt and aldosterone-salt, as well as in models of hypertension such as the Dahl-salt-sensitive rat. The mechanism whereby the immune system is activated is unclear, but it has been suggested that neo-antigens may be generated by the elevation of blood pressure or other stimuli, leading to the activation of the immune response. Activated Th1 may contribute to vascular remodelling directly on blood vessels via effects of the cytokines produced or indirectly by actions on the kidney. The protective effect of Treg may be mediated similarly directly or via renal effects. These data offer promise for the discovery of new therapeutic targets to ameliorate vascular remodelling, which could lead to improved outcome in cardiovascular disease in humans.

  9. Evidence of outward flow of plasma in a coronal hole

    NASA Technical Reports Server (NTRS)

    Cushman, G. W.; Rense, W. A.

    1976-01-01

    The solar spectrum was photographed in the range 200-700 A with a grazing-incidence stigmatic rocket spectrograph. Doppler shifts of the three coronal lines Si XI (303 A), Mg X (610 A), and Mg IX (368 A) were measured for various regions of the solar disk, including a coronal hole. From the relative shifts in the latter region, an average outward velocity of 16 km/s was computed for the plasma in the coronal hole. The full widths at half-maximum for the above lines were appreciably less in the coronal-hole region than in a quiet region, indicating a lower temperature in the hole. Both the measured velocity and the temperature results are consistent with solar-wind data and with current theories of coronal holes.

  10. 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

  11. Calcium-induced transitions between the spontaneous miniature outward and the transient outward currents in retinal amacrine cells.

    PubMed

    Mitra, Pratip; Slaughter, Malcolm M

    2002-04-01

    Spontaneous miniature outward currents (SMOCs) occur in a subset of retinal amacrine cells at membrane potentials between -60 and -40 mV. At more depolarized potentials, a transient outward current (I(to)) appears and SMOCs disappear. Both SMOCs and the I(to) are K(+) currents carried by BK channels. They both arise from Ca(2+) influx through high voltage-activated (HVA) Ca(2+) channels, which stimulates release of internal Ca(2+) from caffeine- and ryanodine-sensitive stores. An increase in Ca(2+) influx resulted in an increase in SMOC frequency, but also led to a decline in SMOC mean amplitude. This reduction showed a temporal dependence: the effect being greater in the latter part of a voltage step. Thus, Ca(2+) influx, although required to generate SMOCs, also produced a negative modulation of their amplitudes. Increasing Ca(2+) influx also led to a decline in the first latency to SMOC occurrence. A combination of these effects resulted in the disappearance of SMOCs, along with the concomitant appearance of the I(to) at high levels of Ca(2+) influx. Therefore, low levels of Ca(2+) influx, arising from low levels of activation of the HVA Ca(2+) channels, produce randomly occurring SMOCs within the range of -60 to -40 mV. Further depolarization leads to greater activation of the HVA Ca(2+) channels, larger Ca(2+) influx, and the disappearance of discontinuous SMOCs, along with the appearance of the I(to). Based on their characteristics, SMOCs in retinal neurons may function as synaptic noise suppressors at quiescent glutamatergic synapses.

  12. Chromatin Remodeling and Plant Immunity.

    PubMed

    Chen, W; Zhu, Q; Liu, Y; Zhang, Q

    2017-01-01

    Chromatin remodeling, an important facet of the regulation of gene expression in eukaryotes, is performed by two major types of multisubunit complexes, covalent histone- or DNA-modifying complexes, and ATP-dependent chromosome remodeling complexes. Snf2 family DNA-dependent ATPases constitute the catalytic subunits of ATP-dependent chromosome remodeling complexes, which accounts for energy supply during chromatin remodeling. Increasing evidence indicates a critical role of chromatin remodeling in the establishment of long-lasting, even transgenerational immune memory in plants, which is supported by the findings that DNA methylation, histone deacetylation, and histone methylation can prime the promoters of immune-related genes required for disease defense. So what are the links between Snf2-mediated ATP-dependent chromosome remodeling and plant immunity, and what mechanisms might support its involvement in disease resistance?

  13. 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

  14. 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.

  15. Outward Bound and Confluent Education: A Demonstration Project Accentuating Affective Learning.

    ERIC Educational Resources Information Center

    Nadler, Reldan S.

    In 1976 a demonstration project at the Connecticut Wilderness School integrated a Confluent Education curriculum in Outward Bound type courses, to facilitate affective learning for a more meaningful and relevant experience. A review of Outward Bound literature identified the need for affective learning as a significant program constituent. Five…

  16. Outward Bound U.S.A.: Learning Through Experience in Adventure-Based Education.

    ERIC Educational Resources Information Center

    Miner, Joshua L.; Boldt, Joe

    Joshua Miner recounts his 30 years' experience with people and places significant to the history of Adventure-Based Education and Outward Bound in the United States. Fourteen Outward Bound schools visited or assisted by Miner are described in chapters recording events such as the school's inception, daily activities, individuals enrolled, and…

  17. A Means-End Investigation of Outcomes Associated with Outward Bound and NOLS Programs

    ERIC Educational Resources Information Center

    Goldenberg, Marni; Pronsolino, Dan

    2008-01-01

    This study compares outcomes associated with participation in Outward Bound (OB) and National Outdoor Leadership Schools (NOLS) courses in the United States. OB and NOLS (two of the largest providers of outdoor adventure education [OAE] courses) combined saw more than 30,000 students in 2006 (NOLS, n.d.; Outward Bound, n.d.). Comparing these two…

  18. From "Character-Training" to "Personal Growth": The Early History of Outward Bound 1941-1965

    ERIC Educational Resources Information Center

    Freeman, Mark

    2011-01-01

    This article examines the approach to "character training" in the early years of the Outward Bound movement in Britain between c.1940 and c.1965. It examines the key components of the concept of "character-training" promoted in the Outward Bound schools by Kurt Hahn and his early followers, and some of the criticisms to which…

  19. Outward Bound Giwaykiwin: Connecting to Land and Culture through Indigenous Outdoor Education

    ERIC Educational Resources Information Center

    Lowan, Greg

    2007-01-01

    Outward Bound Canada's (OBC) Giwaykiwin Program was founded in 1985 in response to a recognized need for programming specific to students from Indigenous backgrounds. The Giwaykiwin program aims to integrate Outward Bound (OB) and Indigenous philosophies and traditions. Giwaykiwin means "coming home" in Ojibwa and signifies the program's…

  20. CRITERIA FOR DECIDING TO REMODEL THE EXISTING SCHOOL.

    ERIC Educational Resources Information Center

    SHOBE, EARL J.

    MODERNIZATION OF SCHOOL BUILDINGS REQUIRES ADAPTATION OF EDUCATIONAL AND ENVIRONMENTAL REQUIREMENTS. PRELIMINARY ANALYSIS OF--(1) CONSTRUCTION QUALITY, (2) ROOM SIZE, (3) SITE CAPABILITY, AND (4) ARCHITECTURAL REMODELING POTENTIAL HELPS TO DETERMINE FEASIBILITY AND APPROACH METHOD. ANALYSIS OF FIVE APPROACHES FOR CREATING ADDITIONS TO A SPECIFIC…

  1. 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.

  2. 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.

  3. Effects of calcium ions on outward membrane currents in rat uterine smooth muscle.

    PubMed Central

    Mironneau, J; Savineau, J P

    1980-01-01

    1. The outward membrane current underlying delayed rectification in uterine smooth muscle has been studied by means of a double sucrose gap apparatus with particular reference to the effects of the external calcium. 2. The outward current was reversibly reduced in calcium-free solution and in the presence of manganese (5 mM), or increased in high-calcium solution. 3. In reference solution, when depolarizing steps activated the outward current to its maximal value, the current tails measured at the end of the pulse were made up of two exponentially declining components. The slower of the two components was suppressed in calcium-free solution. The fast component reached full, steady-state activation at about +75 mV and the slow one at less positive potentials, i.e. +50 mV. Altering the external calcium did not shift the activation curves of the outward current along the voltage axis. 4. The reversal potential of the outward current was not affected by alterations of the external calcium concentration. 5. The outward current components can also be separated on the basis of their sensitivity to 4-aminopyridine (4-AP) and tetracethylammonium (TEA). The fast component was selectively blocked by externally applied 4-AP. TEA blocked both fast and slow components. 6. It is suggested that two sets of potassium channels contribute to the outward current in myometrium and that these channels can be separated pharmacologically. PMID:7411461

  4. 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

  5. Interstitial fluid flow in canaliculi as a mechanical stimulus for cancellous bone remodeling: in silico validation.

    PubMed

    Kameo, Yoshitaka; Adachi, Taiji

    2014-08-01

    Cancellous bone has a dynamic 3-dimensional architecture of trabeculae, the arrangement of which is continually reorganized via bone remodeling to adapt to the mechanical environment. Osteocytes are currently believed to be the major mechanosensory cells and to regulate osteoclastic bone resorption and osteoblastic bone formation in response to mechanical stimuli. We previously developed a mathematical model of trabecular bone remodeling incorporating the possible mechanisms of cellular mechanosensing and intercellular communication in which we assumed that interstitial fluid flow activates the osteocytes to regulate bone remodeling. While the proposed model has been validated by the simulation of remodeling of a single trabecula, it remains unclear whether it can successfully represent in silico the functional adaptation of cancellous bone with its multiple trabeculae. In the present study, we demonstrated the response of cancellous bone morphology to uniaxial or bending loads using a combination of our remodeling model with the voxel finite element method. In this simulation, cancellous bone with randomly arranged trabeculae remodeled to form a well-organized architecture oriented parallel to the direction of loading, in agreement with the previous simulation results and experimental findings. These results suggested that our mathematical model for trabecular bone remodeling enables us to predict the reorganization of cancellous bone architecture from cellular activities. Furthermore, our remodeling model can represent the phenomenological law of bone transformation toward a locally uniform state of stress or strain at the trabecular level.

  6. Building and Remodeling Synapses

    PubMed Central

    Benson, Deanna L.; Huntley, George W.

    2011-01-01

    Synaptic junctions are generated by adhesion proteins that bridge the synaptic cleft to firmly anchor pre- and postsynaptic membranes. Several cell adhesion molecule (CAM) families localize to synapses, but it is not yet completely understood how each synaptic CAM family contributes to synapse formation and/or structure, and whether or how smaller groups of CAMs serve as minimal, functionally cooperative adhesive units upon which structure is based. Synapse structure and function evolve over the course of development, and in mature animals, synapses are composed of a greater number of proteins, surrounded by a stabilizing extracellular matrix, and often contacted by astrocytic processes. Thus, in mature networks undergoing plasticity, persistent changes in synapse strength, morphology or number must be accompanied by selective and regulated remodeling of the neuropil. Recent work indicates that regulated, extracellular proteolysis may be essential for this, and rather than simply acting permissively to enable synapse plasticity, is more likely playing a proactive role in driving coordinated synaptic structural and functional modifications that underlie persistent changes in network activity. PMID:20882551

  7. Outward Bound Bridging Course 1981: An Investigation and Evaluation of an Outward Bound Remedial Programme (Unlocking Achievement Ability through Experiential Education).

    ERIC Educational Resources Information Center

    Richards, Garry E.; Richards, Mary J. F.

    In 1981, 12 under-achieving boys (average age 15 years) from a Sydney (Australia) inner-city Catholic school with a predominantly low socio-economic and high ethnic population were exposed to a 6-week long residential Outward Bound Bridging Course Remedial Programme. The aim of the programme was to produce significant gains in the cognitive…

  8. Regulation and impairments of dynamic desmosome and corneodesmosome remodeling.

    PubMed

    Kitajima, Yasuo

    2013-04-30

    Desmosomes and corneodesmosomes are the most important adhering junctions to provide strength for the epidermal sheet structure made of living keratinocytes and enucleated corneocytes, respectively. These junctions are connected directly with transmembrane desmosomal cadherins, desmogleins (Dsgs) and desmocollins (Dscs), mainly Dsg1/Dsc1 and Dsg3/Dsc3 in desmosomes and Dsg1/Dsc1 with corneodesmosin in corneodesmosomes. Dsgs and Dscs are associated with several proteins at their inner cytoplasmic domains to anchor keratin intermediate filaments. Desmosomes are not static, but dynamic units that undergo regular remodeling to allow for keratinocyte outward-migration in the epidermis. Recently, two mutually-reversible desmosomal adhesion states have been recognized, i.e., "stable hyper-adhesion (Ca(2+)-independent)" and "dynamic weak-adhesion (Ca(2+)-dependent)". A remarkable impairment of this remodeling is observed in pemphigus vulgaris (an autoimmune blistering disease), caused by anti-Dsg3 antibodies, generating a weak-adhesion desmosome state. Immediately after formation, corneodesmosomes normally commit to degradation, which is complicatedly regulated by proteolytic cleavage of their respective extracellular portion(s), via kallikrein-regulated peptidases and cathepsins. This proteolytic activity is in turn controlled by a variety of inhibitory agents, including protease inhibitors, cholesterol sulfate, and an acidic gradient. The impairment of protease control causes keratinization disorders. This review focuses on the dynamic regulation of desmosomes and corneodesmosomes in relation to keratinization disorders.

  9. Decreased transient outward K+ current in ventricular myocytes from acromegalic rats.

    PubMed

    Xu, X P; Best, P M

    1991-03-01

    Cardiac hypertrophy and heart failure are common to acromegalic patients who have abnormally high serum growth hormone (GH). While the function of cardiac muscle is clearly affected by chronically elevated GH, the electrical activity of myocytes from hearts with GH-dependent hypertrophy has not been studied. We used adult, female Wistar-Furth rats with induced GH-secreting tumors to study the effect of excessive GH on ion channels of cardiac myocytes. GH-secreting tumors were induced by subcutaneous inoculation of GH3 cells. Eight weeks after inoculation, the rats had doubled their body weight and heart size compared with age-matched controls. There were no differences in either action potential amplitude or resting potential of right ventricular myocytes from control and tumor-bearing rats. However, action potential duration increased significantly in tumor-bearing rats; the time to 50% repolarization was 23 +/- 14 ms (n = 10) compared with 6.6 +/- 1.5 ms (n = 14) in controls. The prolongation of the action potential was mainly due to a decrease in density of a transient outward current (It,o) carried by K+. The normalized conductance for It,o decreased from 0.53 +/- 0.10 nS/pF (n = 25) in controls to 0.33 +/- 0.09 nS/pF (n = 26) in tumor-bearing rats. The decrease in It,o) and increase in heart weight occurred with a similar time course. The increased action potential duration prolongs Ca2+ influx through L-type Ca2+ channels in the tumor-bearing animals; this may be important in cardiovascular adaptation.

  10. 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

  11. 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

  12. 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

  13. ATP alone triggers the outward facing conformation of the maltose ATP-binding cassette transporter.

    PubMed

    Bao, Huan; Duong, Franck

    2013-02-01

    The maltose transporter MalFGK(2) is a study prototype for ABC importers. During catalysis, the MalFG membrane domain alternates between inward and outward facing conformations when the MalK dimer closes and hydrolyzes ATP. Because a rapid ATP hydrolysis depends on MalE and maltose, it has been proposed that closed liganded MalE facilitates the transition to the outward facing conformation. Here we find that, in contrast to the expected, ATP is sufficient for the closure of MalK and for the conversion of MalFG to the outward facing state. The outward facing transporter binds MalE with nanomolar affinity, yet neither MalE nor maltose is necessary or facilitates the transition. Thus, the rapid hydrolysis of ATP observed in the presence of MalE and maltose is not because closed liganded MalE accelerates the formation of the outward facing conformation. These findings have fundamental implications for the description of the transport reaction.

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

    NASA Astrophysics Data System (ADS)

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

    2016-09-01

    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.

  15. Trabecular bone remodelling simulation considering osteocytic response to fluid-induced shear stress.

    PubMed

    Adachi, Taiji; Kameo, Yoshitaka; Hojo, Masaki

    2010-06-13

    In bone functional adaptation by remodelling, osteocytes in the lacuno-canalicular system are believed to play important roles in the mechanosensory system. Under dynamic loading, bone matrix deformation generates an interstitial fluid flow in the lacuno-canalicular system; this flow induces shear stress on the osteocytic process membrane that is known to stimulate the osteocytes. In this sense, the osteocytes behave as mechanosensors and deliver mechanical information to neighbouring cells through the intercellular communication network. In this study, bone remodelling is assumed to be regulated by the mechanical signals collected by the osteocytes. From the viewpoint of multi-scale biomechanics, we propose a mathematical model of trabecular bone remodelling that takes into account the osteocytic mechanosensory network system. Based on this model, a computational simulation of trabecular bone remodelling was conducted for a single trabecula under cyclic uniaxial loading, demonstrating functional adaptation to the applied mechanical loading as a load-bearing construct.

  16. Chronic enalapril treatment increases transient outward potassium current in cardiomyocytes isolated from right ventricle of spontaneously hypertensive rats.

    PubMed

    Rodrigues Junior, Luiz Fernando; de Azevedo Carvalho, Ana Carolina; Pimentel, Enildo Broetto; Mill, José Geraldo; Nascimento, José Hamilton Matheus

    2017-03-01

    It has been well established that chronic pressure overload resulting from hypertension leads to ventricular hypertrophy and electrophysiological remodeling. The transient outward potassium current (I to) reduction described in hypertensive animals delays ventricular repolarization, leading to complex ventricular arrhythmias and sudden death. Antihypertensive drugs, as angiotensin-converting enzyme inhibitors (ACEi), can restore I to and reduce the incidence of arrhythmic events. The purpose of this study was to evaluate the differential effects of long-term treatment with ACEi or direct-acting smooth muscle relaxant on the I to of left and right ventricle myocytes of spontaneously hypertensive rats (SHR). Animals were divided into four groups: normotensive Wistar-Kyoto rats (WKY), hypertensive (SHR), SHR treated for 6 weeks with enalapril 10 mg/kg/day (SHRE), or hydralazine 20 mg/kg/day (SHRH). Systolic blood pressure (SBP) and hypertrophy index (heart weight/body weight (HW/BW)) were determined at the end of treatment period. Cell membrane capacitance (C m) and I to were assessed in cardiomyocytes isolated from left and right ventricles. The SHR exhibited significantly increased SBP and HW/BW when compared to the WKY. The treated groups, SHRE and SHRH, restored normal SBP but not HW/BW. The SHR group exhibited a diminished I to in the left but not the right ventricle. Both the treated groups restored I to in the left ventricle. However, in the right ventricle, only enalapril treatment modified I to. The SHRE group exhibited a significant increase in I to compared to all the other groups. These findings suggest that enalapril may increase I to by a pressure overload independent mechanism.

  17. The effects of outward forced convective flow on inward diffusion in human dentine in vitro.

    PubMed

    Pashley, D H; Matthews, W G

    1993-07-01

    In vitro experiments were conducted to evaluate the influence of outward forced convective flow on the inward diffusion of radioactive iodide. When the smear layer was present, application of 15 cmH2O (1.47 kPa) outward-directed filtration pressure reduced the inward flux of iodide by about 10-20% depending upon the hydraulic conductance of each specimen. When the smear layer was removed by acid etching, the same 1.47 kPa pressure lowered the inward iodide flux by as much as 60%, depending on the hydraulic conductance. The results demonstrate the importance of the balance between inward diffusion and outward bulk-fluid movement on the rate of permeation of exogenous solutes.

  18. Outward transport of high-temperature materials around the midplane of the solar nebula.

    PubMed

    Ciesla, Fred J

    2007-10-26

    The Stardust samples collected from Comet 81P/Wild 2 indicate that large-scale mixing occurred in the solar nebula, carrying materials from the hot inner regions to cooler environments far from the Sun. Similar transport has been inferred from telescopic observations of protoplanetary disks around young stars. Models for protoplanetary disks, however, have difficulty explaining the observed levels of transport. Here I report the results of a new two-dimensional model that shows that outward transport of high-temperature materials in protoplanetary disks is a natural outcome of disk formation and evolution. This outward transport occurs around the midplane of the disk.

  19. Mechanisms of ATP Dependent Chromatin Remodeling

    PubMed Central

    Gangaraju, Vamsi K.; Bartholomew, Blaine

    2007-01-01

    The inter-relationship between DNA repair and ATP dependent chromatin remodeling has begun to become very apparent with recent discoveries. ATP dependent remodeling complexes mobilize nucleosomes along DNA, promote the exchange of histones, or completely displace nucleosomes from DNA. These remodeling complexes are often categorized based on the domain organization of their catalytic subunit. The biochemical properties and structural information of several of these remodeling complexes are reviewed. The different models for how these complexes are able to mobilize nucleosomes and alter nucleosome structure are presented incorporating several recent findings. Finally the role of histone tails and their respective modifications in ATP-dependent remodeling are discussed. PMID:17306844

  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. 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…

  2. 19 CFR 192.14 - Electronic information for outward cargo required in advance of departure.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... or its authorized agent must use a CBP-approved electronic data interchange system (currently, the... the CBP-approved electronic system has received and accepted this data, the system will generate and... 19 Customs Duties 2 2010-04-01 2010-04-01 false Electronic information for outward cargo...

  3. 19 CFR 192.14 - Electronic information for outward cargo required in advance of departure.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... or its authorized agent must use a CBP-approved electronic data interchange system (currently, the... the CBP-approved electronic system has received and accepted this data, the system will generate and... 19 Customs Duties 2 2012-04-01 2012-04-01 false Electronic information for outward cargo...

  4. 19 CFR 192.14 - Electronic information for outward cargo required in advance of departure.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... or its authorized agent must use a CBP-approved electronic data interchange system (currently, the... the CBP-approved electronic system has received and accepted this data, the system will generate and... 19 Customs Duties 2 2011-04-01 2011-04-01 false Electronic information for outward cargo...

  5. 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

  6. 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…

  7. 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…

  8. A Review of Research and Evaluation Literature on Outward Bound and Related Educational Programs.

    ERIC Educational Resources Information Center

    Godfrey, Robert

    The paper presents a rapid scanning of the state of the art of research and evaluation of Outward Bound and related educational programs. Initial comments outline criteria for assessing internal and external validity of studies. Distinctions are made between research, evaluation, measurement, judgement, and public relations. The work of Rosen,…

  9. The role of fluency in preferences for inward over outward words.

    PubMed

    Bakhtiari, Giti; Körner, Anita; Topolinski, Sascha

    2016-11-01

    The present studies examined a novel explanation for the in-out effect, the phenomenon that words with inward wanderings of consonantal articulation spots are preferred over words with outward wanderings. We hypothesized that processing fluency might account for the in-out effect instead of, or in addition to, the originally proposed mechanism of motor-associated motivational states. Inward words could be more fluently processed than outward words, which could lead to the preference effect. Corpus analyses (Studies 1a and 1b) revealed more inward than outward words in English and German, which could account for their differing fluency. Additionally, inward compared to outward words were pronounced faster (Study 2) and were rated as being easier to pronounce (Studies 3a and 3b), indicating greater fluency. Crucially, a mediation analysis (Study 4) suggests that the influence of consonantal direction on preference was partially mediated by fluency. However, accounting for the influence of fluency still left a significant residual in-out effect, not accounted for by our fluency measure. This evidence supports a partial causal contribution of articulation fluency to the in-out effect.

  10. Participants' Perceptions of Their Outward Bound Final Expedition and the Relationship to Instructor Supervisory Position

    ERIC Educational Resources Information Center

    Bobilya, Andrew J.; Kalisch, Kenneth R.; Daniel, Brad

    2014-01-01

    The purpose of this mixed-method study was to understand participants' perceptions of their Outward Bound Final Expedition experience and more specifically the relationship between the instructor supervisory position and participant's perception of learning. A sample of 331 students consented to participate and completed a survey at the conclusion…

  11. An Evaluation of Dropouts from Outward Bound Programs for the Unemployed

    ERIC Educational Resources Information Center

    Maxwell, Robert; Perry, Martin; Martin, Andrew John

    2008-01-01

    Outward Bound New Zealand provides 21-day residential motivational intervention courses (Catalyst courses) to long-term unemployed clients approved by the Ministry of Social Development. During the period 2002/03, 20% of participants starting the course dropped out before course completion; which was double the contracted acceptable level set by…

  12. Practice-Theories of Facilitating Experiential Learning in Outward Bound: A Research Report.

    ERIC Educational Resources Information Center

    Hovelynck, Johan

    2001-01-01

    Interviews with facilitators of eight Outward Bound Belgium programs examined the tacit knowledge that guides their program facilitation. Findings focus on experiential learning as a process of developing awareness of one's own behaviors, group development as a condition for learning, and program facilitation as enactment of a theory of relational…

  13. The effect of exercise training on transverse tubules in normal, remodeled, and reverse remodeled hearts.

    PubMed

    Kemi, Ole J; Hoydal, Morten A; Macquaide, Niall; Haram, Per M; Koch, Lauren G; Britton, Steven L; Ellingsen, Oyvind; Smith, Godfrey L; Wisloff, Ulrik

    2011-09-01

    The response of transverse (T)-tubules to exercise training in health and disease remains unclear. Therefore, we studied the effect of exercise training on the density and spacing of left ventricle cardiomyocyte T-tubules in normal and remodeled hearts that associate with detubulation, by confocal laser scanning microscopy. First, exercise training in normal rats increased cardiomyocyte volume by 16% (P < 0.01), with preserved T-tubule density. Thus, the T-tubules adapted to the physiologic hypertrophy. Next, we studied T-tubules in a rat model of metabolic syndrome with pressure overload-induced concentric left ventricle hypertrophy, evidenced by 15% (P < 0.01) increased cardiomyocyte size. These rats had only 85% (P < 0.01) of the T-tubule density of control rats. Exercise training further increased cardiomyocyte volume by 8% (P < 0.01); half to that in control rats, but the T-tubule density remained unchanged. Finally, post-myocardial infarction heart failure induced severe cardiac pathology, with a 70% (P < 0.01) increased cardiomyocyte volume that included both eccentric and concentric hypertrophy and 55% (P < 0.01) reduced T-tubule density. Exercise training reversed 50% (P < 0.01) of the pathologic hypertrophy, whereas the T-tubule density increased by 40% (P < 0.05) compared to sedentary heart failure, but remained at 60% of normal hearts (P < 0.01). Physiologic hypertrophy associated with conserved T-tubule spacing (~1.8-1.9 µm), whereas in pathologic hypertrophy, T-tubules appeared disorganized without regular spacing. In conclusion, cardiomyocytes maintain the relative T-tubule density during physiologic hypertrophy and after mild concentric pathologic hypertrophy, whereas after severe pathologic remodeling with a substantial loss of T-tubules; exercise training reverses the remodeling and partly corrects the T-tubule density.

  14. 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

  15. A dipeptidyl aminopeptidase-like protein remodels gating charge dynamics in Kv4.2 channels.

    PubMed

    Dougherty, Kevin; Covarrubias, Manuel

    2006-12-01

    Dipeptidyl aminopeptidase-like proteins (DPLPs) interact with Kv4 channels and thereby induce a profound remodeling of activation and inactivation gating. DPLPs are constitutive components of the neuronal Kv4 channel complex, and recent observations have suggested the critical functional role of the single transmembrane segment of these proteins (Zagha, E., A. Ozaita, S.Y. Chang, M.S. Nadal, U. Lin, M.J. Saganich, T. McCormack, K.O. Akinsanya, S.Y. Qi, and B. Rudy. 2005. J. Biol. Chem. 280:18853-18861). However, the underlying mechanism of action is unknown. We hypothesized that a unique interaction between the Kv4.2 channel and a DPLP found in brain (DPPX-S) may remodel the channel's voltage-sensing domain. To test this hypothesis, we implemented a robust experimental system to measure Kv4.2 gating currents and study gating charge dynamics in the absence and presence of DPPX-S. The results demonstrated that coexpression of Kv4.2 and DPPX-S causes a -26 mV parallel shift in the gating charge-voltage (Q-V) relationship. This shift is associated with faster outward movements of the gating charge over a broad range of relevant membrane potentials and accelerated gating charge return upon repolarization. In sharp contrast, DPPX-S had no effect on gating charge movements of the Shaker B Kv channel. We propose that DPPX-S destabilizes resting and intermediate states in the voltage-dependent activation pathway, which promotes the outward gating charge movement. The remodeling of gating charge dynamics may involve specific protein-protein interactions of the DPPX-S's transmembrane segment with the voltage-sensing and pore domains of the Kv4.2 channel. This mechanism may determine the characteristic fast operation of neuronal Kv4 channels in the subthreshold range of membrane potentials.

  16. 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

  17. Evaluation of the Effects of Outward Bound. Part One: Research Reports [and] Part Two: Participant Observation. Educational Reports.

    ERIC Educational Resources Information Center

    Smith, Mary Lee; And Others

    Researchers developed an instrument based on definitions of the variables of self-esteem, self-awareness, self-assertion, and acceptance of others to be used as outcome criteria to define and measure the outcomes of the Colorado Outward Bound School experience and to determine if the outcomes were caused by the program. The Outward Bound course…

  18. 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…

  19. Extracellular Matrix Remodeling During the Progression of Volume Overload-Induced Heart Failure

    PubMed Central

    Hutchinson, Kirk R.; Stewart, James A.; Lucchesi, Pamela A.

    2009-01-01

    Volume overload-induced heart failure results in progressive left ventricular remodeling characterized by chamber dilation, eccentric cardiac myocyte hypertrophy and changes in extracellular matrix (ECM) remodeling changes. The ECM matrix scaffold is an important determinant of the structural integrity of the myocardium and actively participates in force transmission across the LV wall. In response to this hemodynamic overload, the ECM undergoes a distinct pattern of remodeling that differs from pressure overload. Once thought to be a static entity, the ECM is now regarded to be a highly adaptive structure that is dynamically regulated by mechanical stress, neurohormonal activation, inflammation and oxidative stress, that result in alterations in collagen and other matrix components and a net change in matrix metalloproteinase (MMP) expression and activation. These changes dictate overall ECM turnover during volume overload hear failure progression. This review will discuss the cellular and molecular mechanisms that dictate the temporal patterns of ECM remodeling during heart disease progression. PMID:19524591

  20. 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.

  1. Local alignment vectors reveal cancer cell-induced ECM fiber remodeling dynamics.

    PubMed

    Lee, Byoungkoo; Konen, Jessica; Wilkinson, Scott; Marcus, Adam I; Jiang, Yi

    2017-01-03

    Invasive cancer cells interact with the surrounding extracellular matrix (ECM), remodeling ECM fiber network structure by condensing, degrading, and aligning these fibers. We developed a novel local alignment vector analysis method to quantitatively measure collagen fiber alignment as a vector field using Circular Statistics. This method was applied to human non-small cell lung carcinoma (NSCLC) cell lines, embedded as spheroids in a collagen gel. Collagen remodeling was monitored using second harmonic generation imaging under normal conditions and when the LKB1-MARK1 pathway was disrupted through RNAi-based approaches. The results showed that inhibiting LKB1 or MARK1 in NSCLC increases the collagen fiber alignment and captures outward alignment vectors from the tumor spheroid, corresponding to high invasiveness of LKB1 mutant cancer cells. With time-lapse imaging of ECM micro-fiber morphology, the local alignment vector can measure the dynamic signature of invasive cancer cell activity and cell-migration-induced ECM and collagen remodeling and realigning dynamics.

  2. Local alignment vectors reveal cancer cell-induced ECM fiber remodeling dynamics

    PubMed Central

    Lee, Byoungkoo; Konen, Jessica; Wilkinson, Scott; Marcus, Adam I.; Jiang, Yi

    2017-01-01

    Invasive cancer cells interact with the surrounding extracellular matrix (ECM), remodeling ECM fiber network structure by condensing, degrading, and aligning these fibers. We developed a novel local alignment vector analysis method to quantitatively measure collagen fiber alignment as a vector field using Circular Statistics. This method was applied to human non-small cell lung carcinoma (NSCLC) cell lines, embedded as spheroids in a collagen gel. Collagen remodeling was monitored using second harmonic generation imaging under normal conditions and when the LKB1-MARK1 pathway was disrupted through RNAi-based approaches. The results showed that inhibiting LKB1 or MARK1 in NSCLC increases the collagen fiber alignment and captures outward alignment vectors from the tumor spheroid, corresponding to high invasiveness of LKB1 mutant cancer cells. With time-lapse imaging of ECM micro-fiber morphology, the local alignment vector can measure the dynamic signature of invasive cancer cell activity and cell-migration-induced ECM and collagen remodeling and realigning dynamics. PMID:28045069

  3. The formation of the Kuiper belt by the outward transport of bodies during Neptune's migration.

    PubMed

    Levison, Harold F; Morbidelli, Alessandro

    2003-11-27

    The 'dynamically cold Kuiper belt' consists of objects on low-inclination orbits between approximately 40 and approximately 50 au from the Sun. It currently contains material totalling less than a tenth the mass of the Earth, which is surprisingly low because, according to accretion models, the objects would not have grown to their present size unless the cold Kuiper belt originally contained tens of Earth masses of solids. Although several mechanisms have been proposed to produce the observed mass depletion, they all have significant limitations. Here we show that the objects currently observed in the dynamically cold Kuiper belt were most probably formed within approximately 35 au and were subsequently pushed outward by Neptune's 1:2 mean motion resonance during its final phase of migration. Combining our mechanism with previous work, we conclude that the entire Kuiper belt formed closer to the Sun and was transported outward during the final stages of planet formation.

  4. LONG RANGE OUTWARD MIGRATION OF GIANT PLANETS, WITH APPLICATION TO FOMALHAUT b

    SciTech Connect

    Crida, Aurelien; Masset, Frederic

    2009-11-10

    Recent observations of exoplanets by direct imaging reveal that giant planets orbit at a few dozens to more than a hundred AU from their central star. The question of the origin of these planets challenges the standard theories of planet formation. We propose a new way of obtaining such far planets, by outward migration of a pair of planets formed in the 10 AU region. Two giant planets in mean motion resonance in a common gap in the protoplanetary disk migrate outward, if the inner one is significantly more massive than the outer one. Using hydrodynamical simulations, we show that their semimajor axes can increase by almost 1 order of magnitude. In a flared disk, the pair of planets should reach an asymptotic radius. This mechanism could account for the presence of Fomalhaut b; then, a second, more massive planet, should be orbiting Fomalhaut at about 75 AU.

  5. 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.

  6. Actions of cromakalim on outward currents of CA1 neurones in hippocampal slices.

    PubMed Central

    Erdemli, G; Krnjević, K

    1994-01-01

    1. Membrane effects of cromakalim (Crom; 50-300 microM) were examined in CA1 neurones recorded mainly by intracellular, single-electrode voltage-clamping in slices (from Sprague-Dawley rats) kept in an interface chamber at 33 degrees C. 2. In 14 cells held at -63 +/- 3.5 mV, in the presence of tetrodotoxin, kynurenic acid and (in most cases) bicuculline, bath applied Crom produced no consistent change in holding current (-59 +/- 66 pA) or input conductance (GN) (-3.9 +/- 5.2%). 3. Overall there were no significant changes in instantaneous inward rectification or in Q-current inward relaxations. 4. In 18 out of 22 cells, outward currents, evoked by 0.5 s pulses to voltages > -50 and < -20 mV, were depressed by Crom (by 42 +/- 11%, for n = 22). Because this effect was consistently seen in Ca current-blocking media, containing either Mn and low Ca, or Cd (and also carbachol), the K channels depressed by Crom were probably of the delayed rectifier (IDR) type. 5. The Crom-control difference current (ICrom), obtained with slow depolarizing ramps, had a biphasic character, inward in the voltage (V) range > -50 < -20 mV (where outward currents are depressed by Crom) and tending outward for V > or = -20 mV. 6. In 10 out of 11 cells, Crom potentiated a D-like, slowly-inactivating outward current (by 88 +/- 31%, for n = 11).(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7530570

  7. 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

  8. Alterations in Three-dimensional Knee Kinematics and Kinetics during Neutral, Squeeze and Outward Squat

    PubMed Central

    Han, Shuyang; Ge, Shirong; Liu, Hongtao; Liu, Rong

    2013-01-01

    The squat exercise was usually performed with varying feet and hip angles by different populations. The objective of this study was to compare and contrast the three-dimensional knee angles, moments, and forces during dynamic squat exercises with varying feet and hip angles. Lower extremity motions and ground reaction forces for fifteen healthy subjects (9 females and 6 males) were recorded while performing the squat with feet pointing straight ahead (neutral squat), 30º feet adduction (squeeze squat) and 30º feet abduction (outward squat). Nonparametric procedures were used to detect differences in the interested measures between the conditions. No significant difference in three-dimensional peak knee angles was observed for three squat exercises (p>0.05), however, the overall tendency of knee rotations was affected by varying feet and hip positions. During the whole cycle, the outward squat mainly displayed adduction moments, while the neutral and squeeze squat demonstrated abduction moments. Peak abduction moments were significantly affected by feet positions (p<0.05). Moreover, the tibiofemoral and patellofemoral joint forces progressively increased as knee flexed and decreased as knee extended, yet peak forces were not affected by varying feet positions (p>0.05). In conclusion, a neutral position is recommended to perform the squat exercise, while the squeeze squat and outward squat might contribute to the occurrence of joint pathologies. PMID:24511341

  9. 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.

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

    DOE PAGES

    Khantwal, Chandra M.; Abraham, Sherwin J.; Han, Wei; ...

    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

  11. 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.

  12. Cesium blockade of delayed outward currents and electrically induced pacemaker activity in mammalian ventricular myocardium.

    PubMed

    Meier, C F; Katzung, B G

    1981-05-01

    The effects of Cs+, 5-25 mM, were studied in cat and guinea pig papillary muscles using voltage clamp and current clamp techniques. In solutions containing normal K+, the major effects of Cs+ were depolarization of the resting potential and reduction of the delayed outward current (ixl) between -80 and -20 mV. Both inward and outward portions of the isochronal current voltage relation (l-s clamps) were reduced by extracellular Cs+. This resulted in a substantial reduction of inward rectification and, by subtraction from the normal I-V relationship, the definition of a Cs+-sensitive component of current. Under current clamp conditions, 5-10 mM Cs+ produced a dose-dependent slowing of repetitive firing induced by depolarization. At higher concentrations (25 mM) the resting potential was depolarized and repetitive activity could not be induced by further depolarization. However, release of hyperpolarizing pulses was followed by prolonged bursts of repetitive action potentials, suggesting partial reversal of blockade or participation of another pacemaker process. The experimental results and a numerical simulation show that under readily attainable conditions, reduction in an outward pacemaker current may slow pacemaker activity.

  13. 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

  14. HEAVY ION HEATING DUE TO INTERACTIONS WITH OUTWARD AND INWARD ALFVEN WAVE PACKETS

    SciTech Connect

    Galinsky, V. L.; Shevchenko, V. I.

    2012-06-01

    The study of simultaneous cyclotron interactions of heavy ions with outward- and inward-propagating Alfven wave packets in the solar wind was self-consistently conducted with wave-packet dynamics. It was shown that, even when the ratio of intensities of the Alfven waves propagating from the Sun and the inward propagating waves are rather large (a factor of 10 or more), the distribution function of the ions simultaneously interacting with both of the wave packets drastically differs from the distribution function formed by the interaction of ions with waves only propagating from the Sun. In the latter case, the ions acquire a shell-like distribution; in the former case, a new non-shell-type distribution with much larger effective temperatures is formed. The temporal dynamics of the ion-distribution function and the self-consistent modification of the wave-power spectral density for both the outward and inward waves were also investigated. The results refute claims by Isenberg and Hollweg that the outward-propagating waves generate the inward waves through the instability of their resonant particle shell distribution.

  15. Alterations in Three-dimensional Knee Kinematics and Kinetics during Neutral, Squeeze and Outward Squat.

    PubMed

    Han, Shuyang; Ge, Shirong; Liu, Hongtao; Liu, Rong

    2013-12-18

    The squat exercise was usually performed with varying feet and hip angles by different populations. The objective of this study was to compare and contrast the three-dimensional knee angles, moments, and forces during dynamic squat exercises with varying feet and hip angles. Lower extremity motions and ground reaction forces for fifteen healthy subjects (9 females and 6 males) were recorded while performing the squat with feet pointing straight ahead (neutral squat), 30º feet adduction (squeeze squat) and 30º feet abduction (outward squat). Nonparametric procedures were used to detect differences in the interested measures between the conditions. No significant difference in three-dimensional peak knee angles was observed for three squat exercises (p>0.05), however, the overall tendency of knee rotations was affected by varying feet and hip positions. During the whole cycle, the outward squat mainly displayed adduction moments, while the neutral and squeeze squat demonstrated abduction moments. Peak abduction moments were significantly affected by feet positions (p<0.05). Moreover, the tibiofemoral and patellofemoral joint forces progressively increased as knee flexed and decreased as knee extended, yet peak forces were not affected by varying feet positions (p>0.05). In conclusion, a neutral position is recommended to perform the squat exercise, while the squeeze squat and outward squat might contribute to the occurrence of joint pathologies.

  16. Small artery remodelling in diabetes

    PubMed Central

    Rosei, Enrico Agabiti; Rizzoni, Damiano

    2010-01-01

    Abstract The aim of this article is to briefly review available data regarding changes in the structure of microvessels observed in patients with diabetes mellitus, and possible correction by effective treatment. The development of structural changes in the systemic vasculature is the end result of established hypertension. In essential hypertension, small arteries of smooth muscle cells are restructured around a smaller lumen and there is no net growth of the vascular wall, although in some secondary forms of hypertension, a hypertrophic remodelling may be detected. Moreover, in non-insulin-dependent diabetes mellitus a hypertrophic remodelling of subcutaneous small arteries is present. Indices of small resistance artery structure, such as the tunica media to internal lumen ratio, may have a strong prognostic significance in hypertensive and diabetic patients, over and above all other known cardiovascular risk factors. Therefore, regression of vascular alterations is an appealing goal of antihypertensive treatment. Different antihypertensive drugs seem to have different effect on vascular structure. In diabetic hypertensive patients, a significant regression of structural alterations of small resistance arteries with drugs blocking the renin–angiotensin system (angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers) was demonstrated. Alterations in the microcirculation represent a common pathological finding, and microangiopathy is one of the most important mechanisms involved in the development of organ damage as well as of clinical events in patients with diabetes mellitus. Renin–angiotensin system blockade seems to be effective in preventing/regressing alterations in microvascular structure. PMID:20646125

  17. Bone remodeling after renal transplantation.

    PubMed

    Bellorin-Font, Ezequiel; Rojas, Eudocia; Carlini, Raul G; Suniaga, Orlando; Weisinger, José R

    2003-06-01

    Several studies have indicated that bone alterations after transplantation are heterogeneous. Short-term studies after transplantation have shown that many patients exhibit a pattern consistent with adynamic bone disease. In contrast, patients with long-term renal transplantation show a more heterogeneous picture. Thus, while adynamic bone disease has also been described in these patients, most studies show decreased bone formation and prolonged mineralization lag-time faced with persisting bone resorption, and even clear evidence of generalized or focal osteomalacia in many patients. Thus, the main alterations in bone remodeling are a decrease in bone formation and mineralization up against persistent bone resorption, suggesting defective osteoblast function, decreased osteoblastogenesis, or increased osteoblast death rates. Indeed, recent studies from our laboratory have demonstrated that there is an early decrease in osteoblast number and surfaces, as well as in reduced bone formation rate and delayed mineralization after transplantation. These alterations are associated with an early increase in osteoblast apoptosis that correlates with low levels of serum phosphorus. These changes were more frequently observed in patients with low turnover bone disease. In contrast, PTH seemed to preserve osteoblast survival. The mechanisms of hypophosphatemia in these patients appear to be independent of PTH, suggesting that other phosphaturic factors may play a role. However, further studies are needed to determine the nature of a phosphaturic factor and its relationship to the alterations of bone remodeling after transplantation.

  18. 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

  19. Remodeling, Renovation, & Conversion of Educational Facilities.

    ERIC Educational Resources Information Center

    Association of Physical Plant Administrators of Universities and Colleges, Washington, DC.

    Based on a series of workshops, this collection of papers provides a framework for thought--emphasizing planning within time, flexibility, and maintenance constraints--as well as a practical guide for actual engineering of remodeling/renovation/conversion projects. Is remodeling always less expensive than new construction? Should high initial…

  20. Chromatin remodeling: nucleosomes bulging at the seams.

    PubMed

    Peterson, Craig L

    2002-04-02

    ATP-dependent chromatin remodeling enzymes, such as SWI/SNF, hydrolyze thousands of ATPs to regulate gene expression on chromatin fibers. Recent mechanistic studies suggest that these enzymes generate localized changes in DNA topology that drive formation of multiple, remodeled nucleosomal states.

  1. Remodeling dynamics in the alveolar process in skeletally mature dogs.

    PubMed

    Huja, Sarandeep S; Fernandez, Soledad A; Hill, Kara J; Li, Yan

    2006-12-01

    Bone turnover rates can be altered by metabolic and mechanical demands. Due to the difference in the pattern of loading, we hypothesized that there are differences in bone remodeling rates between the maxillary and mandibular alveolar processes. Furthermore, in a canine model, the alveolar process of teeth that lack contact (e.g., second premolars) would have a different turnover rate than bone supporting teeth with functional contact (e.g., first molars). Six skeletally mature male dogs were given a pair of calcein labels. After sacrifice, specimens representing the anterior and posterior locations of both jaws were prepared for examination by histomorphometric methods to evaluate the bone volume/total volume (BV/TV; %), bone volume (mm2), mineral apposition rate (MAR; microm/day), and bone formation rate (BFR; %/year) in the alveolar process. There were no significant differences (P>0.05) in the BV/TV within the jaws. The bone volume within the alveolar process of the mandible was 2.8-fold greater than in the maxilla. The MAR was not significantly different between the jaws and anteroposterior locations. However, the BFR was significantly (P<0.0001) greater in the mandible than in the maxilla. The anterior location had higher (P=0.002) remodeling than the posterior location in the maxilla but not in the mandible. While there was a greater bone mass and increased remodeling in the mandible, no remodeling gradient in the coronal-apical direction was apparent in the alveolar process. Bone adaptation probably involves a complex interplay of bone turnover, mass, and architecture.

  2. Intracortical remodeling parameters are associated with measures of bone robustness.

    PubMed

    Goldman, Haviva M; Hampson, Naomi A; Guth, J Jared; Lin, David; Jepsen, Karl J

    2014-10-01

    Prior work identified a novel association between bone robustness and porosity, which may be part of a broader interaction whereby the skeletal system compensates for the natural variation in robustness (bone width relative to length) by modulating tissue-level mechanical properties to increase stiffness of slender bones and to reduce mass of robust bones. To further understand this association, we tested the hypothesis that the relationship between robustness and porosity is mediated through intracortical, BMU-based (basic multicellular unit) remodeling. We quantified cortical porosity, mineralization, and histomorphometry at two sites (38% and 66% of the length) in human cadaveric tibiae. We found significant correlations between robustness and several histomorphometric variables (e.g., % secondary tissue [R(2)  = 0.68, P < 0.004], total osteon area [R(2)  = 0.42, P < 0.04]) at the 66% site. Although these associations were weaker at the 38% site, significant correlations between histological variables were identified between the two sites indicating that both respond to the same global effects and demonstrate a similar character at the whole bone level. Thus, robust bones tended to have larger and more numerous osteons with less infilling, resulting in bigger pores and more secondary bone area. These results suggest that local regulation of BMU-based remodeling may be further modulated by a global signal associated with robustness, such that remodeling is suppressed in slender bones but not in robust bones. Elucidating this mechanism further is crucial for better understanding the complex adaptive nature of the skeleton, and how interindividual variation in remodeling differentially impacts skeletal aging and an individuals' potential response to prophylactic treatments.

  3. Nucleosome dynamics during chromatin remodeling in vivo.

    PubMed

    Ramachandran, Srinivas; Henikoff, Steven

    2016-01-01

    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.

  4. Role of thyroid hormones in ventricular remodeling.

    PubMed

    Rajagopalan, Viswanathan; Gerdes, A Martin

    2015-04-01

    Cardiac remodeling includes alterations in molecular, cellular, and interstitial systems contributing to changes in size, shape, and function of the heart. This may be the result of injury, alterations in hemodynamic load, neurohormonal effects, electrical abnormalities, metabolic changes, etc. Thyroid hormones (THs) serve as master regulators for diverse remodeling processes of the cardiovascular system-from the prenatal period to death. THs promote a beneficial cardiomyocyte shape and improve contractility, relaxation, and survival via reversal of molecular remodeling. THs reduce fibrosis by decreasing interstitial collagen and reduce the incidence and duration of arrhythmias via remodeling ion channel expression and function. THs restore metabolic function and also improve blood flow both by direct effects on the vessel architecture and decreasing atherosclerosis. Optimal levels of THs both in the circulation and in cardiac tissues are critical for normal homeostasis. This review highlights TH-based remodeling and clinically translatable strategies for diverse cardiovascular disorders.

  5. Analogy of strain energy density based bone-remodeling algorithm and structural topology optimization.

    PubMed

    Jang, In Gwun; Kim, Il Yong; Kwak, Byung Ban

    2009-01-01

    In bone-remodeling studies, it is believed that the morphology of bone is affected by its internal mechanical loads. From the 1970s, high computing power enabled quantitative studies in the simulation of bone remodeling or bone adaptation. Among them, Huiskes et al. (1987, "Adaptive Bone Remodeling Theory Applied to Prosthetic Design Analysis," J. Biomech. Eng., 20, pp. 1135-1150) proposed a strain energy density based approach to bone remodeling and used the apparent density for the characterization of internal bone morphology. The fundamental idea was that bone density would increase when strain (or strain energy density) is higher than a certain value and bone resorption would occur when the strain (or strain energy density) quantities are lower than the threshold. Several advanced algorithms were developed based on these studies in an attempt to more accurately simulate physiological bone-remodeling processes. As another approach, topology optimization originally devised in structural optimization has been also used in the computational simulation of the bone-remodeling process. The topology optimization method systematically and iteratively distributes material in a design domain, determining an optimal structure that minimizes an objective function. In this paper, we compared two seemingly different approaches in different fields-the strain energy density based bone-remodeling algorithm (biomechanical approach) and the compliance based structural topology optimization method (mechanical approach)-in terms of mathematical formulations, numerical difficulties, and behavior of their numerical solutions. Two numerical case studies were conducted to demonstrate their similarity and difference, and then the solution convergences were discussed quantitatively.

  6. [Ventricular "remodeling" after myocardial infarction].

    PubMed

    Cohen-Solal, A; Himbert, D; Guéret, P; Gourgon, R

    1991-06-01

    Cardiac failure is the principal medium-term complication of myocardial infarction. Changes in left ventricular geometry are observed after infarction, called ventricular remodeling, which, though compensatory initially, cause ventricular failure in the long-term. Experimental and clinical studies suggest that early treatment by coronary recanalisation, trinitrin and angiotensin converting enzyme inhibitors may prevent or limit the expansion and left ventricular dilatation after infarction, so improving ventricular function, and, at least in the animal, reduce mortality. Large scale trials with converting enzyme inhibitors are currently under way to determine the effects of this new therapeutic option. It would seem possible at present, independently of any reduction in the size of the infarction, to reduce or delay left ventricular dysfunction by interfering with the natural process of dilatation and ventricular modeling after infarction.

  7. Exercise-induced cardiac remodeling.

    PubMed

    Weiner, Rory B; Baggish, Aaron L

    2012-01-01

    Early investigations in the late 1890s and early 1900s documented cardiac enlargement in athletes with above-normal exercise capacity and no evidence of cardiovascular disease. Such findings have been reported for more than a century and continue to intrigue scientists and clinicians. It is well recognized that repetitive participation in vigorous physical exercise results in significant changes in myocardial structure and function. This process, termed exercise-induced cardiac remodeling (EICR), is characterized by structural cardiac changes including left ventricular hypertrophy with sport-specific geometry (eccentric vs concentric). Associated alterations in both systolic and diastolic functions are emerging as recognized components of EICR. The increasing popularity of recreational exercise and competitive athletics has led to a growing number of individuals exhibiting these findings in routine clinical practice. This review will provide an overview of EICR in athletes.

  8. Calcium signalling remodelling and disease.

    PubMed

    Berridge, Michael J

    2012-04-01

    A wide range of Ca2+ signalling systems deliver the spatial and temporal Ca2+ signals necessary to control the specific functions of different cell types. Release of Ca2+ by InsP3 (inositol 1,4,5-trisphosphate) plays a central role in many of these signalling systems. Ongoing transcriptional processes maintain the integrity and stability of these cell-specific signalling systems. However, these homoeostatic systems are highly plastic and can undergo a process of phenotypic remodelling, resulting in the Ca2+ signals being set either too high or too low. Such subtle dysregulation of Ca2+ signals have been linked to some of the major diseases in humans such as cardiac disease, schizophrenia, bipolar disorder and Alzheimer's disease.

  9. Zika Virus Induced Cellular Remodeling.

    PubMed

    Rossignol, Evan D; Peters, Kristen N; Connor, John H; Bullitt, Esther

    2017-03-20

    Zika virus (ZIKV) has been associated with morbidities such as Guillain-Barré, infant microcephaly, and ocular disease. The spread of this positive-sense, single-stranded RNA virus and its growing public health threat underscore gaps in our understanding of basic ZIKV virology. To advance knowledge of the virus replication cycle within mammalian cells, we use serial section three-dimensional electron tomography to demonstrate the widespread remodeling of intracellular membranes upon infection with ZIKV. We report extensive structural rearrangements of the endoplasmic reticulum and reveal stages of the ZIKV viral replication cycle. Structures associated with RNA genome replication and virus assembly are observed integrated within the endoplasmic reticulum, and we show viruses in transit through the Golgi apparatus for viral maturation, and subsequent cellular egress. This study characterizes in detail the three-dimensional ultrastructural organization of the ZIKV replication cycle stages. Our results show close adherence of the ZIKV replication cycle to the existing flavivirus replication paradigm.

  10. Tissue remodelling in pulmonary fibrosis.

    PubMed

    Knudsen, Lars; Ruppert, Clemens; Ochs, Matthias

    2017-03-01

    Many lung diseases result in fibrotic remodelling. Fibrotic lung disorders can be divided into diseases with known and unknown aetiology. Among those with unknown aetiology, idiopathic pulmonary fibrosis (IPF) is a common diagnosis. Because of its progressive character leading to a rapid decline in lung function, it is a fatal disease with poor prognosis and limited therapeutic options. Thus, IPF has motivated many studies in the last few decades in order to increase our mechanistic understanding of the pathogenesis of the disease. The current concept suggests an ongoing injury of the alveolar epithelium, an impaired regeneration capacity, alveolar collapse and, finally, a fibroproliferative response. The origin of lung injury remains elusive but a diversity of factors, which will be discussed in this article, has been shown to be associated with IPF. Alveolar epithelial type II (AE2) cells play a key role in lung fibrosis and their crucial role for epithelial regeneration, stabilisation of alveoli and interaction with fibroblasts, all known to be responsible for collagen deposition, will be illustrated. Whereas mechanisms of collagen deposition and fibroproliferation are the focus of many studies in the field, the awareness of other mechanisms in this disease is currently limited to biochemical and imaging studies including quantitative assessments of lung structure in IPF and animal models assigning alveolar collapse and collapse induration crucial roles for the degradation of the lung resulting in de-aeration and loss of surface area. Dysfunctional AE2 cells, instable alveoli and mechanical stress trigger remodelling that consists of collapsed alveoli absorbed by fibrotic tissue (i.e., collapse induration).

  11. Intracellular magnesium blocks sodium outward currents in a voltage- and dose-dependent manner.

    PubMed Central

    Pusch, M; Conti, F; Stühmer, W

    1989-01-01

    Tail currents through Na+ channels have been measured in inside-out patches from Xenopus laevis oocytes injected with cDNA-derived mRNA coding for the rat brain type II Na+ channel. It is shown that intracellular Mg2+ blocks outward currents in a voltage- and dose-dependent manner with a half blocking concentration between 3 and 4 mM at 0 mV and a voltage dependence of e-fold per 49 mV. PMID:2548634

  12. A fast transient outward current in the rat sympathetic neurone studied under voltage-clamp conditions.

    PubMed Central

    Belluzzi, O; Sacchi, O; Wanke, E

    1985-01-01

    Post-ganglionic neurones of the isolated rat superior cervical ganglion were voltage clamped at 37 degrees C using separate intracellular voltage and current micro-electrodes. Control experiments in current clamp suggested that the neurone is electrotonically compact, the soma and the proximal dendritic membranes being under good spatial voltage uniformity. Depolarizing voltage steps from membrane potentials near -50 mV evoked: (i) a voltage-dependent inward Na+ current, (ii) an inward Ca2+ current, (iii) a voltage-dependent outward K+ current, (iv) a Ca2+-activated K+ outward current. Depolarizations from holding potentials more negative than -60 mV elicited, besides the currents mentioned above, a fast transient outward current IA which peaked in 1-2.5 ms and then decayed to zero following an exponential time course. The IA current was shown to be primarily, if not exclusively, carried by K+. It was unaffected by removal of external Ca2+ or addition of Cd2+ and was weakly blocked by tetraethylammonium ions and partially by 4-aminopyridine. The IA current showed a linear instantaneous current-voltage relationship. Its activation ranged from -60 to 0 mV with a mid-point at -30 mV. The A conductance could be described in terms of a simple Boltzmann distribution for a single gating particle with a valency of +3. Both the development and removal of inactivation followed a single exponential time course with a voltage-dependent time constant which was large near the resting potential (42 ms at -70 mV) and small (11 ms) near -100 and -40 mV. Steady-state inactivation h infinity ranged from -100 to -50 mV, with a mid-point at -78 mV, suggesting that approximately 50% of the IA channels are available at the physiological resting potential. Action potentials elicited from various holding potentials showed maximal repolarization rates dependent on the holding potential itself. This voltage dependence was found to be in reasonably good agreement with that of h infinity curve

  13. 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.

  14. 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

  15. Airway remodeling in asthma: what really matters.

    PubMed

    Fehrenbach, Heinz; Wagner, Christina; Wegmann, Michael

    2017-03-01

    Airway remodeling is generally quite broadly defined as any change in composition, distribution, thickness, mass or volume and/or number of structural components observed in the airway wall of patients relative to healthy individuals. However, two types of airway remodeling should be distinguished more clearly: (1) physiological airway remodeling, which encompasses structural changes that occur regularly during normal lung development and growth leading to a normal mature airway wall or as an acute and transient response to injury and/or inflammation, which ultimately results in restoration of a normal airway structures; and (2) pathological airway remodeling, which comprises those structural alterations that occur as a result of either disturbed lung development or as a response to chronic injury and/or inflammation leading to persistently altered airway wall structures and function. This review will address a few major aspects: (1) what are reliable quantitative approaches to assess airway remodeling? (2) Are there any indications supporting the notion that airway remodeling can occur as a primary event, i.e., before any inflammatory process was initiated? (3) What is known about airway remodeling being a secondary event to inflammation? And (4), what can we learn from the different animal models ranging from invertebrate to primate models in the study of airway remodeling? Future studies are required addressing particularly pheno-/endotype-specific aspects of airway remodeling using both endotype-specific animal models and "endotyped" human asthmatics. Hopefully, novel in vivo imaging techniques will be further advanced to allow monitoring development, growth and inflammation of the airways already at a very early stage in life.

  16. Maternal Uterine Vascular Remodeling During Pregnancy

    PubMed Central

    Osol, George; Mandala, Maurizio

    2009-01-01

    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. PMID:19196652

  17. Two outward potassium current types are expressed during the neural differentiation of neural stem cells

    PubMed Central

    Bai, Ruiying; Gao, Guowei; Xing, Ying; Xue, Hong

    2013-01-01

    The electrophysiological properties of potassium ion channels are regarded as a basic index for determining the functional differentiation of neural stem cells. In this study, neural stem cells from the hippocampus of newborn rats were induced to differentiate with neurotrophic growth factor, and the electrophysiological properties of the voltage-gated potassium ion channels were observed. Immunofluorescence staining showed that the rapidly proliferating neural stem cells formed spheres in vitro that expressed high levels of nestin. The differentiated neurons were shown to express neuron-specific enolase. Flow cytometric analysis revealed that the neural stem cells were actively dividing and the percentage of cells in the S + G2/M phase was high. However, the ratio of cells in the S + G2/M phase decreased obviously as differentiation proceeded. Whole-cell patch-clamp recordings revealed apparent changes in potassium ion currents as the neurons differentiated. The potassium ion currents consisted of one transient outward potassium ion current and one delayed rectifier potassium ion current, which were blocked by 4-aminopyridine and tetraethylammonium, respectively. The experimental findings indicate that neural stem cells from newborn rat campus could be cultured and induced to differentiate into functional neurons under defined conditions in vitro. The differentiated neurons expressed two types of outward potassium ion currents similar to those of mature neurons in vivo. PMID:25206577

  18. 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

  19. 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.

  20. 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

  1. 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.

  2. Effects of imipramine on the transient outward current in rabbit atrial single cells.

    PubMed

    Delpón, E; Tamargo, J; Sánchez-Chapula, J

    1992-06-01

    1. The effects of imipramine on action potential characteristics and transient outward potassium current (It) of rabbit isolated atrial myocytes were studied using the whole-cell configuration of the patch-clamp technique. 2. Imipramine, 3 microM, decreased action potential amplitude and lengthened the action potential duration measured at 50% of repolarization, whereas it did not modify the final phase of repolarization or the resting membrane potential. These results are similar to those reported in multicellular rabbit atrial preparations. 3. Imipramine, 0.1-100 microM, induced a concentration-dependent inhibition of the peak amplitude of It, a shortening of the time to peak current and an increase in the inactivation rate. The acceleration of the current inactivation is to a major extent responsible for the decrease in the integral of the outward current measured at 50 ms after the start of the pulse. 4. The drug-induced block of It was not associated with changes in the voltage-dependence of the steady-state inactivation curve or in the process of recovery from inactivation of the current. Extrapolation to zero block shows that imipramine did not block It before its activation at the onset of the depolarization. These results suggested that imipramine does not affect the inactivated or the resting state of It channels. 5. It is concluded that in rabbit isolated atrial cells, imipramine inhibits It and that this effect is responsible for the lengthening of the action potential duration produced by this drug.

  3. Effects of imipramine on the transient outward current in rabbit atrial single cells.

    PubMed Central

    Delpón, E.; Tamargo, J.; Sánchez-Chapula, J.

    1992-01-01

    1. The effects of imipramine on action potential characteristics and transient outward potassium current (It) of rabbit isolated atrial myocytes were studied using the whole-cell configuration of the patch-clamp technique. 2. Imipramine, 3 microM, decreased action potential amplitude and lengthened the action potential duration measured at 50% of repolarization, whereas it did not modify the final phase of repolarization or the resting membrane potential. These results are similar to those reported in multicellular rabbit atrial preparations. 3. Imipramine, 0.1-100 microM, induced a concentration-dependent inhibition of the peak amplitude of It, a shortening of the time to peak current and an increase in the inactivation rate. The acceleration of the current inactivation is to a major extent responsible for the decrease in the integral of the outward current measured at 50 ms after the start of the pulse. 4. The drug-induced block of It was not associated with changes in the voltage-dependence of the steady-state inactivation curve or in the process of recovery from inactivation of the current. Extrapolation to zero block shows that imipramine did not block It before its activation at the onset of the depolarization. These results suggested that imipramine does not affect the inactivated or the resting state of It channels. 5. It is concluded that in rabbit isolated atrial cells, imipramine inhibits It and that this effect is responsible for the lengthening of the action potential duration produced by this drug. PMID:1382783

  4. Structure of a fucose transporter in an outward-open conformation.

    PubMed

    Dang, Shangyu; Sun, Linfeng; Huang, Yongjian; Lu, Feiran; Liu, Yufeng; Gong, Haipeng; Wang, Jiawei; Yan, Nieng

    2010-10-07

    The major facilitator superfamily (MFS) transporters are an ancient and widespread family of secondary active transporters. In Escherichia coli, the uptake of l-fucose, a source of carbon for microorganisms, is mediated by an MFS proton symporter, FucP. Despite intensive study of the MFS transporters, atomic structure information is only available on three proteins and the outward-open conformation has yet to be captured. Here we report the crystal structure of FucP at 3.1 Å resolution, which shows that it contains an outward-open, amphipathic cavity. The similarly folded amino and carboxyl domains of FucP have contrasting surface features along the transport path, with negative electrostatic potential on the N domain and hydrophobic surface on the C domain. FucP only contains two acidic residues along the transport path, Asp 46 and Glu 135, which can undergo cycles of protonation and deprotonation. Their essential role in active transport is supported by both in vivo and in vitro experiments. Structure-based biochemical analyses provide insights into energy coupling, substrate recognition and the transport mechanism of FucP.

  5. The impulse exerted on the outward particle flux from a plasma ball

    NASA Astrophysics Data System (ADS)

    Makrinich, Gennady; Fruchtman, Amnon

    2010-11-01

    A plasma ball has been produced near the anode in a configuration that, when magnetized, operates as a radial plasma source (RPS) [1]. The plasma particle flux outward of the plasma ball seems to be larger than that expected by the Langmuir relation in double layers [2]. The forced oscillations of a pendulum induced by the flow in the vicinity of the plasma ball are also of an unexpectedly large amplitude. We examine the possibility 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. The electric force is being felt by ions for a longer time; their residence time in the acceleration region is increased due to their slowing-down collisions with neutrals. We previously suggested the ion-neutral collisions as a source of impulse enhancement in the RPS of a radially- outward flow with magnetized electrons. [1] G. Makrinich and A. Fruchtman, Phys. Plasmas 16, 043507, 2009; Appl. Phys. Lett. 95, 181504 (2009). [2] I. Langmuir, Phys. Rev. 33, 954 (1929); B. Song, N. D'Angelo, R.L. Merlino, J. Phys. D: Appl. Phys. 24, 1789 (1991).

  6. 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.

  7. 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.

  8. 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.

  9. Simulations of trabecular remodeling and fatigue: is remodeling helpful or harmful?

    PubMed

    van Oers, René F M; van Rietbergen, Bert; Ito, Keita; Huiskes, Rik; Hilbers, Peter A J

    2011-05-01

    Microdamage-targeted resorption is paradoxal, because it entails the removal of bone from a region that was already overloaded. Under continued intense loading, resorption spaces could potentially cause more damage than they remove. To investigate this problem, we incorporated damage algorithms in a computer-simulation model for trabecular remodeling. We simulated damage accumulation and bone remodeling in a trabecular architecture, for two fatigue regimens, a 'moderate' regimen, and an 'intense' regimen with a higher number of loading cycles per day. Both simulations were also performed without bone remodeling to investigate if remodeling removed or exacerbated the damage. We found that remodeling tends to remove damage under the 'moderate' fatigue regimen, but it exacerbates damage under the 'intense' regimen. This harmful effect of remodeling may play a role in the development of stress fractures.

  10. Electrical remodeling in a canine model of ischemic cardiomyopathy.

    PubMed

    Liu, Xian-Sheng; Jiang, Min; Zhang, Mei; Tang, Daniel; Clemo, Henry F; Higgins, Robert S D; Tseng, Gea-Ny

    2007-01-01

    The nature of electrical remodeling in a canine model of ischemic cardiomyopathy (ICM; induced by repetitive intracoronary microembolizations) that exhibits spontaneous ventricular tachycardia is not entirely clear. We used the patch-clamp technique to record action potentials and ionic currents of left ventricular myocytes isolated from the region affected by microembolizations. We also used the immunoblot technique to examine channel subunit expression in adjacent affected tissue. Ventricular myocytes and tissue isolated from the corresponding region of normal hearts served as control. ICM myocytes had prolonged action potential duration (APD) and more pronounced APD dispersion. Slow delayed rectifier current (I(Ks)) was reduced at voltages positive to 0 mV, along with a negative shift in its voltage dependence of activation. Immunoblots showed that there was no change in KCNQ1.1 (I(Ks) pore-forming or alpha-subunit), but KCNE1 (I(Ks) auxiliary or beta-subunit) was reduced, and KCNQ1.2 (a truncated KCNQ1 splice variant with a dominant-negative effect on I(Ks)) was increased. Transient outward current (I(to)) was reduced, along with an acceleration of the slow phase of recovery from inactivation. Immunoblots showed that there was no change in Kv4.3 (alpha-subunit of fast-recovering I(to) component), but KChIP2 (beta-subunit of fast-recovering component) and Kv1.4 (alpha-subunit of slow-recovering component) were reduced. Inward rectifier current was reduced. L-type Ca current was unaltered. The immunoblot data provide mechanistic insights into the observed changes in current amplitude and gating kinetics of I(Ks) and I(to). We suggest that these changes, along with the decrease in inward rectifier current, contribute to APD prolongation in ICM hearts.

  11. 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)

  12. 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)

  13. B.B. Contracting & Remodeling Information Sheet

    EPA Pesticide Factsheets

    B.B. Contracting & Remodeling (the Company) is located in St. Louis, Missouri. The settlement involves renovation activities conducted at property constructed prior to 1978, located in St. Louis, Missouri.

  14. Ventricular remodeling in global ischemia.

    PubMed

    Anversa, P; Zhang, X; Li, P; Olivetti, G; Cheng, W; Reiss, K; Sonnenblick, E H; Kajstura, J

    1995-06-01

    To determine the effects of chronic constriction of the left coronary artery on the function and structure of the heart, coronary artery narrowing was surgically induced in rats and ventricular pump performance, extent and distribution of myocardial damage, and the hypertrophic and hyperplastic response of myocytes were examined. Alterations in cardiac hemodynamics were found in all rats, but the characteristics of the physiological properties of the heart allowed a separation of the animals into two groups which exhibited left ventricular dysfunction and failure, respectively. Left ventricular hypertrophy occurred in both groups and was characterized by ventricular dilatation and wall thinning which were more severe in the failing animals. Multiple foci of myocardial damage across the wall were seen in all animals but tissue injury was more prominent in the endomyocardium and in failing rats. The anatomical and hemodynamic changes resulted in a significant increase in diastolic wall stress which paralleled the depression in ventricular performance. Myocyte cell loss and myocyte cellular hypertrophy were more severe with ventricular failure than with dysfunction. Finally, diastolic overload appeared to be coupled with activation of the DNA synthetic machinery of myocytes and nuclear mitotic division. In conclusion, a fixed lesion of the left coronary artery leads to abnormalities in cardiac dynamics with marked increases in diastolic wall stress and extensive ventricular remodeling in spite of compensatory myocyte cellular hypertrophy and hyperplasia in the remaining viable tissue.

  15. 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

  16. Bone remodeling as a spatial evolutionary game.

    PubMed

    Ryser, Marc D; Murgas, Kevin A

    2017-04-07

    Bone remodeling is a complex process involving cell-cell interactions, biochemical signaling and mechanical stimuli. Early models of the biological aspects of remodeling were non-spatial and focused on the local dynamics at a fixed location in the bone. Several spatial extensions of these models have been proposed, but they generally suffer from two limitations: first, they are not amenable to analysis and are computationally expensive, and second, they neglect the role played by bone-embedded osteocytes. To address these issues, we developed a novel model of spatial remodeling based on the principles of evolutionary game theory. The analytically tractable framework describes the spatial interactions between zones of bone resorption, bone formation and quiescent bone, and explicitly accounts for regulation of remodeling by bone-embedded, mechanotransducing osteocytes. Using tools from the theory of interacting particle systems we systematically classified the different dynamic regimes of the spatial model and identified regions of parameter space that allow for global coexistence of resorption, formation and quiescence, as observed in physiological remodeling. In coexistence scenarios, three-dimensional simulations revealed the emergence of sponge-like bone clusters. Comparison between spatial and non-spatial dynamics revealed substantial differences and suggested a stabilizing role of space. Our findings emphasize the importance of accounting for spatial structure and bone-embedded osteocytes when modeling the process of bone remodeling. Thanks to the lattice-based framework, the proposed model can easily be coupled to a mechanical model of bone loading.

  17. Regulation of airway inflammation and remodeling in asthmatic mice by TLR3/TRIF signal pathway.

    PubMed

    Yang, Mei; Wang, Hao-Ying; Chen, Jian-Chang; Zhao, Jing

    2017-03-23

    This paper aims to investigate the effect of Toll-like receptors 3 (TLR3)/TIR-domain-containing adapter-inducing interferon-β (TRIF) signal pathway on the airway inflammation and remodeling in asthmatic mice. C57BL/6 and TLR3(-/-) mice were randomly divided into three groups (10 mice per group), including Control group (mice inhaled phosphate buffer saline (PBS)), Asthma group (mice inhaled ovalbumin (OVA)) and polyriboinosinic-ribocytidylic acid (poly (I: C)) group (asthmatic mice were injected intraperitoneally with TLR3 agonist poly (I: C)). Hematoxylin-eosin (HE) staining, Wright-Giemsa staining, Enzyme-linked immunosorbent assay (ELISA), Immunohistochemistry, Hydroxyproline assay, quantitative real time polymerase chain reaction (qRT-PCR) and Western blot were used to assess for the indices of airway inflammation and remodeling. In terms of WT mice, all asthma groups with or without the addition of poly (I: C) showed exaggerated inflammation and remodeling in the airways as compared to Control group, which were more seriously in poly (I: C) group than Asthma group. Furthermore, we observed the significant inhibition of airway inflammation and remodeling in the TLR3(-/-) mice in both Asthma no matter with or without addition of poly (I: C) than the WT mice. TLR3 knockout could obviously relieve the airway inflammation and remodeling in asthma through inhibiting TLR3/TRIF signaling pathway.

  18. Outward-dipping ring-fault structure at rabaul caldera as shown by earthquake locations.

    PubMed

    Mori, J; McKee, C

    1987-01-09

    The locations of a large number of earthquakes recorded at Rabaul caldera in Papua New Guinea from late 1983 to mid-1985 have produced a picture of this active caldera's structural boundary. The earthquake epicenters form an elliptical annulus about 10 kilometers long by 4 kilometers wide, centered in the southern part of the Rabaul volcanic complex. A set of events with well-constrained depth determinations shows a ring-fault structure that extends from the surface to a depth of about 4 kilometers and slopes steeply outward from the center of the caldera. This is the first geophysical data set that clearly outlines the orientation of an active caldera's bounding faults. This orientation, however, conflicts with the configuration of many other calderas and is not in keeping with currently preferred models of caldera formation.

  19. Mechanism of generation of spontaneous miniature outward currents (SMOCs) in retinal amacrine cells.

    PubMed

    Mitra, Pratip; Slaughter, Malcolm M

    2002-04-01

    A subtype of retinal amacrine cells displayed a distinctive array of K(+) currents. Spontaneous miniature outward currents (SMOCs) were observed in the narrow voltage range of -60 to -40 mV. Depolarizations above approximately -40 mV were associated with the disappearance of SMOCs and the appearance of transient (I(to)) and sustained (I(so)) outward K(+) currents. I(to) appeared at about -40 mV and its apparent magnitude was biphasic with voltage, whereas I(so) appeared near -30 mV and increased linearly. SMOCs, I(to), and a component of I(so) were Ca(2+) dependent. SMOCs were spike shaped, occurred randomly, and had decay times appreciably longer than the time to peak. In the presence of cadmium or cobalt, SMOCs with pharmacologic properties identical to those seen in normal Ringer's could be generated at voltages of -20 mV and above. Their mean amplitude was Nernstian with respect to [K(+)](ext) and they were blocked by tetraethylammonium. SMOCs were inhibited by iberiotoxin, were insensitive to apamin, and eliminated by nominally Ca(2+)-free solutions, indicative of BK-type Ca(2+)-activated K(+) currents. Dihydropyridine Ca(2+) channel antagonists and agonists decreased and increased SMOC frequencies, respectively. Ca(2+) permeation through the kainic acid receptor had no effect. Blockade of organelle Ca(2+) channels by ryanodine, or intracellular Ca(2+) store depletion with caffeine, eradicated SMOCs. Internal Ca(2+) chelation with 10 mM BAPTA eliminated SMOCs, whereas 10 mM EGTA had no effect. These results suggest a mechanism whereby Ca(2+) influx through L-type Ca(2+) channels and its subsequent amplification by Ca(2+)-induced Ca(2+) release via the ryanodine receptor leads to a localized elevation of internal Ca(2+). This amplified Ca(2+) signal in turn activates BK channels in a discontinuous fashion, resulting in randomly occurring SMOCs.

  20. Cardiac remodelling and RAS inhibition

    PubMed Central

    Ferrario, Carlos M.

    2016-01-01

    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

  1. Evaluation of remodeling in left and right ventricular myocytes from heterozygous (mRen2)27 transgenic rats.

    PubMed

    Chouabe, Christophe; Ricci, Estelle; Kurdi, Mazen; Legrand, Claude; Bricca, Giampiero; Bonvallet, Robert

    2009-03-01

    Cardiac remodeling was assessed both in the pressure-overloaded left ventricle and in the normotensive right ventricle of hypertensive transgenic rats (mRen2)27 (TGR27). The present study combined histology, electrophysiology, molecular biology and biochemistry techniques. A significant increase in action potential (AP) duration was recorded both in right and left ventricular myocytes wheareas only in the latter ones were hypertrophic. The increase in AP duration is mainly supported by the reduction of the transient outward K current (I(to)) density since no significant modification was observed for the L-type calcium current (I(Ca,L)), the sodium-calcium exchange current (I(NCX)), the delayed rectifier current (I(K)) and the inward rectifier current (I(K1)). The lower amplitude of I(to) current was associated with a lower Kv4.3 protein expression both in right and left ventricles while Kv4.3 mRNA levels was decreased only in left ventricle. Thus, a differential ventricular remodeling takes place in the TGR27 model. The possible cause of electrical remodeling in right ventricular myocytes of TGR27 is discussed.

  2. Flow-induced remodeling in resistance arteries from obese Zucker rats is associated with endothelial dysfunction.

    PubMed

    Bouvet, Céline; Belin de Chantemèle, Eric; Guihot, Anne-Laure; Vessières, Emilie; Bocquet, Arnaud; Dumont, Odile; Jardel, Alain; Loufrani, Laurent; Moreau, Pierre; Henrion, Daniel

    2007-07-01

    Chronic increases in blood flow increase arterial diameter and NO-dependent dilation in resistance arteries. Because endothelial dysfunction accompanies metabolic syndrome, we hypothesized that flow-mediated remodeling might be impaired in obese rat resistance arteries. Obese and lean Zucker rat mesenteric resistance arteries were exposed to chronic flow increases through arterial ligation in vivo: arteries exposed to high flow were compared with normal flow arteries. Diameter was measured in vitro in cannulated arteries using pressure arteriography. After 7 days, outward remodeling (diameter increased from 346+/-9 to 412+/-11 mum at 100 mm Hg) occurred in lean high-flow arteries. Endothelium-dependent tone was reduced in high-flow arteries from obese rats by contrast with lean animals. On the other hand, diameter enlargement occurred similarly in the 2 strains. The involvement of NO in endothelium-dependent dilation (evidenced by NO blockade) and endothelial NO synthase phosphorylation was smaller in obese than in lean rats. Superoxide anion and reduced nicotinamide-adenine dinucleotide phosphate oxidase subunit expression (p67phox and gp91phox) increased in obese rats and were higher in high-flow than in control arteries. Acute Tempol (a catalase mimetic), catalase plus superoxide dismutase, and l-arginine plus tetrahydrobiopterin restored endothelium-dependent dilation in obese rat normal and high-flow arteries to the level found in lean control arteries. Thus, flow-induced remodeling in obese resistance arteries was associated with a reduced endothelium-mediated dilation because of a decreased NO bioavailability and an excessive superoxide production. This dysfunction might have negative consequences in ischemic diseases in patients with obesity or metabolic syndrome.

  3. 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

  4. Connecting Mechanics and Bone Cell Activities in the Bone Remodeling Process: An Integrated Finite Element Modeling

    PubMed Central

    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

  5. Structural Stability and Functional Remodeling of High-Density Lipoproteins

    PubMed Central

    Gursky, Olga

    2015-01-01

    Lipoproteins are protein-lipid nanoparticles that transport lipids in circulation and are central in atherosclerosis and other disorders of lipid metabolism. Apolipoproteins form flexible structural scaffolds and important functional ligands on the particle surface and direct lipoprotein metabolism. Lipoproteins undergo multiple rounds of metabolic remodeling that is crucial to lipid transport. Important aspects of this remodeling, including apolipoprotein dissociation and particle fusion, are mimicked in thermal or chemical denaturation and are modulated by free energy barriers. Here we review our biophysical studies that revealed kinetic mechanism of lipoprotein stabilization and unraveled its structural basis. The main focus is on high-density lipoprotein (HDL). An inverse correlation between stability and functions of various HDLs in cholesterol transport suggests functional role of structural disorder. A mechanism for conformational adaptation of the major HDL proteins, apoA-I and apoA-II, to the increasing lipid load is proposed. Together, these studies help understand why HDL form discrete subclasses separated by kinetic barriers, which have distinct composition, conformation and functional properties. Understanding these properties may help improve HDL quality and develop novel therapies for cardiovascular disease. PMID:25749369

  6. Structural remodeling and mechanical function in heart failure.

    PubMed

    Leonard, Bridget Louise; Smaill, Bruce Henry; LeGrice, Ian John

    2012-02-01

    The cardiac extracellular matrix (ECM) is the three-dimensional scaffold that defines the geometry and muscular architecture of the cardiac chambers and transmits forces produced during the cardiac cycle throughout the heart wall. The cardiac ECM is an active system that responds to the stresses to which it is exposed and in the normal heart is adapted to facilitate efficient mechanical function. There are marked differences in the short- and medium-term changes in ventricular geometry and cardiac ECM that occur as a result of volume overload, hypertension, and ischemic cardiomyopathy. Despite this, there is a widespread view that a common remodeling "phenotype" governs the final progression to end-stage heart failure in different forms of heart disease. In this review article, we make the case that this interpretation is not consistent with the clinical and experimental data on the topic. We argue that there is a need for new theoretical and experimental models that will enable stresses acting on the ECM and resultant deformations to be estimated more accurately and provide better spatial resolution of local signaling mechanisms that are activated as a result. These developments are necessary to link the effects of structural remodeling with altered cardiac mechanical function.

  7. Retinal remodeling in inherited photoreceptor degenerations.

    PubMed

    Marc, Robert E; Jones, Bryan W

    2003-10-01

    Photoreceptor degenerations initiated in rods or the retinal pigmented epithelium usually evoke secondary cone death and sensory deafferentation of the surviving neural retina. In the mature central nervous system, deafferentation evokes atrophy and connective re-patterning. It has been assumed that the neural retina does not remodel, and that it is a passive survivor. Screening of advanced stages of human and rodent retinal degenerations with computational molecular phenotyping has exposed a prolonged period of aggressive negative remodeling in which neurons migrate along aberrant glial columns and seals, restructuring the adult neural retina (1). Many neurons die, but survivors rewire the remnant inner plexiform layer (IPL), forming thousands of novel ectopic microneuromas in the remnant inner nuclear layer (INL). Bipolar and amacrine cells engage in new circuits that are most likely corruptive. Remodeling in human and rodent retinas emerges regardless of the molecular defects that initially trigger retinal degenerations. Although remodeling may constrain therapeutic intervals for molecular, cellular, or bionic rescue, the exposure of intrinsic retinal remodeling by the removal of sensory control in retinal degenerations suggests that neuronal organization in the normal retina may be more plastic than previously believed.

  8. Temperature-induced cardiac remodelling in fish

    PubMed Central

    Keen, Adam N.; Klaiman, Jordan M.; Shiels, Holly A.

    2017-01-01

    ABSTRACT Thermal acclimation causes the heart of some fish species to undergo significant remodelling. This includes changes in electrical activity, energy utilization and structural properties at the gross and molecular level of organization. The purpose of this Review is to summarize the current state of knowledge of temperature-induced structural remodelling in the fish ventricle across different levels of biological organization, and to examine how such changes result in the modification of the functional properties of the heart. The structural remodelling response is thought to be responsible for changes in cardiac stiffness, the Ca2+ sensitivity of force generation and the rate of force generation by the heart. Such changes to both active and passive properties help to compensate for the loss of cardiac function caused by a decrease in physiological temperature. Hence, temperature-induced cardiac remodelling is common in fish that remain active following seasonal decreases in temperature. This Review is organized around the ventricular phases of the cardiac cycle – specifically diastolic filling, isovolumic pressure generation and ejection – so that the consequences of remodelling can be fully described. We also compare the thermal acclimation-associated modifications of the fish ventricle with those seen in the mammalian ventricle in response to cardiac pathologies and exercise. Finally, we consider how the plasticity of the fish heart may be relevant to survival in a climate change context, where seasonal temperature changes could become more extreme and variable. PMID:27852752

  9. Aging increases capacitance and spontaneous transient outward current amplitude of smooth muscle cells from murine superior epigastric arteries

    PubMed Central

    Hayoz, Sebastien; Bradley, Vanessa; Boerman, Erika M.; Nourian, Zahra; Segal, Steven S.

    2014-01-01

    Large conductance Ca2+-activated K+ channels (BKCa) contribute to negative feedback regulation of smooth muscle cell (SMC) tone. However, the effects of aging on BKCa function are unclear. We tested the hypothesis that aging alters SMC BKCa function in superior epigastric arteries (SEAs) by using perforated patch recording of enzymatically isolated SMCs from 3- to 4-mo-old male C57BL/6 mice (Young) and 24- to 26-mo-old male C57BL/6 mice (Old). SMC capacitance from Young (15.7 ± 0.4 pF; n = 110) was less than Old (17.9 ± 0.5 pF; n = 104) (P < 0.05). SMCs displayed spontaneous transient outward currents (STOCs) at membrane potentials more positive than −30 mV; depolarization increased STOC amplitude and frequency (P < 0.05; n = 19–24). STOC frequency in Young (2.2 ± 0.6 Hz) was less than Old (4.2 ± 0.7 Hz) at −10 mV (P < 0.05, n = 27–30), with no difference in amplitude (1.0 ± 0.1 vs. 0.9 ± 0.1 pA/pF, respectively). At +30 mV, STOC amplitude in Young (3.2 ± 0.3 pA/pF) was less than Old (5.0 ± 0.5 pA/pF; P < 0.05, n = 61–67) with no difference in frequency (3.9 ± 0.4 vs. 3.2 ± 0.3 Hz, respectively). BKCa blockers (1 μM paxilline, 100 nM iberiotoxin, 1 mM tetraethylammonium) or a ryanodine receptor antagonist (100 μM tetracaine) inhibited STOCs (n ≥ 6; P < 0.05 each). Western blots revealed increased expression of BKCa α-subunit protein in Old. Pressure myography revealed no effect of age on SEA maximal diameter, myogenic tone, or paxilline-induced constriction (n = 10–12; P > 0.05). Enhanced functional expression of SMC BKCa-dependent STOCs in Old may represent an adaptation of resistance arteries to maintain functional integrity. PMID:24705555

  10. The transient outward current in mice lacking the potassium channel gene Kv1.4

    PubMed Central

    London, Barry; Wang, Dao W; Hill, Joseph A; Bennett, Paul B

    1998-01-01

    The transient outward current (Ito) plays a prominent role in the repolarization phase of the cardiac action potential. Several K+ channel genes, including Kv1.4, are expressed in the heart, produce rapidly inactivating currents when heterologously expressed, and may be the molecular basis of Ito.We engineered mice homozygous for a targeted disruption of the K+ channel gene Kv1.4 and compared Ito in wild-type (Kv1.4+/+), heterozygous (Kv1.4+/-) and homozygous ‘knockout’ (Kv1.4−/−) mice. Kv1.4 RNA was truncated in Kv1.4−/− mice and protein expression was absent.Adult myocytes isolated from Kv1.4+/+, Kv1.4+/− and Kv1.4−/− mice had large rapidly inactivating outward currents. The peak current densities at 60 mV (normalized by cellular capacitance, in pA pF−1; means ± s.e.m.) were 53.8 ± 5.3, 45.3 ± 2.2 and 44.4 ± 2.8 in cells from Kv1.4+/+, Kv1.4+/− and Kv1.4−/− mice, respectively (P < 0.02 for Kv1.4+/+ vs. Kv1.4−/−). The steady-state values (800 ms after the voltage clamp step) were 30.9 ± 2.9, 26.9 ± 3.8 and 23.5 ± 2.2, respectively (P < 0.02 for Kv1.4+/+ vs. Kv1.4−/−). The inactivating portion of the current was unchanged in the targeted mice.The voltage dependence and time course of inactivation were not changed by targeted disruption of Kv1.4. The mean best-fitting V½ (membrane potential at 50 % inactivation) values for myocytes from Kv1.4 +/+, Kv1.4+/− and Kv1.4−/− mice were -53.5 ± 3.7, -51.1 ± 2.6 and -54.2 ± 2.4 mV, respectively. The slope factors (k) were -10.1 ± 1.4, -8.8 ± 1.4 and -9.5 ± 1.2 mV, respectively. The fast time constants for development of inactivation at -30 mV were 27.8 ± 2.2, 26.2 ± 5.1 and 19.6 ± 2.1 ms in Kv1.4+/+, Kv1.4+/− and Kv1.4−/− myocytes, respectively. At +30 mV, they were 35.5 ± 2.6, 30.0 ± 2.1 and 28.7 ± 1.6 ms, respectively. The time constants for the rapid phase of recovery from inactivation at -80 mV were 32.5 ± 8.2, 23.3 ± 1.8 and 39.0 ± 3.7 ms, respectively

  11. 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

  12. H-89 inhibits transient outward and inward rectifier potassium currents in isolated rat ventricular myocytes

    PubMed Central

    Pearman, Charles; Kent, William; Bracken, Nicolas; Hussain, Munir

    2006-01-01

    Voltage clamp was used to investigate the effects of N-[2-p-bromo-cinnamylamino)ethyl]-5-isoquinolinesulfonamide (H-89), a potent inhibitor of PKA, on transient outward K+ current (Ito) and inward rectifying K+ current (IK1) in rat cardiac muscle. Initial experiments, performed using descending voltage ramps, showed that H-89 inhibited both the outward and inward ramp currents in a concentration-dependent manner at concentrations between 5 and 60 μmol l−1. A similar degree of inhibition was observed when Ito and IK1 were recorded using square wave depolarising and hyperpolarising voltage steps, respectively. The IC50 was 35.8 μmol l−1 for Ito and 27.8 μmol l−1 for IK1 compared to 5.4 μmol l−1 for L-type Ca2+ current (ICa). The Hill coefficients for Ito, IK1 and ICa were −1.97, −1.60 and −1.21, respectively. In addition to inhibiting Ito amplitude, H-89 also accelerated the time to peak and the rate of voltage-dependent inactivation so that the time course of Ito was abbreviated. Paired-pulse protocols were performed to study the effects of H-89 on steady-state activation and inactivation as well as recovery from voltage-dependent inactivation. H-89 produced a concentration-dependent rightward shift in voltage-dependent activation but had no significant effect on steady-state inactivation. Recovery from voltage-dependent inactivation was delayed, although this was only visible at the highest concentration (60 μmol l−1) used. In experiments investigating the effects of elevated cyclic AMP, the β-adrenergic agonist isoprenaline and the phosphatase inhibitor calyculin A had no major effects on Ito or IK1. Data suggest that the effects of H-89 on K+ currents are more complex than simple inhibition of PKA-mediated phosphorylation. PMID:16799649

  13. City Kids in the Wilderness: A Pilot-Test of Outward Bound for Foster Care Group Home Youth.

    ERIC Educational Resources Information Center

    Fischer, Robert L.; Attah, E. B.

    2001-01-01

    A study examined perceptions of a 7-day Outward Bound program among 23 urban youths, foster parents, and foster care workers from group homes in Atlanta (Georgia). Foster parents reported improved self-esteem and behavior among the teens, but foster care workers reported worse behavior. Negative program impressions lessened among male youths but…

  14. 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.

  15. Relative Impact of Course Components at Outward Bound Singapore: A Retrospective Study of Long-Term Outcomes

    ERIC Educational Resources Information Center

    Gassner, Michael E.; Russell, Keith C.

    2008-01-01

    This study examined the long-term impact of specific course components on participants who attended a 21-day Outward Bound Singapore course between 1997 and 2005. In total, 1029 questionnaires were sent out by mail. Participants were given a choice to complete the questionnaire on paper or online. A total of 318 questionnaires were successfully…

  16. 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…

  17. Ion-controlled conformational dynamics in the outward-open transition from an occluded state of LeuT.

    PubMed

    Zhao, Chunfeng; Stolzenberg, Sebastian; Gracia, Luis; Weinstein, Harel; Noskov, Sergei; Shi, Lei

    2012-09-05

    Neurotransmitter:sodium symporter (NSS) proteins are secondary Na(+)-driven active transporters that terminate neurotransmission by substrate uptake. Despite the availability of high-resolution crystal structures of a bacterial homolog of NSSs-Leucine Transporter (LeuT)-and extensive computational and experimental structure-function studies, unanswered questions remain regarding the transport mechanisms. We used microsecond atomistic molecular-dynamics (MD) simulations and free-energy computations to reveal ion-controlled conformational dynamics of LeuT in relation to binding affinity and selectivity of the more extracellularly positioned Na(+) binding site (Na1 site). In the course of MD simulations starting from the occluded state with bound Na(+), but in the absence of substrate, we find a spontaneous transition of the extracellular vestibule of LeuT into an outward-open conformation. The outward opening is enhanced by the absence of Na1 and modulated by the protonation state of the Na1-associated Glu-290. Consistently, the Na(+) affinity for the Na1 site is inversely correlated with the extent of outward-open character and is lower than in the occluded state with bound substrate; however, the Na1 site retains its selectivity for Na(+) over K(+) in such conformational transitions. To the best of our knowledge, our findings shed new light on the Na(+)-driven transport cycle and on the symmetry in structural rearrangements for outward- and inward-open transitions.

  18. Outward Bound in the Professional Education of Teachers. A Study of an Experimental Component in Field Experiences.

    ERIC Educational Resources Information Center

    Smathers, Keener M.

    In an effort to measure the impact of Outward Bound (OB) education on teacher candidates, an 18-day stress experience was arranged for 12 Appalachian State University students and then compared with the effects of the normal 11-week student teacher experiences of two other groups. The OB group underwent a series of individual and group wilderness…

  19. The Chd Family of Chromatin Remodelers

    PubMed Central

    Marfella, Concetta G.A.; Imbalzano, Anthony N.

    2007-01-01

    Chromatin remodeling enzymes contribute to the dynamic changes that occur in chromatin structure during cellular processes such as transcription, recombination, repair, and replication. Members of the chromodomain helicase DNA-binding (Chd) family of enzymes belong to the SNF2 superfamily of ATP-dependent chromatin remodelers. The Chd proteins are distinguished by the presence of two N-terminal chromodomains that function as interaction surfaces for a variety of chromatin components. Genetic, biochemical, and structural studies demonstrate that Chd proteins are important regulators of transcription and play critical roles during developmental processes. Numerous Chd proteins are also implicated in human disease. PMID:17350655

  20. 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

  1. Carvacrol presynaptically enhances spontaneous excitatory transmission and produces outward current in adult rat spinal substantia gelatinosa neurons.

    PubMed

    Luo, Qing-Tian; Fujita, Tsugumi; Jiang, Chang-Yu; Kumamoto, Eiichi

    2014-12-10

    Carvacrol, which is abundantly contained in oregano essential oils, has various pharmacological actions including antinociception. Although the oral administration of carvacrol results in antinociception, cellular mechanisms for this action have not been examined yet. We investigated the action of carvacrol on glutamatergic spontaneous excitatory transmission in substantia gelatinosa neurons which play a pivotal role in regulating nociceptive transmission from the periphery by using the patch-clamp technique in adult rat spinal cord slices. Carvacrol superfused for 2 min produced either spontaneous excitatory postsynaptic current frequency increase or outward current at −70 mV, or both of them in many of the neurons tested. The frequency increase and outward current had the EC(50) values of 0.69 mM and 0.55 mM, respectively. The former action was inhibited by a selective TRPA1 antagonist HC-030031 but not a selective TRPV1 antagonist capsazepine, while the latter action was unaffected by their antagonists. The current–voltage relationship for the outward current indicated an involvement in the current of a change in the membrane permeability of K(+) and its outward rectification. The outward current was inhibited in 10 mM-K((+) 0but not K(+)-channel blockers [tetraethylammonium and Ba(2+)]-containing and 11.0 mM-Cl- Krebs solution. These results indicate that carvacrol increases the spontaneous release of l-glutamate from nerve terminals by activating TRPA1 but not TRPV1 channels and produces membrane hyperpolarization, which is possibly mediated by tetraethylammonium- and Ba(2+)-insensitive K(+) channels, in substantia gelatinosa neurons. It is suggested that the hyperpolarizing effect of carvacrol could contribute to its antinociceptive action.

  2. Characterization of right ventricular remodeling and failure in a chronic pulmonary hypertension model

    PubMed Central

    Ishikawa, Kiyotake; Hadri, Lahouaria; Santos-Gallego, Carlos; Fish, Kenneth; Hammoudi, Nadjib; Chaanine, Antoine; Torquato, Samantha; Naim, Charbel; Ibanez, Borja; Pereda, Daniel; García-Alvarez, Ana; Fuster, Valentin; Sengupta, Partho P.; Leopold, Jane A.; Hajjar, Roger J.

    2014-01-01

    In pulmonary hypertension (PH), right ventricular (RV) dysfunction and failure is the main determinant of a poor prognosis. We aimed to characterize RV structural and functional differences during adaptive RV remodeling and progression to RV failure in a large animal model of chronic PH. Postcapillary PH was created surgically in swine (n = 21). After an 8- to 14-wk follow-up, two groups were identified based on the development of overt heart failure (HF): PH-NF (nonfailing, n = 12) and PH-HF (n = 8). In both groups, invasive hemodynamics, pressure-volume relationships, and echocardiography confirmed a significant increase in pulmonary pressures and vascular resistance consistent with PH. Histological analysis also demonstrated distal pulmonary arterial (PA) remodeling in both groups. Diastolic dysfunction, defined by a steeper RV end-diastolic pressure-volume relationship and longitudinal strain, was found in the absence of HF as an early marker of RV remodeling. RV contractility was increased in both groups, and RV-PA coupling was preserved in PH-NF animals but impaired in the PH-HF group. RV hypertrophy was present in PH-HF, although there was evidence of increased RV fibrosis in both PH groups. In the PH-HF group, RV sarcoplasmic reticulum Ca2+-ATPase2a expression was decreased, and endoplasmic reticulum stress was increased. Aldosterone levels were also elevated in PH-HF. Thus, in the swine pulmonary vein banding model of chronic postcapillary PH, RV remodeling occurs at the structural, histological, and molecular level. Diastolic dysfunction and fibrosis are present in adaptive RV remodeling, whereas the onset of RV failure is associated with RV-PA uncoupling, defective calcium handling, and hyperaldosteronism. PMID:25158063

  3. 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.

  4. 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.

  5. 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.

  6. 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

  7. Imaging inward and outward trafficking of gold nanoparticles in whole animals.

    PubMed

    Marchesano, Valentina; Hernandez, Yulan; Salvenmoser, Willi; Ambrosone, Alfredo; Tino, Angela; Hobmayer, Bert; de la Fuente, Jesus M; Tortiglione, Claudia

    2013-03-26

    Gold nanoparticles have emerged as novel safe and biocompatible tools for manifold applications, including biological imaging, clinical diagnostics, and therapeutics. The understanding of the mechanisms governing their interaction with living systems may help the design and development of new platforms for nanomedicine. Here we characterized the dynamics and kinetics of the events underlying the interaction of gold nanoparticles with a living organism, from the first interaction nanoparticle/cell membrane, to the intracellular trafficking and final extracellular clearance. By treating a simple water invertebrate (the cnidarian Hydra polyp) with functionalized gold nanoparticles, multiple inward and outward routes were imaged by ultrastructural analyses, including exosomes as novel undescribed carriers to shuttle the nanoparticles in and out the cells. From the time course imaging a highly dynamic picture emerged in which nanoparticles are rapidly internalized (from 30 min onward), recruited into vacuoles/endosome (24 h onward), which then fuse, compact and sort out the internalized material either to storage vacuoles or to late-endosome/lysosomes, determining almost complete clearance within 48 h from challenging. Beside classical routes, new portals of entry/exit were captured, including exosome-like structures as novel undescribed nanoparticle shuttles. The conservation of the endocytic/secretory machinery through evolution extends the value of our finding to mammalian systems providing dynamics and kinetics clues to take into account when designing nanomaterials to interface with biological entities.

  8. 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.

  9. Transient outward K+ channels in vesicles derived from frog skeletal muscle plasma membranes.

    PubMed Central

    Camacho, J; Delay, M J; Vazquez, M; Argüello, C; Sánchez, J A

    1996-01-01

    Whole-cell voltage-clamp experiments were performed in vesicles derived from frog skeletal muscle plasma membranes. Capacitance measurements showed that these vesicles lack invaginations. In solutions containing K+, transient outward currents with reversal potentials close to EK were recorded with a maximum potassium conductance of 0.3 mS/cm2. These currents inactivated in a voltage-dependent manner with a time constant of decay that reached a limiting value of 26 ms at large depolarizations. The steady-state inactivation reached half-maximum values at -66 mV. Transient currents were completely blocked with 5 mM 4-aminopyridine. Single-channel recordings made in inside-out excised patches from the vesicles had ensemble averages with characteristics similar to those of the macroscopic currents, although with significantly faster inactivation time constants. The single-channel chord conductance was 21 pS when the pipette and bath solutions contained 2.5 mM and 120 mM KCl, respectively. It is concluded that these vesicles contain potassium channels that are very similar to A channels found in neurons and other cells. Images FIGURE 8 PMID:8804601

  10. 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.

  11. 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.

  12. Re-Modelling as De-Professionalisation

    ERIC Educational Resources Information Center

    Thompson, Meryl

    2006-01-01

    The article sets out the consequences of the British Government's remodelling agenda and its emphasis on less demarcation, for the professional status of teachers in England. It describes how the National Agreement on Raising Standards and Tackling Workload, reached between five of the six trade unions for teachers and headteachers paves the way…

  13. 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…

  14. 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.

  15. 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.

  16. Endothelial cell dynamics in vascular remodelling.

    PubMed

    Barbacena, Pedro; Carvalho, Joana R; Franco, Claudio A

    2016-01-01

    In this ESCHM 2016 conference talk report, we summarise two recently published original articles Franco et al. PLoS Biology 2015 and Franco et al. eLIFE 2016. The vascular network undergoes extensive vessel remodelling to become fully functional. Is it well established that blood flow is a main driver for vascular remodelling. It has also been proposed that vessel pruning is a central process within physiological vessel remodelling. However, despite its central function, the cellular and molecular mechanisms regulating vessel regression, and their interaction with blood flow patterns, remain largely unexplained. We investigated the cellular process governing developmental vascular remodelling in mouse and zebrafish. We established that polarised reorganization of endothelial cells is at the core of vessel regression, representing vessel anastomosis in reverse. Moreover, we established for the first time an axial polarity map for all endothelial cells together with an in silico method for the computation of the haemodynamic forces in the murine retinal vasculature. Using network-level analysis and microfluidics, we showed that endothelial non-canonical Wnt signalling regulates endothelial sensitivity to shear forces. Loss of Wnt5a/11 renders endothelial cells more sensitive to shear, resulting in axial polarisation at lower shear stress levels. Collectively our data suggest that non-canonical Wnt signalling stabilizes forming vascular networks by reducing endothelial shear sensitivity, thus keeping vessels open under low flow conditions that prevail in the primitive plexus.

  17. 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

  18. 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

  19. A homogenized constrained mixture (and mechanical analog) model for growth and remodeling of soft tissue.

    PubMed

    Cyron, C J; Aydin, R C; Humphrey, J D

    2016-12-01

    Most mathematical models of the growth and remodeling of load-bearing soft tissues are based on one of two major approaches: a kinematic theory that specifies an evolution equation for the stress-free configuration of the tissue as a whole or a constrained mixture theory that specifies rates of mass production and removal of individual constituents within stressed configurations. The former is popular because of its conceptual simplicity, but relies largely on heuristic definitions of growth; the latter is based on biologically motivated micromechanical models, but suffers from higher computational costs due to the need to track all past configurations. In this paper, we present a temporally homogenized constrained mixture model that combines advantages of both classical approaches, namely a biologically motivated micromechanical foundation, a simple computational implementation, and low computational cost. As illustrative examples, we show that this approach describes well both cell-mediated remodeling of tissue equivalents in vitro and the growth and remodeling of aneurysms in vivo. We also show that this homogenized constrained mixture model suggests an intimate relationship between models of growth and remodeling and viscoelasticity. That is, important aspects of tissue adaptation can be understood in terms of a simple mechanical analog model, a Maxwell fluid (i.e., spring and dashpot in series) in parallel with a "motor element" that represents cell-mediated mechanoregulation of extracellular matrix. This analogy allows a simple implementation of homogenized constrained mixture models within commercially available simulation codes by exploiting available models of viscoelasticity.

  20. How did the Tibetan Plateau growth outward to the southwestern Qinling?

    NASA Astrophysics Data System (ADS)

    Tian, Xiaobo; Liu, Zhen; Wu, Zhenbo; Zhou, Beibei; Wang, Gaochun; Zhu, Gaohua; Tan, Ping; Nie, Shitan; Yu, Guiping; Liang, Xiaofeng; Bai, Zhiming; Chen, Yun; Xu, Tao; Zhang, Xi

    2016-04-01

    In the northeast of the Tibetan Plateau and north of the Sichuan Basin, the topography is decreasing eastward smoothly from 4.5 km in the Ruoergai Basin to 1.5 km in the Qinling. This feature can be interpreted to indicate that lower crustal flow has been diverted around the Sichuan Basin and beneath the southwestern Qinling, resulting in plateau uplift and growth eastward in this area. To address the problem how the Plateau growth outward, we have carried out a densy 160-km long, W-E shot-period seismograph array during July and Augest 2015 with a station spacing of ~500 m and a total 380 shot-peroid seismographs. During one month observation, 35 teleseismic event with a magnitude larger than 5.0 mw and a epicentral distance of 30-90 degree are recorded. P-wave receiver functions are calculated from 3-component-waveforms and used to imaging interfaces (or discontinuity of velocity of S-wave) in the crust and upper mantle. Our results show that the Moho is flat and imaged at 50 km depth by a strong P-to-S amplitude beneath the Ruoergai Basin. A weak interface can be found at depth ~20 km beneath the Basin. In contrast, a weak and flexural Moho is presented in a depth range of 40-50 km beneath the Minshan. A strong interface is also shown in the crust beneath the Minshan. The interface is west dipping steeply with a maximum depth of 40 km beneath the Minjiang Fault, and eastward become flat with a depth of 15 km beneath Minshan. This structure feature can be interpreted to indicate thrusting block by block eastward rather than lower crustal flow causing active plateau uplift in this area.

  1. 3-hydroxybutyrate blocks the transient K+ outward current in myocardial mouse cells in a stereoselective fashion.

    PubMed

    Doepner, B; Thierfelder, S; Hirche, H; Benndorf, K

    1997-04-01

    1. Mouse ventricular myocytes develop a large transient K+ outward current (I(TO)) which accelerates repolarization and is a crucial determinant for the regulation of the action potential duration at various heart rates. The effect of 3-hydroxybutyrate on I(TO) was investigated under voltage- and current-clamp conditions. 2. The drug blocked I(TO) in a stereoselective manner with the L-enantiomer being the effective and the D-enantiomer, the ineffective form. The blocking action of the L-enantiomer was established immediately and it could be completely washed out within several tens of seconds. 3. The dose-response characteristic for the peak I(TO) showed a strict 1:1 binding of the drug to the receptor with a concentration of half-maximum effect of 2.1 mmol l(-1). 4. The action of L-hydroxybutyrate was voltage independent, did not need channel opening and preferentially affected the slow component of both inactivation and recovery from inactivation. 5. At the high concentration of 20 mmol l(-1) the optically inactive form, the racemate, did not affect I(TO), indicating that the ineffective D-enantiomer interacts with the channels at much lower concentrations. 6. At a concentration of 10 mmol l(-1), L-hydroxybutyrate prolonged the action potential by 218 +/- 26 and 127 +/- 10% (means +/- S.E.M.) at 50 and 90% repolarization, respectively. 7. It is concluded that the non-physiological L-hydroxybutyrate is a novel type of blocker of I(TO), It interacts either with the channel itself, or with a receptor protein closely related to the channel and preferentially affects slow inactivation.

  2. The New Worlds Observer: Direct Detection and Study of Exoplanets from the Habitable Zone Outward

    NASA Astrophysics Data System (ADS)

    Cash, Webster C.; New Worlds Study Team

    2009-01-01

    Direct detection and spectroscopic study of the planets around the nearby stars is generally recognized as a prime goal of astronomy. The New Worlds Observer mission concept is being studied as an Astrophysics Strategic Mission Concept Study for this purpose. NWO features two spacecraft: a general purpose 4m telescope that operates from the UV to the Near IR, and a starshade, a flower-shaped occulter about 50m in diameter flying in alignment about 70,000km away. Our study shows this is the most effective way to map nearby planetary systems. Images will show dust and debris down to a fraction of our zodiacal light level. Planets fainter than the Earth can be seen from the Habitable Zone outward, at distances up to 20pc. High throughput and low noise enable immediate follow-up spectroscopy of discovered planets. NWO can discover many more Earth-like planets than all competing approaches including astrometric, interferometric, and internal coronagraphic. Within hours of discovery, a high quality spectrum can determine the true nature of the exoplanet and open the search for biomarkers and life. Over half of the time will be spent with the starshade in transit to the next target. During those times the telescope will be available to for general astrophysics purposes. Operating from the ultraviolet to the near infrared, this will be a true HST follow-on. The study shows all needed technologies already exist. The cost scales primarily with telescope size. The mission is definitely within the financial and technical reach of NASA for the coming decade.

  3. Remodeling of blood vessels: responses of diameter and wall thickness to hemodynamic and metabolic stimuli.

    PubMed

    Pries, Axel R; Reglin, Bettina; Secomb, Timothy W

    2005-10-01

    Vascular functions, including tissue perfusion and peripheral resistance, reflect continuous structural adaptation (remodeling) of blood vessels in response to several stimuli. Here, a theoretical model is presented that relates the structural and functional properties of microvascular networks to the adaptive responses of individual segments to hemodynamic and metabolic stimuli. All vessels are assumed to respond, according to a common set of adaptation rules, to changes in wall shear stress, circumferential wall stress, and tissue metabolic status (indicated by partial pressure of oxygen). An increase in vessel diameter with increasing wall shear stress and an increase in wall mass with increased circumferential stress are needed to ensure stable vascular adaptation. The model allows quantitative predictions of the effects of changes in systemic hemodynamic conditions or local adaptation characteristics on vessel structure and on peripheral resistance. Predicted effects of driving pressure on the ratio of wall thickness to vessel diameter are consistent with experimental observations. In addition, peripheral resistance increases by approximately 65% for an increase in driving pressure from 50 to 150 mm Hg. Peripheral resistance is predicted to be markedly increased in response to a decrease in vascular sensitivity to wall shear stress, and to be decreased in response to increased tissue metabolic demand. This theoretical approach provides a framework for integrating available information on structural remodeling in the vascular system and predicting responses to changing conditions or altered vascular reactivity, as may occur in hypertension.

  4. Association Between Myocardial Mechanics and Ischemic LV Remodeling.

    PubMed

    D'Elia, Nicholas; D'hooge, Jan; Marwick, Thomas H

    2015-12-01

    The outcomes associated with heart failure after myocardial infarction are still poor. Both global and regional left ventricular (LV) remodeling are associated with the progression of the post-infarct patient to heart failure, but although global remodeling can be accurately measured, regional LV remodeling has been more difficult to investigate. Preliminary evidence suggests that post-MI assessment of LV mechanics using stress and strain may predict global (and possibly regional) LV remodeling. A method of predicting both global and regional LV remodeling might facilitate earlier, targeted, and more extensive clinical intervention in those most likely to benefit from novel interventions such as cell therapy.

  5. 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.

  6. 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.

  7. Informing phenomenological structural bone remodelling with a mechanistic poroelastic model.

    PubMed

    Villette, Claire C; Phillips, Andrew T M

    2016-02-01

    Studies suggest that fluid motion in the extracellular space may be involved in the cellular mechanosensitivity at play in the bone tissue adaptation process. Previously, the authors developed a mesoscale predictive structural model of the femur using truss elements to represent trabecular bone, relying on a phenomenological strain-based bone adaptation algorithm. In order to introduce a response to bending and shear, the authors considered the use of beam elements, requiring a new formulation of the bone adaptation drivers. The primary goal of the study presented here was to isolate phenomenological drivers based on the results of a mechanistic approach to be used with a beam element representation of trabecular bone in mesoscale structural modelling. A single-beam model and a microscale poroelastic model of a single trabecula were developed. A mechanistic iterative adaptation algorithm was implemented based on fluid motion velocity through the bone matrix pores to predict the remodelled geometries of the poroelastic trabecula under 42 different loading scenarios. Regression analyses were used to correlate the changes in poroelastic trabecula thickness and orientation to the initial strain outputs of the beam model. Linear (R(2) > 0.998) and third-order polynomial (R(2) > 0.98) relationships were found between change in cross section and axial strain at the central axis, and between beam reorientation and ratio of bending strain to axial strain, respectively. Implementing these relationships into the phenomenological predictive algorithm for the mesoscale structural femur has the potential to produce a model combining biofidelic structure and mechanical behaviour with computational efficiency.

  8. Bile-induced peptidoglycan remodelling in Salmonella enterica.

    PubMed

    Hernández, Sara B; Cava, Felipe; Pucciarelli, M Graciela; García-Del Portillo, Francisco; de Pedro, Miguel A; Casadesús, Josep

    2015-04-01

    Changes in the peptidoglycan (PG) structure of Salmonella enterica are detected in the presence of a sublethal concentration of sodium deoxycholate (DOC): (i) lower proportions of Braun lipoprotein (Lpp)-bound muropeptides; (ii) reduced levels of muropeptides cross-linked by L(meso)-diaminopimelyl-D(meso)-diaminopimelic acid (L-D) peptide bridges (3-3 cross-links). Similar structural changes are found in S. enterica cultures adapted to grow in the presence of a lethal concentration of DOC, suggesting that reduced anchoring of Braun protein to PG and low occurrence of 3-3 cross-links may increase S. enterica resistance to bile. This view is further supported by additional observations: (i) A triple mutant lacking L,D-transpeptidases YbiS, ErfK, and YcfS, which does not contain Lpp anchored to PG, is hyper-resistant to bile; (ii) enhanced 3-3 cross-linking upon overexpression of YnhG transpeptidase causes a decrease in bile resistance. These observations suggest that remodelling of the cell wall may be added to the list of adaptive responses that permit survival of S. enterica in the presence of bile.

  9. 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

  10. TRPC3 positively regulates reactive oxygen species driving maladaptive cardiac remodeling

    PubMed Central

    Kitajima, Naoyuki; Numaga-Tomita, Takuro; Watanabe, Masahiko; Kuroda, Takuya; Nishimura, Akiyuki; Miyano, Kei; Yasuda, Satoshi; Kuwahara, Koichiro; Sato, Yoji; Ide, Tomomi; Birnbaumer, Lutz; Sumimoto, Hideki; Mori, Yasuo; Nishida, Motohiro

    2016-01-01

    Reactive oxygen species (ROS) produced by NADPH oxidase 2 (Nox2) function as key mediators of mechanotransduction during both physiological adaptation to mechanical load and maladaptive remodeling of the heart. This is despite low levels of cardiac Nox2 expression. The mechanism underlying the transition from adaptation to maladaptation remains obscure, however. We demonstrate that transient receptor potential canonical 3 (TRPC3), a Ca2+-permeable channel, acts as a positive regulator of ROS (PRROS) in cardiomyocytes, and specifically regulates pressure overload-induced maladaptive cardiac remodeling in mice. TRPC3 physically interacts with Nox2 at specific C-terminal sites, thereby protecting Nox2 from proteasome-dependent degradation and amplifying Ca2+-dependent Nox2 activation through TRPC3-mediated background Ca2+ entry. Nox2 also stabilizes TRPC3 proteins to enhance TRPC3 channel activity. Expression of TRPC3 C-terminal polypeptide abolished TRPC3-regulated ROS production by disrupting TRPC3-Nox2 interaction, without affecting TRPC3-mediated Ca2+ influx. The novel TRPC3 function as a PRROS provides a mechanistic explanation for how diastolic Ca2+ influx specifically encodes signals to induce ROS-mediated maladaptive remodeling and offers new therapeutic possibilities. PMID:27833156

  11. Ventricular remodeling: from bedside to molecule.

    PubMed

    Jaffe, R; Flugelman, M Y; Halon, D A; Lewis, B S

    1997-01-01

    The multiple mechanisms that bring about the decompensation of the hypertrophic remodeled myocardium are synergistic and not fully understood. Our current hypothesis is that the increased stress on the ventricle is initially offset by compensatory myocardial hypertrophy. In many instances, however, progressive ventricular dilatation and heart failure occur as a result of maladaptive hypertrophy (abnormal myosin-actin production), programmed cell death (apoptosis) and/or changes in the interstitial vasculature and collagen composition. The molecular and genetic background to these processes includes changes in myocardial gene expression, activation of the local tissue renin-angiotensin and other neurohormonal systems, increased matrix metalloproteinase activity (including collagenase), and expression of certain components of the immune system, such as TNF-alpha. Future research will hopefully provide better methods for limiting the remodeling-ventricular dilatation process by novel pharmacotherapies, gene therapy and, possibly, surgical therapy, and determine the impact of such interventions on survival.

  12. 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

  13. [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.

  14. 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.

  15. Mechanisms of epigenetic remodelling during preimplantation development.

    PubMed

    Ross, Pablo Juan; Canovas, Sebastian

    2016-01-01

    Epigenetics involves mechanisms independent of modifications in the DNA sequence that result in changes in gene expression and are maintained through cell divisions. Because all cells in the organism contain the same genetic blueprint, epigenetics allows for cells to assume different phenotypes and maintain them upon cell replication. As such, during the life cycle, there are moments in which the epigenetic information needs to be reset for the initiation of a new organism. In mammals, the resetting of epigenetic marks occurs at two different moments, which both happen to be during gestation, and include primordial germ cells (PGCs) and early preimplantation embryos. Because epigenetic information is reversible and sensitive to environmental changes, it is probably no coincidence that both these extensive periods of epigenetic remodelling happen in the female reproductive tract, under a finely controlled maternal environment. It is becoming evident that perturbations during the extensive epigenetic remodelling in PGCs and embryos can lead to permanent and inheritable changes to the epigenome that can result in long-term changes to the offspring derived from them, as indicated by the Developmental Origins of Health and Disease (DOHaD) hypothesis and recent demonstration of inter- and trans-generational epigenetic alterations. In this context, an understanding of the mechanisms of epigenetic remodelling during early embryo development is important to assess the potential for gametic epigenetic mutations to contribute to the offspring and for new epimutations to be established during embryo manipulations that could affect a large number of cells in the offspring. It is of particular interest to understand whether and how epigenetic information can be passed on from the gametes to the embryo or offspring, and whether abnormalities in this process could lead to transgenerationally inheritable phenotypes. The aim of this review is to highlight recent progress made in

  16. 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

  17. [Remodeling in asthma: review of the literature].

    PubMed

    Montero Mora, Patricia; González Espinosa, Alicia Ma; Guidos Foguelbach, Guillermo A; Tinajero Castañeda, Olga Adriana; Serrano Cuevas, Saúl

    2003-01-01

    Remodeling, understood as a new or different reconstruction, has been observed in every organ after a chronic inflammatory response. In allergy, it has very important clinical consequences. As an example, in asthma this process is responsible for functional deterioration. In this case, the myofibroblasts play a central role in the process, together with a succession of products that are involved. In this bibliographic review we analyze the most important factors.

  18. Right ventricular remodeling in pulmonary hypertension.

    PubMed

    Franco, Veronica

    2012-07-01

    The right ventricle (RV) is in charge of pumping blood to the lungs for oxygenation. Pulmonary arterial hypertension (PAH) is characterized by high pulmonary vascular resistance and vascular remodeling, which results in a striking increase in RV afterload and subsequent failure. There is still unexploited potential for therapies that directly target the RV with the aim of supporting and protecting the right side of the heart, striving to prolong survival in patients with PAH.

  19. 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.

  20. Retinal remodeling triggered by photoreceptor degenerations.

    PubMed

    Jones, Bryan W; Watt, Carl B; Frederick, Jeanne M; Baehr, Wolfgang; Chen, Ching-Kang; Levine, Edward M; Milam, Ann H; Lavail, Matthew M; Marc, Robert E

    2003-09-08

    Many photoreceptor degenerations initially affect rods, secondarily leading to cone death. It has long been assumed that the surviving neural retina is largely resistant to this sensory deafferentation. New evidence from fast retinal degenerations reveals that subtle plasticities in neuronal form and connectivity emerge early in disease. By screening mature natural, transgenic, and knockout retinal degeneration models with computational molecular phenotyping, we have found an extended late phase of negative remodeling that radically changes retinal structure. Three major transformations emerge: 1) Müller cell hypertrophy and elaboration of a distal glial seal between retina and the choroid/retinal pigmented epithelium; 2) apparent neuronal migration along glial surfaces to ectopic sites; and 3) rewiring through evolution of complex neurite fascicles, new synaptic foci in the remnant inner nuclear layer, and new connections throughout the retina. Although some neurons die, survivors express molecular signatures characteristic of normal bipolar, amacrine, and ganglion cells. Remodeling in human and rodent retinas is independent of the initial molecular targets of retinal degenerations, including defects in the retinal pigmented epithelium, rhodopsin, or downstream phototransduction elements. Although remodeling may constrain therapeutic intervals for molecular, cellular, or bionic rescue, it suggests that the neural retina may be more plastic than previously believed.

  1. Psoriatic architecture constructed by epidermal remodeling.

    PubMed

    Iizuka, Hajime; Takahashi, Hidetoshi; Ishida-Yamamoto, Akemi

    2004-08-01

    Epidermal remodeling is the concept that epidermal architecture is determined by a simple self-organizing mechanism; epidermal hyperproliferation constructs typical psoriatic architecture. This is based on the assumption that the enlargements in both the two-dimensional proliferative compartment (basal cell layer) and three-dimensional whole epidermal volume coexist. During this process, the dermal papillae become markedly, but passively, expanded by enlargement of the proliferative compartment. This creates a considerable shrinkage force against the crowded basal cell layer, which is forced to lose adherence to the dermal extracellular matrix (ECM). This results in anoikis, a type of apoptosis characterized by cell detachment, and, consequently, a markedly diminished epidermal turnover time in psoriasis. The papillary shrinkage force also explains the fact that dermal papillary height does not exceed a certain limit. At the cessation of hyperproliferation a normalisation remodeling takes place toward normal tissue architecture. Thus the concept of epidermal remodeling explains the self-organizing mechanism of the architectural change in psoriasis, which is essentially a reversible disorder depending on epidermal hyperproliferation.

  2. Role of Arginase in Vessel Wall Remodeling

    PubMed Central

    Durante, William

    2013-01-01

    Arginase metabolizes the semi-essential amino acid l-arginine to l-ornithine and urea. There are two distinct isoforms of arginase, arginase I and II, which are encoded by separate genes and display differences in tissue distribution, subcellular localization, and molecular regulation. Blood vessels express both arginase I and II but their distribution appears to be cell-, vessel-, and species-specific. Both isoforms of arginase are induced by numerous pathologic stimuli and contribute to vascular cell dysfunction and vessel wall remodeling in several diseases. Clinical and experimental studies have documented increases in the expression and/or activity of arginase I or II in blood vessels following arterial injury and in pulmonary and arterial hypertension, aging, and atherosclerosis. Significantly, pharmacological inhibition or genetic ablation of arginase in animals ameliorates abnormalities in vascular cells and normalizes blood vessel architecture and function in all of these pathological states. The detrimental effect of arginase in vascular remodeling is attributable to its ability to stimulate vascular smooth muscle cell and endothelial cell proliferation, and collagen deposition by promoting the synthesis of polyamines and l-proline, respectively. In addition, arginase adversely impacts arterial remodeling by directing macrophages toward an inflammatory phenotype. Moreover, the proliferative, fibrotic, and inflammatory actions of arginase in the vasculature are further amplified by its capacity to inhibit nitric oxide (NO) synthesis by competing with NO synthase for substrate, l-arginine. Pharmacologic or molecular approaches targeting specific isoforms of arginase represent a promising strategy in treating obstructive fibroproliferative vascular disease. PMID:23717309

  3. Application of Petri nets in bone remodeling.

    PubMed

    Li, Lingxi; Yokota, Hiroki

    2009-07-06

    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.

  4. 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."

  5. 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

  6. Membrane fluidization triggers membrane remodeling which affects the thermotolerance in Escherichia coli.

    PubMed

    Shigapova, Natalia; Török, Zsolt; Balogh, Gábor; Goloubinoff, Pierre; Vígh, László; Horváth, Ibolya

    2005-03-25

    Treatment of Escherichia coli with non-lethal doses of heat or benzyl alcohol (BA) causes transient membrane fluidization and permeabilization, and induces the rapid transcription of heat-shock genes in a sigma32-dependent manner. This early response is followed by a rapid adaptation (priming) of the cells to otherwise lethal elevated temperature, in strong correlation with an observed remodeling of the composition and alkyl chain unsaturation of membrane lipids. The acquisition of cellular thermotolerance in BA-primed cells is unrelated to protein denaturation and is not accompanied by the formation of major heat-shock proteins, such as GroEL and DnaK. This suggests that the rapid remodeling of membrane composition is sufficient for the short-term bacterial thermotolerance.

  7. Zebrafish larva as a reliable model for in vivo assessment of membrane remodeling involvement in the hepatotoxicity of chemical agents.

    PubMed

    Podechard, Normand; Chevanne, Martine; Fernier, Morgane; Tête, Arnaud; Collin, Aurore; Cassio, Doris; Kah, Olivier; Lagadic-Gossmann, Dominique; Sergent, Odile

    2016-11-28

    The easy-to-use in vivo model, zebrafish larva, is being increasingly used to screen chemical-induced hepatotoxicity, with a good predictivity for various mechanisms of liver injury. However, nothing is known about its applicability in exploring the mechanism called membrane remodeling, depicted as changes in membrane fluidity or lipid raft properties. The aim of this study was, therefore, to substantiate the zebrafish larva as a suitable in vivo model in this context. Ethanol was chosen as a prototype toxicant because it is largely described, both in hepatocyte cultures and in rodents, as capable of inducing a membrane remodeling leading to hepatocyte death and liver injury. The zebrafish larva model was demonstrated to be fully relevant as membrane remodeling was maintained even after a 1-week exposure without any adaptation as usually reported in rodents and hepatocyte cultures. It was also proven to exhibit a high sensitivity as it discriminated various levels of cytotoxicity depending on the extent of changes in membrane remodeling. In this context, its sensitivity appeared higher than that of WIF-B9 hepatic cells, which is suited for analyzing this kind of hepatotoxicity. Finally, the protection afforded by a membrane stabilizer, ursodeoxycholic acid (UDCA), or by a lipid raft disrupter, pravastatin, definitely validated zebrafish larva as a reliable model to quickly assess membrane remodeling involvement in chemical-induced hepatotoxicity. In conclusion, this model, compatible with a high throughput screening, might be adapted to seek hepatotoxicants via membrane remodeling, and also drugs targeting membrane features to propose new preventive or therapeutic strategies in chemical-induced liver diseases. Copyright © 2016 John Wiley & Sons, Ltd.

  8. Activity and loading influence the predicted bone remodeling around cemented hip replacements.

    PubMed

    Dickinson, Alexander S

    2014-04-01

    Periprosthetic bone remodeling is frequently observed after total hip replacement. Reduced bone density increases the implant and bone fracture risk, and a gross loss of bone density challenges fixation in subsequent revision surgery. Computational approaches allow bone remodeling to be predicted in agreement with the general clinical observations of proximal resorption and distal hypertrophy. However, these models do not reproduce other clinically observed bone density trends, including faster stabilizing mid-stem density losses, and loss-recovery trends around the distal stem. These may resemble trends in postoperative joint loading and activity, during recovery and rehabilitation, but the established remodeling prediction approach is often used with identical pre- and postoperative load and activity assumptions. Therefore, this study aimed to evaluate the influence of pre- to postoperative changes in activity and loading upon the predicted progression of remodeling. A strain-adaptive finite element model of a femur implanted with a cemented Charnley stem was generated, to predict 60 months of periprosthetic remodeling. A control set of model input data assumed identical pre- and postoperative loading and activity, and was compared to the results obtained from another set of inputs with three varying activity and load profiles. These represented activity changes during rehabilitation for weak, intermediate and strong recoveries, and pre- to postoperative joint force changes due to hip center translation and the use of walking aids. Predicted temporal bone density change trends were analyzed, and absolute bone density changes and the time to homeostasis were inspected, alongside virtual X-rays. The predicted periprosthetic bone density changes obtained using modified loading inputs demonstrated closer agreement with clinical measurements than the control. The modified inputs also predicted the clinically observed temporal density change trends, but still under

  9. 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.

  10. Electronegative LDL-mediated cardiac electrical remodeling in a rat model of chronic kidney disease

    PubMed Central

    Lee, An-Sheng; Chen, Wei-Yu; Chan, Hua-Chen; Chung, Ching-Hu; Peng, Hsien-Yu; Chang, Chia-Ming; Su, Ming-Jai; Chen, Chu-Huang; Chang, Kuan-Cheng

    2017-01-01

    The mechanisms underlying chronic kidney disease (CKD)–associated higher risks for life-threatening ventricular tachyarrhythmias remain poorly understood. In rats subjected to unilateral nephrectomy (UNx), we examined cardiac electrophysiological remodeling and relevant mechanisms predisposing to ventricular arrhythmias. Adult male Sprague-Dawley rats underwent UNx (n = 6) or sham (n = 6) operations. Eight weeks later, the UNx group had higher serum blood urea nitrogen and creatinine levels and a longer electrocardiographic QTc interval than did the sham group. Patch-clamp studies revealed epicardial (EPI)-predominant prolongation of the action potential duration (APD) at 50% and 90% repolarization in UNx EPI cardiomyocytes compared to sham EPI cardiomyocytes. A significant reduction of the transient outward potassium current (Ito) in EPI but not in endocardial (ENDO) cardiomyocytes of UNx rats led to a decreased transmural gradient of Ito. The reduction of Ito currents in UNx EPI cardiomyocytes was secondary to downregulation of KChIP2 but not Kv4.2, Kv4.3, and Kv1.4 protein expression. Incubation of plasma electronegative low-density lipoprotein (LDL) from UNx rats with normal EPI and ENDO cardiomyocytes recapitulated the electrophysiological phenotype of UNx rats. In conclusion, CKD disrupts the physiological transmural gradient of Ito via downregulation of KChIP2 proteins in the EPI region, which may promote susceptibility to ventricular tachyarrhythmias. Electronegative LDL may underlie downregulation of KChIP2 in CKD. PMID:28094801

  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. 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.

  14. Nucleosome remodelers in double-strand break repair.

    PubMed

    Seeber, Andrew; Hauer, Michael; Gasser, Susan M

    2013-04-01

    ATP-dependent nucleosome remodelers use ATP hydrolysis to shift, evict and exchange histone dimers or octamers and have well-established roles in transcription. Earlier work has suggested a role for nucleosome remodelers such as INO80 in double-strand break (DSB) repair. This review will begin with an update on recent studies that explore how remodelers are recruited to DSBs. We then examine their impact on various steps of repair, focusing on resection and the formation of the Rad51-ssDNA nucleofilament. Finally, we will explore new studies that implicate remodelers in the physical movement of chromatin in response to damage.

  15. 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.

  16. LRP1 regulates remodeling of the extracellular matrix by fibroblasts

    PubMed Central

    Gaultier, Alban; Hollister, Margaret; Reynolds, Irene; Hsieh, En-hui; Gonias, Steven L.

    2009-01-01

    Low density lipoprotein receptor-related protein (LRP1) is an endocytic receptor for diverse proteases, protease inhibitors, and other plasma membrane proteins, including the urokinase receptor (uPAR). LRP1 also functions in cell-signaling and regulates gene expression. The goal of this study was to determine whether LRP1 regulates remodeling of provisional extracellular matrix (ECM) by fibroblasts. To address this problem, we utilized an in vitro model in which type I collagen was reconstituted and overlaid with fibronectin. Either the collagen or fibronectin was fluorescently-labeled. ECM remodeling by fibroblasts deficient in LRP1, uPAR, or MT1-MMP was studied. MT1-MMP was required for efficient remodeling of the deep collagen layer but not involved in fibronectin remodeling. Instead, fibronectin was remodeled by a system that required urokinase-type plasminogen activator (uPA), uPAR, and exogenously-added plasminogen. LRP1 markedly inhibited fibronectin remodeling by regulating cell-surface uPAR and plasminogen activation. LRP1 also regulated remodeling of the deep collagen layer but not by controlling MT1-MMP. Instead, LRP1 deficiency or inhibition de-repressed a secondary pathway for collagen remodeling, which was active in MT1-MMP-deficient cells but not in uPAR-deficient cells. These results demonstrate that LRP1 regulates ECM remodeling principally by repressing pathways that require plasminogen activation by uPA in association with uPAR. PMID:19699300

  17. A whole-cell and single-channel study of the voltage-dependent outward potassium current in avian hepatocytes

    PubMed Central

    1988-01-01

    Voltage-dependent membrane currents were studied in dissociated hepatocytes from chick, using the patch-clamp technique. All cells had voltage-dependent outward K+ currents; in 10% of the cells, a fast, transient, tetrodotoxin-sensitive Na+ current was identified. None of the cells had voltage-dependent inward Ca2+ currents. The K+ current activated at a membrane potential of about -10 mV, had a sigmoidal time course, and did not inactivate in 500 ms. The maximum outward conductance was 6.6 +/- 2.4 nS in 18 cells. The reversal potential, estimated from tail current measurements, shifted by 50 mV per 10-fold increase in the external K+ concentration. The current traces were fitted by n2 kinetics with voltage-dependent time constants. Omitting Ca2+ from the external bath or buffering the internal Ca2+ with EGTA did not alter the outward current, which shows that Ca2+-activated K+ currents were not present. 1-5 mM 4-aminopyridine, 0.5-2 mM BaCl2, and 0.1-1 mM CdCl2 reversibly inhibited the current. The block caused by Ba was voltage dependent. Single-channel currents were recorded in cell- attached and outside-out patches. The mean unitary conductance was 7 pS, and the channels displayed bursting kinetics. Thus, avian hepatocytes have a single type of K+ channel belonging to the delayed rectifier class of K+ channels. PMID:2453605

  18. 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.

  19. 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.

  20. Delay of planet formation at large radius and the outward decrease in mass and gas content of Jovian planets

    NASA Astrophysics Data System (ADS)

    Jin, Li-Ping; Liu, Chun-Jian; Zhang, Yu

    2015-09-01

    A prominent observation of the solar system is that the mass and gas content of Jovian planets decrease outward with orbital radius, except that, in terms of these properties, Neptune is almost the same as Uranus. In previous studies, the solar nebula was assumed to preexist and the formation process of the solar nebula was not considered. It was therefore assumed that planet formation at different radii started at the same time in the solar nebula. We show that planet formation at different radii does not start at the same time and is delayed at large radii. We suggest that this delay might be one of the factors that causes the outward decrease in the masses of Jovian planets. The nebula starts to form from its inner part because of the inside-out collapse of its progenitorial molecular cloud core. The nebula then expands outward due to viscosity. Material first reaches a small radius and then reaches a larger radius, so planet formation is delayed at the large radius. The later the material reaches a planet's location, the less time it has to gain mass and gas content. Hence, the delay tends to cause the outward decrease in mass and gas content of Jovian planets. Our nebula model shows that the material reaches Jupiter, Saturn, Uranus and Neptune at t = 0.40, 0.57, 1.50 and 6.29 × 106 yr, respectively. We discuss the effects of time delay on the masses of Jovian planets in the framework of the core accretion model of planet formation. Saturn's formation is not delayed by much time relative to Jupiter so that they both reach the rapid gas accretion phase and become gas giants. However, the delay in formation of Uranus and Neptune is long and might be one of the factors that cause them not to reach the rapid gas accretion phase before the gas nebula is dispersed. Saturn has less time to go through the rapid gas accretion, so Saturn's mass and gas content are significantly less than those of Jupiter.

  1. Vascular remodeling underlies rebleeding in hemophilic arthropathy.

    PubMed

    Bhat, Vikas; Olmer, Merissa; Joshi, Shweta; Durden, Donald L; Cramer, Thomas J; Barnes, Richard Fw; Ball, Scott T; Hughes, Tudor H; Silva, Mauricio; Luck, James V; Moore, Randy E; Mosnier, Laurent O; von Drygalski, Annette

    2015-11-01

    Hemophilic arthropathy is a debilitating condition that can develop as a consequence of frequent joint bleeding despite adequate clotting factor replacement. The mechanisms leading to repeated spontaneous bleeding are unknown. We investigated synovial, vascular, stromal, and cartilage changes in response to a single induced hemarthrosis in the FVIII-deficient mouse. We found soft-tissue hyperproliferation with marked induction of neoangiogenesis and evolving abnormal vascular architecture. While soft-tissue changes were rapidly reversible, abnormal vascularity persisted for months and, surprisingly, was also seen in uninjured joints. Vascular changes in FVIII-deficient mice involved pronounced remodeling with expression of α-Smooth Muscle Actin (SMA), Endoglin (CD105), and vascular endothelial growth factor, as well as alterations of joint perfusion as determined by in vivo imaging. Vascular architecture changes and pronounced expression of α-SMA appeared unique to hemophilia, as these were not found in joint tissue obtained from mouse models of rheumatoid arthritis and osteoarthritis and from patients with the same conditions. Evidence that vascular changes in hemophilia were significantly associated with bleeding and joint deterioration was obtained prospectively by dynamic in vivo imaging with musculoskeletal ultrasound and power Doppler of 156 joints (elbows, knees, and ankles) in a cohort of 26 patients with hemophilia at baseline and during painful episodes. These observations support the hypothesis that vascular remodeling contributes significantly to bleed propagation and development of hemophilic arthropathy. Based on these findings, the development of molecular targets for angiogenesis inhibition may be considered in this disease.

  2. Specific remodeling of splenic architecture by cytomegalovirus.

    PubMed

    Benedict, Chris A; De Trez, Carl; Schneider, Kirsten; Ha, Sukwon; Patterson, Ginelle; Ware, Carl F

    2006-03-01

    Efficient immune defenses are facilitated by the organized microarchitecture of lymphoid organs, and this organization is regulated by the compartmentalized expression of lymphoid tissue chemokines. Mouse cytomegalovirus (MCMV) infection induces significant remodeling of splenic microarchitecture, including loss of marginal zone macrophage populations and dissolution of T and B cell compartmentalization. MCMV preferentially infected the splenic stroma, targeting endothelial cells (EC) as revealed using MCMV-expressing green fluorescent protein. MCMV infection caused a specific, but transient transcriptional suppression of secondary lymphoid chemokine (CCL21). The loss of CCL21 was associated with the failure of T lymphocytes to locate within the T cell zone, although trafficking to the spleen was unaltered. Expression of CCL21 in lymphotoxin (LT)-alpha-deficient mice is dramatically reduced, however MCMV infection further reduced CCL21 levels, suggesting that viral modulation of CCL21 was independent of LTalpha signaling. Activation of LTbeta-receptor signaling with an agonistic antibody partially restored CCL21 mRNA expression and redirected transferred T cells to the splenic T cell zone in MCMV-infected mice. These results indicate that virus-induced alterations in lymphoid tissues can occur through an LT-independent modulation of chemokine transcription, and targeting of the LT cytokine system can counteract lymphoid tissue remodeling by MCMV.

  3. 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

  4. Impact of Short-Term Treatment with Telmisartan on Cerebral Arterial Remodeling in SHR

    PubMed Central

    Foulquier, Sébastien; Lartaud, Isabelle; Dupuis, François

    2014-01-01

    Background and Purpose Chronic hypertension decreases internal diameter of cerebral arteries and arterioles. We recently showed that short-term treatment with the angiotensin II receptor blocker telmisartan restored baseline internal diameter of small cerebral arterioles in spontaneously hypertensive rats (SHR), via reversal of structural remodeling and inhibition of the angiotensin II vasoconstrictor response. As larger arteries also participate in the regulation of cerebral circulation, we evaluated whether similar short-term treatment affects middle cerebral arteries of SHR. Methods Baseline internal diameters of pressurised middle cerebral arteries from SHR and their respective controls, Wistar Kyoto rats (WKY) and responses to angiotensin II were studied in a small vessel arteriograph. Pressure myogenic curves and passive internal diameters were measured following EDTA deactivation, and elastic modulus from stress-strain relationships. Results Active baseline internal diameter was 23% lower in SHR compared to WKY, passive internal diameter (EDTA) 28% lower and elastic modulus unchanged. Pressure myogenic curves were shifted to higher pressure values in SHR. Telmisartan lowered blood pressure but had no effect on baseline internal diameter nor on structural remodeling (passive internal diameter and elastic modulus remained unchanged compared to SHR). Telmisartan shifted the pressure myogenic curve to lower pressure values than SHR. Conclusion In the middle cerebral arteries of SHR, short-term treatment with telmisartan had no effect on structural remodeling and did not restore baseline internal diameter, but allowed myogenic tone to adapt towards lower pressure values. PMID:25333878

  5. Left atrial remodelling in competitive adolescent soccer players.

    PubMed

    D'Ascenzi, F; Cameli, M; Lisi, M; Zacà, V; Natali, B; Malandrino, A; Benincasa, S; Catanese, S; Causarano, A; Mondillo, S

    2012-10-01

    Left atrial (LA) enlargement and improved myocardial diastolic properties are a component of athlete's heart. We performed a longitudinal study involving adolescent athletes to investigate the impact of training on LA remodelling and diastolic function. 21 competitive adolescent soccer players were enrolled and engaged in an 8-month training program. Echocardiographic analysis was performed at baseline, after 4 and 8 months. We assessed diastolic function by Doppler tissue imaging and we analyzed LA adaptations by 2D speckle-tracking echocardiography. After 4 months, LA mean volume index significantly increased (Δ=5.47 ± 4.38 mL/m2, p ≤ 0.0001). After 8 months, a further increase occurred (Δ=8.95 ± 4.47 mL/m2, p ≤ 0.0001). A higher E velocity (p=0.001; p=0.001), a greater E/A ratio (p=0.002; p=0.0009), a higher e' peak (p= 0.005; p=0.001), and a greater e'/a' ratio (p=0.01; p=0.0006) were observed at 4 and at 8 months, respectively. E/e' ratio significantly decreased after 8 months (p ≤ 0.005). Global peak atrial longitudinal strain and global peak atrial contraction strain values significantly decreased after 8 months (p=0.0004, p=0.01, respectively). An 8-month training program is associated with LA dimensional and functional training-specific adaptations in competitive adolescent soccer players. Myocardial diastolic properties can improve after training also in subjects already presenting with features of athlete's heart.

  6. 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

  7. Acute p38-mediated inhibition of NMDA-induced outward currents in hippocampal CA1 neurons by interleukin-1beta.

    PubMed

    Zhang, Ruoyu; Sun, Li; Hayashi, Yoshinori; Liu, Xia; Koyama, Susumu; Wu, Zhou; Nakanishi, Hiroshi

    2010-04-01

    Interleukin-1beta (IL-1beta) is a potent pro-inflammatory cytokine that is primarily produced by microglia in the brain. IL-1beta inhibits N-methyl-d-aspartate (NMDA)-induced outward currents (I(NMDA-OUT)) through IL-1 type I receptor (IL-1RI) in hippocampal CA1 neurons (Zhang, R., Yamada, J., Hayashi, Y., Wu, Z, Koyama, S., Nakanishi, H., 2008. Inhibition of NMDA-induced outward currents by interleukin-1beta in hippocampal neurons, Biochem. Biophys. Res. Commun. 372, 816-820). Although IL-1RI is associated with mitogen-activated protein kinases, their involvement in the effect of IL-1beta on I(NMDA-OUT) remains unclear. In the present study, we demonstrate that IL-1beta caused activation of p38 mitogen-activated protein kinase and that the p38 inhibitor SB203580 significantly blocked the effect of IL-1beta on I(NMDA-OUT) in hippocampal CA1 neurons. Furthermore, the intracellular perfusion of active recombinant p38alpha significantly decreased the mean amplitude of I(NMDA-OUT). In neurons prepared from inflamed hippocampus, the mean amplitude of I(NMDA-OUT) was significantly reduced. In the inflamed hippocampus, IL-1beta and IL-1RI were expressed mainly in microglia and neurons, respectively. These results suggest that IL-1beta increases the excitability of hippocampal CA1 neurons in the p38-dependent inhibition of I(NMDA-OUT).

  8. The role of echocardiography in the evaluation of cardiac re-modelling and differentiation between physiological and pathological hypertrophy in teenagers engaged in competitive amateur sports.

    PubMed

    Sulovic, Ljiljana S; Mahmutovic, Meho; Lazic, Snezana; Sulovic, Nenad

    2016-10-18

    Aims "Athlete's heart" is a cardiac adaptation to long-term intensive training. The aims of this study were to show the prevalence of left ventricular hypertrophy in teenagers who participate in sports, to define the different types of cardiac re-modelling, and to differentiate between physiological and pathological hypertrophy.

  9. Evaluation of the National Remodelling Team: Year 3. Final Report

    ERIC Educational Resources Information Center

    Easton, Claire; Eames, Anna; Wilson, Rebekah; Walker, Matthew; Sharp, Caroline

    2006-01-01

    The aim of the National Foundation for Educational Research (NFER) evaluation was to examine the effectiveness and impact of the work of the National Remodelling Team (NRT) in completing the third phase of the remodeling program and its effectiveness in applying its model, tools and techniques to the extended schools program. This evaluation has…

  10. CCR3 Blockade Attenuates Eosinophilic Ileitis and Associated Remodeling.

    PubMed

    Masterson, Joanne C; McNamee, Eóin N; Jedlicka, Paul; Fillon, Sophie; Ruybal, Joseph; Hosford, Lindsay; Rivera-Nieves, Jesús; Lee, James J; Furuta, Glenn T

    2011-11-01

    Intestinal remodeling and stricture formation is a complication of inflammatory bowel disease (IBD) that often requires surgical intervention. Although eosinophils are associated with mucosal remodeling in other organs and are increased in IBD tissues, their role in IBD-associated remodeling is unclear. Histological and molecular features of ileitis and remodeling were assessed using immunohistochemical, histomorphometric, flow cytometric, and molecular analysis (real-time RT-PCR) techniques in a murine model of chronic eosinophilic ileitis. Collagen protein was assessed by Sircol assay. Using a spontaneous eosinophilic Crohn's-like mouse model SAMP1/SkuSlc, we demonstrate an association between ileitis progression and remodeling over the course of 40 weeks. Mucosal and submucosal eosinophilia increased over the time course and correlated with increased histological inflammatory indices. Ileitis and remodeling increased over the 40 weeks, as did expression of fibronectin. CCR3-specific antibody-mediated reduction of eosinophils resulted in significant decrease in goblet cell hyperplasia, muscularis propria hypertrophy, villus blunting, and expression of inflammatory and remodeling genes, including fibronectin. Cellularity of local mesenteric lymph nodes, including T- and B-lymphocytes, was also significantly reduced. Thus, eosinophils participate in intestinal remodeling, supporting eosinophils as a novel therapeutic target.

  11. 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).

  12. Thrombospondin-4 regulates fibrosis and remodeling of the myocardium in response to pressure overload

    PubMed Central

    Frolova, Ella G.; Sopko, Nikolai; Blech, Lauren; Popović, Zoran B.; Li, Jianbo; Vasanji, Amit; Drumm, Carla; Krukovets, Irene; Jain, Mukesh K.; Penn, Marc S.; Plow, Edward F.; Stenina, Olga I.

    2012-01-01

    Thrombospondin-4 (TSP-4) expression increases dramatically in hypertrophic and failing hearts in rodent models and in humans. The aim of this study was to address the function of TSP-4 in the heart. TSP-4-knockout (Thbs4−/−) and wild-type (WT) mice were subjected to transverse aortic constriction (TAC) to increase left ventricle load. After 2 wk, Thbs4−/− mice had a significantly higher heart weight/body weight ratio than WT mice. The additional increase in the heart weight in TAC Thbs4−/− mice was due to increased deposition of extracellular matrix (ECM). The levels of interstitial collagens were higher in the knockout mice, but the size of cardiomyocytes and apoptosis in the myocardium was unaffected by TSP-4 deficiency, suggesting that increased reactive fibrosis was the primary cause of the higher heart weight. The increased ECM deposition in Thbs4−/− mice was accompanied by changes in functional parameters of the heart and decreased vessel density. The expression of inflammatory and fibrotic genes known to be influential in myocardial remodeling changed as a result of TSP-4 deficiency in vivo and as a result of incubation of cells with recombinant TSP-4 in vitro. Thus, TSP-4 is involved in regulating the adaptive responses of the heart to pressure overload, suggesting its important role in myocardial remodeling. Our study showed a direct influence of TSP-4 on heart function and to identify the mechanism of its effects on heart remodeling.—Frolova, E. G., Sopko, N., Blech, L., Popović, Z. B., Li, J., Vasanji, A., Drumm, C., Krukovets, I., Jain, M. K., Penn, M. S., Plow, E. F., Stenina, O. I. Thrombospondin-4 regulates fibrosis and remodeling of the myocardium in response to pressure overload. PMID:22362893

  13. Vessel remodelling, pregnancy hormones and extravillous trophoblast function.

    PubMed

    Chen, Jessie Z-J; Sheehan, Penelope M; Brennecke, Shaun P; Keogh, Rosemary J

    2012-02-26

    During early human pregnancy, extravillous trophoblast (EVT) cells from the placenta invade the uterine decidual spiral arterioles and mediate the remodelling of these vessels such that a low pressure, high blood flow can be supplied to the placenta. This is essential to facilitate normal growth and development of the foetus. Defects in remodelling can manifest as the serious pregnancy complication pre-eclampsia. During the period of vessel remodelling three key pregnancy-associated hormones, human chorionic gonadotrophin (hCG), progesterone (P(4)) and oestradiol (E(2)), are found in high concentrations at the maternal-foetal interface. Potentially these hormones may control EVT movement and thus act as regulators of vessel remodelling. This review will discuss what is known about how these hormones affect EVT proliferation, migration and invasion during vascular remodelling and the potential relationship between hCG, P(4), E(2) and the development of pre-eclampsia.

  14. Proliferation and tissue remodeling in cancer: the hallmarks revisited.

    PubMed

    Markert, E K; Levine, A J; Vazquez, A

    2012-10-04

    Although cancers are highly heterogeneous at the genomic level, they can manifest common patterns of gene expression. Here, we use gene expression signatures to interrogate two major processes in cancer, proliferation and tissue remodeling. We demonstrate that proliferation and remodeling signatures are partially independent and result in four distinctive cancer subtypes. Cancers with the proliferation signature are characterized by signatures of p53 and PTEN inactivation and concomitant Myc activation. In contrast, remodeling correlates with RAS, HIF-1α and NFκB activation. From the metabolic point of view, proliferation is associated with upregulation of glycolysis and serine/glycine metabolism, whereas remodeling is characterized by a downregulation of oxidative phosphorylation. Notably, the proliferation signature correlates with poor outcome in lung, prostate, breast and brain cancer, whereas remodeling increases mortality rates in colorectal and ovarian cancer.

  15. Chromatin remodeling in DNA double-strand break repair.

    PubMed

    Bao, Yunhe; Shen, Xuetong

    2007-04-01

    ATP-dependent chromatin remodeling complexes use ATP hydrolysis to remodel nucleosomes and have well-established functions in transcription. However, emerging lines of evidence suggest that chromatin remodeling complexes are important players in DNA double-strand break (DSB) repair as well. The INO80 and SWI2 subfamilies of chromatin remodeling complexes have been found to be recruited to the double-strand lesions and to function directly in both homologous recombination and non-homologous end-joining, the two major conserved DSB repair pathways. Improperly repaired DSBs are implicated in cancer development in higher organisms. Understanding how chromatin remodeling complexes contribute to DSB repair should provide new insights into the mechanisms of carcinogenesis and might suggest new targets for cancer treatment.

  16. Left Atrial Reverse Remodeling: Mechanisms, Evaluation, and Clinical Significance.

    PubMed

    Thomas, Liza; Abhayaratna, Walter P

    2017-01-01

    The left atrium is considered a biomarker for adverse cardiovascular outcomes, particularly in patients with left ventricular diastolic dysfunction and atrial fibrillation in whom left atrial (LA) enlargement is of prognostic importance. LA enlargement with a consequent decrease in LA function represents maladaptive structural and functional "remodeling" that in turn promotes electrical remodeling and a milieu conducive for incident atrial fibrillation. Medical and nonmedical interventions may arrest this pathophysiologic process to the extent that subsequent reverse remodeling results in a reduction in LA size and improvement in LA function. This review examines cellular and basic mechanisms involved in LA remodeling, evaluates the noninvasive techniques that can assess these changes, and examines potential mechanisms that may initiate reverse remodeling.

  17. Chondromodulin I Is a Bone Remodeling Factor

    PubMed Central

    Nakamichi, Yuko; Shukunami, Chisa; Yamada, Takashi; Aihara, Ken-ichi; Kawano, Hirotaka; Sato, Takashi; Nishizaki, Yuriko; Yamamoto, Yoko; Shindo, Masayo; Yoshimura, Kimihiro; Nakamura, Takashi; Takahashi, Naoyuki; Kawaguchi, Hiroshi; Hiraki, Yuji; Kato, Shigeaki

    2003-01-01

    Chondromodulin I (ChM-I) was supposed from its limited expression in cartilage and its functions in cultured chondrocytes as a major regulator in cartilage development. Here, we generated mice deficient in ChM-I by targeted disruption of the ChM-I gene. No overt abnormality was detected in endochondral bone formation during embryogenesis and cartilage development during growth stages of ChM-I−/− mice. However, a significant increase in bone mineral density with lowered bone resorption with respect to formation was unexpectedly found in adult ChM-I−/− mice. Thus, the present study established that ChM-I is a bone remodeling factor. PMID:12509461

  18. Molecular mechanisms of synaptic remodeling in alcoholism.

    PubMed

    Kyzar, Evan J; Pandey, Subhash C

    2015-08-05

    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.

  19. Matrix Remodeling in Pulmonary Fibrosis and Emphysema.

    PubMed

    Kulkarni, Tejaswini; O'Reilly, Philip; Antony, Veena B; Gaggar, Amit; Thannickal, Victor J

    2016-06-01

    Pulmonary fibrosis and emphysema are chronic lung diseases characterized by a progressive decline in lung function, resulting in significant morbidity and mortality. A hallmark of these diseases is recurrent or persistent alveolar epithelial injury, typically caused by common environmental exposures such as cigarette smoke. We propose that critical determinants of the outcome of the injury-repair processes that result in fibrosis versus emphysema are mesenchymal cell fate and associated extracellular matrix dynamics. In this review, we explore the concept that regulation of mesenchymal cells under the influence of soluble factors, in particular transforming growth factor-β1, and the extracellular matrix determine the divergent tissue remodeling responses seen in pulmonary fibrosis and emphysema.

  20. RNA helicase proteins as chaperones and remodelers

    PubMed Central

    Jarmoskaite, Inga; Russell, Rick

    2014-01-01

    Superfamily 2 helicase proteins are ubiquitous in RNA biology and have an extraordinarily broad set of functional roles. Central among these roles are to promote rearrangements of structured RNAs and to remodel RNA-protein complexes (RNPs), allowing formation of native RNA structure or progression through a functional cycle of structures. While all superfamily 2 helicases share a conserved helicase core, they are divided evolutionarily into several families, and it is principally proteins from three families, the DEAD-box, DEAH/RHA and Ski2-like families, that function to manipulate structured RNAs and RNPs. Strikingly, there are emerging differences in the mechanisms of these proteins, both between families and within the largest family (DEAD-box), and these differences appear to be tuned to their RNA or RNP substrates and their specific roles. This review outlines basic mechanistic features of the three families and surveys individual proteins and the current understanding of their biological substrates and mechanisms. PMID:24635478

  1. 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

  2. Bone Remodeling and Energy Metabolism: New Perspectives

    PubMed Central

    de Paula, Francisco J. A.; Rosen, Clifford J.

    2013-01-01

    Bone mineral, adipose tissue and energy metabolism are interconnected by a complex and multilevel series of networks. Calcium and phosphorus are utilized for insulin secretion and synthesis of high energy compounds. Adipose tissue store lipids and cholecalciferol, which, in turn, can influence calcium balance and energy expenditure. Hormones long-thought to solely modulate energy and mineral homeostasis may influence adipocytic function. Osteoblasts are a target of insulin action in bone. Moreover, endocrine mediators, such as osteocalcin, are synthesized in the skeleton but regulate carbohydrate disposal and insulin secretion. Finally, osteoblasts and adipocytes originate from the same mesenchymal progenitor. The mutual crosstalk between osteoblasts and adipocytes within the bone marrow microenvironment plays a crucial role in bone remodeling. In the present review we provide an overview of the reciprocal control between bone and energy metabolism and its clinical implications. PMID:26273493

  3. Chromatin remodeling: from transcription to cancer.

    PubMed

    Yaniv, Moshe

    2014-09-01

    In this short review article, I have tried to trace the path that led my laboratory from the early studies of the structure of papova minichromosomes and transcription control to the investigation of chromatin remodeling complexes of the SWI/SNF family. I discuss briefly the genetic and biochemical studies that lead to the discovery of the SWI/SNF complex in yeast and drosophila and summarize some of the studies on the developmental role of the murine complex. The discovery of the tumor suppressor function of the SNF5/INI1/SMARCB1 gene in humans and the identification of frequent mutations in other subunits of this complex in different human tumors opened a fascinating field of research on this epigenetic regulator. The hope is to better understand tumor development and to develop novel treatments.

  4. Remodeling of the fovea in Parkinson disease.

    PubMed

    Spund, B; Ding, Y; Liu, T; Selesnick, I; Glazman, S; Shrier, E M; Bodis-Wollner, I

    2013-05-01

    To quantify the thickness of the inner retinal layers in the foveal pit where the nerve fiber layer (NFL) is absent, and quantify changes in the ganglion cells and inner plexiform layer. Pixel-by-pixel volumetric measurements were obtained via Spectral-Domain optical coherence tomography (SD-OCT) from 50 eyes of Parkinson disease (PD) (n = 30) and 50 eyes of healthy control subjects (n = 27). Receiver operating characteristics (ROC) were used to classify individual subjects with respect to sensitivity and specificity calculations at each perifoveolar distance. Three-dimensional topographic maps of the healthy and PD foveal pit were created. The foveal pit is thinner and broader in PD. The difference becomes evident in an annular zone between 0.5 and 2 mm from the foveola and the optimal (ROC-defined) zone is from 0.75 to 1.5 mm. This zone is nearly devoid of NFL and partially overlaps the foveal avascular zone. About 78 % of PD eyes can be discriminated from HC eyes based on this zone. ROC applied to OCT pixel-by-pixel analysis helps to discriminate PD from HC retinae. Remodeling of the foveal architecture is significant because it may provide a visible and quantifiable signature of PD. The specific location of remodeling in the fovea raises a novel concept for exploring the mechanism of oxidative stress on retinal neurons in PD. OCT is a promising quantitative tool in PD research. However, larger scale studies are needed before the method can be applied to clinical follow-ups.

  5. Evaluation of bone remodeling around single dental implants of different lengths: a mechanobiological numerical simulation and validation using clinical data.

    PubMed

    Sotto-Maior, Bruno Salles; Mercuri, Emílio Graciliano Ferreira; Senna, Plinio Mendes; Assis, Neuza Maria Souza Picorelli; Francischone, Carlos Eduardo; Del Bel Cury, Altair Antoninha

    2016-01-01

    Algorithmic models have been proposed to explain adaptive behavior of bone to loading; however, these models have not been applied to explain the biomechanics of short dental implants. Purpose of present study was to simulate bone remodeling around single implants of different lengths using mechanoregulatory tissue differentiation model derived from the Stanford theory, using finite elements analysis (FEA) and to validate the theoretical prediction with the clinical findings of crestal bone loss. Loading cycles were applied on 7-, 10-, or 13-mm-long dental implants to simulate daily mastication and bone remodeling was assessed by changes in the strain energy density of bone after a 3, 6, and 12 months of function. Moreover, clinical findings of marginal bone loss in 45 patients rehabilitated with same implant designs used in the simulation (n = 15) were computed to validate the theoretical results. FEA analysis showed that although the bone density values reduced over time in the cortical bone for all groups, bone remodeling was independent of implant length. Clinical data showed a similar pattern of bone resorption compared with the data generated from mathematical analyses, independent of implant length. The results of this study showed that the mechanoregulatory tissue model could be employed in monitoring the morphological changes in bone that is subjected to biomechanical loads. In addition, the implant length did not influence the bone remodeling around single dental implants during the first year of loading.

  6. Shal-type channels contribute to the Ca2+-independent transient outward K+ current in rat ventricle.

    PubMed Central

    Fiset, C; Clark, R B; Shimoni, Y; Giles, W R

    1997-01-01

    1. The hypothesis that Kv4.2 and Kv4.3 are two of the essential K+ channel isoforms underlying the Ca2+-independent transient outward K+ current (It) in rat ventricle has been tested using a combination of electrophysiological measurements and antisense technology in both native myocytes and a stably transfected mammalian cell line, mouse Ltk- cells (L-cells). 2. The transient outward currents generated by Kv4.2 channels in L-cells exhibit rapid activation and inactivation properties similar to those produced by It in rat ventricular cells. The current-voltage relationships and the voltage dependence of steady-state inactivation are also very similar in these two preparations. However, the recovery from inactivation of Kv4.2 is much slower (time constant, 378 ms) than that of It in rat ventricular cells (58 ms). 3. The K+ current due to Kv4.2 can be blocked by millimolar concentrations of 4-aminopyridine in L-cells; a similar pharmacological response has been observed in rat ventricular myocytes. 4. Quinidine inhibits Kv4.2 in L-cells and It in rat ventricular cells in a similar fashion. In L-cells quinidine reduced the amplitude of Kv4.2 and accelerated its time course of inactivation, suggesting that quinidine may act as an open channel blocker of Kv4.2, as has been described for It in rat ventricle. 5. To provide further independent evidence that Kv4.2 and Kv4.3 channel isoforms contribute to It in rat ventricular cells, the effects of 20-mer antisense phosphorothioate oligodeoxynucleotides directed against Kv4.2 and Kv4.3 mRNAs were examined in ventricular myocytes isolated from 14- and 20-day-old rats, and in L-cells. In both preparations, Kv4.2 antisense pretreatment significantly reduced the transient outward K+ current (by approximately 55-60%). Similar reduction of It was produced by the Kv4.3 antisense oligonucleotide on the 14-day-old rat myocytes. 6. In 14-day rat ventricular cells, combination of Kv4.2 and Kv4.3 antisense oligonucleotides did not

  7. 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.

  8. Nonenzymatic biomimetic remodeling of phospholipids in synthetic liposomes.

    PubMed

    Brea, Roberto J; Rudd, Andrew K; Devaraj, Neal K

    2016-08-02

    Cell membranes have a vast repertoire of phospholipid species whose structures can be dynamically modified by enzymatic remodeling of acyl chains and polar head groups. Lipid remodeling plays important roles in membrane biology and dysregulation can lead to disease. Although there have been tremendous advances in creating artificial membranes to model the properties of native membranes, a major obstacle has been developing straightforward methods to mimic lipid membrane remodeling. Stable liposomes are typically kinetically trapped and are not prone to exchanging diacylphospholipids. Here, we show that reversible chemoselective reactions can be harnessed to achieve nonenzymatic spontaneous remodeling of phospholipids in synthetic membranes. Our approach relies on transthioesterification/acyl shift reactions that occur spontaneously and reversibly between tertiary amides and thioesters. We demonstrate exchange and remodeling of both lipid acyl chains and head groups. Using our synthetic model system we demonstrate the ability of spontaneous phospholipid remodeling to trigger changes in vesicle spatial organization, composition, and morphology as well as recruit proteins that can affect vesicle curvature. Membranes capable of chemically exchanging lipid fragments could be used to help further understand the specific roles of lipid structure remodeling in biological membranes.

  9. PECAM-1 is necessary for flow-induced vascular remodeling

    PubMed Central

    Chen, Zhongming; Tzima, Ellie

    2009-01-01

    OBJECTIVE Vascular remodeling is a physiological process that occurs in response to long-term changes in hemodynamic conditions, but may also contribute to the pathophysiology of intima-media thickening (IMT) and vascular disease. Shear stress detection by the endothelium is thought to be an important determinant of vascular remodeling. Previous work showed that Platelet endothelial cell adhesion molecule-1 (PECAM-1) is a component of a mechanosensory complex that mediates endothelial cell (EC) responses to shear stress. METHODS AND RESULTS We tested the hypothesis that PECAM-1 contributes to vascular remodeling by analyzing the response to partial carotid artery ligation in PECAM-1 knockout mice and wild-type littermates. PECAM-1 deficiency resulted in impaired vascular remodeling and significantly reduced IMT in areas of low flow. Inward remodeling was associated with PECAM-1-dependent NFκB activation, surface adhesion molecule expression and leukocyte infiltration as well as Akt activation and vascular cell proliferation. CONCLUSIONS PECAM-1 plays a crucial role in the activation of the NFκB and Akt pathways and inflammatory cell accumulation during vascular remodeling and IMT. Elucidation of some of the signals that drive vascular remodeling represent pharmacologically tractable targets for the treatment of restenosis after balloon angioplasty or stent placement. PMID:19390054

  10. Extracellular chloride regulation of Kv2.1, contributor to the major outward Kv current in mammalian outer hair cells

    PubMed Central

    Li, Xiantao; Surguchev, Alexei; Bian, Shumin; Navaratnam, Dhasakumar

    2012-01-01

    Outer hair cells (OHC) function as both receptors and effectors in providing a boost to auditory reception. Amplification is driven by the motor protein prestin, which is under anionic control. Interestingly, we now find that the major, 4-AP-sensitive, outward K+ current of the OHC (IK) is also sensitive to Cl−, although, in contrast to prestin, extracellularly. IK is inhibited by reducing extracellular Cl− levels, with a linear dependence of 0.4%/mM. Other voltage-dependent K+ (Kv) channel conductances in supporting cells, such as Hensen and Deiters' cells, are not affected by reduced extracellular Cl−. To elucidate the molecular basis of this Cl−-sensitive IK, we looked at potential molecular candidates based on Cl− sensitivity and/or similarities in kinetics. For IK, we identified three different Ca2+-independent components of IK based on the time constant of inactivation: a fast, transient outward current, a rapidly activating, slowly inactivating current (Ik1), and a slowly inactivating current (Ik2). Extracellular Cl− differentially affects these components. Because the inactivation time constants of Ik1 and Ik2 are similar to those of Kv1.5 and Kv2.1, we transiently transfected these constructs into CHO cells and found that low extracellular Cl− inhibited both channels with linear current reductions of 0.38%/mM and 0.49%/mM, respectively. We also tested heterologously expressed Slick and Slack conductances, two intracellularly Cl−-sensitive K+ channels, but found no extracellular Cl− sensitivity. The Cl− sensitivity of Kv2.1 and its robust expression within OHCs verified by single-cell RT-PCR indicate that these channels underlie the OHC's extracellular Cl− sensitivity. PMID:21940671

  11. The outwardly rectifying chloride channel in rat peritoneal mast cells is regulated by serine/threonine kinases and phosphatases.

    PubMed

    Seebeck, Jörg; Tritschler, Stefan; Roloff, Tim; Kruse, Marie-Luise; Schmidt, Wolfgang E; Ziegler, Albrecht

    2002-02-01

    A slowly activating, outwardly rectifying Cl- channel (ORCC) has been described in rat peritoneal mast cells (RPMCs). This channel is activated by intracellular application of cAMP, an effect that might be mediated by a PKA-type serine/threonine protein kinase. To test this hypothesis, whole-cell patch-clamp experiments (nystatin-perforated patch) were performed and 8-bromoadenosine 3',5'-cyclic monophosphothioate, Sp-enantiomer (Sp-8Br-cAMPS), a cell membrane-permeable activator of PKA, and three inhibitors of different serine/threonine protein phosphatases (okadaic acid, cantharidin, calyculin A), were tested. In RPMCs application of repetitive series of step hyper- and depolarizations (holding potential 0 mV, test potentials -80 to +80 mV, step size +20 mV) induced a slowly increasing, [half-maximal activation time ( t0.5) 11.0+/-1.1 min, Imax (at +80 mV) 18.7+/-3.1 pA pF-1], DIDS-sensitive, outwardly rectifying Cl- current I(Cl,OR). The activation of this current could be accelerated by Sp-8Br-cAMPS, okadaic acid or cantharidin in the extracellular solution. Co-application of Sp-8Br-cAMPS and okadaic acid increased Imax supra-additively. Calyculin A and higher concentrations of cantharidin inhibited the Cl- current via unknown mechanisms. Our findings suggest that I(Cl,OR) in RPMCs is activated by a PKA-type protein kinase, a process which is antagonized functionally by okadaic acid- and cantharidin-sensitive protein phosphatases.

  12. 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.

  13. An in vivo rat model of artery buckling for studying wall remodeling.

    PubMed

    Zhang, Jinzhou; Liu, Qin; Han, Hai-Chao

    2014-08-01

    Theoretical modeling and in vitro experiments have demonstrated that arterial buckling is a possible mechanism for the development of artery tortuosity. However, there has been no report of whether artery buckling develops into tortuosity, partially due to the lack of in vivo models for long-term studies. The objective of this study was to establish an in vivo buckling model in rat carotid arteries for studying arterial wall remodeling after buckling. Rat left carotid arteries were transplanted to the right carotid arteries to generate buckling under in vivo pressure and were maintained for 1 week to examine wall remodeling and adaptation. Our results showed that a significant buckling was achieved in the carotid arterial grafts with altered wall stress. Cell proliferation and matrix metalloprotinease-2 (MMP-2) expression in the buckled arteries increased significantly compared with the controls. The tortuosity level of the grafts also slightly increased 1 week post-surgery, while there was no change in vessel dimensions, blood pressure, and blood flow velocity. The artery buckling model provides a useful tool for further study of the adaptation of arteries into tortuous shapes.

  14. 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.

  15. An in vivo Rat Model of Artery Buckling for Studying Wall Remodeling

    PubMed Central

    Zhang, Jinzhou; Liu, Qin; Han, Hai-Chao

    2014-01-01

    Theoretical modeling and in vitro experiments have demonstrated that arterial buckling is a possible mechanism for the development of artery tortuosity. However, there has been no report of whether artery buckling develops into tortuosity, partially due to the lack of in vivo models for long-term studies. The objective of this study was to establish an in vivo buckling model in rat carotid arteries for studying arterial wall remodeling after buckling. Rat left carotid arteries were transplanted to the right carotid arteries to generate buckling under in vivo pressure and were maintained for 1 week to examine wall remodeling and adaptation. Our results showed that a significant buckling was achieved in the carotid arterial grafts with altered wall stress. Cell proliferation and matrix metalloprotinease-2 (MMP-2) expression in the buckled arteries increased significantly compared with the controls. The tortuosity level of the grafts also slightly increased 1 week post-surgery, while there was no change in vessel dimensions, blood pressure, and blood flow velocity. The artery buckling model provides a useful tool for further study of the adaptation of arteries into tortuous shapes. PMID:24793586

  16. 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

  17. Computer-simulated bone architecture in a simple bone-remodeling model based on a reaction-diffusion system.

    PubMed

    Tezuka, Ken-ichi; Wada, Yoshitaka; Takahashi, Akiyuki; Kikuchi, Masanori

    2005-01-01

    Bone is a complex system with functions including those of adaptation and repair. To understand how bone cells can create a structure adapted to the mechanical environment, we propose a simple bone remodeling model based on a reaction-diffusion system influenced by mechanical stress. Two-dimensional bone models were created and subjected to mechanical loads. The conventional finite element method (FEM) was used to calculate stress distribution. A stress-reactive reaction-diffusion model was constructed and used to simulate bone remodeling under mechanical loads. When an external mechanical stress was applied, stimulated bone formation and subsequent activation of bone resorption produced an efficient adaptation of the internal shape of the model bone to a given stress, and demonstrated major structures of trabecular bone seen in the human femoral neck. The degree of adaptation could be controlled by modulating the diffusion constants of hypothetical local factors. We also tried to demonstrate the deformation of bone structure during osteoporosis by the modulation of a parameter affecting the balance between formation and resorption. This simple model gives us an insight into how bone cells can create an architecture adapted to environmental stress, and will serve as a useful tool to understand both physiological and pathological states of bone based on structural information.

  18. Polycyclic aromatic hydrocarbons, tobacco smoke, and epigenetic remodeling in asthma

    PubMed Central

    Klingbeil, E. C.; Hew, K. M.; Nygaard, U. C.; Nadeau, K. C.

    2014-01-01

    Environmental determinants including aerosolized pollutants such as polycyclic aromatic hydrocarbons (PAHs) and tobacco smoke have been associated with exacerbation and increased incidence of asthma. The influence of aerosolized pollutants on the development of immune dysfunction in asthmatics has been suggested to be mediated through epigenetic remodeling. Genome accessibility and transcription are regulated primarily through DNA methylation, histone modification, and microRNA transcript silencing. Epigenetic remodeling has been shown in studies to be associated with Th2 polarization and associated cytokine and chemokine regulation in the development of asthma. This review will present evidence for the contribution of the aerosolized pollutants PAH and environmental tobacco smoke to epigenetic remodeling in asthma. PMID:24760221

  19. 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

  20. [Differences in atrial remodelling between right and left atria in patients with chronic atrial fibrillation].

    PubMed

    Tamargo Menéndez, Juan

    2011-01-01

    Atrial fibrillation starts in the left atrium and from there the activity invades the atrial tissues and causes an inhomogeneous shortening the duration of atrial action potential duration and refractoriness. The purpose of this study was to compare the voltage-dependent potassium currents in human cells isolated from the right and left atria and to determine whether electrical remodeling produced by chronic atrial fibrillation (CAF) differentially affects voltage-dependent potassium currents involved in atrial repolarization in each atrium as compared to sinus rhythm (SR). The currents were recorded using the whole-cell configuration of the patch-clamp technique. We found that in atrial cardiomyocytes of patients both in SR and in CAF there are three types of cells according to their main voltage-dependent repolarizing potassium current: the Ca(2+)-independent 4-aminopyridine sensitive component of the transient outward current (I(to1)) and the ultrarapid (I(Kur)), rapid (I(Kr)) and slow (I(Ks)) components of the delayed rectifier current. CAF differentially modified the proportion of these 3 types of cells on each atrium: CAF reduced the I(to1) more markedly in the left than in the right atria, while I(Kur) was more markedly reduced in the right than in the left atria. Interestingly, in both atria, CAF markedly increased the I(Ks). This increase was enhanced by isoproterenol and suppressed by atenolol. These changes produce a non-uniform shortening of atrial repolarization that facilitates the reentry of the cardiac impulse and the perpetuation of the arrhythmia.

  1. Structural remodeling, trafficking and functions of glycosylphosphatidylinositol-anchored proteins.

    PubMed

    Maeda, Yusuke; Kinoshita, Taroh

    2011-10-01

    Glycosylphosphatidylinositol (GPI) is a glycolipid that is covalently attached to proteins as a post-translational modification. Such modification leads to the anchoring of the protein to the outer leaflet of the plasma membrane. Proteins that are decorated with GPIs have unique properties in terms of their physical nature. In particular, these proteins tend to accumulate in lipid rafts, which are critical for the functions and trafficking of GPI-anchored proteins (GPI-APs). Recent studies mainly using mutant cells revealed that various structural remodeling reactions occur to GPIs present in GPI-APs as they are transported from the endoplasmic reticulum to the cell surface. This review examines the recent progress describing the mechanisms of structural remodeling of mammalian GPI-anchors, such as inositol deacylation, glycan remodeling and fatty acid remodeling, with particular focus on their trafficking and functions, as well as the pathogenesis involving GPI-APs and their deficiency.

  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. Prostacyclin receptor-dependent modulation of pulmonary vascular remodeling.

    PubMed

    Hoshikawa, Y; Voelkel, N F; Gesell, T L; Moore, M D; Morris, K G; Alger, L A; Narumiya, S; Geraci, M W

    2001-07-15

    Prostacyclin (PGI(2)) reduces pulmonary vascular resistance and attenuates vascular smooth muscle cell proliferation through signal transduction following ligand binding to its receptor. Because patients with severe pulmonary hypertension have a reduced PGI(2) receptor (PGI-R) expression in the remodeled pulmonary arterial smooth muscle, we hypothesized that pulmonary vascular remodeling may be modified PGI-R dependently. To test this hypothesis, PGI-R knockout (KO) and wild-type (WT) mice were subjected to a simulated altitude of 17,000 ft or Denver altitude for 3 wk, and right ventricular pressure and lung histology were assessed. The PGI-R KO mice developed more severe pulmonary hypertension and vascular remodeling after chronic hypoxic exposure when compared to the WT mice. Our results indicate that PGI(2) and its receptor play an important role in the regulation of hypoxia-induced pulmonary vascular remodeling, and that the absence of a functional receptor worsens pulmonary hypertension.

  4. Roles of chromatin remodellers in DNA double strand break repair.

    PubMed

    Jeggo, Penny A; Downs, Jessica A

    2014-11-15

    Now that we have a good understanding of the DNA double strand break (DSB) repair mechanisms and DSB-induced damage signalling, attention is focusing on the changes to the chromatin environment needed for efficient DSB repair. Mutations in chromatin remodelling complexes have been identified in cancers, making it important to evaluate how they impact upon genomic stability. Our current understanding of the DSB repair pathways suggests that each one has distinct requirements for chromatin remodelling. Moreover, restricting the extent of chromatin modifications could be a significant factor regulating the decision of pathway usage. In this review, we evaluate the distinct DSB repair pathways for their potential need for chromatin remodelling and review the roles of ATP-driven chromatin remodellers in the pathways.

  5. Determining School District Renovation/Remodeling/Repair Needs.

    ERIC Educational Resources Information Center

    MacKenzie, Donald G.; Phillips, Paul

    1991-01-01

    Bond issue funds were earmarked for remodeling 10 schools in a Florida school district. Describes a physical plant survey instrument used to examine each district school building to determine the district needs and the method that prioritizes those needs. (MLF)

  6. Balancing chromatin remodeling and histone modifications in transcription

    PubMed Central

    Petty, Emily; Pillus, Lorraine

    2013-01-01

    Chromatin remodelers use the energy of ATP hydrolysis to reposition or evict nucleosomes or to replace canonical histones with histone variants. By regulating nucleosome dynamics, remodelers gate access to the underlying DNA for replication, repair, and transcription. Nucleosomes are subject to extensive post-translational modifications that can recruit regulatory proteins or alter the local chromatin structure. Just as extensive cross-talk has been observed between different histone post-translational modifications, there is growing evidence for both coordinated and antagonistic functional relationships between nucleosome remodeling and modifying machineries. Defining the combined functions of the complexes that alter nucleosome interactions, position, and stability is key to understanding processes that require access to DNA, particularly with growing appreciation of their contributions to human health and disease. Here, we highlight recent advances in the interactions between histone modifications and the ISWI and CHD1 chromatin remodelers from studies in budding yeast, fission yeast, flies, and mammalian cells, with a focus on yeast. PMID:23870137

  7. 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

  8. Roles and activities of chromatin remodeling ATPases in plants.

    PubMed

    Han, Soon-Ki; Wu, Miin-Feng; Cui, Sujuan; Wagner, Doris

    2015-07-01

    Chromatin remodeling ATPases and their associated complexes can alter the accessibility of the genome in the context of chromatin by using energy derived from the hydrolysis of ATP to change the positioning, occupancy and composition of nucleosomes. In animals and plants, these remodelers have been implicated in diverse processes ranging from stem cell maintenance and differentiation to developmental phase transitions and stress responses. Detailed investigation of their roles in individual processes has suggested a higher level of selectivity of chromatin remodeling ATPase activity than previously anticipated, and diverse mechanisms have been uncovered that can contribute to the selectivity. This review summarizes recent advances in understanding the roles and activities of chromatin remodeling ATPases in plants.

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

    PubMed

    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

    2014-05-01

    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 with 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.

  10. Cardiovascular remodeling and the peripheral serotonergic system.

    PubMed

    Ayme-Dietrich, Estelle; Aubertin-Kirch, Gaëlle; Maroteaux, Luc; Monassier, Laurent

    2017-01-01

    Plasma 5-hydroxytryptamine (5-HT; serotonin), released from blood platelets, plays a major role in the human cardiovascular system. Besides the effect of endogenous serotonin, many drugs targeting serotonergic receptors are widely used in the general population (antiobesity agents, antidepressants, antipsychotics, antimigraine agents), and may enhance the cardiovascular risk. Depending on the type of serotonin receptor activated and its location, the use of these compounds triggers acute and chronic effects. The acute cardiovascular response to 5-HT, named the Bezold-Jarish reflex, leads to intense bradycardia associated with atrioventricular block, and involves 5-HT3, 5-HT1B/1D, 5-HT7 and 5-HT2A/2B receptors. The chronic contribution of 5-HT and its receptors (5-HT4 and 5-HT2A/2B) in cardiovascular tissue remodeling, with a particular emphasis on cardiac hypertrophy, fibrosis and valve degeneration, will be explored in this review. Finally, through the analysis of the effects of sarpogrelate, some new aspects of 5-HT2A receptor pharmacology in vasomotor tone regulation and the interaction between endothelial and smooth muscle cells will also be discussed. The aim of this review is to emphasize the cardiac side effects caused by serotonin receptor activation, and to highlight their possible prevention by the development of new drugs targeting this system.

  11. 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

  12. 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

  13. 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

  14. KyoT2 downregulates airway remodeling in asthma.

    PubMed

    Hu, Mei; Ou-Yang, Hai-Feng; Han, Xing-Peng; Ti, Xin-Yu; Wu, Chang-Gui

    2015-01-01

    The typical pathological features of asthma are airway remodeling and airway hyperresponsiveness (AHR). KyoT2, a negative modulator of Notch signaling, has been linked to asthma in several previous studies. However, whether KyoT2 is involved in the regulation of airway remodeling or the modulation of airway resistance in asthma is unclear. In this study, we aimed to evaluate the therapeutic potential of KyoT2 in preventing asthma-associated airway remodeling and AHR. BALB/c mice were used to generate a mouse model of asthma. Additionally, the expression of Hes1 and Notch1 in airway was analyzed using Immunofluorescence examination. The asthmatic mice were intranasally administered adenovirus expressing KyoT2 and were compared to control groups. Furthermore, subepithelial fibrosis and other airway remodeling features were analyzed using hematoxylin and eosin staining, Van Gieson's staining and Masson's trichrome staining. AHR was also evaluated. This study revealed that KyoT2 downregulated the expression of Hes1, repressed airway remodeling, and alleviated AHR in asthmatic mice. It is reasonable to assume that KyoT2 downregulates airway remodeling and resistance in asthmatic mice through a Hes1-dependent mechanism. Therefore, KyoT2 is a potential clinical treatment strategy for asthma.

  15. FSTL1 PROMOTES ASTHMATIC AIRWAY REMODELING BY INDUCING ONCOSTATIN M

    PubMed Central

    Miller, Marina; Beppu, Andrew; Rosenthal, Peter; Pham, Alexa; Das, Sudipta; Karta, Maya; Song, Dae Jin; Vuong, Christine; Doherty, Taylor; Croft, Michael; Zuraw, Bruce; Zhang, Xu; Gao, Xiang; Aceves, Seema; Chouiali, Fazila; Hamid, Qutayba; Broide, David H.

    2016-01-01

    Chronic asthma is associated with airway remodeling and decline in lung function. Here we show that follistatin like 1 (Fstl1), a mediator not previously associated with asthma is highly expressed by macrophages in the lungs of severe human asthmatics. Chronic allergen challenged Lys-Cretg/Fstl1Δ/Δ mice in whom Fstl1 is inactivated in macrophages/myeloid cells had significantly reduced airway remodeling and reduced levels of oncostatin M (OSM) a cytokine previously not known to be regulated by Fstl1. The importance of the Fstl1 induction of OSM to airway remodeling was demonstrated in murine studies in which administration of Fstl1 induced airway remodeling and increased OSM, while administration of an anti-OSM antibody blocked the effect of Fstl1 on inducing airway remodeling, eosinophilic airway inflammation, and airway hyperresponsiveness all cardinal features of asthma. Overall, these studies demonstrate that the Fstl1/oncostatin M pathway may be a novel pathway to inhibit airway remodeling in severe human asthma. PMID:26355153

  16. 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

  17. Visual Adaptation

    PubMed Central

    Webster, Michael A.

    2015-01-01

    Sensory systems continuously mold themselves to the widely varying contexts in which they must operate. Studies of these adaptations have played a long and central role in vision science. In part this is because the specific adaptations remain a powerful tool for dissecting vision, by exposing the mechanisms that are adapting. That is, “if it adapts, it's there.” Many insights about vision have come from using adaptation in this way, as a method. A second important trend has been the realization that the processes of adaptation are themselves essential to how vision works, and thus are likely to operate at all levels. That is, “if it's there, it adapts.” This has focused interest on the mechanisms of adaptation as the target rather than the probe. Together both approaches have led to an emerging insight of adaptation as a fundamental and ubiquitous coding strategy impacting all aspects of how we see. PMID:26858985

  18. 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…

  19. Assessing the Development of Environmental Virtue in 7th and 8th Grade Students in an Expeditionary Learning Outward Bound School

    ERIC Educational Resources Information Center

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

    2009-01-01

    This study attempted to assess the development of environmental virtue in 7th and 8th grade students in an Expeditionary Learning Outward Bound (ELOB) school using an instrument developed for this study--the Children's Environmental Virtue Scale (CEVS). Data for this study were obtained by administering the CEVS survey (pretest and posttest) to…

  20. 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.

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

    PubMed

    Krishnamurthy, Harini; Gouaux, Eric

    2012-01-09

    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 (γ-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.

  2. 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

  3. Soluble Endoglin Modulates Aberrant Cerebral Vascular Remodeling

    PubMed Central

    Chen, Yongmei; Hao, Qi; Kim, Helen; Su, Hua; Letarte, Michelle; Karumanchi, S. Ananth; Lawton, Michael T.; Barbaro, Nicholas M.; Yang, Guo-Yuan; Young, William L.

    2009-01-01

    Objective Brain arteriovenous malformations (AVMs) are an important cause of neurological morbidity in young adults. The pathophysiology of these lesions is poorly understood. A soluble form of endoglin (sEng) has been shown to cause endothelial dysfunction and induce preeclampsia. We tested if sEng would be elevated in brain AVM tissues relative to epilepsy brain tissues, and also investigated whether sEng overexpression via gene transfer in the mouse brain would induce vascular dysplasia and associated changes in downstream signaling pathways. Methods Expression levels of sEng in surgical specimens were determined by Western blot assay and ELISA. Vascular dysplasia, levels of MMP and oxidative stress were determined by immunohistochemistry and gelatin zymography. Results Brain AVMs (n=33) had higher mean sEng levels (245 ± 175 vs 100 ± 60, % of control, P=0.04) compared with controls (n=8), as determined by Western blot. In contrast, membrane-bound Eng was not significantly different (108 ± 79 vs 100 ± 63, % of control, P=0.95). sEng gene transduction in the mouse brain induced abnormal vascular structures. It also increased matrix metalloproteinase (MMP) activity by 490 ± 30% (MMP-9), 220 ± 30% (MMP-2), and oxidants by 260 ± 20% (4-hydroxy-2-nonenal) at 2 weeks after injection, suggesting that MMPs and oxidative radicals may mediate sEng-induced pathological vascular remodeling. Interpretation The results suggest that elevated sEng may play a role in the generation of sporadic brain AVMs. Our findings may provide new targets for therapeutic intervention for patients with brain AVMs. PMID:19670444

  4. 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.

  5. Inhibition of K(+) outward currents by linopirdine in the cochlear outer hair cells of circling mice within the first postnatal week.

    PubMed

    Kang, Shin Wook; Ahn, Ji Woong; Ahn, Seung Cheol

    2017-03-01

    Inhibition of K(+) outward currents by linopirdine in the outer hair cells (OHCs) of circling mice (homozygous (cir/cir) mice), an animal model for human deafness (DFNB6 type), was investigated using a whole cell patch clamp technique. Littermate heterozygous (+/cir) and ICR mice of the same age (postnatal day (P) 0 -P6) were used as controls. Voltage steps from -100 mV to 40 mV elicited small inward currents (-100 mV~-70 mV) and slow rising K(+) outward currents (-60 mV ~40 mV) which activated near -50 mV in all OHCs tested. Linopirdine, a known blocker of K(+) currents activated at negative potentials (IK,n), did cause inhibition at varying degree (severe, moderate, mild) in K(+) outward currents of heterozygous (+/cir) or homozygous (cir/cir) mice OHCs in the concentration range between 1 and 100 µM, while it was apparent only in one ICR mice OHC out of nine OHCs at 100 µM. Although the half inhibition concentrations in heterozygous (+/cir) or homozygous (cir/cir) mice OHCs were close to those reported in IK,n, biophysical and pharmacological properties of K(+) outward currents, such as the activation close to -50 mV, small inward currents evoked by hyperpolarizing steps and TEA sensitivity, were not in line with IK,n reported in other tissues. Our results show that the delayed rectifier type K(+) outward currents, which are not similar to IK,n with respect to biophysical and pharmacological properties, are inhibited by linopirdine in the developing (P0~P6) homozygous (cir/cir) or heterozygous (+/cir) mice OHCs.

  6. Outward Migration of Jupiter and Saturn in 3:2 or 2:1 Resonance in Radiative Disks: Implications for the Grand Tack and Nice models

    NASA Astrophysics Data System (ADS)

    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 disk ≈ M MMSN, where MMSN is the "minimum-mass solar nebula") disks with viscous stress parameter α between 10-3 and 10-2. In disks with relatively low-mass (M disk <~ M MMSN), Jupiter and Saturn get captured in 2:1 resonance and can even migrate outward in low-viscosity disks (α <= 10-4). 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 <= 10-4. 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.

  7. Inhibition of K+ outward currents by linopirdine in the cochlear outer hair cells of circling mice within the first postnatal week

    PubMed Central

    Kang, Shin Wook; Ahn, Ji Woong

    2017-01-01

    Inhibition of K+ outward currents by linopirdine in the outer hair cells (OHCs) of circling mice (homozygous (cir/cir) mice), an animal model for human deafness (DFNB6 type), was investigated using a whole cell patch clamp technique. Littermate heterozygous (+/cir) and ICR mice of the same age (postnatal day (P) 0 –P6) were used as controls. Voltage steps from –100 mV to 40 mV elicited small inward currents (–100 mV~–70 mV) and slow rising K+ outward currents (–60 mV ~40 mV) which activated near –50 mV in all OHCs tested. Linopirdine, a known blocker of K+ currents activated at negative potentials (IK,n), did cause inhibition at varying degree (severe, moderate, mild) in K+ outward currents of heterozygous (+/cir) or homozygous (cir/cir) mice OHCs in the concentration range between 1 and 100 µM, while it was apparent only in one ICR mice OHC out of nine OHCs at 100 µM. Although the half inhibition concentrations in heterozygous (+/cir) or homozygous (cir/cir) mice OHCs were close to those reported in IK,n, biophysical and pharmacological properties of K+ outward currents, such as the activation close to –50 mV, small inward currents evoked by hyperpolarizing steps and TEA sensitivity, were not in line with IK,n reported in other tissues. Our results show that the delayed rectifier type K+ outward currents, which are not similar to IK,n with respect to biophysical and pharmacological properties, are inhibited by linopirdine in the developing (P0~P6) homozygous (cir/cir) or heterozygous (+/cir) mice OHCs. PMID:28280419

  8. A novel chemo-mechano-biological model of arterial tissue growth and remodelling.

    PubMed

    Aparício, Pedro; Thompson, Mark S; Watton, Paul N

    2016-08-16

    Arterial growth and remodelling (G&R) is mediated by vascular cells in response to their chemical and mechanical environment. To date, mechanical and biochemical stimuli tend to be modelled separately, however this ignores their complex interplay. Here, we present a novel mathematical model of arterial chemo-mechano-biology. We illustrate its application to the development of an inflammatory aneurysm in the descending human aorta. The arterial wall is modelled as a bilayer cylindrical non-linear elastic membrane, which is internally pressurised and axially stretched. The medial degradation that accompanies aneurysm development is driven by an inflammatory response. Collagen remodelling is simulated by adaption of the natural reference configuration of constituents; growth is simulated by changes in normalised mass-densities. We account for the distribution of attachment stretches that collagen fibres are configured to the matrix and, innovatively, allow this distribution to remodel. This enables the changing functional role of the adventitia to be simulated. Fibroblast-mediated collagen growth is represented using a biochemical pathway model: a system of coupled non-linear ODEs governs the evolution of fibroblast properties and levels of key biomolecules under the regulation of Transforming Growth Factor (TGF)-β, a key promoter of matrix deposition. Given physiologically realistic targets, different modes of aneurysm development can be captured, while the predicted evolution of biochemical variables is qualitatively consistent with trends observed experimentally. Interestingly, we observe that increasing the levels of collagen-promoting TGF-β results in arrest of aneurysm growth, which seems to be consistent with experimental evidence. We conclude that this novel Chemo-Mechano-Biological (CMB) mathematical model has the potential to provide new mechanobiological insight into vascular disease progression and therapy.

  9. 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.

  10. Volume-sensitive outwardly rectifying chloride channel blockers protect against high glucose-induced apoptosis of cardiomyocytes via autophagy activation.

    PubMed

    Wang, Lin; Shen, Mingzhi; Guo, Xiaowang; Wang, Bo; Xia, Yuesheng; Wang, Ning; Zhang, Qian; Jia, Lintao; Wang, Xiaoming

    2017-03-16

    Hyperglycemia is a well-characterized contributing factor for cardiac dysfunction and heart failure among diabetic patients. Apoptosis of cardiomyocytes plays a major role during the onset and pathogenesis of diabetic cardiomyopathy (DCM). Nonetheless, the molecular machinery underlying hyperglycemia-induced cardiac damage and cell death remains elusive. In the present study, we found that chloride channel blockers, 4,4'-diisothiocya-natostilbene-2,2'- disulfonic acid (DIDS) and 4-(2-butyl-6,7-dichlor-2-cyclopentyl-indan-1-on-5-yl) oxybutyric acid (DCPIB), inhibited high glucose-activated volume-sensitive outwardly rectifying (VSOR) Cl(-) channel and improved the viability of cardiomyocytes. High glucose induced cardiomyocyte apoptosis by suppressing the autophagic stress, which can be reversed via blockade of VSOR Cl(-) channel. VSOR activation in high glucose-treated cardiomyocytes was attributed to increased intracellular levels of reactive oxygen species (ROS). Taken together, our study unraveled a role of VSOR chloride currents in impaired autophagy and increased apoptosis of high glucose-exposed cardiomyocyte, and has implications for a therapeutic potential of VSOR chloride channel blockers in DCM.

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

    PubMed

    Akita, T; Okada, Y

    2014-09-05

    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.

  12. Pharmacological inhibition of outwardly rectifying Cl- currents in rat peritoneal mast cells: a comparison of different stilbene derivatives.

    PubMed

    Roloff, Tim; Ziegler, Albrecht; Heber, Dieter; Seebeck, Jörg

    2003-10-08

    Diethylstilbestrol and other stilbene derivatives can provide some inhibition of the outwardly rectifying Cl- current (I(Cl-,OR)) in rat peritoneal mast cells. In order to elucidate structure-activity relationships of diethylstilbestrol, 12 stilbenes as well as 17beta-estradiol and hexestrol were tested in rat peritoneal mast cells using the nystatin-perforated patch approach of the whole-cell patch-clamp technique. Since trans-stilbene showed no effect, the substituents of diethylstilbestrol must be of importance. The introduction of only one hydroxy group in trans-stilbene produced potent inhibition of the I(Cl-,OR) (IC50: 3.3 microM). But in contrast, resveratrol with hydroxy groups at positions 4, 3', and 5' as well as methoxy substituted stilbene derivatives and 17beta-estradiol were ineffective. On the other hand, hexestrol potently inhibited I(Cl-,OR) indicating that the aromatic ring systems can also be connected by an ethyl bridge. In summary, a hydroxy group at position 4 (or 4') is a prerequisite for diethylstilbestrol-mediated inhibition of I(Cl-,OR).

  13. Volume-sensitive outwardly rectifying chloride channel blockers protect against high glucose-induced apoptosis of cardiomyocytes via autophagy activation

    PubMed Central

    Wang, Lin; Shen, Mingzhi; Guo, Xiaowang; Wang, Bo; Xia, Yuesheng; Wang, Ning; Zhang, Qian; Jia, Lintao; Wang, Xiaoming

    2017-01-01

    Hyperglycemia is a well-characterized contributing factor for cardiac dysfunction and heart failure among diabetic patients. Apoptosis of cardiomyocytes plays a major role during the onset and pathogenesis of diabetic cardiomyopathy (DCM). Nonetheless, the molecular machinery underlying hyperglycemia-induced cardiac damage and cell death remains elusive. In the present study, we found that chloride channel blockers, 4,4′-diisothiocya-natostilbene-2,2′- disulfonic acid (DIDS) and 4-(2-butyl-6,7-dichlor-2-cyclopentyl-indan-1-on-5-yl) oxybutyric acid (DCPIB), inhibited high glucose-activated volume-sensitive outwardly rectifying (VSOR) Cl− channel and improved the viability of cardiomyocytes. High glucose induced cardiomyocyte apoptosis by suppressing the autophagic stress, which can be reversed via blockade of VSOR Cl− channel. VSOR activation in high glucose-treated cardiomyocytes was attributed to increased intracellular levels of reactive oxygen species (ROS). Taken together, our study unraveled a role of VSOR chloride currents in impaired autophagy and increased apoptosis of high glucose-exposed cardiomyocyte, and has implications for a therapeutic potential of VSOR chloride channel blockers in DCM. PMID:28300155

  14. 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.

  15. Hodgkin-Huxley analysis of whole-cell outward rectifying K(+)-currents in protoplasts from tobacco cell suspension cultures.

    PubMed

    Van Duijn, B

    1993-02-01

    The voltage and time dependence of outward-rectifying K+ currents (IK,out) measured in protoplasts from tobacco cell suspension cultures in the whole-cell configuration of the patch-clamp technique are quantitatively analyzed. The voltage and time dependence was described according to the Hodgkin and Huxley model for IK,out currents in the squid giant axon, and to allow comparison, in analogy with the quantitative analysis of IK,out currents in Vicia faba guard cell protoplasts as described by Schroeder (J. Membrane Biol., 107:229-235, 1989). The IK,out from tobacco could be described by a similar model as the IK,out from guard cell protoplasts (i.e., sigmoid activation time course, activation variable raised to second power, single exponential deactivating tail currents, absence of inactivation). However, in contrast to guard cells, both the activation and deactivation time constants were strongly voltage dependent in tobacco protoplasts. The voltage dependence of the transition rates for channel opening and channel closing was slightly asymmetrical and inverse to the asymmetry found in guard cells. The data presented show that the voltage-dependent kinetic properties of the IK,out conductance of tobacco protoplasts are different from these properties in guard cell protoplasts. This analysis provides a basis for the study of IK,out conductance function and modulation.

  16. A transient outward current related to calcium release and development of tension in elephant seal atrial fibres.

    PubMed Central

    Maylie, J; Morad, M

    1984-01-01

    Membrane currents and development of tension in atrial trabeculae from elephant seal hearts were studied using a single sucrose-gap voltage-clamp technique. A transient outward current (Ito) was observed with kinetics, voltage and beat dependence, similar to those of tension. Ito had a bell-shaped voltage dependence similar to that of tension and the slow inward current (Isi). Ito, unlike Isi, showed beat dependence quite similar to developed tension. Increases in [Ca]o, frequency of stimulation, and addition of adrenaline enhanced Ito and developed tension. Ito was suppressed by addition of Mn2+, tetracaine, or by depolarizing pre-pulses (to -40 mV for 250 ms). Caffeine at low concentrations (1 mM) blocked beat dependence of Ito. At higher concentrations (greater than 5 mM) caffeine suppressed the activation of Ito, phasic tension, and the second component of the birefringence signal (related to Ca2+-releasing activity of the sarcoplasmic reticulum (s.r.]. Similar to Isi phasic tension and Ito, the voltage dependence of the second component of the birefringence signal was bell-shaped. Our studies suggest that activation of Ito is related to triggered release of Ca2+ from the s.r. which generates the phasic tension. An excitation-contraction coupling scheme is presented which incorporates these findings and suggests that Ito may be responsible for shorter action potentials found in atrial fibres. Images Plate 1 PMID:6512692

  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. 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.

  19. 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...

  20. Klotho and Phosphate Are Modulators of Pathologic Uremic Cardiac Remodeling

    PubMed Central

    Shi, Mingjun; Cho, Han Jun; Adams-Huet, Beverley; Paek, Jean; Hill, Kathy; Shelton, John; Amaral, Ansel P.; Faul, Christian; Taniguchi, Masatomo; Wolf, Myles; Brand, Markus; Takahashi, Masaya; Kuro-o, Makoto; Hill, Joseph A.

    2015-01-01

    Cardiac dysfunction in CKD is characterized by aberrant cardiac remodeling with hypertrophy and fibrosis. CKD is a state of severe systemic Klotho deficiency, and restoration of Klotho attenuates vascular calcification associated with CKD. We examined the role of Klotho in cardiac remodeling in models of Klotho deficiency—genetic Klotho hypomorphism, high dietary phosphate intake, aging, and CKD. Klotho-deficient mice exhibited cardiac dysfunction and hypertrophy before 12 weeks of age followed by fibrosis. In wild-type mice, the induction of CKD led to severe cardiovascular changes not observed in control mice. Notably, non-CKD mice fed a high-phosphate diet had lower Klotho levels and greatly accelerated cardiac remodeling associated with normal aging compared with those on a normal diet. Chronic elevation of circulating Klotho because of global overexpression alleviated the cardiac remodeling induced by either high-phosphate diet or CKD. Regardless of the cause of Klotho deficiency, the extent of cardiac hypertrophy and fibrosis correlated tightly with plasma phosphate concentration and inversely with plasma Klotho concentration, even when adjusted for all other covariables. High-fibroblast growth factor–23 concentration positively correlated with cardiac remodeling in a Klotho-deficient state but not a Klotho-replete state. In vitro, Klotho inhibited TGF-β1–, angiotensin II–, or high phosphate–induced fibrosis and abolished TGF-β1– or angiotensin II–induced hypertrophy of cardiomyocytes. In conclusion, Klotho deficiency is a novel intermediate mediator of pathologic cardiac remodeling, and fibroblast growth factor–23 may contribute to cardiac remodeling in concert with Klotho deficiency in CKD, phosphotoxicity, and aging. PMID:25326585

  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.

  3. Masturbation, sexuality, and adaptation: normalization in adolescence.

    PubMed

    Shapiro, Theodore

    2008-03-01

    During adolescence the central masturbation fantasy that is formulated during childhood takes its final form and paradoxically must now be directed outward for appropriate object finding and pair matching in the service of procreative aims. This is a step in adaptation that requires a further developmental landmark that I have called normalization. The path toward airing these private fantasies is facilitated by chumship relationships as a step toward further exposure to the social surround. Hartmann's structuring application of adaptation within psychoanalysis is used as a framework for understanding the process that simultaneously serves intrapsychic and social demands and permits goals that follow evolutionary principles. Variations in the normalization process from masturbatory isolation to a variety of forms of sexual socialization are examined in sociological data concerning current adolescent sexual behavior and in case examples that indicate some routes to normalized experience and practice.

  4. Looking Outwards, Not Inwards

    ERIC Educational Resources Information Center

    Field, John

    2007-01-01

    Too much thinking and research views learner autonomy in an instruction-centred way, with a focus on equipping the learner to function better in the classroom or learning centre. This article argues that true learner empowerment consists of the freedom to learn outside the teaching context and the ability to continue learning after instruction has…

  5. Patterns and Implications of Intracranial Arterial Remodeling in Stroke Patients

    PubMed Central

    Qiao, Ye; Anwar, Zeeshan; Intrapiromkul, Jarunee; liu, Li; Zeiler, Steven R.; Leigh, Richard; Zhang, Yiyi; Guallar, Eliseo; Wasserman, Bruce A.

    2015-01-01

    Background and Purpose Preliminary studies suggest ntracranial arteries are capable of accommodating plaque formation by remodeling. We sought to study the ability and extent of intracranial arteries to remodel using 3D high-resolution black blood MRI (BBMRI) and investigate its relation to ischemic events. Methods 42 patients with cerebrovascular ischemic events underwent 3D time-of-flight MRA and contrast-enhanced BBMRI examinations at 3T for intracranial atherosclerotic disease. Each plaque was classified by location (e.g., posterior vs. anterior circulation) and its likelihood to have caused a stroke identified on MRI (culprit, indeterminate, or non-culprit). Lumen area (LA), outer wall area (OWA), and wall area (WA) were measured at the lesion and reference sites. Plaque burden was calculated as WA divided by OWA. The arterial remodeling ratio (RR) was calculated as OWA at the lesion site divided by OWA at the reference site, after adjusting for vessel tapering. Arterial remodeling was categorized as positive if RR >1.05, intermediate if 0.95≤RR ≤ 1.05, and negative if RR <0.95. Results 137 plaques were identified in 42 patients (37% [50] posterior, 63% [87] anterior). Compared with anterior circulation plaques, posterior circulation plaques had a larger plaque burden (77.7±15.7 vs. 69.0±14.0, p=0.008), higher RR (1.14±0.38 vs. 0.95±0.32, p=0.002), and more often exhibited positive remodeling (54.0% vs.29.9%, p=0.011). Positive remodeling was marginally associated with downstream stroke presence when adjusted for plaque burden (OR 1.34, 95% CI: 0.99–1.81). Conclusions Intracranial arteries remodel in response to plaque formation, and posterior circulation arteries have a greater capacity for positive remodeling and, consequently, may more likely elude angiographic detection. Arterial remodeling may provide insight into stroke risk. PMID:26742795

  6. 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

  7. 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

  8. Structural and functional remodeling of skeletal muscle microvasculature is induced by simulated microgravity

    NASA Technical Reports Server (NTRS)

    Delp, M. D.; Colleran, P. N.; Wilkerson, M. K.; McCurdy, M. R.; Muller-Delp, J.

    2000-01-01

    Hindlimb unloading of rats results in a diminished ability of skeletal muscle arterioles to constrict in vitro and elevate vascular resistance in vivo. The purpose of the present study was to determine whether alterations in the mechanical environment (i.e., reduced fluid pressure and blood flow) of the vasculature in hindlimb skeletal muscles from 2-wk hindlimb-unloaded (HU) rats induces a structural remodeling of arterial microvessels that may account for these observations. Transverse cross sections were used to determine media cross-sectional area (CSA), wall thickness, outer perimeter, number of media nuclei, and vessel luminal diameter of feed arteries and first-order (1A) arterioles from soleus and the superficial portion of gastrocnemius muscles. Endothelium-dependent dilation (ACh) was also determined. Media CSA of resistance arteries was diminished by hindlimb unloading as a result of decreased media thickness (gastrocnemius muscle) or reduced vessel diameter (soleus muscle). ACh-induced dilation was diminished by 2 wk of hindlimb unloading in soleus 1A arterioles, but not in gastrocnemius 1A arterioles. These results indicate that structural remodeling and functional adaptations of the arterial microvasculature occur in skeletal muscles of the HU rat; the data suggest that these alterations may be induced by reductions in transmural pressure (gastrocnemius muscle) and wall shear stress (soleus muscle).

  9. 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.

  10. [Early left ventricular remodelling following acute coronary accident].

    PubMed

    Gaertner, Roger; Logeart, Damien; Michel, Jean-Baptiste; Mercadier, Jean-Jacques

    2004-01-01

    Ventricular remodelling following acute coronary syndromes is both complex and multiform. It is due to the response of the myocardium to the different agressions associated with these syndromes, in particular the ischemia and necrosis downstream of the occluded artery. We must not however neglect the role of the remodelling of the lesions resulting from spontaneous reperfusion or provoked by the cells and tissues associated with coronary microcirculation embolisms and the no-reflow phenomenon. Acute post-infarct remodelling is dominated by early ventricular dilatation which largely affects late prognosis, necrosis elimination and its replacement by a fibrotic scar in parallel with a compensatory hypertrophy of the non-infarcted myocardium. The diverse cellular and molecular components of this remodelling are increasingly well-known, allowing us to better explain the beneficial effects of the currently available medications and providing us with new potential therapeutic targets. A grading of this knowledge associated with the identification of new risk factors and early therapeutic interventions should help us to further limit the deleterious aspects of this remodelling in the goal of preventing, or at least delaying, the devolution towards heart failure.

  11. Subtype-specific neuronal remodeling during Drosophila metamorphosis.

    PubMed

    Veverytsa, Lyubov; Allan, Douglas W

    2013-01-01

    During metamorphosis in holometabolous insects, the nervous system undergoes dramatic remodeling as it transitions from its larval to its adult form. Many neurons are generated through post-embryonic neurogenesis to have adult-specific roles, but perhaps more striking is the dramatic remodeling that occurs to transition neurons from functioning in the larval to the adult nervous system. These neurons exhibit a remarkable degree of plasticity during this transition; many subsets undergo programmed cell death, others remodel their axonal and dendritic arbors extensively, whereas others undergo trans-differentiation to alter their terminal differentiation gene expression profiles. Yet other neurons appear to be developmentally frozen in an immature state throughout larval life, to be awakened at metamorphosis by a process we term temporally-tuned differentiation. These multiple forms of remodeling arise from subtype-specific responses to a single metamorphic trigger, ecdysone. Here, we discuss recent progress in Drosophila melanogaster that is shedding light on how subtype-specific programs of neuronal remodeling are generated during metamorphosis.

  12. Wall tissue remodeling regulates longitudinal tension in arteries.

    PubMed

    Jackson, Zane S; Gotlieb, Avrum I; Langille, B Lowell

    2002-05-03

    Changes in blood pressure or flow induce arterial remodeling that normalizes mechanical loads that are imposed on arterial tissue. Arteries are also under substantial longitudinal stretch (axial strain) that may be altered by growth or atrophy of tissues to which they are attached. We therefore tested whether axial strain is also regulated in a negative feedback manner through arterial remodeling. Axial strain in rabbit carotid arteries was increased from 62+/-2% to 97+/-2% without altering other mechanical loads on wall tissues. Strain was reduced within 3 days and completely normalized by 7 days. Remodeling involved tissue elaboration, endothelial cell replication rates were increased by >50-fold and smooth muscle cell replication rates were increased by >15-fold, and substantially elevated DNA, elastin, and collagen contents were recorded. Also, increased rates of apoptosis were indicated by degradation of DNA into oligonucleosomes, and matrix remodeling was reflected in enlarged fenestrae in the internal elastic lamina and increased expression and activation of gelatinases, especially matrix metalloproteinase-2. Intriguingly, reduced axial strain was not normalized, presumably because remodeling processes, apart from cell contraction, are ineffective in decreasing strain, and arterial smooth muscle orientation precludes large effects of contraction on axial strain.

  13. 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.

  14. Chromatin dynamics: Interplay between remodeling enzymes and histone modifications

    PubMed Central

    Swygert, Sarah G.; Peterson, Craig L.

    2014-01-01

    Chromatin dynamics play an essential role in regulating the accessibility of genomic DNA for a variety of nuclear processes, including gene transcription and DNA repair. The posttranslational modification of the core histones and the action of ATP-dependent chromatin remodeling enzymes represent two primary mechanisms by which chromatin dynamics are controlled and linked to nuclear events. Although there are examples in which a histone modification or a remodeling enzyme may be sufficient to drive a chromatin transition, these mechanisms typically work in concert to integrate regulatory inputs, leading to a coordinated alteration in chromatin structure and function. Indeed, site-specific histone modifications can facilitate the recruitment of chromatin remodeling enzymes to particular genomic regions, or they can regulate the efficiency or the outcome of a chromatin remodeling reaction. Conversely, chromatin remodeling enzymes can also influence, and sometimes directly modulate, the modification state of histones. These functional interactions are generally complex, frequently transient, and often require the association of myriad additional factors. PMID:24583555

  15. Biological remodelling: Stationary energy, configurational change, internal variables and dissipation

    NASA Astrophysics Data System (ADS)

    Garikipati, K.; Olberding, J. E.; Narayanan, H.; Arruda, E. M.; Grosh, K.; Calve, S.

    2006-07-01

    Remodelling is defined as an evolution of microstructure or variations in the configuration of the underlying manifold. The manner in which a biological tissue and its subsystems remodel their structure is treated in a continuum mechanical setting. While some examples of remodelling are conveniently modelled as evolution of the reference configuration—Case I—others are more suited to an internal variable description—Case II. In this paper, we explore the applicability of stationary energy states to remodelled systems. A variational treatment is introduced by assuming that stationary energy states are attained by changes in microstructure via one of the two mechanisms—Cases I and II. The configurational change of a long-chain molecule is presented as an example of Case I, and collagen fibre reorientation in in vitro tissue constructs as an example of Case II. The second example is further studied for its thermodynamic dissipation characteristics. This leads to an important finding on the limitation of purely mechanical treatments of some types of remodelling phenomena.

  16. Cortical remodeling during menopause, rheumatoid arthritis, glucocorticoid and bisphosphonate therapy.

    PubMed

    Aeberli, Daniel; Schett, Georg

    2013-03-21

    Bone mass, bone geometry and its changes are based on trabecular and cortical bone remodeling. Whereas the effects of estrogen loss, rheumatoid arthritis (RA), glucocorticoid (GC) and bisphosphonate (BP) on trabecular bone remodeling have been well described, the effects of these conditions on the cortical bone geometry are less known. The present review will report current knowledge on the effects of RA, GC and BP on cortical bone geometry and its clinical relevance. Estrogen deficiency, RA and systemic GC lead to enhanced endosteal bone resorption. While in estrogen deficiency and under GC therapy endosteal resorption is insufficiently compensated by periosteal apposition, RA is associated with some periosteal bone apposition resulting in a maintained load-bearing capacity and stiffness. In contrast, BP treatment leads to filling of endosteal bone cavities at the epiphysis; however, periosteal apposition at the bone shaft seems to be suppressed. In summary, estrogen loss, RA and GC show similar effects on endosteal bone remodeling with an increase in bone resorption, whereas their effect on periosteal bone remodeling may differ. Despite over 50 years of GC therapy and over 25 years of PB therapy, there is still need for better understanding of the skeletal effects of these drugs as well as of inflammatory disease such as RA on cortical bone remodeling.

  17. 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

  18. Neurovascular unit remodelling in the subacute stage of stroke recovery.

    PubMed

    Lake, Evelyn M R; Bazzigaluppi, Paolo; Mester, James; Thomason, Lynsie A M; Janik, Rafal; Brown, Mary; McLaurin, JoAnne; Carlen, Peter L; Corbett, Dale; Stanisz, Greg J; Stefanovic, Bojana

    2017-02-01

    Brain plasticity following focal cerebral ischaemia has been observed in both stroke survivors and in preclinical models of stroke. Endogenous neurovascular adaptation is at present incompletely understood yet its potentiation may improve long-term functional outcome. We employed longitudinal MRI, intracranial array electrophysiology, Montoya Staircase testing, and immunofluorescence to examine function of brain vessels, neurons, and glia in addition to forelimb skilled reaching during the subacute stage of ischemic injury progression. Focal ischemic stroke (~100mm(3) or ~20% of the total brain volume) was induced in adult Sprague-Dawley rats via direct injection of endothelin-1 (ET-1) into the right sensori-motor cortex, producing sustained impairment in left forelimb reaching ability. Resting perfusion and vascular reactivity to hypercapnia in the peri-lesional cortex were elevated by approximately 60% and 80% respectively seven days following stroke. At the same time, the normal topological pattern of local field potential (LFP) responses to peripheral somatosensory stimulation was abolished and the average power of spontaneous LFP activity attenuated by approximately 50% relative to the contra-lesional cortex, suggesting initial response attenuation within the peri-infarct zone. By 21 days after stroke, perilesional blood flow resolved, but peri-lesional vascular reactivity remained elevated. Concomitantly, the LFP response amplitudes increased with distance from the site of ET-1 injection, suggesting functional remodelling from the core of the lesion to its periphery. This notion was further buttressed by the lateralization of spontaneous neuronal activity: by day 21, the average ipsi-lesional power of spontaneous LFP activity was almost twice that of the contra-lesional cortex. Over the observation period, the peri-lesional cortex exhibited increased vascular density, along with neuronal loss, astrocytic activation, and recruitment and activation of microglia

  19. 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

  20. Determinants of Mexico-U.S. Outward and Return Migration Flows: A State-Level Panel Data Analysis.

    PubMed

    Chort, Isabelle; de la Rupelle, Maëlys

    2016-10-01

    Using a unique panel data set of state-to-state outward and return migration flows between Mexico and the United States from 1995 to 2012, this study is the first to analyze Mexico-U.S. migration at the state level and explore simultaneously the effect of economic, environmental, and social factors in Mexico over two decades. Pairing origin and destination states and controlling for a rich structure of fixed effects, we find that income positively impacts migration outflows, especially for Mexican states of origin with a recent migration history and for low-educated migrant flows, suggesting the existence of credit constraints. We find evidence that drought causes more out-migration, while other climatic shocks have no effect. Violence is found to increase out-migration flows from border states and to decrease migration from other Mexican states, especially where violence is directed at migrants. Last, return flows are larger when income growth at destination is lower, consistent with the accumulation of savings as a primary motivation of migrants. Exploring the impact of the crisis, we find evidence of significant changes in the geography of migration flows. Traditional flows are drying up, and new migration corridors are rising, with implications on the composition of the Mexican population in the United States. Although the effect of income on flows in both directions is unchanged by the crisis, the negative effect of violence on out-migration tends to reverse at the end of the period. Overall, this study emphasizes the interest of analyzing disaggregated flows at the infra-country level.

  1. Modulation of ventricular transient outward K+ current by acidosis and its effects on excitation-contraction coupling

    PubMed Central

    Saegusa, Noriko; Garg, Vivek

    2013-01-01

    The contribution of transient outward current (Ito) to changes in ventricular action potential (AP) repolarization induced by acidosis is unresolved, as is the indirect effect of these changes on calcium handling. To address this issue we measured intracellular pH (pHi), Ito, L-type calcium current (ICa,L), and calcium transients (CaTs) in rabbit ventricular myocytes. Intracellular acidosis [pHi 6.75 with extracellular pH (pHo) 7.4] reduced Ito by ∼50% in myocytes with both high (epicardial) and low (papillary muscle) Ito densities, with little effect on steady-state inactivation and activation. Of the two candidate α-subunits underlying Ito, human (h)Kv4.3 and hKv1.4, only hKv4.3 current was reduced by intracellular acidosis. Extracellular acidosis (pHo 6.5) shifted Ito inactivation toward less negative potentials but had negligible effect on peak current at +60 mV when initiated from −80 mV. The effects of low pHi-induced inhibition of Ito on AP repolarization were much greater in epicardial than papillary muscle myocytes and included slowing of phase 1, attenuation of the notch, and elevation of the plateau. Low pHi increased AP duration in both cell types, with the greatest lengthening occurring in epicardial myocytes. The changes in epicardial AP repolarization induced by intracellular acidosis reduced peak ICa,L, increased net calcium influx via ICa,L, and increased CaT amplitude. In summary, in contrast to low pHo, intracellular acidosis has a marked inhibitory effect on ventricular Ito, perhaps mediated by Kv4.3. By altering the trajectory of the AP repolarization, low pHi has a significant indirect effect on calcium handling, especially evident in epicardial cells. PMID:23585132

  2. Attenuated outward potassium currents in carotid body glomus cells of heart failure rabbit: involvement of nitric oxide

    PubMed Central

    Li, Yu-Long; Sun, Shu-Yu; Overholt, Jeffery L; Prabhakar, Nanduri R; Rozanski, George J; Zucker, Irving H; Schultz, Harold D

    2004-01-01

    It has been shown that peripheral chemoreceptor sensitivity is enhanced in both clinical and experimental heart failure (HF) and that impairment of nitric oxide (NO) production contributes to this enhancement. In order to understand the cellular mechanisms associated with the alterations of chemoreceptor function and the actions of NO in the carotid body (CB), we compared the outward K+ currents (IK) of glomus cells in sham rabbits with that in HF rabbits and monitored the effects of NO on these currents. Ik was measured in glomus cells using conventional and perforated whole-cell configurations. IK was attenuated in glomus cells of HF rabbits, and their resting membrane potentials (−34.7 ± 1.0 mV) were depolarized as compared with those in sham rabbits (−47.2 ± 1.9 mV). The selective Ca2+-dependent K+ channel (KCa) blocker iberiotoxin (IbTx, 100 nm) reduced IK in glomus cells from sham rabbits, but had no effect on IK from HF rabbits. In perforated whole-cell mode, the NO donor SNAP (100 μm) increased IK in glomus cells from HF rabbits to a greater extent than that in sham rabbits (P < 0.01), and IbTx inhibited the effects of SNAP. However, in conventional whole-cell mode, SNAP had no effect. Nω-nitro-L-arginine (L-NNA, NO synthase inhibitor) decreased Ik in sham rabbits but not in HF rabbits. The guanylate cyclase inhibitor 1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one (ODQ) inhibited the effect of SNAP on Ik. These results demonstrate that IK is reduced in CB glomus cells from HF rabbits. This effect is due mainly to the suppression of KCa channel activity caused by decreased availability of NO. In addition, intracellular cGMP is necessary for the KCa channel modulation by NO. PMID:14673183

  3. KChIP2 genotype dependence of transient outward current (Ito) properties in cardiomyocytes isolated from male and female mice

    PubMed Central

    Waldschmidt, Lara; Junkereit, Vera; Bähring, Robert

    2017-01-01

    The transient outward current (Ito) in cardiomyocytes is largely mediated by Kv4 channels associated with Kv Channel Interacting Protein 2 (KChIP2). A knockout model has documented the critical role of KChIP2 in Ito expression. The present study was conducted to characterize in both sexes the dependence of Ito properties, including current magnitude, inactivation kinetics, recovery from inactivation and voltage dependence of inactivation, on the number of functional KChIP2 alleles. For this purpose we performed whole-cell patch-clamp experiments on isolated left ventricular cardiomyocytes from male and female mice which had different KChIP2 genotypes; i.e., wild-type (KChIP2+/+), heterozygous knockout (KChIP2+/-) or complete knockout of KChIP2 (KChIP2-/-). We found in both sexes a KChIP2 gene dosage effect (i.e., a proportionality between number of alleles and phenotype) on Ito magnitude, however, concerning other Ito properties, KChIP2+/- resembled KChIP2+/+. Only in the total absence of KChIP2 (KChIP2-/-) we observed a slowing of Ito kinetics, a slowing of recovery from inactivation and a negative shift of a portion of the voltage dependence of inactivation. In a minor fraction of KChIP2-/- myocytes Ito was completely lost. The distinct KChIP2 genotype dependences of Ito magnitude and inactivation kinetics, respectively, seen in cardiomyocytes were reproduced with two-electrode voltage-clamp experiments on Xenopus oocytes expressing Kv4.2 and different amounts of KChIP2. Our results corroborate the critical role of KChIP2 in controlling Ito properties. They demonstrate that the Kv4.2/KChIP2 interaction in cardiomyocytes is highly dynamic, with a clear KChIP2 gene dosage effect on Kv4 channel surface expression but not on inactivation gating. PMID:28141821

  4. 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

  5. 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.

  6. 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.

  7. 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

  8. Diabetes mellitus and atrial remodeling: mechanisms and potential upstream therapies.

    PubMed

    Zhang, Qitong; Liu, Tong; Ng, Chee Y; Li, Guangping

    2014-10-01

    Atrial fibrillation (AF) is the most common cardiac arrhythmia in clinical practice, and its prevalence has increasing substantially over the last decades. Recent data suggest that there is an increased risk of AF among the patients with diabetes mellitus (DM). However, the potential molecular mechanisms regarding DM-related AF and diabetic atrial remodeling are not fully understood. In this comprehensive review, we would like to summarize the potential relationship between diabetes and atrial remodeling, including structural, electrical, and autonomic remodeling. Also, some upstream therapies, such as thiazolidinediones, probucol, ACEI/ARBs, may play an important role in the prevention and treatment of AF. Therefore, large prospective randomized, controlled trials and further experimental studies should be challengingly continued.

  9. 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.

  10. Root architecture remodeling induced by phosphate starvation.

    PubMed

    Sato, Aiko; Miura, Kenji

    2011-08-01

    Plants have evolved efficient strategies for utilizing nutrients in the soil in order to survive, grow, and reproduce. Inorganic phosphate (Pi) is a major macroelement source for plant growth; however, the availability and distribution of Pi are varying widely across locations. Thus, plants in many areas experience Pi deficiency. To maintain cellular Pi homeostasis, plants have developed a series of adaptive responses to facilitate external Pi acquisition, limit Pi consumption, and adjust Pi recycling internally under Pi starvation conditions. This review focuses on the molecular regulators that modulate Pi starvation-induced root architectural changes.

  11. 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

  12. Electrical remodeling of preoptic GABAergic neurons involves the Kv1.5 subunit.

    PubMed

    Tabarean, Iustin V

    2014-01-01

    The electrogenic machinery of an excitable cell can adapt in response to changes in input, genetic deficit or in pathological conditions, however the underlying molecular mechanisms are not understood. In cases of genetic deletion it is commonly observed that a channel subunit from the same family replaces the missing one. We have previously reported that Kv4.2-/- preoptic GABAergic neurons display identical firing characteristics to those of wild-type neurons despite having reduced A-type currents, and that, surprisingly, they present a robust upregulation of a delayed rectifier current, the nature of which is unknown. Here, using pharmacology, qPCR and Western blots we report that, although the wild-type neurons express several Kv subunits, the upregulated current is conducted by the Kv1.5 subunit exclusively. Thus, this study reveals the molecular nature of a novel mechanism of electrical remodeling in central neurons.

  13. 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.

  14. Analysis of microstructural and mechanical alterations of trabecular bone in a simulated three-dimensional remodeling process.

    PubMed

    Wang, Hong; Ji, Baohua; Liu, X Sherry; Guo, X Edward; Huang, Yonggang; Hwang, Keh-Chih

    2012-09-21

    Bone remodeling is a complex dynamic process, which modulates both bone mass and bone microstructure. In addition to bone mass, bone microstructure is an important contributor to bone quality in osteoporosis and fragility fractures. However, the quantitative knowledge of evolution of three-dimensional (3D) trabecular microstructure in adaptation to the external forces is currently limited. In this study, a new 3D simulation method of remodeling of human trabecular bone was developed to quantitatively study the dynamic evolution of bone mass and trabecular microstructure in response to different external loading conditions. The morphological features of trabecular plate and rod, such as thickness and number density in different orientations were monitored during the remodeling process using a novel imaging analysis technique, namely Individual Trabecula Segmentation (ITS). We showed that the volume fraction and microstructures of trabecular bone including, trabecular type and orientation, were determined by the applied mechanical load. Particularly, the morphological parameters of trabecular plates were more sensitive to the applied load, indicating that they played the major role in the mechanical properties of the trabecular bone. Reducing the applied load caused severe microstructural deteriorations of trabecular bone, such as trabecular plate perforation, rod breakage, and a conversion from plates to rods.

  15. 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

  16. Epac2-mediated dendritic spine remodeling: implications for disease

    PubMed Central

    Woolfrey, Kevin M.; Srivastava, Deepak P.

    2010-01-01

    In the mammalian forebrain, most glutamatergic excitatory synapses occur on small dendritic protrusions called dendritic spines. Dendritic spines are highly plastic and can rapidly change morphology in response to numerous stimuli. This dynamic remodeling of dendritic spines is thought to be critical for information processing, memory and cognition. Conversely, multiple studies have revealed that neuropathologies such as autism spectrum disorders (ASDs) are linked with alterations in dendritic spine morphologies and miswiring of neural circuitry. One compelling hypothesis is that abnormal dendritic spine remodeling is a key contributing factor for this miswiring. Ongoing research has identified a number of mechanisms that are critical for the control of dendritic spine remodeling. Among these mechanisms, regulation of small GTPase signaling by guanine-nucleotide exchange factors (GEFs) is emerging as a critical mechanism for integrating physiological signals in the control of dendritic spine remodeling. Furthermore, multiple proteins associated with regulation of dendritic spine remodeling have also been implicated with multiple neuropathologies, including ASDs. Epac2, a GEF for the small GTPase Rap, has recently been described as a novel cAMP(yet PKA-independent) target localized to dendritic spines. Signaling via this protein in response to pharmacological stimulation or cAMP accumulation, via the dopamine D1/5 receptor, results in Rap activation, promotes structural destabilization, in the form of dendritic spine shrinkage, and functional depression due to removal of GluR2/3-containing AMPA receptors. In addition, Epac2 forms macromolecular complexes with ASD-associated proteins, which are sufficient to regulate Epac2 localization and function. Furthermore, rare nonsynonymous variants of the EPAC2 gene associated with the ASD phenotype alter protein function, synaptic protein distribution, and spine morphology. We review here the role of Epac2 in the remodeling

  17. 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

  18. Nasomaxillary remodeling and facial form in robust Australopithecus: a reassessment.

    PubMed

    McCollum, Melanie A

    2008-01-01

    In a previous study of the patterns of facial growth remodeling characteristic of early hominid taxa, Bromage (1989) demonstrated that the nasoalveolar clivus of A. robustus was resorptive throughout ontogeny. Based upon the remodeling information provided by small samples (n=6 each) of chimpanzees and modern humans, he concluded that the clival resorption pattern characteristic of robust Australopithecus differed significantly from that of chimpanzees and was instead somewhat convergent upon that of modern humans, in that it served to emphasize a downward facial growth vector. The present study used the SEM/replica technique to assess nasomaxillary remodeling in larger, more age-varied samples of chimpanzee (n=33) and modern human crania (n=22). Results indicate far more intraspecific variability in nasomaxillary remodeling than suggested by Bromage's earlier study. In particular, results from an expanded sample demonstrate that the nasoalveolar clivus of chimpanzees is frequently resorptive, especially at later stages of ontogeny. However, the pattern of clival remodeling observed in chimpanzees is unlike that typical of robust Australopithecus, in which clival resorption occurs throughout ontogeny and in expansive fields that cover the entire clival surface. Although Bromage (1989) considered the pattern of nasomaxillary remodeling observed in robust Australopithecus to have been a byproduct of an extreme maxillary growth rotation, the failure of A. africanus to display a similar pattern suggests that some other factor(s) may have been involved. Regardless, it is unlikely that clival resorption in robust Australopithecus would have significantly impacted the overall vector of facial growth. Instead, the primary morphogenetic effect of this pattern of clival resorption would have been one of local surface sculpting.

  19. 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.

  20. The pathophysiologic process of ventricular remodeling: from infarct to failure.

    PubMed

    Paul, S

    1995-05-01

    In the past, hypertensive heart disease was the principal cause of congestive heart failure, but currently ischemic heart disease is the major etiologic factor. In the last 20 years, the role of myocardial infarction (MI) and the subsequent alteration in ventricular architecture of the infarcted and noninfarcted myocardium have become increasingly associated with a phenomenon known as ventricular remodelling. This process consists of left ventricular wall thinning in the infarction area, ventricular chamber dilatation, and compensatory hypertrophy of the noninfarcted portion of the myocardium. This article describes the pathophysiologic transformation that begins with MI and ventricular remodeling and ends in congestive heart failure.

  1. Mechanisms of ATP-Dependent Chromatin Remodeling Motors.

    PubMed

    Zhou, Coral Y; Johnson, Stephanie L; Gamarra, Nathan I; Narlikar, Geeta J

    2016-07-05

    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.

  2. Remodeling of cell-cell junctions in arrhythmogenic cardiomyopathy.

    PubMed

    Asimaki, Angeliki; Saffitz, Jeffrey E

    2014-02-01

    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.

  3. 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

  4. Myometrial mechanoadaptation during pregnancy: implications for smooth muscle plasticity and remodelling.

    PubMed

    Wu, X; Morgan, K G; Jones, C J; Tribe, R M; Taggart, M J

    2008-08-01

    The smooth muscle of the uterus during pregnancy presents a unique circumstance of physiological mechanotransduction as the tissue remodels in response to stretches imposed by the growing foetus(es), yet the nature of the molecular and functional adaptations remain unresolved. We studied, in myometrium isolated from non-pregnant (NP) and pregnant mice, the active and passive length-tension curves by myography and the expression and activation by immunoblotting of focal adhesion-related proteins known in other systems to participate in mechanosensing and mechanotransduction. In situ uterine mass correlated with pup number and weight throughout pregnancy. In vitro myometrial active, and passive, length-tension curves shifted significantly to the right during pregnancy indicative of altered mechanosensitivity; at term, maximum active tension was generated following 3.94+/-0.33-fold stretch beyond slack length compared to 1.91+/-0.12-fold for NP mice. Moreover, mechanotransduction was altered during pregnancy as evidenced by the progressive increase in absolute force production at each optimal stretch. Pregnancy was concomitantly associated with an increased expression of the dense plaque-associated proteins FAK and paxillin, and elevated activation of FAK, paxillin, c-Src and extracellular signal-regulated kinase (ERK1/2) which reversed 1 day post-partum. Electron microscopy revealed close appositioning of neighbouring myometrial cells across a narrow extracellular cleft adjoining plasmalemmal dense plaques. Collectively, these results suggest a physiological basis of myometrial length adaptation, long known to be a property of many smooth muscles, whereupon plasmalemmal dense plaque proteins serve as molecular signalling and structural platforms contributing to functional (contractile) remodelling in response to chronic stretch.

  5. Acquisition of temozolomide chemoresistance in gliomas leads to remodeling of mitochondrial electron transport chain.

    PubMed

    Oliva, Claudia R; Nozell, Susan E; Diers, Anne; McClugage, Samuel G; Sarkaria, Jann N; Markert, James M; Darley-Usmar, Victor M; Bailey, Shannon M; Gillespie, G Yancey; Landar, Aimee; Griguer, Corinne E

    2010-12-17

    Temozolomide (TMZ) is an oral alkylating agent used for the treatment of high-grade gliomas. Acquired chemoresistance is a severe limitation to this therapy with more than 90% of recurrent gliomas showing no response to a second cycle of chemotherapy. Efforts to better understand the underlying mechanisms of acquired chemoresistance to TMZ and potential strategies to overcome chemoresistance are, therefore, critically needed. TMZ methylates nuclear DNA and induces cell death; however, the impact on mitochondria DNA (mtDNA) and mitochondrial bioenergetics is not known. Herein, we tested the hypothesis that TMZ-mediated alterations in mtDNA and respiratory function contribute to TMZ-dependent acquired chemoresistance. Using an in vitro model of TMZ-mediated acquired chemoresistance, we report 1) a decrease in mtDNA copy number and the presence of large heteroplasmic mtDNA deletions in TMZ-resistant glioma cells, 2) remodeling of the entire electron transport chain with significant decreases of complexes I and V and increases of complexes II/III and IV, and 3) pharmacologic and genetic manipulation of cytochrome c oxidase, which restores sensitivity to TMZ-dependent apoptosis in resistant glioma cells. Importantly, human primary and recurrent pairs of glioblastoma multiforme (GBM) biopsies as well as primary and TMZ-resistant GBM xenograft lines exhibit similar remodeling of the ETC. Overall these results suggest that TMZ-dependent acquired chemoresistance may be due to a mitochondrial adaptive response to TMZ genotoxic stress with a major contribution from cytochrome c oxidase. Thus, abrogation of this adaptive response may reverse chemoresistance and restore sensitivity to TMZ, providing a strategy for improved therapeutic outcomes in GBM patients.

  6. 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

  7. A model of reverse spike frequency adaptation and repetitive firing of subthalamic nucleus neurons.

    PubMed

    Wilson, Charles J; Weyrick, Angela; Terman, David; Hallworth, Nicholas E; Bevan, Mark D

    2004-05-01

    Subthalamic nucleus neurons exhibit reverse spike-frequency adaptation. This occurs only at firing rates of 20-50 spikes/s and higher. Over this same frequency range, there is an increase in the steady-state frequency-intensity (F-I) curve's slope (the secondary range). Specific blockade of high-voltage activated calcium currents reduced the F-I curve slope and reverse adaptation. Blockade of calcium-dependent potassium current enhanced secondary range firing. A simple model that exhibited these properties used spike-triggered conductances similar to those in subthalamic neurons. It showed: 1) Nonaccumulating spike afterhyperpolarizations produce positively accelerating F-I curves and spike-frequency adaptation that is complete after the second spike. 2) Combinations of accumulating aftercurrents result in a linear F-I curve, whose slope depends on the relative contributions of inward and outward currents. Spike-frequency adaptation can be gradual. 3) With both accumulating and nonaccumulating aftercurrents, primary and secondary ranges will be present in the F-I curve. The slope of the primary range is determined by the nonaccumulating conductance; the accumulating conductances govern the secondary range. The transition is determined by the relative strengths of accumulating and nonaccumulating currents. 4) Spike-threshold accommodation contributes to the secondary range, reducing its slope at high firing rates. Threshold accommodation can stabilize firing when inward aftercurrents exceed outward ones. 5) Steady-state reverse adaptation results when accumulated inward aftercurrents exceed outward ones. This requires spike-threshold accommodation. Transient speedup arises when inward currents are smaller than outward ones at steady state, but accumulate more rapidly. 6) The same mechanisms alter firing in response to irregular patterns of synaptic conductances, as cell excitability fluctuates with changes in firing rate.

  8. Tracheal remodelling in response to hypoxia

    PubMed Central

    Centanin, Lazaro; Gorr, Thomas A.; Wappner, Pablo

    2010-01-01

    The insect tracheal system is a continuous tubular network that ramifies into progressively thinner branches to provide air directly to every organ and tissue throughout the body. During embryogenesis the basic architecture of the tracheal system develops in a stereotypical and genetically controlled manner. Later, in larval stages, the tracheal system becomes plastic, and adapts to particular oxygen needs of the different tissues of the body. Oxygen sensing is mediated by specific prolyl-4-hydroxylases that regulate protein stability of the alpha subunit of oxygen-responsive transcription factors from the HIF family. Tracheal cells are exquisitely sensitive to oxygen levels, modulating the expression of hypoxia-inducible proteins that mediate sprouting of tracheal branches in direction to oxygen-deprived tissues. PMID:19482033

  9. Changes in the action potential and transient outward potassium current in cardiomyocytes during acute cardiac rejection in rats

    PubMed Central

    Luo, Wenqi; Jia, Yixin; Zheng, Shuai; Li, Yan; Han, Jie

    2017-01-01

    Background Acute cardiac rejection contributes to the changes in the electrophysiological properties of grafted hearts. However, the electrophysiological changes of cardiomyocytes during acute cardiac rejection are still unknown. An understanding of the electrophysiological mechanisms of cardiomyocytes could improve the diagnosis and treatment of acute cardiac rejection. So it is important to characterize the changes in the action potential (AP) and the transient outward potassium current (Ito) in cardiomyocytes during acute cardiac rejection. Methods Heterotopic heart transplantation was performed in allogeneic [Brown Norway (BN)-to-Lewis] and isogeneic (BN-to-BN) rats. Twenty models were established in each group. Ten recipients were sacrificed at the 2nd day and the other ten recipients were sacrificed at the 4th day after the operation in each group. Histopathological examinations of the grafted hearts were performed in half of the recipients in each group randomly. The other half of the grafted hearts were excised rapidly and enzymatically dissociated to obtain single cardiomyocytes. The AP and Ito current were recorded using the whole cell patch-clamp technique. Results Forty grafted hearts were successfully harvested and used in experiments. Histologic examination showed mild rejection at the 2nd day and moderate rejection at the 4th day in the allogeneic group after cardiac transplantation, while no evidence of histologic lesions of rejection were observed in the isogeneic group. Compared with the isogeneic group, the action potential duration (APD) of cardiomyocytes in the allogeneic group was significantly prolonged (APD90 was 49.28±5.621 mV in the isogeneic group and 88.08±6.445 mV in the allogeneic group at the 2nd day, P=0.0016; APD90 was 59.34±5.183 mV in the isogeneic group and 104.0±9.523 mV in the allogeneic group at the 4th day, P=0.0064). The current density of Ito was significantly decreased at the 4th day after cardiac transplantation

  10. 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

  11. 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

    2013-02-07

    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

  12. 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.

  13. 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…

  14. Probing Nucleosome Remodeling by Unzipping Single DNA Molecules

    NASA Astrophysics Data System (ADS)

    Wang, Michelle

    2006-03-01

    At the core of eukaryotic chromatin is the nucleosome, which consists of 147 bp of DNA wrapped 1.65 turns around an octamer of histone proteins. Even this lowest level of genomic compaction presents a strong barrier to DNA-binding cellular factors that are required for essential processes such as transcription, DNA replication, recombination and repair. Chromatin remodeling enzymes use the energy of ATP hydrolysis to regulate accessibility of the genetic code by altering chromatin structure. While remodeling enzymes have been the subject of extensive research in recent years, their precise mechanism remains unclear. In order to probe the structure of individual nucleosomes and their remodeling, we assembled a histone octamer onto a DNA segment containing a strong nucleosome positioning sequence. As the DNA double helix was unzipped through the nucleosome using a feedback-enhanced optical trap, the presence of the nucleosome was detected as a series of dramatic increases in the tension in the DNA, followed by sudden tension reductions. Analysis of the unzipping force throughout the disruption accurately revealed the spatial location and fine structure of the nucleosome to near base pair precision. Using this approach, we investigate how remodeling enzymes may alter the location and structure of a nucleosome.

  15. 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.

  16. 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

  17. Integrated mechanisms of CaMKII-dependent ventricular remodeling

    PubMed Central

    Kreusser, Michael M.; Backs, Johannes

    2014-01-01

    CaMKII has been shown to be activated during different cardiac pathological processes, and CaMKII-dependent mechanisms contribute to pathological cardiac remodeling, cardiac arrhythmias, and contractile dysfunction during heart failure. Activation of CaMKII during cardiac stress results in a broad number of biological effects such as, on the one hand, acute effects due to phosphorylation of distinct cellular proteins as ion channels and calcium handling proteins and, on the other hand, integrative mechanisms by changing gene expression. This review focuses on transcriptional and epigenetic effects of CaMKII activation during chronic cardiac remodeling. Multiple mechanisms have been described how CaMKII mediates changes in cardiac gene expression. CaMKII has been shown to directly phosphorylate components of the cardiac gene regulation machinery. CaMKII phosphorylates several transcription factors such as CREB that induces the activation of specific gene programs. CaMKII activates transcriptional regulators also indirectly by phosphorylating histone deacetylases, especially HDAC4, which in turn inhibits transcription factors that drive cardiac hypertrophy, fibrosis, and dysfunction. Recent studies demonstrate that CaMKII also phosphorylate directly histones, which may contribute to changes in gene expression. These findings of CaMKII-dependent gene regulation during cardiac remodeling processes suggest novel strategies for CaMKII-dependent “transcriptional or epigenetic therapies” to control cardiac gene expression and function. Manipulation of CaMKII-dependent signaling pathways in the settings of pathological cardiac growth, remodeling, and heart failure represents an auspicious therapeutic approach. PMID:24659967

  18. 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

  19. Role of microRNAs in Vascular Remodeling

    PubMed Central

    Fang, Y.-C.; Yeh, C.-H.

    2015-01-01

    Besides being involved in the gradual formation of blood vessels during embryonic development, vascular remodeling also contributes to the progression of various cardiovascular diseases, such as; myocardial infarction, heart failure, atherosclerosis, pulmonary artery hypertension, restenosis, aneurysm, etc. The integrated mechanisms; proliferation of medial smooth muscle cell, dysregulation of intimal endothelial cell, activation of adventitial fibroblast, inflammation of macrophage, and the participation of extracellular matrix proteins are important factors in vascular remodeling. In the recent studies, microRNAs (miRs) have been shown to be expressed in all of these cell-types and play important roles in the mechanisms of vascular remodeling. Therefore, some miRs may be involved in prevention and others in the aggravation of the vascular lesions. miRs are small, endogenous, conserved, single-stranded, non-coding RNAs; which degrade target RNAs or inhibit translation post-transcriptionally. In this paper, we reviewed the function and mechanisms of miRs, which are highly expressed in various cells types, especially endothelial and smooth muscle cells, which are closely involved in the process of vascular remodeling. We also assess the functions of these miRs in the hope that they may provide new possibilities of diagnosis and treatment choices for the related diseases. PMID:26391551

  20. "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…

  1. Drosophila Brahma complex remodels nucleosome organizations in multiple aspects.

    PubMed

    Shi, Jiejun; Zheng, Meizhu; Ye, Youqiong; Li, Min; Chen, Xiaolong; Hu, Xinjie; Sun, Jin; Zhang, Xiaobai; Jiang, Cizhong

    2014-09-01

    ATP-dependent chromatin remodeling complexes regulate nucleosome organizations. In Drosophila, gene Brm encodes the core Brahma complex, the ATPase subunit of SWI/SNF class of chromatin remodelers. Its role in modulating the nucleosome landscape in vivo is unclear. In this study, we knocked down Brm in Drosophila third instar larvae to explore the changes in nucleosome profiles and global gene transcription. The results show that Brm knockdown leads to nucleosome occupancy changes throughout the entire genome with a bias in occupancy decrease. In contrast, the knockdown has limited impacts on nucleosome position shift. The knockdown also alters another important physical property of nucleosome positioning, fuzziness. Nucleosome position shift, gain or loss and fuzziness changes are all enriched in promoter regions. Nucleosome arrays around the 5' ends of genes are reorganized in five patterns as a result of Brm knockdown. Intriguingly, the concomitant changes in the genes adjacent to the Brahma-dependent remodeling regions have important roles in development and morphogenesis. Further analyses reveal abundance of AT-rich motifs for transcription factors in the remodeling regions.

  2. 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…

  3. Analgesic Drugs Alter Connective Tissue Remodeling and Mechanical Properties

    PubMed Central

    Carroll, Chad C.

    2015-01-01

    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. PMID:26509485

  4. Protein-Remodeling Factors As Potential Therapeutics for Neurodegenerative Disease

    PubMed Central

    Jackrel, Meredith E.; Shorter, James

    2017-01-01

    Protein misfolding is implicated in numerous neurodegenerative disorders including amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, and Huntington's disease. A unifying feature of patients with these disorders is the accumulation of deposits comprised of misfolded protein. Aberrant protein folding can cause toxicity through a loss or gain of protein function, or both. An intriguing therapeutic approach to counter these disorders is the application of protein-remodeling factors to resolve these misfolded conformers and return the proteins to their native fold and function. Here, we describe the application of protein-remodeling factors to alleviate protein misfolding in neurodegenerative disease. We focus on Hsp104, Hsp110/Hsp70/Hsp40, NMNAT, and HtrA1, which can prevent and reverse protein aggregation. While many of these protein-remodeling systems are highly promising, their activity can be limited. Thus, engineering protein-remodeling factors to enhance their activity could be therapeutically valuable. Indeed, engineered Hsp104 variants suppress neurodegeneration in animal models, which opens the way to novel therapeutics and mechanistic probes to help understand neurodegenerative disease. PMID:28293166

  5. 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.

  6. Lymph node biophysical remodeling is associated with melanoma lymphatic drainage.

    PubMed

    Rohner, Nathan Andrew; McClain, Jacob; Tuell, Sara Lydia; Warner, Alex; Smith, Blair; Yun, Youngho; Mohan, Abhinav; Sushnitha, Manuela; Thomas, Susan Napier

    2015-11-01

    Tissue remodeling is a characteristic of many solid tumor malignancies including melanoma. By virtue of tumor lymphatic transport, remodeling pathways active within the local tumor microenvironment have the potential to be operational within lymph nodes (LNs) draining the tumor interstitium. Here, we show that lymphatic drainage from murine B16 melanomas in syngeneic, immune-competent C57Bl/6 mice is associated with LN enlargement as well as nonuniform increases in bulk tissue elasticity and viscoelasticity, as measured by the response of whole LNs to compression. These remodeling responses, which quickly manifest in tumor-draining lymph nodes (TDLNs) after tumor inoculation and before apparent metastasis, were accompanied by changes in matrix composition, including up to 3-fold increases in the abundance of soluble collagen and hyaluronic acid. Intranodal pressures were also significantly increased in TDLNs (+1 cmH2O) relative to both non-tumor-draining LNs (-1 cmH2O) and LNs from naive animals (-1 to 2 cmH2O). These data suggest that the reorganization of matrix structure, composition, and fluid microenvironment within LNs associated with tumor lymphatic drainage parallels remodeling seen in primary malignancies and has the potential to regulate the adhesion, proliferation, and signaling function of LN-resident cells involved in directing melanoma disease progression.

  7. Systems analysis of bone remodelling as a homeostatic regulator.

    PubMed

    Chen, A; Hamamura, K; Zhang, P; Chen, Y; Yokota, H

    2010-01-01

    Bone remodelling in adult skeleton is a process of maintaining bone mass through combined activities of bone forming osteoblasts and bone resorbing osteoclasts. Focusing on a molecular pathway mediated by osteoprotegerin, the authors derived a mathematical formulation for molecular interactions and cellular behaviours. The authors also treated this remodelling process as a homeostatic regulator in a framework of linear quadratic problems. A primary question was: does a solution of a matrix Riccati equation provide a guideline for therapeutic interventions for prevention of bone loss? In order to elucidate the systems dynamics, the authors analysed the perturbed set of equations around a stable equilibrium state together with the original equations. The results demonstrate that a homeostatic regulator with the selected control variables effectively reduces bone degradation activities and restore a physiological remodelling process. To partially validate efficacy of the described intervention strategy, biological experiments were conducted with an osteoblast cell line using one of the control variables, salubrinal (chemical agent). The authors observed that administration of salubrinal activated mRNA levels of transcription factors and an osteogenic marker gene as well as enhancement of mineralisation. Taken together, the current study supports a potential usage of control theories in active regulation of bone remodelling homeostasis.

  8. Chd5 orchestrates chromatin remodeling during sperm development

    PubMed Central

    Li, Wangzhi; Wu, Jie; Kim, Sang-Yong; Zhao, Ming; Hearn, Stephen A.; Zhang, Michael Q.; Meistrich, Marvin L.

    2014-01-01

    One of the most remarkable chromatin remodeling processes occurs during spermiogenesis, the post-meiotic phase of sperm development during which histones are replaced with sperm-specific protamines to repackage the genome into the highly compact chromatin structure of mature sperm. Here we identify Chromodomain helicase DNA binding protein 5 (Chd5) as a master regulator of the histone-to-protamine chromatin remodeling process. Chd5 deficiency leads to defective sperm chromatin compaction and male infertility in mice, mirroring the observation of low CHD5 expression in testes of infertile men. Chd5 orchestrates a cascade of molecular events required for histone removal and replacement, including histone 4 (H4) hyperacetylation, histone variant expression, nucleosome eviction, and DNA damage repair. Chd5 deficiency also perturbs expression of transition proteins (Tnp1/Tnp2) and protamines (Prm1/2). These findings define Chd5 as a multi-faceted mediator of histone-to-protamine replacement and depict the cascade of molecular events underlying chromatin remodeling during this process of extensive chromatin remodeling. PMID:24818823

  9. 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.

  10. Galectin-3 and post-myocardial infarction cardiac remodeling.

    PubMed

    Meijers, Wouter C; van der Velde, A Rogier; Pascual-Figal, Domingo A; de Boer, Rudolf A

    2015-09-15

    This review summarizes the current literature regarding the involvement and the putative role(s) of galectin-3 in post-myocardial infarction cardiac remodeling. Post-myocardial infarction remodeling is characterized by acute loss of myocardium, which leads to structural and biomechanical changes in order to preserve cardiac function. A hallmark herein is fibrosis formation, both in the early and late phase following acute myocardial infarction. Galectin-3, a β-galactoside-binding lectin, which is a shared factor in fibrosis formation in multiple organs, has an established role in cardiac fibrosis in the setting of pressure overload, neuro-endocrine activation and hypertension, but its role in post- myocardial infarction remodeling has received less attention. However, accumulative experimental studies have shown that myocardial galectin-3 expression is upregulated after myocardial infarction, both on mRNA and protein level. This already occurs shortly after myocardial infarction in the infarcted and border zone area, and also at a later stage in the spared myocardium, contributing to tissue repair and fibrosis. This is associated with typical aspects of fibrosis formation, such as apposition of matricellular proteins and increased factors of collagen turnover. Interestingly, myocardial fibrosis in experimental post-myocardial infarction cardiac remodeling could be attenuated by galectin-3 inhibition. In clinical studies, circulating galectin-3 levels have been shown to identify patients at risk for new-onset heart failure and atrial fibrillation. Circulating galectin-3 levels also predict progressive left ventricular dilatation after myocardial infarction. From literature we conclude that galectin-3 is an active player in cardiac remodeling after myocardial infarction. Future studies should focus on the dynamics of galectin-3 activation after myocardial infarction, and study the possibilities to target galectin-3.

  11. Elastin-insufficient mice show normal cardiovascular remodeling in 2K1C hypertension despite higher baseline pressure and unique cardiovascular architecture.

    PubMed

    Wagenseil, Jessica E; Knutsen, Russell H; Li, Dean Y; Mecham, Robert P

    2007-07-01

    Mice heterozygous for the elastin gene (ELN(+/-)) show unique cardiovascular properties, including increased blood pressure and smaller, thinner arteries with an increased number of lamellar units. Some of these properties are also observed in humans with supravalvular aortic stenosis, a disease caused by functional heterozygosity of the elastin gene. The arterial geometry in ELN(+/-) mice is contrary to the increased thickness that would be expected in an animal demonstrating hypertensive remodeling. To determine whether this is due to a decreased capability for cardiovascular remodeling or to a novel adaptation of the ELN(+/-) cardiovascular system, we increased blood pressure in adult ELN(+/+) and ELN(+/-) mice using the two-kidney, one-clip Goldblatt model of hypertension. Successfully clipped mice have a systolic pressure increase of at least 15 mmHg over sham-operated animals. ELN(+/+) and ELN(+/-)-clipped mice show significant increases over sham-operated mice in cardiac weight, arterial thickness, and arterial cross-sectional area with no changes in lamellar number. There are no significant differences in most mechanical properties with clipping in either genotype. These results indicate that ELN(+/+) and ELN(+/-) hearts and arteries remodel similarly in response to adult induced hypertension. Therefore, the cardiovascular properties of ELN(+/-) mice are likely due to developmental remodeling in response to altered hemodynamics and reduced elastin levels.

  12. 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

  13. 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)

  14. [UTP regulates spontaneous transient outward currents in porcine coronary artery smooth muscle cells through PLC-IP(3) signaling pathway].

    PubMed

    Li, Peng-Yun; Zeng, Xiao-Rong; Yang, Yan; Cai, Fang; Li, Miao-Ling; Liu, Zhi-Fei; Pei, Jie; Zhou, Wen

    2008-02-25

    The aim of the present study was to investigate the effects of inositol 1,4,5-trisphosphate (IP(3))-generating agonist UTP on spontaneous transient outward currents (STOCs), and explore the role of intracellular Ca(2+) release in the current response mediated by IP(3) in porcine coronary artery smooth muscle cells (CASMCs). The coronary artery was excised from the fresh porcine heart and cut into small segments (2 mm × 5 mm) and then transferred to enzymatic dissociation solution for incubation. Single CASMCs were obtained by two-step enzyme digestion at 37 °C. STOCs were recorded and characterized using the perforated whole-cell patch-clamp configuration in freshly isolated porcine CASMCs. The currents were amplified and filtered by patch-clamp amplifier (Axopatch 200B), and then the digitized data were recorded by pClamp 9.0 software and further analyzed by MiniAnalysis 6.0 program. The results were as follows: (1) UTP led to conspicuous increases in STOC amplitude by (57.54±5.34)% and in frequency by (77.46±8.42)% (P<0.01, n=38). (2) The specific blocker of phospholipase C (PLC) - U73122 (5 μmol/L) remarkably reduced STOC amplitude by (31.04±7.46)% and frequency by (41.65±16.59)%, respectively (P<0.05, n=10). In the presence of U73122, UTP failed to reactivate STOCs (n=7). (3) Verapamil (20 μmol/L) and CdCl2 (200 μmol/L), two blockers of L-type voltage-dependent Ca(2+) channels, had little effects on STOCs initiated by UTP (n=8). (4) 1 μmol/L bisindolylmaleimide I (BisI), a potent blocker of protein kinase C (PKC), significantly increased STOC amplitude by (65.44±24.66)% and frequency by (61.35±21.47)% (P<0.01, n=12); UTP (40 μmol/L), applied in the presence of 1 μmol/L BisI, could further increase STOC activity (P<0.05, P<0.01, n=12). Subsequent application of ryanodine (50 μmol/L) abolished STOC activity. (5) In the presence of UTP (40 μmol/L), inhibition of IP(3) receptors (IP(3)Rs) by 2-aminoethoxydiphenyl borate (2-APB, 40 μmol/L) reduced

  15. SWI/SNF-dependent chromatin remodeling of RNR3 requires TAFIIs and the general transcription machinery

    PubMed Central

    Sharma, Vishva Mitra; Li, Bing; Reese, Joseph C.

    2003-01-01

    Gene expression requires the recruitment of chromatin remodeling activities and general transcription factors (GTFs) to promoters. Whereas the role of activators in recruiting chromatin remodeling activities has been clearly demonstrated, the contributions of the transcription machinery have not been firmly established. Here we demonstrate that the remodeling of the RNR3 promoter requires a number of GTFs, mediator and RNA polymerase II. We also show that remodeling is dependent upon the SWI/SNF complex, and that TFIID and RNA polymerase II are required for its recruitment to the promoter. In contrast, Gcn5p-dependent histone acetylation occurs independently of TFIID and RNA polymerase II function, and we provide evidence that acetylation increases the extent of nucleosome remodeling, but is not required for SWI/SNF recruitment. Thus, the general transcription machinery can contribute to nucleosome remodeling by mediating the association of SWI/SNF with promoters, thereby revealing a novel pathway for the recruitment of chromatin remodeling activities. PMID:12600943

  16. 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

  17. Ionic remodeling underlying action potential changes in a canine model of atrial fibrillation.

    PubMed

    Yue, L; Feng, J; Gaspo, R; Li, G R; Wang, Z; Nattel, S

    1997-10-01

    Rapid electrical activation, as occurs during atrial fibrillation (AF), is known to cause reductions in atrial refractoriness and in adaptation to heart rate of the atrial refractory period, which promote the maintenance of AF, but the underlying ionic mechanisms are unknown. In order to determine the cellular and ionic changes caused by chronic atrial tachycardia, we studied right atrial myocytes from dogs subjected to 1, 7, or 42 days of atrial pacing at 400/min and compared them with myocytes from sham-operated dogs (pacemaker inserted but not activated). Rapid pacing led to progressive increases in the duration of AF induced by bursts of 10-Hz stimuli (from 3 +/- 2 seconds in sham-operated dogs to 3060 +/- 707 seconds in dogs after 42 days of pacing, P < .001) and reduced atrial refractoriness and adaptation to rate of the atrial refractory period. Voltage-clamp studies showed that chronic rapid pacing did not alter inward rectifier K+ current, rapid or slow components of the delayed rectifier current, the ultrarapid delayed rectifier current, T-type Ca2+ current, or Ca(2+)-dependent Cl- current. In contrast, the densities of transient outward current (Ito) and L-type Ca2+ current (ICa) were progressively reduced as the duration of rapid pacing increased, without concomitant changes in kinetics or voltage dependence. In keeping with in vivo changes in refractoriness, action potential duration (APD) and APD adaptation to rate were decreased by rapid pacing. The response of the action potential and ionic currents flowing during the action potential (as exposed by action-potential voltage clamp) to nifedipine in normal canine cells and in cells from rapidly paced dogs suggested that the APD changes in paced dogs were largely due to reductions in ICa. We conclude that sustained atrial tachycardia reduces Ito and ICa, that the reduced ICa decreases APD and APD adaptation to rate, and that these cellular changes likely account for the alterations in atrial

  18. 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.

  19. Gene expression in human hippocampus from cocaine abusers identifies genes which regulate extracellular matrix remodeling.

    PubMed

    Mash, Deborah C; ffrench-Mullen, Jarlath; Adi, Nikhil; Qin, Yujing; Buck, Andrew; Pablo, John

    2007-11-14

    The chronic effects of cocaine abuse on brain structure and function are blamed for the inability of most addicts to remain abstinent. Part of the difficulty in preventing relapse is the persisting memory of the intense euphoria or cocaine "rush". Most abused drugs and alcohol induce neuroplastic changes in brain pathways subserving emotion and cognition. Such changes may account for the consolidation and structural reconfiguration of synaptic connections with exposure to cocaine. Adaptive hippocampal plasticity could be related to specific patterns of gene expression with chronic cocaine abuse. Here, we compare gene expression profiles in the human hippocampus from cocaine addicts and age-matched drug-free control subjects. Cocaine abusers had 151 gene transcripts upregulated, while 91 gene transcripts were downregulated. Topping the list of cocaine-regulated transcripts was RECK in the human hippocampus (FC = 2.0; p<0.05). RECK is a membrane-anchored MMP inhibitor that is implicated in the coordinated regulation of extracellular matrix integrity and angiogenesis. In keeping with elevated RECK expression, active MMP9 protein levels were decreased in the hippocampus from cocaine abusers. Pathway analysis identified other genes regulated by cocaine that code for proteins involved in the remodeling of the cytomatrix and synaptic connections and the inhibition of blood vessel proliferation (PCDH8, LAMB1, ITGB6, CTGF and EphB4). The observed microarray phenotype in the human hippocampus identified RECK and other region-specific genes that may promote long-lasting structural changes with repeated cocaine abuse. Extracellular matrix remodeling in the hippocampus may be a persisting effect of chronic abuse that contributes to the compulsive and relapsing nature of cocaine addiction.

  20. Excessive interatrial adiposity is associated with left atrial remodeling, augmented contractile performance in asymptomatic population

    PubMed Central

    Lai, Yau-Huei; Yun, Chun-Ho; Su, Cheng-Huang; Yang, Fei-Shih; Yeh, Hung-I; Hou, Charles Jia-Yin; Wu, Tung-Hsin; Cury, Ricardo C; Bezerra, Hiram G

    2016-01-01

    Abstract Purpose Pericardial adipose tissue had been shown to exert local effects on adjacent cardiac structures. Data regarding the mechanistic link between such measures and left atrial (LA) structural/functional remodeling, a clinical hallmark of early stage heart failure (HF) and atrial fibrillation (AF) incidence, in asymptomatic population remain largely unexplored. Methods This retrospective analysis includes 356 subjects free from significant valvular disorders, atrial fibrillation, or clinical HF. Regional adipose tissue including pericardial and periaortic fat volumes, interatrial septal (IAS), and left atrioventricular groove (AVG) fat thickness were all measured by multidetector computed tomography (MDCT) (Aquarius 3D Workstation, TeraRecon, San Mateo, CA, USA). We measured LA volumes, booster performance, reservoir capacity as well as conduit function, and analyzed their association with adiposity measures. Results All four adiposity measures were positively associated with greater LA volumes (all P < 0.05), while IAS and AVG fat were also related to larger LA kinetic energy and worse reservoir capacity (both P < 0.01). In multivariate models, IAS fat thickness remained independently associated with larger LA volumes, increased LA kinetic energy and ejection force (β-coef: 0.17 & 0.15, both P < 0.05), and impaired LA reservoir and conduit function (β-coef: −0.20 & −0.12, both P < 0.05) after adjusting for clinical variables. Conclusion Accumulated visceral adiposity, especially interatrial fat depots, was associated with certain LA structural/functional remodeling characterized by impaired LA reservoir and conduit function though augmented kinetic energy and ejection performance. Our data suggested that interatrial fat burden may be associated with certain detrimental LA functions with compensatory LA adaptation in an asymptomatic population. PMID:27249809

  1. The mast cell - B-cell axis in lung vascular remodeling and pulmonary hypertension.

    PubMed

    Breitling, Siegfried; Hui, Zhang; Zabini, Diana; Hu, Yijie; Hoffmann, Julia; Goldenberg, Neil M; Tabuchi, Arata; Buelow, Roland; Dos Santos, Claudia; Kuebler, Wolfgang Michael

    2017-02-24

    Over the past years, a critical role for the immune system and in particular, for mast cells, in the pathogenesis of pulmonary hypertension (PH) has emerged. However, the way in which mast cells promote PH is still poorly understood. Here, we investigated the mechanisms by which mast cells may contribute to PH, specifically focusing on the interaction between the innate and adaptive immune response and the role of B-cells and autoimmunity. Experiments were performed in Sprague Dawley rats and B-cell deficient JH-KO rats in the monocrotaline, sugen-hypoxia and the aortic banding model of PH. Hemodynamics, cell infiltration, IL-6 expression, and vascular remodeling were analyzed. Gene array analyses revealed constituents of immunoglobulins as most prominently regulated mast cell dependent genes in the lung in experimental PH. IL-6 was shown to link mast cells to B-cells, as a) IL-6 was upregulated and colocalized with mast cells and was reduced by mast cell stabilizers, and b) IL-6 or mast cell blockade reduced B-cells in lungs of monocrotaline-treated rats. A functional role for B-cells in PH was demonstrated, in that either blocking B-cells by an anti-CD20 antibody or B-cell deficiency in JH-KO rats attenuated right ventricular systolic pressure and vascular remodeling in experimental PH. We here identify a mast cell - B-cell axis driven by IL-6 as critical immune pathway in the pathophysiology of PH. Our results provide novel insights into the role of the immune system in PH, which may be therapeutically exploited by targeted immunotherapy.

  2. JMV5656, A Novel Derivative of TLQP-21, Triggers the Activation of a Calcium-Dependent Potassium Outward Current in Microglial Cells.

    PubMed

    Rivolta, Ilaria; Binda, Anna; Molteni, Laura; Rizzi, Laura; Bresciani, Elena; Possenti, Roberta; Fehrentz, Jean-Alain; Verdié, Pascal; Martinez, Jean; Omeljaniuk, Robert J; Locatelli, Vittorio; Torsello, Antonio

    2017-01-01

    TLQP-21 (TLQPPASSRRRHFHHALPPAR) is a multifunctional peptide that is involved in the control of physiological functions, including feeding, reproduction, stress responsiveness, and general homeostasis. Despite the huge interest in TLQP-21 biological activity, very little is known about its intracellular mechanisms of action. In microglial cells, TLQP-21 stimulates increases of intracellular Ca(2+) that may activate functions, including proliferation, migration, phagocytosis and production of inflammatory molecules. Our aim was to investigate whether JMV5656 (RRRHFHHALPPAR), a novel short analogue of TLQP-21, stimulates intracellular Ca(2+) in the N9 microglia cells, and whether this Ca(2+) elevation is coupled with the activation Ca(2+)-sensitive K(+) channels. TLQP-21 and JMV5656 induced a sharp, dose-dependent increment in intracellular calcium. In 77% of cells, JMV5656 also caused an increase in the total outward currents, which was blunted by TEA (tetraethyl ammonium chloride), a non-selective blocker of voltage-dependent and Ca(2+)-activated potassium (K(+)) channels. Moreover, the effects of ion channel blockers charybdotoxin and iberiotoxin, suggested that multiple calcium-activated K(+) channel types drove the outward current stimulated by JMV5656. Additionally, inhibition of JMV5656-stimulated outward currents by NS6180 (4-[[3-(trifluoromethyl)phenyl]methyl]-2H-1,4 benzothiazin-3(4H)-one) and TRAM-34 (triarylmethane-34), indicated that KCa3.1 channels are involved in this JMV5656 mechanisms of action. In summary, we demonstrate that, in N9 microglia cells, the interaction of JMV5656 with the TLQP-21 receptors induced an increase in intracellular Ca(2+), and, following extracellular Ca(2+) entry, the opening of KCa3.1 channels.

  3. JMV5656, A Novel Derivative of TLQP-21, Triggers the Activation of a Calcium-Dependent Potassium Outward Current in Microglial Cells

    PubMed Central

    Rivolta, Ilaria; Binda, Anna; Molteni, Laura; Rizzi, Laura; Bresciani, Elena; Possenti, Roberta; Fehrentz, Jean-Alain; Verdié, Pascal; Martinez, Jean; Omeljaniuk, Robert J.; Locatelli, Vittorio; Torsello, Antonio

    2017-01-01

    TLQP-21 (TLQPPASSRRRHFHHALPPAR) is a multifunctional peptide that is involved in the control of physiological functions, including feeding, reproduction, stress responsiveness, and general homeostasis. Despite the huge interest in TLQP-21 biological activity, very little is known about its intracellular mechanisms of action. In microglial cells, TLQP-21 stimulates increases of intracellular Ca2+ that may activate functions, including proliferation, migration, phagocytosis and production of inflammatory molecules. Our aim was to investigate whether JMV5656 (RRRHFHHALPPAR), a novel short analogue of TLQP-21, stimulates intracellular Ca2+ in the N9 microglia cells, and whether this Ca2+ elevation is coupled with the activation Ca2+-sensitive K+ channels. TLQP-21 and JMV5656 induced a sharp, dose-dependent increment in intracellular calcium. In 77% of cells, JMV5656 also caused an increase in the total outward currents, which was blunted by TEA (tetraethyl ammonium chloride), a non-selective blocker of voltage-dependent and Ca2+-activated potassium (K+) channels. Moreover, the effects of ion channel blockers charybdotoxin and iberiotoxin, suggested that multiple calcium-activated K+ channel types drove the outward current stimulated by JMV5656. Additionally, inhibition of JMV5656-stimulated outward currents by NS6180 (4-[[3-(trifluoromethyl)phenyl]methyl]-2H-1,4 benzothiazin-3(4H)-one) and TRAM-34 (triarylmethane-34), indicated that KCa3.1 channels are involved in this JMV5656 mechanisms of action. In summary, we demonstrate that, in N9 microglia cells, the interaction of JMV5656 with the TLQP-21 receptors induced an increase in intracellular Ca2+, and, following extracellular Ca2+ entry, the opening of KCa3.1 channels. PMID:28280458

  4. Recombination-mediated remodelling of host–pathogen interactions during Staphylococcus aureus niche adaptation

    PubMed Central

    Spoor, Laura E.; Richardson, Emily; Richards, Amy C.; Wilson, Gillian J.; Mendonca, Chriselle; Gupta, Ravi Kr.; McAdam, Paul R.; Nutbeam-Tuffs, Stephen; Black, Nikki S.; O'Gara, James P.; Lee, Chia Y.; Corander, Jukka

    2015-01-01

    Large-scale recombination events have led to the emergence of epidemic clones of several major bacterial pathogens. However, the functional impact of the recombination on clonal success is not understood. Here, we identified a novel widespread hybrid clone (ST71) of livestock-associated Staphylococcus aureus that evolved from an ancestor belonging to the major bovine lineage CC97, through multiple large-scale recombination events with other S. aureus lineages occupying the same ruminant niche. The recombination events, affecting a 329 kb region of the chromosome spanning the origin of replication, resulted in allele replacement and loss or gain of an array of genes influencing host–pathogen interactions. Of note, molecular functional analyses revealed that the ST71 hybrid clone has acquired multiple novel pathogenic traits associated with acquired and innate immune evasion and bovine extracellular matrix adherence. These findings provide a paradigm for the impact of large-scale recombination events on the rapid evolution of bacterial pathogens within defined ecological niches. PMID:28348819

  5. Phosphoproteome Analysis Links Protein Phosphorylation to Cellular Remodeling and Metabolic Adaptation during Magnaporthe oryzae Appressorium Development.

    PubMed

    Franck, William L; Gokce, Emine; Randall, Shan M; Oh, Yeonyee; Eyre, Alex; Muddiman, David C; Dean, Ralph A

    2015-06-05

    The rice pathogen, Magnaporthe oryzae, undergoes a complex developmental process leading to formation of an appressorium prior to plant infection. In an effort to better understand phosphoregulation during appressorium development, a mass spectrometry based phosphoproteomics study was undertaken. A total of 2924 class I phosphosites were identified from 1514 phosphoproteins from mycelia, conidia, germlings, and appressoria of the wild type and a protein kinase A (PKA) mutant. Phosphoregulation during appressorium development was observed for 448 phosphosites on 320 phosphoproteins. In addition, a set of candidate PKA targets was identified encompassing 253 phosphosites on 227 phosphoproteins. Network analysis incorporating regulation from transcriptomic, proteomic, and phosphoproteomic data revealed new insights into the regulation of the metabolism of conidial storage reserves and phospholipids, autophagy, actin dynamics, and cell wall metabolism during appressorium formation. In particular, protein phosphorylation appears to play a central role in the regulation of autophagic recycling and actin dynamics during appressorium formation. Changes in phosphorylation were observed in multiple components of the cell wall integrity pathway providing evidence that this pathway is highly active during appressorium development. Several transcription factors were phosphoregulated during appressorium formation including the bHLH domain transcription factor MGG_05709. Functional analysis of MGG_05709 provided further evidence for the role of protein phosphorylation in regulation of glycerol metabolism and the metabolic reprogramming characteristic of appressorium formation. The data presented here represent a comprehensive investigation of the M. oryzae phosphoproteome and provide key insights on the role of protein phosphorylation during infection-related development.

  6. 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

  7. 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

  8. The role of adaptive bone formation in the etiology of stress fracture.

    PubMed

    Hughes, Julie M; Popp, Kristin L; Yanovich, Ran; Bouxsein, Mary L; Matheny, Ronald W

    2016-08-05

    Stress fractures are common injuries with load-bearing activities. Stress fractures have been reported in the scientific literature for over a century; however, the etiology continues to be investigated with important distinctions made between the contributions of the tissue-level processes of bone remodeling and modeling. In response to novel repetitive loading, increased bone remodeling may serve to replace fatigue-damaged bone while at the same time creating temporary porosity. Much attention has been given to the role of remodeling in the etiology of stress fracture; however, the role of bone modeling has received less attention. Modest increases in modeling, via bone formation on the periosteal surface of long bones in response to mechanical loading, greatly increases the fatigue resistance of bone. Thus, enhancing this adaptive bone formation is a promising target for stress fracture prevention, and a focus on adaptive bone formation may reveal novel risk factors for stress fracture.

  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. Ventricular remodeling in heart failure: the role of myocardial collagen.

    PubMed

    Janicki, J S; Brower, G L; Henegar, J R; Wang, L

    1995-01-01

    Collagen which is present in the myocardium in relatively small amounts is the most abundant structural protein of the connective tissue network. Its structural organization consists of a complex weave of collagen fibers that surrounds and interconnects myocytes, groups of myocytes, muscle fibers and muscle bundles. The conformation of interstitial fibrillar collagen makes it highly resistant to degradation by all proteinases other than specific collagenases. In hearts with myocardial damage secondary to myocardial infarction, chronic ischemia, inflammation, or cardiomyopathy, a complex sequence of compensatory events occur that eventually result in an adverse left ventricular remodeling. This continual state of remodeling is characterized by persistent collagenase activity, fibrillar collagen degradation, and progressive myocyte loss. The net effect is a shift in the balance between collagen synthesis and degradation which leads to an inadequate fibrillar collagen matrix, progressive ventricular dilatation and sphericalization with wall thinning and eventual congestive heart failure.

  11. 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

  12. 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.

  13. Rapid formation and remodeling of postsynaptic densities in developing dendrites.

    PubMed

    Marrs, G S; Green, S H; Dailey, M E

    2001-10-01

    The dynamics of postsynaptic density (PSD) formation and remodeling were investigated in live developing hippocampal tissue slices. Time lapse imaging of transfected neurons expressing GFP-tagged PSD95, a prominent PSD protein, revealed that up to 40% of PSDs in developing dendrites are structurally dynamic; they rapidly (<15 min) appear or disappear, but also grow, shrink and move within shafts and spines. New spines containing PSDs were formed by conversion of dynamic filopodia-like spine precursors in which PSDs appeared de novo, or by direct extension of spines or spine precursors carrying preformed PSDs from the shaft. PSDs are therefore highly dynamic structures that can undergo rapid structural alteration within dendrite shafts, spines and spine precursors, permitting rapid formation and remodeling of synaptic connections in developing CNS tissues.

  14. Transcriptional regulation of bone and joint remodeling by NFAT

    PubMed Central

    Sitara, Despina; Aliprantis, Antonios O.

    2010-01-01

    Summary Osteoporosis and arthritis are highly prevalent diseases and a significant cause of morbidity and mortality worldwide. These diseases result from aberrant tissue remodeling leading to weak, fracture-prone bones or painful, dysfunctional joints. The nuclear factor of activated T cells (NFAT) transcription factor family controls diverse biologic processes in vertebrates. Here, we review the scientific evidence that links NFAT-regulated gene transcription to bone and joint pathology. A particular emphasis is placed on the role of NFATs in bone resorption and formation by osteoclasts and osteoblasts, respectively. In addition, emerging data that connect NFATs with cartilage biology, angiogenesis, nociception, and neurogenic inflammation are explored. The goal of this article is to highlight the importance of tissue remodeling in musculoskeletal disease and situate NFAT-driven cellular responses within this context to inspire future research endeavors. PMID:20193006

  15. ATP dependent chromatin remodeling enzymes in embryonic stem cells.

    PubMed

    Saladi, Srinivas Vinod; de la Serna, Ivana L

    2010-03-01

    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.

  16. Rapid remodeling of airway vascular architecture at birth.

    PubMed

    Ni, Amy; Lashnits, Erin; Yao, Li-Chin; Baluk, Peter; McDonald, Donald M

    2010-09-01

    Recent advances have documented the development of lung vasculature before and after birth, but less is known of the growth and maturation of airway vasculature. We sought to determine whether airway vasculature changes during the perinatal period and when the typical adult pattern develops. On embryonic day 16.5 mouse tracheas had a primitive vascular plexus unlike the adult airway vasculature, but instead resembling the yolk sac vasculature. Soon after birth (P0), the primitive vascular plexus underwent abrupt and extensive remodeling. Blood vessels overlying tracheal cartilage rings regressed from P1 to P3 but regrew from P4 to P7 to form the hierarchical, segmented, ladder-like adult pattern. Hypoxia and HIF-1α were present in tracheal epithelium over vessels that survived but not where they regressed. These findings reveal the plasticity of airway vasculature after birth and show that these vessels can be used to elucidate factors that promote postnatal vascular remodeling and maturation.

  17. Fat body remodeling and homeostasis control in Drosophila.

    PubMed

    Zheng, Huimei; Yang, Xiaohang; Xi, Yongmei

    2016-12-15

    Remarkable advances have been made in recent years in our understanding of the Drosophila fat body and its functions in energy storage, immune response and nutrient sensing. The fat body interplays with other tissues to respond to the physiological needs of the body's growth and coordinates various metabolic processes at different developmental stages and under different environmental conditions. The identification of various conserved genetic functions and signaling pathways relating to the Drosophila fat body may provide clues to lipometabolic disease and other aspects of tissue remodeling in humans. Here, we discuss recent insights into how regulation of fat body remodeling contributes to hemostasis with a special focus on how signaling networks and internal physiological states shape different aspects of the lipid metabolism in Drosophila.

  18. 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

  19. Structural remodeling of astrocytes in the injured CNS.

    PubMed

    Sun, Daniel; Jakobs, Tatjana C

    2012-12-01

    Astrocytes respond to all forms of CNS insult and disease by becoming reactive, a nonspecific but highly characteristic response that involves various morphological and molecular changes. Probably the most recognized aspect of reactive astrocytes is the formation of a glial scar that impedes axon regeneration. Although the reactive phenotype was first suggested more than 100 years ago based on morphological changes, the remodeling process is not well understood. We know little about the actual structure of a reactive astrocyte, how an astrocyte remodels during the progression of an insult, and how populations of these cells reorganize to form the glial scar. New methods of labeling astrocytes, along with transgenic mice, allow the complete morphology of reactive astrocytes to be visualized. Recent studies show that reactivity can induce a remarkable change in the shape of a single astrocyte, that not all astrocytes react in the same way, and that there is plasticity in the reactive response.

  20. 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

  1. Engineered Split-TET2 Enzyme for Inducible Epigenetic Remodeling

    PubMed Central

    2017-01-01

    The Ten-eleven translocation (TET) family of 5-methylcytosine (5mC) dioxygenases catalyze the conversion of 5mC into 5-hydroxymethylcytosine (5hmC) and further oxidized species to promote active DNA demethylation. Here we engineered a split-TET2 enzyme to enable temporal control of 5mC oxidation and subsequent remodeling of epigenetic states in mammalian cells. We further demonstrate the use of this chemically inducible system to dissect the correlation between DNA hydroxymethylation and chromatin accessibility in the mammalian genome. This chemical-inducible epigenome remodeling tool will find broad use in interrogating cellular systems without altering the genetic code, as well as in probing the epigenotype–phenotype relations in various biological systems. PMID:28294608

  2. Notch signal integration in the vasculature during remodeling

    PubMed Central

    Rostama, Bahman; Peterson, Sarah M.; Vary, Calvin P. H.; Liaw, Lucy

    2014-01-01

    Notch signaling plays many important roles in homeostasis and remodeling in the vessel wall, and serves a critical role in the communication between endothelial cells and smooth muscle cells. Within blood vessels, Notch signaling integrates with multiple pathways by mechanisms including direct protein-protein interaction, cooperative or synergistic regulation of signal cascades, and co-regulation of transcriptional targets. After establishment of the mature blood vessel, the spectrum and intensity of Notch signaling changes during phases of active remodeling or disease progression. These changes can be mediated by regulation via microRNAs and protein stability or signaling, and corresponding changes in complementary signaling pathways. Notch also affects endothelial cells on a systems level by regulating key metabolic components. This review will outline the most recent findings of Notch activity in blood vessels, with a focus on how Notch signals integrate with other molecular signaling pathways controlling vascular phenotype. PMID:25464152

  3. Compensatory Effect between Aortic Stiffening and Remodelling during Ageing

    PubMed Central

    Guala, Andrea; Camporeale, Carlo; Ridolfi, Luca

    2015-01-01

    The arterial tree exhibits a complex spatio-temporal wave pattern, whose healthy behaviour depends on a subtle balance between mechanical and geometrical properties. Several clinical studies demonstrated that such a balance progressively breaks down during ageing, when the aorta stiffens and remodels by increasing its diameter. These two degenerative processes however, have different impacts on the arterial wave pattern. They both tend to compensate for each other, thus reducing the detrimental effect they would have had if they had arisen individually. This remarkable compensatory mechanism is investigated by a validated multi-scale model, with the aim to elucidate how aortic stiffening and remodelling quantitatively impact the complex interplay between forward and reflected backward waves in the arterial network. We focus on the aorta and on the pressure at the ventricular-aortic interface, which epidemiological studies demonstrate to play a key role in cardiovascular diseases. PMID:26426360

  4. 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

  5. Emphysema and mechanical stress-induced lung remodeling.

    PubMed

    Suki, Béla; Sato, Susumu; Parameswaran, Harikrishnan; Szabari, Margit V; Takahashi, Ayuko; Bartolák-Suki, Erzsébet

    2013-11-01

    Transpulmonary pressure and the mechanical stresses of breathing modulate many essential cell functions in the lung via mechanotransduction. We review how mechanical factors could influence the pathogenesis of emphysema. Although the progression of emphysema has been linked to mechanical rupture, little is known about how these stresses alter lung remodeling. We present possible new directions and an integrated multiscale view that may prove useful in finding solutions for this disease.

  6. Maximizing practice management in the newly remodeled practice.

    PubMed

    Moore, Virginia; Castagna, Debbie

    2010-07-01

    Embarking on the building of a new facility, or remodeling an existing space, can be an exciting time. In the midst of planning and decision-making, do not overlook two groups of people who represent driving forces behind the overall success of this investment--patients and staff. In rejuvenating a facility, it is important to remember that at every level, patients' needs must be taken into consideration, including a fundamental review--and potential "overhaul"--of internal systems.

  7. Monitoring in vivo (re)modeling: a computational approach using 4D microCT data to quantify bone surface movements.

    PubMed

    Birkhold, Annette I; Razi, Hajar; Weinkamer, Richard; Duda, Georg N; Checa, Sara; Willie, Bettina M

    2015-06-01

    Bone undergoes continual damage repair and structural adaptation to changing external loads with the aim of maintaining skeletal integrity throughout life. The ability to monitor bone (re)modeling would allow for a better understanding in how various pathologies and interventions affect bone turnover and subsequent bone strength. To date, however, current methods to monitor bone (re)modeling over time and in space are limited. We propose a novel method to visualize and quantify bone turnover, based on in vivo microCT imaging and a 4D computational approach. By in vivo tracking of spatially correlated formation and resorption sites over time it classifies bone restructuring into (re)modeling sequences, the spatially and temporally linked sequences of formation, resorption and quiescent periods on the bone surface. The microCT based method was validated using experimental data from an in vivo mouse tibial loading model and ex vivo data of the mouse tibia. In this application, the method allows the visualization of time-resolved cortical (re)modeling and the quantification of short-term and long-term modeling on the endocortical and periosteal surface at the mid-diaphysis of loaded and control mice tibiae. Both short-term and long-term modeling processes, independent formation and resorption events, could be monitored and modeling (spatially not correlated formation and resorption) and remodeling (resorption followed by new formation at the same site) could be distinguished on the bone surface. This novel method that combines in vivo microCT with a computational approach is a powerful tool to monitor bone turnover in animal models now and is waiting to be applied to human patients in the near future.

  8. 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.

  9. [Physiopathology of left ventricular remodeling after myocardial infarction].

    PubMed

    Bassand, J P; Anguenot, T

    1991-12-01

    The geometry of both the infarcted and non-infarcted zone of the left ventricle changes after myocardial infarction. Two mechanisms are involved: expansion of the infarcted zone and secondary dilatation of the non-infarcted zone. The necrosed area undergoes an inflammatory reaction followed by fibrosis which end up as a sca within a period of a few days to a few weeks. During this period if fibrous scarring the infarcted, thinned myocardium undergoes progressive expansion which starts in the first hours of the myocardial infarction. The loss of left ventricular systolic function related to the infarct and volumic overload created by expansion of the infarct influence the secondary development of dilatation of the non-infarcted zones. This dilatation results in restoration of left ventricular stroke volume but at the price of increased wall stress, which itself induces compensatory wall hypertrophy. These phenomena are more pronounced when the initial infarction is extensive and if they are sustained, they result in definitive myocardial failure. Several factors influence remodeling: the size of the infarct, arterial patency, wall stress and the quality of the scarring process itself. Therapeutic interventions of each of these factors can influence the remodeling. Limitation of infarct size by thrombolytic therapy, arterial revascularisation, even when performed late, seem capable of limiting expansion of the necrosed zone. Pharmacodynamic intervention of left ventricular afterload also affects ventricular remodeling. Nitrate derivatives, vasodilator therapy in general and converting enzyme inhibitors have been shown to be effective.

  10. Chromatin remodeling and bivalent histone modifications in embryonic stem cells.

    PubMed

    Harikumar, Arigela; Meshorer, Eran

    2015-12-01

    Pluripotent embryonic stem cells (ESCs) are characterized by distinct epigenetic features including a relative enrichment of histone modifications related to active chromatin. Among these is tri-methylation of lysine 4 on histone H3 (H3K4me3). Several thousands of the H3K4me3-enriched promoters in pluripotent cells also contain a repressive histone mark, namely H3K27me3, a situation referred to as "bivalency". While bivalent promoters are not unique to pluripotent cells, they are relatively enriched in these cell types, largely marking developmental and lineage-specific genes which are silent but poised for immediate action. The H3K4me3 and H3K27me3 modifications are catalyzed by lysine methyltransferases which are usually found within, although not entirely limited to, the Trithorax group (TrxG) and Polycomb group (PcG) protein complexes, respectively, but these do not provide selective bivalent specificity. Recent studies highlight the family of ATP-dependent chromatin remodeling proteins as regulators of bivalent domains. Here, we discuss bivalency in general, describe the machineries that catalyze bivalent chromatin domains, and portray the emerging connection between bivalency and the action of different families of chromatin remodelers, namely INO80, esBAF, and NuRD, in pluripotent cells. We posit that chromatin remodeling proteins may enable "bivalent specificity", often selectively acting on, or selectively depleted from, bivalent domains.

  11. Remodeling of the postsynaptic plasma membrane during neural development

    PubMed Central

    Tulodziecka, Karolina; Diaz-Rohrer, Barbara B.; Farley, Madeline M.; Chan, Robin B.; Di Paolo, Gilbert; Levental, Kandice R.; Waxham, M. Neal; Levental, Ilya

    2016-01-01

    Neuronal synapses are the fundamental units of neural signal transduction and must maintain exquisite signal fidelity while also accommodating the plasticity that underlies learning and development. To achieve these goals, the molecular composition and spatial organization of synaptic terminals must be tightly regulated; however, little is known about the regulation of lipid composition and organization in synaptic membranes. Here we quantify the comprehensive lipidome of rat synaptic membranes during postnatal development and observe dramatic developmental lipidomic remodeling during the first 60 postnatal days, including progressive accumulation of cholesterol, plasmalogens, and sphingolipids. Further analysis of membranes associated with isolated postsynaptic densities (PSDs) suggests the PSD-associated postsynaptic plasma membrane (PSD-PM) as one specific location of synaptic remodeling. We analyze the biophysical consequences of developmental remodeling in reconstituted synaptic membranes and observe remarkably stable microdomains, with the stability of domains increasing with developmental age. We rationalize the developmental accumulation of microdomain-forming lipids in synapses by proposing a mechanism by which palmitoylation of the immobilized scaffold protein PSD-95 nucleates domains at the postsynaptic plasma membrane. These results reveal developmental changes in lipid composition and palmitoylation that facilitate the formation of postsynaptic membrane microdomains, which may serve key roles in the function of the neuronal synapse. PMID:27535429

  12. Quantitative computed tomography imaging of airway remodeling in severe asthma

    PubMed Central

    Fetita, Catalin I.; Brillet, Pierre-Yves

    2016-01-01

    Asthma is a heterogeneous condition and approximately 5–10% of asthmatic subjects have severe disease associated with structure changes of the airways (airway remodeling) that may develop over time or shortly after onset of disease. Quantitative computed tomography (QCT) imaging of the tracheobronchial tree and lung parenchyma has improved during the last 10 years, and has enabled investigators to study the large airway architecture in detail and assess indirectly the small airway structure. In severe asthmatics, morphologic changes in large airways, quantitatively assessed using 2D-3D airway registration and recent algorithms, are characterized by airway wall thickening, luminal narrowing and bronchial stenoses. Extent of expiratory gas trapping, quantitatively assessed using lung densitometry, may be used to assess indirectly small airway remodeling. Investigators have used these quantitative imaging techniques in order to attempt severity grading of asthma, and to identify clusters of asthmatic patients that differ in morphologic and functional characteristics. Although standardization of image analysis procedures needs to be improved, the identification of remodeling pattern in various phenotypes of severe asthma and the ability to relate airway structures to important clinical outcomes should help target treatment more effectively. PMID:26981458

  13. 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

  14. Quantitative computed tomography imaging of airway remodeling in severe asthma.

    PubMed

    Grenier, Philippe A; Fetita, Catalin I; Brillet, Pierre-Yves

    2016-02-01

    Asthma is a heterogeneous condition and approximately 5-10% of asthmatic subjects have severe disease associated with structure changes of the airways (airway remodeling) that may develop over time or shortly after onset of disease. Quantitative computed tomography (QCT) imaging of the tracheobronchial tree and lung parenchyma has improved during the last 10 years, and has enabled investigators to study the large airway architecture in detail and assess indirectly the small airway structure. In severe asthmatics, morphologic changes in large airways, quantitatively assessed using 2D-3D airway registration and recent algorithms, are characterized by airway wall thickening, luminal narrowing and bronchial stenoses. Extent of expiratory gas trapping, quantitatively assessed using lung densitometry, may be used to assess indirectly small airway remodeling. Investigators have used these quantitative imaging techniques in order to attempt severity grading of asthma, and to identify clusters of asthmatic patients that differ in morphologic and functional characteristics. Although standardization of image analysis procedures needs to be improved, the identification of remodeling pattern in various phenotypes of severe asthma and the ability to relate airway structures to important clinical outcomes should help target treatment more effectively.

  15. 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.

  16. Purine receptor mediated actin cytoskeleton remodeling of human fibroblasts

    PubMed Central

    Goldman, Nanna; Chandler-Militello, Devin; Langevin, Helene; Nedergaard, Maiken; Takano, Takahiro

    2013-01-01

    Earlier studies have shown that activation of adenosine A1 receptors on peripheral pain fibers contributes to acupuncture-induced suppression of painful input. In addition to adenosine, acupuncture triggers the release of other purines, including ATP and ADP that may bind to purine receptors on nearby fibroblasts. We here show that purine agonists trigger increase in cytosolic Ca 2+ signaling in a cultured human fibroblasts cell line. The profile of agonist-induced Ca2+ increases indicates that the cells express functional P2yR2 and P2yR4 receptors, as well as P2yR1 and P2xR7 receptors. Unexpectedly, purine-induced Ca2+ signaling was associated with a remodeling of the actin cytoskeleton. ATP induced a transient loss in F-actin stress fiber. The changes of actin cytoskeleton occurred slowly and peaked at 10 min after agonist exposure. Inhibition of ATP-induced increases in Ca2+ by cyclopiazonic acid blocked receptor-mediated cytoskeleton remodeling. The Ca2+ ionophore failed to induce cytoskeletal remodeling despite triggering robust increases in cytosolic Ca2+. These observations indicate that purine signaling induces transient changes in fibroblast cytoarchitecture that could be related to the beneficial effects of acupuncture. PMID:23462235

  17. 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.

  18. 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

  19. 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.

  20. 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

  1. Localized tissue mineralization regulated by bone remodelling: A computational approach

    PubMed Central

    Decco, Oscar; Adams, George; Cook, Richard B.; García Aznar, José Manuel

    2017-01-01

    Bone is a living tissue whose main mechanical function is to provide stiffness, strength and protection to the body. Both stiffness and strength depend on the mineralization of the organic matrix, which is constantly being remodelled by the coordinated action of the bone multicellular units (BMUs). Due to the dynamics of both remodelling and mineralization, each sample of bone is composed of structural units (osteons in cortical and packets in cancellous bone) created at different times, therefore presenting different levels of mineral content. In this work, a computational model is used to understand the feedback between the remodelling and the mineralization processes under different load conditions and bone porosities. This model considers that osteoclasts primarily resorb those parts of bone closer to the surface, which are younger and less mineralized than older inner ones. Under equilibrium loads, results show that bone volumes with both the highest and the lowest levels of porosity (cancellous and cortical respectively) tend to develop higher levels of mineral content compared to volumes with intermediate porosity, thus presenting higher material densities. In good agreement with recent experimental measurements, a boomerang-like pattern emerges when plotting apparent density at the tissue level versus material density at the bone material level. Overload and disuse states are studied too, resulting in a translation of the apparent–material density curve. Numerical results are discussed pointing to potential clinical applications. PMID:28306746

  2. Bone remodeling during prenatal morphogenesis of the human mental foramen.

    PubMed

    Radlanski, Ralf J; Renz, Herbert; Lajvardi, Souzan; Schneider, Richard A

    2004-08-01

    From a morphogenetic point of view, the mental foramen of the mandible is a highly suitable model to study the interactions of different tissues such as nerves, vessels, mesenchymal cells, cartilage, and bone. In previous work, we provided a three-dimensional description of the mental foramen at different developmental stages, and now we complement those studies with a three-dimensional visualization of different bone remodeling activities around the mental foramen. Histological serial sections of human embryos and fetuses, ranging in size from 25 to 117 mm crown-rump-length (CRL), were used to characterize the bone remodeling activity (apposition, inactivity, and resorption). We quantified and reconstructed this activity in three dimensions, and included information on the spatial relationship of the nerves, vessels, and dental primordia. In general, the mandible showed strong apposition at its outer surfaces. The brim of the mental foramen, however, displayed changing remodeling activity at different stages. In the depth of the bony gutter, which provides space for the nerve and the blood vessels, we found bone resorption beneath the inferior alveolar vein. Bone was also resorbed in proximity to the dental primordia. In future studies, we will relate gene expression data to these morphological findings in order to identify molecular mechanisms that regulate this complex system.

  3. 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

  4. Nebivolol Attenuates Maladaptive Proximal Tubule Remodeling in Transgenic Rats

    PubMed Central

    Hayden, Melvin R.; Habibi, Javad; Whaley-Connell, Adam; Sowers, Dilek; Johnson, Megan; Tilmon, Roger; Jain, Deepika; Ferrario, Carlos; Sowers, James R.

    2010-01-01

    Background/Aims The impact of nebivolol therapy on the renal proximal tubular cell (PTC) structure and function was investigated in a transgenic (TG) rodent model of hypertension and the cardiometabolic syndrome. The TG Ren2 rat develops nephropathy with proteinuria, increased renal angiotensin II levels and oxidative stress, and PTC remodeling. Nebivolol, a β1-antagonist, has recently been shown to reduce albuminuria, in part, through reductions in renal oxidative stress. Accordingly, we hypothesized that nebivolol therapy would attenuate PTC damage and tubulointerstitial fibrosis. Methods Young Ren2 (R2-N) and SD (SD-N) rats were treated with nebivolol (10 mg/kg/day) or vehicle (R2-C; SD-C) for 3 weeks. PTC structure and function were tested using transmission electron microscopy and functional measurements. Results Nebivolol treatment decreased urinary N-acetyl-β-D-glucosaminidase, tubulointerstitial ultrastructural remodeling and fibrosis, NADPH oxidase activity, 3-nitrotyrosine levels, and increased megalin and lysosomal-associated membrane protein-2 immunostaining in PTCs. Ultrastructural abnormalities that were improved with therapy included altered canalicular structure, reduced endosomes/lysosomes and PTC vacuoles, basement membrane thickening, and mitochondrial remodeling/fragmentation. Conclusion These observations support the notion that nebivolol may improve PTC reabsorption of albumin and other glomerular filtered small molecular weight proteins in association with the attenuation of oxidative stress, tubulointerstitial injury and fibrosis in this rat model of metabolic kidney disease. PMID:20110666

  5. Inflammatory and bone remodeling responses to the cytolethal distending toxins.

    PubMed

    Belibasakis, Georgios N; Bostanci, Nagihan

    2014-04-04

    The cytolethal distending toxins (CDTs) are a family of exotoxins produced by a wide range of Gram-negative bacteria. They are known for causing genotoxic stress to the cell, resulting in growth arrest and eventually apoptotic cell death. Nevertheless, there is evidence that CDTs can also perturb the innate immune responses, by regulating inflammatory cytokine production and molecular mediators of bone remodeling in various cell types. These cellular and molecular events may in turn have an effect in enhancing local inflammation in diseases where CDT-producing bacteria are involved, such as Aggregatibacter actinomycetemcomitans, Haemophilus ducreyi, Campylobacter jejuni and Helicobacter hepaticus. One special example is the induction of pathological bone destruction in periodontitis. The opportunistic oral pathogen Aggregatibatcer actinoycemetemcomitans, which is involved in the aggressive form of the disease, can regulate the molecular mechanisms of bone remodeling in a manner that favors bone resorption, with the potential involvement of its CDT. The present review provides an overview of all known to-date inflammatory or bone remodeling responses of CDTs produced by various bacterial species, and discusses their potential contribution to the pathogenesis of the associated diseases.

  6. Tension-dependent nucleosome remodeling at the pericentromere in yeast.

    PubMed

    Verdaasdonk, Jolien S; Gardner, Ryan; Stephens, Andrew D; Yeh, Elaine; Bloom, Kerry

    2012-07-01

    Nucleosome positioning is important for the structural integrity of chromosomes. During metaphase the mitotic spindle exerts physical force on pericentromeric chromatin. The cell must adjust the pericentromeric chromatin to accommodate the changing tension resulting from microtubule dynamics to maintain a stable metaphase spindle. Here we examine the effects of spindle-based tension on nucleosome dynamics by measuring the histone turnover of the chromosome arm and the pericentromere during metaphase in the budding yeast Saccharomyces cerevisiae. We find that both histones H2B and H4 exhibit greater turnover in the pericentromere during metaphase. Loss of spindle-based tension by treatment with the microtubule-depolymerizing drug nocodazole or compromising kinetochore function results in reduced histone turnover in the pericentromere. Pericentromeric histone dynamics are influenced by the chromatin-remodeling activities of STH1/NPS1 and ISW2. Sth1p is the ATPase component of the Remodels the Structure of Chromatin (RSC) complex, and Isw2p is an ATP-dependent DNA translocase member of the Imitation Switch (ISWI) subfamily of chromatin-remodeling factors. The balance between displacement and insertion of pericentromeric histones provides a mechanism to accommodate spindle-based tension while maintaining proper chromatin packaging during mitosis.

  7. Bortezomib protects from varicose-like venous remodeling.

    PubMed

    Pfisterer, Larissa; Meyer, Ralph; Feldner, Anja; Drews, Oliver; Hecker, Markus; Korff, Thomas

    2014-08-01

    Despite the high prevalence of venous diseases that are associated with and based on the structural reorganization of the venous vessel wall, not much is known about their mechanistic causes. In this context, we demonstrated that the quantity of myocardin, a transcriptional regulator of the contractile and quiescent smooth muscle cell phenotype, was diminished in proliferating synthetic venous smooth muscle cells (VSMCs) of human and mouse varicose veins by 51 and 60%, respectively. On the basis of the relevance of proteasomal activity for such phenotypic changes, we hypothesized that the observed VSMC activation is attenuated by the proteasome inhibitor bortezomib. This drug fully abolished VSMC proliferation and loss of myocardin in perfused mouse veins and blocked VSMC invasion in collagen gels by almost 80%. In line with this, topical transdermal treatment with bortezomib diminished VSMC proliferation by 80%, rescued 90% of VSMC myocardin abundance, and inhibited varicose-like venous remodeling by 67 to 72% in a mouse model. Collectively, our data indicate that the proteasome plays a pivotal role in VSMC phenotype changes during venous remodeling processes. Its inhibition protects from varicose-like vein remodeling in mice and may thus serve as a putative therapeutic strategy to treat human varicose veins.

  8. Tyrosine kinase FYN negatively regulates NOX4 in cardiac remodeling

    PubMed Central

    Matsushima, Shouji; Kuroda, Junya; Zhai, Peiyong; Liu, Tong; Ikeda, Shohei; Nagarajan, Narayani; Yokota, Takashi; Kinugawa, Shintaro; Hsu, Chiao-Po; Li, Hong; Tsutsui, Hiroyuki

    2016-01-01

    NADPH oxidases (Noxes) produce ROS that regulate cell growth and death. NOX4 expression in cardiomyocytes (CMs) plays an important role in cardiac remodeling and injury, but the posttranslational mechanisms that modulate this enzyme are poorly understood. Here, we determined that FYN, a Src family tyrosine kinase, interacts with the C-terminal domain of NOX4. FYN and NOX4 colocalized in perinuclear mitochondria, ER, and nuclear fractions in CMs, and FYN expression negatively regulated NOX4-induced O2– production and apoptosis in CMs. Mechanistically, we found that direct phosphorylation of tyrosine 566 on NOX4 was critical for this FYN-mediated negative regulation. Transverse aortic constriction activated FYN in the left ventricle (LV), and FYN-deficient mice displayed exacerbated cardiac hypertrophy and dysfunction and increased ROS production and apoptosis. Deletion of Nox4 rescued the exaggerated LV remodeling in FYN-deficient mice. Furthermore, FYN expression was markedly decreased in failing human hearts, corroborating its role as a regulator of cardiac cell death and ROS production. In conclusion, FYN is activated by oxidative stress and serves as a negative feedback regulator of NOX4 in CMs during cardiac remodeling. PMID:27525436

  9. 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.

  10. Lung parenchyma remodeling in acute respiratory distress syndrome.

    PubMed

    Rocco, P R M; Dos Santos, C; Pelosi, P

    2009-12-01

    Acute respiratory distress syndrome (ARDS), the most severe manifestation of acute lung injury (ALI), is described as a stereotyped response to lung injury with a transition from alveolar capillary damage to a fibroproliferative phase. Most ARDS patients survive the acute initial phase of lung injury and progress to either reparation of the lesion or evolution of the syndrome. Despite advances in the management of ARDS, mortality remains high (40%) and autopsies show extended pulmonary fibrosis in 55% of patients, suggesting the importance of deregulated repair in the morbidity and mortality of these patients. Factors influencing progression to fibroproliferative ARDS versus resolution and reconstitution of the normal pulmonary parenchymal architecture are poorly understood. Abnormal repair and remodeling may be profoundly affected by both environmental and genetic factors. In this line, mechanical ventilation may affect the macromolecules that constitute the extracellular matrix (collagen, elastin, fibronectin, laminin, proteoglycan and glycosaminoglycans), suffer changes and impact the biomechanical behavior of lung parenchyma. Furthermore, evidence suggests that acute inflammation and fibrosis may be partially independent and/or interacting processes that are autonomously regulated, and thus amenable to individual and specific therapies. In this review, we explore recent advances in the field of fibroproliferative ARDS/ALI, with special emphasis on 1) the physiological properties of the extracellular matrix, 2) the mechanisms of remodeling, 3) the impact of mechanical ventilation on lung fibrotic response, and (4) therapeutic interventions in the remodeling process.

  11. PDE1C deficiency antagonizes pathological cardiac remodeling and dysfunction

    PubMed Central

    Knight, Walter E.; Chen, Si; Zhang, Yishuai; Oikawa, Masayoshi; Wu, Meiping; Zhou, Qian; Miller, Clint L.; Cai, Yujun; Mickelsen, Deanne M.; Moravec, Christine; Small, Eric M.; Abe, Junichi; Yan, Chen

    2016-01-01

    Cyclic nucleotide phosphodiesterase 1C (PDE1C) represents a major phosphodiesterase activity in human myocardium, but its function in the heart remains unknown. Using genetic and pharmacological approaches, we studied the expression, regulation, function, and underlying mechanisms of PDE1C in the pathogenesis of cardiac remodeling and dysfunction. PDE1C expression is up-regulated in mouse and human failing hearts and is highly expressed in cardiac myocytes but not in fibroblasts. In adult mouse cardiac myocytes, PDE1C deficiency or inhibition attenuated myocyte death and apoptosis, which was largely dependent on cyclic AMP/PKA and PI3K/AKT signaling. PDE1C deficiency also attenuated cardiac myocyte hypertrophy in a PKA-dependent manner. Conditioned medium taken from PDE1C-deficient cardiac myocytes attenuated TGF-β–stimulated cardiac fibroblast activation through a mechanism involving the crosstalk between cardiac myocytes and fibroblasts. In vivo, cardiac remodeling and dysfunction induced by transverse aortic constriction, including myocardial hypertrophy, apoptosis, cardiac fibrosis, and loss of contractile function, were significantly attenuated in PDE1C-knockout mice relative to wild-type mice. These results indicate that PDE1C activation plays a causative role in pathological cardiac remodeling and dysfunction. Given the continued development of highly specific PDE1 inhibitors and the high expression level of PDE1C in the human heart, our findings could have considerable therapeutic significance. PMID:27791092

  12. Localized tissue mineralization regulated by bone remodelling: A computational approach.

    PubMed

    Berli, Marcelo; Borau, Carlos; Decco, Oscar; Adams, George; Cook, Richard B; García Aznar, José Manuel; Zioupos, Peter

    2017-01-01

    Bone is a living tissue whose main mechanical function is to provide stiffness, strength and protection to the body. Both stiffness and strength depend on the mineralization of the organic matrix, which is constantly being remodelled by the coordinated action of the bone multicellular units (BMUs). Due to the dynamics of both remodelling and mineralization, each sample of bone is composed of structural units (osteons in cortical and packets in cancellous bone) created at different times, therefore presenting different levels of mineral content. In this work, a computational model is used to understand the feedback between the remodelling and the mineralization processes under different load conditions and bone porosities. This model considers that osteoclasts primarily resorb those parts of bone closer to the surface, which are younger and less mineralized than older inner ones. Under equilibrium loads, results show that bone volumes with both the highest and the lowest levels of porosity (cancellous and cortical respectively) tend to develop higher levels of mineral content compared to volumes with intermediate porosity, thus presenting higher material densities. In good agreement with recent experimental measurements, a boomerang-like pattern emerges when plotting apparent density at the tissue level versus material density at the bone material level. Overload and disuse states are studied too, resulting in a translation of the apparent-material density curve. Numerical results are discussed pointing to potential clinical applications.

  13. 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

    2016-02-04

    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.

  14. 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.

  15. Periosteal response in translation-induced bone remodelling.

    PubMed Central

    Feik, S A; Ellender, G; Crowe, D M; Ramm-Anderson, S M

    1990-01-01

    Translation of transplanted bones induces strain in the periosteum and subsequent bone remodelling. This study examines the periosteal response on the leading and trailing sides of translated bones using an in vivo model where internal bone strain is virtually eliminated. Caudal vertebrae from 4 days old rats were threaded onto the arms of pre-stressed helical torsion springs and transplanted subcutaneously. In the experimental rats, the appliances were activated seven days later causing the bones to translate. Tissues were examined both optically and by transmission electron microscopy. A connective tissue sheath or capsule forms around the bones and, as the arms of the appliance move apart, traction on the enveloping soft tissues produces compression of the periosteum on the leading side and tension on the trailing side with remodelling occurring in a direction opposite to translation. The control periosteum has an ordered structure with well-delineated osteogenic, mid- and fibrous zones. During translation the periosteum on the leading side is consistently narrower than on the trailing side and shows a gradual reduction in formative activity followed by resorption in select areas. Cells and fibres are aligned predominantly parallel to the bone surface. Accelerated formation characterises the trailing side during the translation phase with increased activity and widening of all three periosteal layers. The fibrous layer merges with the connective tissue sheath which frequently is oriented approximately perpendicular to the bone surface. The direction of remodelling is reversed when translation ceases with corresponding changes visible in the periosteum, the osteoblastic layer being the last to show changes. A normal periosteal structure and remodelling pattern is regained when equilibrium of the bones within the soft tissues is attained. This study shows that the enveloping soft tissues profoundly influence the nature and rate of bone remodelling. The changes are

  16. 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

  17. 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.

  18. ELF magnetic fields tuned to ion parametric resonance conditions do not affect TEA-sensitive voltage-dependent outward K(+) currents in a human neural cell line.

    PubMed

    Gavoçi, Entelë; Zironi, Isabella; Remondini, Daniel; Virelli, Angela; Castellani, Gastone; Del Re, Brunella; Giorgi, Gianfranco; Aicardi, Giorgio; Bersani, Ferdinando

    2013-12-01

    Despite the experimental evidence of significant biological effects of extremely low frequency (ELF) magnetic fields (MFs), the underlying mechanisms are still unclear. Among the few mechanisms proposed, of particular interest is the so called "ion parametric resonance (IPR)" hypothesis, frequently referred to as theoretical support for medical applications. We studied the effect of different combinations of static (DC) and alternating (AC) ELF MFs tuned on resonance conditions for potassium (K(+)) on TEA-sensitive voltage-dependent outward K(+) currents in the human neuroblastoma BE(2)C cell line. Currents through the cell membrane were measured by whole-cell patch clamp before, during, and after exposure to MF. No significant changes in K(+) current density were found. This study does not confirm the IPR hypothesis at the level of TEA-sensitive voltage-dependent outward K(+) currents in our experimental conditions. However, this is not a direct disprove of the hypothesis, which should be investigated on other ion channels and at single channel levels also.

  19. 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

  20. 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.