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Sample records for ab neurovascular remodeling

  1. Outcomes of Stent-assisted Coil Embolization of Wide-necked Intracranial Aneurysms Using the Solitaire™ AB Neurovascular Remodeling Device

    PubMed Central

    Jeong, Hae Woong

    2015-01-01

    Objective This retrospective study presents our experience with respect to the clinical and angiographic outcomes of patients treated with stent-assisted coil embolization using Solitaire™ AB stents. Materials and Methods From March 2011 to December 2014, 50 patients with 55 wide-necked and/or complex intracranial aneurysms were evaluated. Four patients presented with an acute subarachnoid hemorrhage. Stent deployment was performed with a standard coiling procedure in 49 aneurysms. Three patients underwent bailout stenting, 2 patients were treated by temporary stenting and one patient was treated only by stenting without coiling for dissecting aneurysm. Results Successful placement of the Solitaire AB stent was achieved in all the cases. Based on the postprocedural angiographic results, a Raymond 1 was obtained in 32 (59%) of 54 aneurysms, excluded by one case of dissecting aneurysm, and a Raymond 2 in 13 (24%), and a Raymond 3 in 9 (17%). There was one thromboembolic (2%) and three hemorrhagic complications (6%). However, procedure-related morbidity or mortality was not found. Annual follow-up angiographic results from the embolization were obtained in 40 (74.1%) of 54 cases. These results were represented as Raymond 1 in 27 (67.5%), class 2 in 9 (22.5%), and class 3 in 4 (10%) cases. Angiographic improvement associated with progressive thrombosis of the aneurysm was obtained in 10 aneurysms. Four aneurysms were recanalized without requiring additional treatment. In-stent stenosis was found in one aneurysm, but stent migration was not seen on follow-up angiography. Conclusion Stent-assisted coil embolization using the Solitaire AB stent for treating wide-necked and/or complex intracranial aneurysms was found to be safe and effective immediately post-embolization and after follow-up. Long-term follow-up will be required to identify the effect of the Solitaire AB stent on recanalization rates. PMID:27066440

  2. The Role of Pericytes in Neurovascular Unit Remodeling in Brain Disorders

    PubMed Central

    ElAli, Ayman; Thériault, Peter; Rivest, Serge

    2014-01-01

    Neurons are extremely vulnerable cells that tightly rely on the brain’s highly dynamic and complex vascular network that assures an accurate and adequate distribution of nutrients and oxygen. The neurovascular unit (NVU) couples neuronal activity to vascular function, controls brain homeostasis, and maintains an optimal brain microenvironment adequate for neuronal survival by adjusting blood-brain barrier (BBB) parameters based on brain needs. The NVU is a heterogeneous structure constituted by different cell types that includes pericytes. Pericytes are localized at the abluminal side of brain microvessels and contribute to NVU function. Pericytes play essential roles in the development and maturation of the neurovascular system during embryogenesis and stability during adulthood. Initially, pericytes were described as contractile cells involved in controlling neurovascular tone. However, recent reports have shown that pericytes dynamically respond to stress induced by injury upon brain diseases, by chemically and physically communicating with neighboring cells, by their immune properties and by their potential pluripotent nature within the neurovascular niche. As such, in this paper, we would like to review the role of pericytes in NVU remodeling, and their potential as targets for NVU repair strategies and consequently neuroprotection in two pathophysiologically distinct brain disorders: ischemic stroke and Alzheimer’s disease (AD). PMID:24743889

  3. Neurovascular development

    PubMed Central

    James, Jennifer M

    2009-01-01

    Neurovascular development in the central nervous system has a rich history and compelling significance. The developing central nervous system (CNS) does not produce vascular progenitor cells, and so ingression of blood vessels is required for continued CNS development and function. Classic studies provide elegant descriptions of formation of the vascular plexus that surrounds the embryonic brain and spinal cord, and the subsequent ingression of blood vessels into the neural tissue. Recent work has focused on the molecular pathways responsible for neurovascular cross-talk and development of the blood-brain barrier. Here we review neurovascular development in the central nervous system, with emphasis on the spinal cord. We discuss the historical work, the current status of our knowledge and unanswered questions. The importance of neurovascular development to diseases of the cerebral vasculature and the neural stem cell niche are discussed. PMID:19363295

  4. miR-7a/b attenuates post-myocardial infarction remodeling and protects H9c2 cardiomyoblast against hypoxia-induced apoptosis involving Sp1 and PARP-1

    PubMed Central

    Li, Rui; Geng, Hai-hua; Xiao, Jie; Qin, Xiao-teng; Wang, Fu; Xing, Jun-hui; Xia, Yan-fei; Mao, Yang; Liang, Jing-wen; Ji, Xiao-ping

    2016-01-01

    miRs (microRNAs, miRNAs) intricately regulate physiological and pathological processes. Although miR-7a/b protects against cardiomyocyte injury in ischemia/reperfusion injury, the function of miR-7a/b in myocardial infarction (MI)-induced cardiac remodeling remains unclear. Here, we sought to investigate the function of miR-7a/b in post-MI remodeling in a mouse model and to determine the underlying mechanisms involved. miR-7a/b overexpression improved cardiac function, attenuated cardiac remodeling and reduced fibrosis and apoptosis, whereas miR-7a/b silencing caused the opposite effects. Furthermore, miR-7a/b overexpression suppressed specific protein 1 (Sp1) and poly (ADP-ribose) polymerase (PARP-1) expression both in vivo and in vitro, and a luciferase reporter activity assay showed that miR-7a/b could directly bind to Sp1. Mithramycin, an inhibitor of the DNA binding activity of Sp1, effectively repressed PARP-1 and caspase-3, whereas knocking down miR-7a/b partially counteracted these beneficial effects. Additionally, an immunoprecipitation assay indicated that hypoxia triggered activation of the binding activity of Sp1 to the promoters of PARP-1 and caspase-3, which is abrogated by miR-7a/b. In summary, these findings identified miR-7a/b as protectors of cardiac remodeling and hypoxia-induced injury in H9c2 cardiomyoblasts involving Sp1 and PARP-1. PMID:27384152

  5. Protection after stroke: cellular effectors of neurovascular unit integrity

    PubMed Central

    Posada-Duque, Rafael Andres; Barreto, George E.; Cardona-Gomez, Gloria Patricia

    2014-01-01

    Neurological disorders are prevalent worldwide. Cerebrovascular diseases (CVDs), which account for 55% of all neurological diseases, are the leading cause of permanent disability, cognitive and motor disorders and dementia. Stroke affects the function and structure of blood-brain barrier, the loss of cerebral blood flow regulation, oxidative stress, inflammation and the loss of neural connections. Currently, no gold standard treatments are available outside the acute therapeutic window to improve outcome in stroke patients. Some promising candidate targets have been identified for the improvement of long-term recovery after stroke, such as Rho GTPases, cell adhesion proteins, kinases, and phosphatases. Previous studies by our lab indicated that Rho GTPases (Rac and RhoA) are involved in both tissue damage and survival, as these proteins are essential for the morphology and movement of neurons, astrocytes and endothelial cells, thus playing a critical role in the balance between cell survival and death. Treatment with a pharmacological inhibitor of RhoA/ROCK blocks the activation of the neurodegeneration cascade. In addition, Rac and synaptic adhesion proteins (p120 catenin and N-catenin) play critical roles in protection against cerebral infarction and in recovery by supporting the neurovascular unit and cytoskeletal remodeling activity to maintain the integrity of the brain parenchyma. Interestingly, neuroprotective agents, such as atorvastatin, and CDK5 silencing after cerebral ischemia and in a glutamate-induced excitotoxicity model may act on the same cellular effectors to recover neurovascular unit integrity. Therefore, future efforts must focus on individually targeting the structural and functional roles of each effector of neurovascular unit and the interactions in neural and non-neural cells in the post-ischemic brain and address how to promote the recovery or prevent the loss of homeostasis in the short, medium and long term. PMID:25177270

  6. Hydrogen Sulfide Attenuates Neurodegeneration and Neurovascular Dysfunction Induced by Intracerebral Administered Homocysteine in Mice

    PubMed Central

    Kamat, Pradip K.; Kalani, Anuradha; Givvimani, Srikanth; Sathnur, PB; Tyagi, Suresh C.; Tyagi, Neetu

    2014-01-01

    High levels of homocysteine (Hcy), known as hyperhomocysteinemia (HHcy) are associated with neurovascular diseases. H2S, a metabolite of Hcy, has a potent anti-oxidant and anti-inflammatory activity; however, the effect of H2S has not been explored in Hcy (IC) induced neurodegeneration and neurovascular dysfunction in mice. Therefore, the present study was designed to explore the neuroprotective role of H2S on Hcy induced neurodegeneration and neurovascular dysfunction. To test this hypothesis we employed wild type (WT) males ages 8–10 weeks, WT+ artificial cerebrospinal fluid (aCSF), WT+ Hcy (0.5μmol/μl) intracerebral injection (I.C., one time only prior to NaHS treatment), WT+Hcy +NaHS (sodium hydrogen sulfide, precursor of H2S, 30 μmol/kg, body weight). NaHS was injected intra-peritoneally (I.P.) once daily for the period of 7 days after the Hcy (IC) injection. Hcy treatment significantly increased MDA, nitrite level, acetylcholinestrase activity, TNFα, IL1β, GFAP, iNOS, eNOS and decreased glutathione level indicating oxidative-nitrosative stress and neuroinflammation as compared to control and aCSF treated groups. Further, increased expression of NSE, S100B and decreased expression of (PSD95, SAP97) synaptic protein indicated neurodegeneration. Brain sections of Hcy treated mice showed damage in the cortical area and periventricular cells. TUNEL positive cells and Fluro Jade-C staining indicated apoptosis and neurodegeneration. The increased expression of MMP9, MMP2 and decreased expression of TIMP-1, TIMP-2, tight junction proteins (ZO1, Occuldin) in Hcy treated group indicate neurovascular remodeling. Interestingly, NaHS treatment significantly attenuated Hcy induced oxidative stress, memory deficit, neurodegeneration, neuroinflammation and cerebrovascular remodeling. The results indicate that H2S is effective in providing protection against neurodegeneration and neurovascular dysfunction. PMID:23912038

  7. Neurovascular coupling: a parallel implementation

    PubMed Central

    Dormanns, Katharina; Brown, Richard G.; David, Tim

    2015-01-01

    A numerical model of neurovascular coupling (NVC) is presented based on neuronal activity coupled to vasodilation/contraction models via the astrocytic mediated perivascular K+ and the smooth muscle cell (SMC) Ca2+ pathway termed a neurovascular unit (NVU). Luminal agonists acting on P2Y receptors on the endothelial cell (EC) surface provide a flux of inositol trisphosphate (IP3) into the endothelial cytosol. This concentration of IP3 is transported via gap junctions between EC and SMC providing a source of sarcoplasmic derived Ca2+ in the SMC. The model is able to relate a neuronal input signal to the corresponding vessel reaction (contraction or dilation). A tissue slice consisting of blocks, each of which contain an NVU is connected to a space filling H-tree, simulating a perfusing arterial tree (vasculature) The model couples the NVUs to the vascular tree via a stretch mediated Ca2+ channel on both the EC and SMC. The SMC is induced to oscillate by increasing an agonist flux in the EC and hence increased IP3 induced Ca2+ from the SMC stores with the resulting calcium-induced calcium release (CICR) oscillation inhibiting NVC thereby relating blood flow to vessel contraction and dilation following neuronal activation. The coupling between the vasculature and the set of NVUs is relatively weak for the case with agonist induced where only the Ca2+ in cells inside the activated area becomes oscillatory however, the radii of vessels both inside and outside the activated area oscillate (albeit small for those outside). In addition the oscillation profile differs between coupled and decoupled states with the time required to refill the cytosol with decreasing Ca2+ and increasing frequency with coupling. The solution algorithm is shown to have excellent weak and strong scaling. Results have been generated for tissue slices containing up to 4096 blocks. PMID:26441619

  8. Neurovascular coupling: a parallel implementation.

    PubMed

    Dormanns, Katharina; Brown, Richard G; David, Tim

    2015-01-01

    A numerical model of neurovascular coupling (NVC) is presented based on neuronal activity coupled to vasodilation/contraction models via the astrocytic mediated perivascular K(+) and the smooth muscle cell (SMC) Ca(2+) pathway termed a neurovascular unit (NVU). Luminal agonists acting on P2Y receptors on the endothelial cell (EC) surface provide a flux of inositol trisphosphate (IP3) into the endothelial cytosol. This concentration of IP3 is transported via gap junctions between EC and SMC providing a source of sarcoplasmic derived Ca(2+) in the SMC. The model is able to relate a neuronal input signal to the corresponding vessel reaction (contraction or dilation). A tissue slice consisting of blocks, each of which contain an NVU is connected to a space filling H-tree, simulating a perfusing arterial tree (vasculature) The model couples the NVUs to the vascular tree via a stretch mediated Ca(2+) channel on both the EC and SMC. The SMC is induced to oscillate by increasing an agonist flux in the EC and hence increased IP3 induced Ca(2+) from the SMC stores with the resulting calcium-induced calcium release (CICR) oscillation inhibiting NVC thereby relating blood flow to vessel contraction and dilation following neuronal activation. The coupling between the vasculature and the set of NVUs is relatively weak for the case with agonist induced where only the Ca(2+) in cells inside the activated area becomes oscillatory however, the radii of vessels both inside and outside the activated area oscillate (albeit small for those outside). In addition the oscillation profile differs between coupled and decoupled states with the time required to refill the cytosol with decreasing Ca(2+) and increasing frequency with coupling. The solution algorithm is shown to have excellent weak and strong scaling. Results have been generated for tissue slices containing up to 4096 blocks. PMID:26441619

  9. Neurovascular Unit in Chronic Pain

    PubMed Central

    Radu, Beatrice Mihaela; Bramanti, Placido; Osculati, Francesco; Flonta, Maria-Luisa; Radu, Mihai; Bertini, Giuseppe; Fabene, Paolo Francesco

    2013-01-01

    Chronic pain is a debilitating condition with major socioeconomic impact, whose neurobiological basis is still not clear. An involvement of the neurovascular unit (NVU) has been recently proposed. In particular, the blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB), two NVU key players, may be affected during the development of chronic pain; in particular, transient permeabilization of the barrier is suggested by several inflammatory- and nerve-injury-based pain models, and we argue that the clarification of molecular BBB/BSCB permeabilization events will shed new light in understanding chronic pain mechanisms. Possible biases in experiments supporting this theory and its translational potentials are discussed. Moving beyond an exclusive focus on the role of the endothelium, we propose that our understanding of the mechanisms subserving chronic pain will benefit from the extension of research efforts to the NVU as a whole. In this view, the available evidence on the interaction between analgesic drugs and the NVU is here reviewed. Chronic pain comorbidities, such as neuroinflammatory and neurodegenerative diseases, are also discussed in view of NVU changes, together with innovative pharmacological solutions targeting NVU components in chronic pain treatment. PMID:23840097

  10. Investigating the Limits of Neurovascular Coupling.

    PubMed

    Denfield, George H; Fahey, Paul G; Reimer, Jacob; Tolias, Andreas S

    2016-09-01

    O'Herron et al. (2016) perform two-photon imaging of vascular and neural responses in cat and rodent primary visual cortex to investigate the limits of neurovascular coupling. Their results suggest important constraints on making inferences about neuronal responses from hemodynamic activity. PMID:27608758

  11. Involvement of astrocytes in neurovascular communication.

    PubMed

    Nuriya, M; Hirase, H

    2016-01-01

    The vascular interface of the brain is distinct from that of the peripheral tissue in that astrocytes, the most numerous glial cell type in the gray matter, cover the vasculature with their endfeet. This morphological feature of the gliovascular junction has prompted neuroscientists to suggest possible functional roles of astrocytes including astrocytic modulation of the vasculature. Additionally, astrocytes develop an intricate morphology that intimately apposes neuronal synapses, making them an ideal cellular mediator of neurovascular coupling. In this article, we first introduce the classical anatomical and physiological findings that led to the proposal of various gliovascular interaction models. Next, we touch on the technological advances in the past few decades that enabled investigations and evaluations of neuro-glio-vascular interactions in situ. We then review recent experimental findings on the roles of astrocytes in neurovascular coupling from the viewpoints of intra- and intercellular signalings in astrocytes. PMID:27130410

  12. 21 CFR 882.5950 - Neurovascular embolization device.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... embolization device. (a) Identification. A neurovascular embolization device is an intravascular implant intended to permanently occlude blood flow to cerebral aneurysms and cerebral ateriovenous...

  13. Persistent trigeminal artery causing "double" neurovascular conflict.

    PubMed

    Clerici, Angelo Maurizio; Merlo, Paola; Rognone, Felice; Noce, Monica; Rognone, Elisa; Bono, Giorgio

    2009-03-01

    We report the case of a 73-year-old woman who presented with right VI nerve palsy and homolateral atypical trigeminal neuralgia; standard neuroradiological investigation of orbital/retroorbital regions and intracranial arteries excluded the most commonly demonstrable underlying causes while brain magnetic resonance (T1-weighted fat suppression; T2-weighted thin-section) and magnetic resonance angiography disclosed the evidence of "double" neurovascular conflict because of persistent trigeminal artery with aneurysmal dilation. A role of this almost rare vascular condition in causing painful ophthalmoplegia is discussed. PMID:19267790

  14. Major neurovascular complications of clavicle fracture surgery

    PubMed Central

    Clitherow, Harry DS

    2014-01-01

    Clavicle fracture fixation is becoming an increasingly common operation, with good clinical outcomes and a low rate of significant complications. However, there are several reports of rare but potentially life or limb threatening, neurovascular complications. Arterial injuries are usually pseudoaneurysms associated with prominent screws. These may be clinically silent for several years before presenting as subcritical upper limb ischaemia. Venous injuries are a result of tearing of the vessel wall by fracture manipulation, drills or implants. This produces intra-operative haemorrhage and potentially air embolism, which can be fatal if not rapidly recognized and managed. Brachial plexopathy is the result of traction on adherent plexus or impingement by fracture fragments or callus. It presents as severe arm pain and paralysis immediately postoperatively. Neurovascular injuries can be avoided by a combination of pre-operative planning, communication with anaesthetic staff and strategic surgical technique. The plane of the surgical exposure, release of the soft tissues, drill direction and depth and screw length are all important factors.

  15. Sphenopalatine Ganglion Stimulation in Neurovascular Headaches.

    PubMed

    Schoenen, Jean

    2015-01-01

    The interest for the sphenopalatine ganglion (SPG) in neurovascular headaches dates back to 1908 when Sluder presented his work on the role of the SPG in 'nasal headaches', which are now part of the trigeminal autonomic cephalalgias and cluster headache (ICHD-III-beta). Since then various interventions with blocking or lesional properties have targeted the SPG (transnasal injection of lidocaine and other agents, alcohol or steroid injections, radiofrequency lesions, or even ganglionectomy); success rates vary, but benefit is usually transient. Here we briefly review some anatomophysiological characteristics of the SPG and hypotheses about its pathophysiological role in neurovascular headaches before describing recent therapeutic results obtained with electrical stimulation of the SPG. Based on results of a prospective randomized controlled study, SPG stimulation appears to be an effective treatment option for patients with chronic cluster headaches; efficacy data indicate that acute electrical stimulation of the SPG provides significant attack pain relief and in many cases pain freedom compared to sham stimulation. Moreover, in some patients SPG stimulation has been associated with a significant and clinically meaningful reduction in cluster headache attack frequency; this preventive effect of SPG stimulation warrants further investigation. For migraine attacks, the outcome of a proof-of-concept study using a temporary electrode implanted in the pterygopalatine fossa was less encouraging; however, an ongoing multicenter trial is evaluating the efficacy of long-term SPG stimulation against sham stimulation for acute and preventive treatment in patients with frequent migraine. PMID:26394372

  16. ALS and Oxidative Stress: The Neurovascular Scenario

    PubMed Central

    Thakur, Keshav; Gupta, Pawan Kumar

    2013-01-01

    Oxidative stress and angiogenic factors have been placed as the prime focus of scientific investigations after an establishment of link between vascular endothelial growth factor promoter (VEGF), hypoxia, and amyotrophic lateral sclerosis (ALS) pathogenesis. Deletion of the hypoxia-response element in the vascular endothelial growth factor promoter and mutant superoxide dismutase 1 (SOD1) which are characterised by atrophy and muscle weakness resulted in phenotype resembling human ALS in mice. This results in lower motor neurodegeneration thus establishing an important link between motor neuron degeneration, vasculature, and angiogenic molecules. In this review, we have presented human, animal, and in vitro studies which suggest that molecules like VEGF have a therapeutic, diagnostic, and prognostic potential in ALS. Involvement of vascular growth factors and hypoxia response elements also highlights the converging role of oxidative stress and neurovascular network for understanding and treatment of various neurodegenerative disorders like ALS. PMID:24367722

  17. Long term follow up of neurovascular island flaps.

    PubMed

    Henderson, H P; Reid, D A

    1980-06-01

    The results of a ten year mean follow up of twenty Neurovascular Island Flaps and two Radial Nerve Innervated Cross Finger Flaps are presented. Sensory acuity sufficient for tactile gnosis was achieved in nineteen cases. In only one case had sensory acuity deteriorated since operation. Use of the flap was hampered in one patient by a pre-existing neuroma. Complete sensory reorientation occurred in five patients. Sensory misreference persisted more commonly on dominant hands. It was our impression that Porter's Letter Test revealed the patients making most use of their neurovascular island flaps. The place of neurovascular island flaps in the management of the mutilated hand is discussed. PMID:7409615

  18. The Neurovascular Retina in Retinopathy of Prematurity

    PubMed Central

    Fulton, Anne B.; Hansen, Ronald M.; Moskowitz, Anne; Akula, James D.

    2009-01-01

    The continuing worldwide epidemic of retinopathy of prematurity (ROP), a leading cause of childhood visual impairment, strongly motivates further research into mechanisms of the disease. Although the hallmark of ROP is abnormal retinal vasculature, a growing body of evidence supports a critical role for the neural retina in the ROP disease process. The age of onset of ROP coincides with the rapid developmental increase in rod photoreceptor outer segment length and rhodopsin content of the retina with escalation of energy demands. Using a combination of non-invasive electroretinographic (ERG), psychophysical, and image analysis procedures, the neural retina and its vasculature have been studied in prematurely born human subjects, both with and without ROP, and in rats that model the key vascular and neural parameters found in human ROP subjects. These data are compared to comprehensive numeric summaries of the neural and vascular features in normally developing human and rat retina. In rats, biochemical, anatomical, and molecular biological investigations are paired with the non-invasive assessments. ROP, even if mild, primarily and persistently alters the structure and function of photoreceptors. Post-receptor neurons and retinal vasculature, which are intimately related, are also affected by ROP; conspicuous neurovascular abnormalities disappear, but subtle structural anomalies and functional deficits may persist years after clinical ROP resolves. The data from human subjects and rat models identify photoreceptor and post-receptor targets for interventions that promise improved outcomes for children at risk for ROP. PMID:19563909

  19. Transcranial Doppler ultrasound in neurovascular diseases: diagnostic and therapeutic aspects.

    PubMed

    Topcuoglu, M Akif

    2012-11-01

    Albeit no direct anatomical information can be obtained, neurosonological methods provide real-time determination of velocity, and spectral waveform of blood flow in basal intracranial arteries adds significant benefit to the care of the patients with neurovascular diseases. Several features, such as relative simplicity in terms of interpretation and performance, significantly low cost, totally non-invasiveness, portability, and excellent temporal resolution, make neurosonology increasingly popular tool for evaluation, planning, and monitoring of treatment, and for determining prognosis in various neurovascular diseases. Usefulness of transcranial Doppler in diagnosing/monitoring subarachnoid hemorrhage related vasospasm and sickle cell vasculopathy is already well known. Utility in diagnosis of intracranial arterial stenosis, acute occlusion and recanalization, intracranial hemodynamic effect of the cervical arterial pathologies, intracranial pressure increase, and cerebral circulatory arrest are also well established. Neurosonological determination of vasomotor reactivity, cerebral autoregulation, neurovascular coupling, and micro-embolic signals detection are useful in the assessment of stroke risk, diagnosis of right-to-left shunting, and monitoring during surgery and interventional procedures. Transcranial Doppler is also an evolving ultrasound method with a therapeutic potential such as augmentation of clot lysis and cerebral delivery of thrombolytic or neuroprotective agent loaded nanobubbles in neurovascular diseases. The aim of this study is to give an overview of current usage of the different ultrasound modalities in different neurovascular diseases. PMID:23050641

  20. Neurovascular anatomy of the embryonic quail hindlimb.

    PubMed

    Bentley, Matthew T; Poole, Thomas J

    2009-10-01

    Blood vessel and nerve development in the vertebrate embryo possess certain similarities in pattern and molecular guidance cues. To study the specific influence of shared guidance molecules on nervous and vascular development, an understanding of the normal neurovascular anatomy must be in place. The present study documents the pattern of nervous and vascular development in the Japanese quail hindlimb using immunohistochemistry and fluorescently labeled intravital injection combined with confocal and epifluorescent microscopy. The developmental patterns of major nerves and blood vessels of embryonic hindlimbs between stages E2.75 (HH18) and E6.0 (HH29) are described. By E2.75, the dorsal aortae have begun to fuse into a single vessel at the level of the hindlimb, and have completely fused by E3 (HH20). The posterior cardinal vein is formed at the level of the hindlimb by E3, as is the main artery of the early hindlimb, the ischiadic artery, as an offshoot of the dorsal aorta. Our data suggest that eight spinal segments, versus seven as reported by others (Tanaka and Landmesser,1986a; Tyrrell et al.,1990), contribute to innervation of the quail hindlimb. Lumbosacral neurites reach the plexus region by E3.5 (HH21 & 22), pause for approximately 24 hr, and then enter the hindlimb along with the ischiadic and crural arteries through shared foramina in the pelvic anlage. The degree of anterior-posterior spatial congruency between major nerves and blood vessels of the quail hindlimb was found to be highest medial to the pelvic girdle precursor, versus in the hindlimb proper. PMID:19685501

  1. Mechanisms of Neurovascular Dysfunction in Acute Ischemic Brain

    PubMed Central

    Terasaki, Y.; Liu, Y.; Hayakawa, K.; Pham, L.D.; Lo, E.H.; Ji, X.; Arai, K.

    2014-01-01

    The neurovascular unit is now well accepted as a conceptual framework for investigating the mechanisms of ischemic stroke. From a molecular and cellular perspective, three broad mechanisms may underlie stroke pathophysiology – excitotoxicity, oxidative stress and inflammation. To date, however, most investigations of these basic mechanisms have focused on neuronal responses. In this mini-review, we ask whether these mechanisms of excitotoxicity, oxidative stress and inflammation can also be examined in terms of non-neuronal interactions in the neurovascular unit, including the release of extracellular vesicles for cell-cell signaling. PMID:24372202

  2. Three-Dimensional Visualization of Developing Neurovascular Architecture in the Craniofacial Region of Embryonic Mice.

    PubMed

    Sugimoto, Toshiaki; Taya, Yuji; Shimazu, Yoshihito; Soeno, Yuuichi; Sato, Kaori; Aoba, Takaaki

    2015-11-01

    Recent studies have highlighted the mechanism of vascular and axonal guidance to ensure proper morphogenesis and organogenesis. We aimed to perform global mapping of developing neurovascular networks during craniofacial development of embryonic mice. To this end, we developed histology-based three-dimensional (3D) reconstructions using paraffin-embedded serial sections obtained from mouse embryos. All serial sections were dual-immunolabeled with Pecam1 and Pgp9.5/Gap43 cocktail antibodies. All immunolabeled serial sections were digitized with virtual microscopy to acquire high spatial resolution images. The 3D reconstructs warranted superior positional accuracy to trace the long-range connectivity of blood vessels and individual cranial nerve axons. It was feasible to depict simultaneously the details of angiogenic sprouting and axon terminal arborization and to assess quantitatively the locoregional proximity between blood vessels and cranial nerve axons. Notably, 3D views of the craniofacial region revealed the following: Branchial arch arteries and blood capillary plexi were formed without accompanying nerves at embryonic day (E) 9.5. Cranial nerve axons began to grow into the branchial arches, developing a labyrinth of small blood vessels at E10.5. Vascular remodeling occurred, and axon terminals of the maxillary, mandibular, chorda tympani, and hypoglossal nerve axons had arborized around the lateral lingual swellings at E11.5. The diverged patterning of trigeminal nerves and the arterial branches from the carotid artery became congruent at E11.5. The overall results support the advantage of dual-immunolabeling and 3D reconstruction technology to document the architecture and wiring of the developing neurovascular networks in mouse embryos. PMID:26054056

  3. Houshiheisan compound prescription protects neurovascular units after cerebral ischemia.

    PubMed

    Wang, Haizheng; Wang, Lei; Zhang, Nan; Zhang, Qi; Zhao, Hui; Zhang, Qiuxia

    2014-04-01

    Houshiheisan is composed of wind-dispelling (chrysanthemun flower, divaricate saposhnikovia root, Manchurian wild ginger, cassia twig, Szechwan lovage rhizome, and platycodon root) and deficiency-nourishing (ginseng, Chinese angelica, large-head atractylodes rhizome, Indian bread, and zingiber) drugs. In this study, we assumed these drugs have protective effects against cerebral ischemia, on neurovascular units. Houshiheisan was intragastrically administered in a rat model of focal cerebral ischemia. Hematoxylin-eosin staining, transmission electron microscopy, immunofluorescence staining, and western blot assays showed that Houshiheisan reduced pathological injury to the ischemic penumbra, protected neurovascular units, visibly up-regulated neuronal nuclear antigen expression, and down-regulated amyloid precursor protein and amyloid-β 42 expression. Wind-dispelling and deficiency-nourishing drugs maintained NeuN expression to varying degrees, but did not affect amyloid precursor protein or amyloid-β 42 expression in the ischemic penumbra. Our results suggest that the compound prescription Houshiheisan effectively suppresses abnormal amyloid precursor protein accumulation, reduces amyloid substance deposition, maintains stabilization of the internal environment of neurovascular units, and minimizes injury to neurovascular units in the ischemic penumbra. PMID:25206882

  4. Imaging of Neurovascular Compression Syndromes: Trigeminal Neuralgia, Hemifacial Spasm, Vestibular Paroxysmia, and Glossopharyngeal Neuralgia.

    PubMed

    Haller, S; Etienne, L; Kövari, E; Varoquaux, A D; Urbach, H; Becker, M

    2016-08-01

    Neurovascular compression syndromes are usually caused by arteries that directly contact the cisternal portion of a cranial nerve. Not all cases of neurovascular contact are clinically symptomatic. The transition zone between the central and peripheral myelin is the most vulnerable region for symptomatic neurovascular compression syndromes. Trigeminal neuralgia (cranial nerve V) has an incidence of 4-20/100,000, a transition zone of 4 mm, with symptomatic neurovascular compression typically proximal. Hemifacial spasm (cranial nerve VII) has an incidence of 1/100,000, a transition zone of 2.5 mm, with symptomatic neurovascular compression typically proximal. Vestibular paroxysmia (cranial nerve VIII) has an unknown incidence, a transition zone of 11 mm, with symptomatic neurovascular compression typically at the internal auditory canal. Glossopharyngeal neuralgia (cranial nerve IX) has an incidence of 0.5/100,000, a transition zone of 1.5 mm, with symptomatic neurovascular compression typically proximal. The transition zone overlaps the root entry zone close to the brain stem in cranial nerves V, VII, and IX, yet it is more distal and does not overlap the root entry zone in cranial nerve VIII. Although symptomatic neurovascular compression syndromes may also occur if the neurovascular contact is outside the transition zone, symptomatic neurovascular compression syndromes are more common if the neurovascular contact occurs at the transition zone or central myelin section, in particular when associated with nerve displacement and atrophy. PMID:26892985

  5. Biphasic Mechanisms of Neurovascular Unit Injury and Protection In CNS Diseases

    PubMed Central

    Maki, Takakuni; Hayakawa, Kazuhide; Pham, Loc-Duyen D.; Xing, Changhong; Lo, Eng H.; Arai, Ken

    2013-01-01

    In the past decade, evidence has emerged that there is a variety of bidirectional cell-cell and/or cell-extracellular matrix interactions within the neurovascular unit (NVU), which is composed of neuronal, glial, and vascular cells along with extracellular matrix. Many central nervous system (CNS) diseases, which lead to NVU dysfunction, have common features such as glial activation/transformation and vascular/blood-brain-barrier alteration. These phenomena show dual opposite roles, harmful at acute phase and beneficial at chronic phase. This diverse heterogeneity may induce biphasic clinical courses, i.e. degenerative and regenerative processes in the context of a dynamically coordinated cell-cell/cell-matrix interactions in the NVU. A deeper understanding of the seemingly contradictory actions in cellular levels is essential for NVU protection or regeneration to suppress the deleterious inflammatory reactions and promote adaptive remodeling after CNS injury. This mini-review will present an overview of recent progress in the biphasic roles of the NVU and discuss the clinical relevance of NVU responses associated with CNS diseases, such as stroke and other chronic neurodegenerative disease. PMID:23469847

  6. Treatment of complex neurovascular lesions: an interdisciplinary angio suite approach

    PubMed Central

    Breyer, Tobias; Wrede, Karsten H.; Stein, Klaus-Peter; Wanke, Isabel; Grams, Astrid E.; Gizewski, Elke R.; Schlamann, Marc; Forsting, Michael; Sandalcioglu, I. Erol; Sure, Ulrich

    2014-01-01

    Objective: The objective of this study was to analyse our initial experience using an interdisciplinary angio suite approach to neurosurgical treatment of complex neurovascular lesions and expound technical feasibility and possible applications. Subjects: Six out of 451 patients with cranial or spinal neurovascular lesions were surgically treated in the angio suite (biplane angiographic system) during a 28-month observation period. Clinical baseline data, radiological and intraoperative findings as well as clinical and radiological outcome were assessed. Results: A ventral spinal perimedullary arteriovenous malformation, a ventral spinal perimedullary fistula, two diffuse frontal dural arteriovenous fistulas, a multifocal temporal arteriovenous malformation and a partially embolized fronto-temporo-basal dural arteriovenous fistula were successfully treated with angiographically confirmed complete occlusion and unimpaired neurological condition of the patients at the 12-month follow up. Conclusion: This study demonstrates the feasibility of this approach and points out possible indications, namely ventrally located spinal lesions and diffuse, deep seated cranial lesions. PMID:24409203

  7. Pericytes of the neurovascular unit: key functions and signaling pathways.

    PubMed

    Sweeney, Melanie D; Ayyadurai, Shiva; Zlokovic, Berislav V

    2016-05-26

    Pericytes are vascular mural cells embedded in the basement membrane of blood microvessels. They extend their processes along capillaries, pre-capillary arterioles and post-capillary venules. CNS pericytes are uniquely positioned in the neurovascular unit between endothelial cells, astrocytes and neurons. They integrate, coordinate and process signals from their neighboring cells to generate diverse functional responses that are critical for CNS functions in health and disease, including regulation of the blood-brain barrier permeability, angiogenesis, clearance of toxic metabolites, capillary hemodynamic responses, neuroinflammation and stem cell activity. Here we examine the key signaling pathways between pericytes and their neighboring endothelial cells, astrocytes and neurons that control neurovascular functions. We also review the role of pericytes in CNS disorders including rare monogenic diseases and complex neurological disorders such as Alzheimer's disease and brain tumors. Finally, we discuss directions for future studies. PMID:27227366

  8. Calcium dynamics in astrocyte processes during neurovascular coupling

    PubMed Central

    Otsu, Yo; Couchman, Kiri; Lyons, Declan G; Collot, Mayeul; Agarwal, Amit; Mallet, Jean-Maurice; Pfrieger, Frank W; Bergles, Dwight E; Charpak, Serge

    2015-01-01

    Enhanced neuronal activity in the brain triggers a local increase in blood flow, termed functional hyperemia, via several mechanisms, including calcium (Ca2+) signaling in astrocytes. However, recent in vivo studies have questioned the role of astrocytes in functional hyperemia because of the slow and sparse dynamics of their somatic Ca2+ signals and the absence of glutamate metabotropic receptor 5 in adults. Here, we reexamined their role in neurovascular coupling by selectively expressing a genetically encoded Ca2+ sensor in astrocytes of the olfactory bulb. We show that in anesthetized mice, the physiological activation of olfactory sensory neuron (OSN) terminals reliably triggers Ca2+ increases in astrocyte processes but not in somata. These Ca2+ increases systematically precede the onset of functional hyperemia by 1–2 s, reestablishing astrocytes as potential regulators of neurovascular coupling. PMID:25531572

  9. Analysis and Visualization of Nerve Vessel Contacts for Neurovascular Decompression

    NASA Astrophysics Data System (ADS)

    Süßmuth, Jochen; Piazza, Alexander; Enders, Frank; Naraghi, Ramin; Greiner, Günther; Hastreiter, Peter

    Neurovascular compression syndromes are caused by a pathological contact between cranial nerves and vascular structures at the surface of the brainstem. Aiming at improved pre-operative analysis of the target structures, we propose calculating distance fields to provide quantitative information of the important nerve-vessel contacts. Furthermore, we suggest reconstructing polygonal models for the nerves and vessels. Color-coding with the respective distance information is used for enhanced visualization. Overall, our new strategy contributes to a significantly improved clinical understanding.

  10. Oral neurovascular hamartoma: an extraordinary verdict in the oral cavity

    PubMed Central

    Junaid, Montasir; Ahmed, Sadaf Qadeer; Kazi, Maliha; Haroon, Saroona

    2014-01-01

    The presence of a neurovascular hamartoma within the oral cavity is truly a rare entity. Scarcely reported in the literature, these hamartomas are smooth, pinkish masses and are painless, and therefore difficult to diagnose. They are benign in nature and apply pressure to their surroundings. The histological diagnosis remains the gold standard as it comprises of neural tissue and vascular components. Treatment is surgical excision with adequate margins. Recurrence is reported in cases of incomplete resection. PMID:24969068

  11. Early neurovascular uncoupling in the brain during community acquired pneumonia

    PubMed Central

    2012-01-01

    Introduction Sepsis leads to microcirculatory dysfunction and therefore a disturbed neurovascular coupling in the brain. To investigate if the dysfunction is also present in less severe inflammatory diseases we studied the neurovascular coupling in patients suffering from community acquired pneumonia. Methods Patients were investigated in the acute phase of pneumonia and after recovery. The neurovascular coupling was investigated with a simultaneous electroencephalogram (EEG)-Doppler technique applying a visual stimulation paradigm. Resting EEG frequencies, visual evoked potentials as well as resting and stimulated hemodynamic responses were obtained. Disease severity was characterized by laboratory and cognitive parameters as well as related scoring systems. Data were compared to a control group. Results Whereas visually evoked potentials (VEP) remained stable a significant slowing and therefore uncoupling of the hemodynamic responses were found in the acute phase of pneumonia (Rate time: control group: 3.6 ± 2.5 vs. acute pneumonia: 1.6 ± 2.4 s; P < 0.0005). In the initial investigation, patients who deteriorated showed a decreased hemodynamic response as compared with those who recovered (gain: recovered: 15% ± 4% vs. deteriorated: 9% ± 3%, P < 0.05; control: 14% ± 5%). After recovery the coupling normalized. Conclusions Our study underlines the role of an early microcirculatory dysfunction in inflammatory syndromes that become evident in pre-septic conditions with a gradual decline according to disease severity. PMID:22520083

  12. Anesthesia and the quantitative evaluation of neurovascular coupling

    PubMed Central

    Masamoto, Kazuto; Kanno, Iwao

    2012-01-01

    Anesthesia has broad actions that include changing neuronal excitability, vascular reactivity, and other baseline physiologies and eventually modifies the neurovascular coupling relationship. Here, we review the effects of anesthesia on the spatial propagation, temporal dynamics, and quantitative relationship between the neural and vascular responses to cortical stimulation. Previous studies have shown that the onset latency of evoked cerebral blood flow (CBF) changes is relatively consistent across anesthesia conditions compared with variations in the time-to-peak. This finding indicates that the mechanism of vasodilation onset is less dependent on anesthesia interference, while vasodilation dynamics are subject to this interference. The quantitative coupling relationship is largely influenced by the type and dosage of anesthesia, including the actions on neural processing, vasoactive signal transmission, and vascular reactivity. The effects of anesthesia on the spatial gap between the neural and vascular response regions are not fully understood and require further attention to elucidate the mechanism of vascular control of CBF supply to the underlying focal and surrounding neural activity. The in-depth understanding of the anesthesia actions on neurovascular elements allows for better decision-making regarding the anesthetics used in specific models for neurovascular experiments and may also help elucidate the signal source issues in hemodynamic-based neuroimaging techniques. PMID:22510601

  13. Neurovascular dysfunction and neurodegeneration in dementia and Alzheimer's disease.

    PubMed

    Nelson, Amy R; Sweeney, Melanie D; Sagare, Abhay P; Zlokovic, Berislav V

    2016-05-01

    Vascular insults can initiate a cascade of molecular events leading to neurodegeneration, cognitive impairment, and dementia. Here, we review the cellular and molecular mechanisms in cerebral blood vessels and the pathophysiological events leading to cerebral blood flow dysregulation and disruption of the neurovascular unit and the blood-brain barrier, which all may contribute to the onset and progression of dementia and Alzheimer's disease (AD). Particularly, we examine the link between neurovascular dysfunction and neurodegeneration including the effects of AD genetic risk factors on cerebrovascular functions and clearance of Alzheimer's amyloid-β peptide toxin, and the impact of vascular risk factors, environment, and lifestyle on cerebral blood vessels, which in turn may affect synaptic, neuronal, and cognitive functions. Finally, we examine potential experimental treatments for dementia and AD based on the neurovascular model, and discuss some critical questions to be addressed by future studies. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive Impairment and Dementia edited by M. Paul Murphy, Roderick A. Corriveau and Donna M. Wilcock. PMID:26705676

  14. Complex rostral neurovascular system in a giant pliosaur

    NASA Astrophysics Data System (ADS)

    Foffa, Davide; Sassoon, Judyth; Cuff, Andrew R.; Mavrogordato, Mark N.; Benton, Michael J.

    2014-05-01

    Pliosaurs were a long-lived, ubiquitous group of Mesozoic marine predators attaining large body sizes (up to 12 m). Despite much being known about their ecology and behaviour, the mechanisms they adopted for prey detection have been poorly investigated and represent a mystery to date. Complex neurovascular systems in many vertebrate rostra have evolved for prey detection. However, information on the occurrence of such systems in fossil taxa is extremely limited because of poor preservation potential. The neurovascular complex from the snout of an exceptionally well-preserved pliosaur from the Kimmeridgian (Late Jurassic, c. 170 Myr ago) of Weymouth Bay (Dorset, UK) is described here for the first time. Using computed tomography (CT) scans, the extensive bifurcating neurovascular channels could be traced through the rostrum to both the teeth and the foramina on the dorsal and lateral surface of the snout. The structures on the surface of the skull and the high concentrations of peripheral rami suggest that this could be a sensory system, perhaps similar to crocodile pressure receptors or shark electroreceptors.

  15. Brain imaging of neurovascular dysfunction in Alzheimer's disease.

    PubMed

    Montagne, Axel; Nation, Daniel A; Pa, Judy; Sweeney, Melanie D; Toga, Arthur W; Zlokovic, Berislav V

    2016-05-01

    Neurovascular dysfunction, including blood-brain barrier (BBB) breakdown and cerebral blood flow (CBF) dysregulation and reduction, are increasingly recognized to contribute to Alzheimer's disease (AD). The spatial and temporal relationships between different pathophysiological events during preclinical stages of AD, including cerebrovascular dysfunction and pathology, amyloid and tau pathology, and brain structural and functional changes remain, however, still unclear. Recent advances in neuroimaging techniques, i.e., magnetic resonance imaging (MRI) and positron emission tomography (PET), offer new possibilities to understand how the human brain works in health and disease. This includes methods to detect subtle regional changes in the cerebrovascular system integrity. Here, we focus on the neurovascular imaging techniques to evaluate regional BBB permeability (dynamic contrast-enhanced MRI), regional CBF changes (arterial spin labeling- and functional-MRI), vascular pathology (structural MRI), and cerebral metabolism (PET) in the living human brain, and examine how they can inform about neurovascular dysfunction and vascular pathophysiology in dementia and AD. Altogether, these neuroimaging approaches will continue to elucidate the spatio-temporal progression of vascular and neurodegenerative processes in dementia and AD and how they relate to each other. PMID:27038189

  16. Mechanism of chromatin remodeling.

    PubMed

    Lorch, Yahli; Maier-Davis, Barbara; Kornberg, Roger D

    2010-02-23

    Results from biochemical and structural studies of the RSC chromatin-remodeling complex prompt a proposal for the remodeling mechanism: RSC binding to the nucleosome releases the DNA from the histone surface and initiates DNA translocation (through one or a small number of DNA base pairs); ATP binding completes translocation, and ATP hydrolysis resets the system. Binding energy thus plays a central role in the remodeling process. RSC may disrupt histone-DNA contacts by affecting histone octamer conformation and through extensive interaction with the DNA. Bulging of the DNA from the octamer surface is possible, and twisting is unavoidable, but neither is the basis of remodeling. PMID:20142505

  17. Near infrared spectroscopy--investigations in neurovascular diseases.

    PubMed

    Schytz, Henrik Winther

    2015-12-01

    The purpose of this thesis was to explore and develop methods, where continuous wave near infrared spectroscopy (CW-NIRS) can be applied in different neurovascular diseases, in order to find biological markers that are useful in clinical neurology. To develop a new method to detect changes in cerebral blood flow (CBF), the first study investigated a multi-source detector separation configuration and indocyanine green (ICG) as a tracer to calculate a corrected blood flow index (BFI) value. The study showed no correlation between CBF changes measured by 133Xenon single photon emission computer tomography (133Xe-SPECT) and the corrected BFI value. It was concluded, that it was not possible to obtain reliable BFI data with the ICG CW-NIRS method. NIRS measurements of low frequency oscillations (LFOs) may be a reliable method to investigate vascular alterations in neurovascular diseases, but this requires an acceptable LFOs variation between hemispheres and over time in the healthy brain. The second study therefore investigated day-to-day and hemispheric variations in LFOs with NIRS. It was shown that NIRS might be useful in assessing LFOs between hemispheres, as well as interhemispheric phase and gain directly and over time. Migraine may be associated with persistent impairment of neurovascular coupling, but there is no experimental evidence to support this. The third study therefore investigated interictal neurovascular coupling during a mental task by a Stroop test in migraine without aura (MO) patients, which is the most common type of migraine. The study showed intact neurovascular coupling in the prefrontal cortex outside of attacks in patients with MO. The fourth study aimed to investigate possible changes in LFOs amplitude following nitric oxide (NO) donor infusion in familial hemiplegic migraine (FHM), which is a rare Mendelian subtype of migraine with aura. This study showed increased LFOs amplitude only in FHM patients with co-existing common type of migraine

  18. Feed the brain: insights into the study of neurovascular coupling.

    PubMed

    Welsh, Donald G; Ledoux, Jonathan

    2015-04-01

    The microcirculation is tightly regulated by a diverse range of mechanisms which share the common goal of matching blood flow delivery with tissue metabolic demand. Despite in-depth examination of tissues like skeletal muscle, brain microcirculation has remained largely unexplored due to methodological limitations. Recent, technological advances have, however, started to grant greater access to this vital microcirculatory bed. This overview is part of a Special Topics Issue centered on the methodology, theory, and mechanistic basis of neurovascular coupling. Solicited manuscripts have been purposely written in an opinionated manner to provoke thought and to illuminate new emerging areas of investigation. PMID:25771945

  19. Digital tomosynthesis: technique modifications and clinical applications for neurovascular anatomy

    SciTech Connect

    Maravilla, K.R.; Murry, R.C. Jr.; Diehl, J.; Suss, R.; Allen, L.; Chang, K.; Crawford, J.; McCoy, R.

    1984-09-01

    Digital tomosynthesis studies (DTS) using a linear tomographic motion can provide good quality clinical images when combined with subtraction angiotomography. By modifying their hardware system and the computer software algorithms, the authors were able to reconstruct tomosynthesis images using an isocentric rotation (IR) motion. Applying a combination of linear tomographic and IR techniques in clinical cases, they performed DTS studies in six patients, five with aneurysms and one with a hypervascular tumor. The results showed detailed definitions of the pathologic entities and the regional neurovascular anatomy. Based on this early experience, DTS would seem to be a useful technique for the preoperative surgical planning of vascular abnormalities.

  20. Neurovascular coupling, cerebral white matter integrity, and response to cocoa in older people

    PubMed Central

    Hurwitz, Shelley; Salat, David H.; Greve, Douglas N.; Fisher, Naomi D.L.

    2013-01-01

    Objective: To investigate the relationship between neurovascular coupling and cognitive function in elderly individuals with vascular risk factors and to determine whether neurovascular coupling could be modified by cocoa consumption. Methods: Sixty older people (aged 72.9 ± 5.4 years) were studied in a parallel-arm, double-blind clinical trial of neurovascular coupling and cognition in response to 24 hours and 30 days of cocoa consumption. Cognitive measures included Mini-Mental State Examination and Trail Making Test A and B. Neurovascular coupling was measured from the beat-to-beat blood flow velocity responses in the middle cerebral arteries to the N-Back Task. In a subset of MRI-eligible participants, cerebral white matter structural integrity was also measured. Results: Neurovascular coupling was associated with Trails B scores (p = 0.002) and performance on the 2-Back Task. Higher neurovascular coupling was also associated with significantly higher fractional anisotropy in cerebral white matter hyperintensities (p = 0.02). Finally, 30 days of cocoa consumption was associated with increased neurovascular coupling (5.6% ± 7.2% vs −2.4% ± 4.8%; p = 0.001) and improved Trails B times (116 ± 78 seconds vs 167 ± 110 seconds; p = 0.007) in those with impaired neurovascular coupling at baseline. Conclusion: There is a strong correlation between neurovascular coupling and cognitive function, and both can be improved by regular cocoa consumption in individuals with baseline impairments. Better neurovascular coupling is also associated with greater white matter structural integrity. PMID:23925758

  1. Patterned optogenetic modulation of neurovascular and metabolic signals

    PubMed Central

    Richner, Thomas J; Baumgartner, Ryan; Brodnick, Sarah K; Azimipour, Mehdi; Krugner-Higby, Lisa A; Eliceiri, Kevin W; Williams, Justin C; Pashaie, Ramin

    2015-01-01

    The hemodynamic and metabolic response of the cortex depends spatially and temporally on the activity of multiple cell types. Optogenetics enables specific cell types to be modulated with high temporal precision and is therefore an emerging method for studying neurovascular and neurometabolic coupling. Going beyond temporal investigations, we developed a microprojection system to apply spatial photostimulus patterns in vivo. We monitored vascular and metabolic fluorescence signals after photostimulation in Thy1-channelrhodopsin-2 mice. Cerebral arteries increased in diameter rapidly after photostimulation, while nearby veins showed a slower smaller response. The amplitude of the arterial response was depended on the area of cortex stimulated. The fluorescence signal emitted at 450/100 nm and excited with ultraviolet is indicative of reduced nicotinamide adenine dinucleotide, an endogenous fluorescent enzyme involved in glycolysis and the citric acid cycle. This fluorescence signal decreased quickly and transiently after optogenetic stimulation, suggesting that glucose metabolism is tightly locked to optogenetic stimulation. To verify optogenetic stimulation of the cortex, we used a transparent substrate microelectrode array to map cortical potentials resulting from optogenetic stimulation. Spatial optogenetic stimulation is a new tool for studying neurovascular and neurometabolic coupling. PMID:25388678

  2. Potassium Buffering in the Neurovascular Unit: Models and Sensitivity Analysis

    PubMed Central

    Witthoft, Alexandra; Filosa, Jessica A.; Karniadakis, George Em

    2013-01-01

    Astrocytes are critical regulators of neural and neurovascular network communication. Potassium transport is a central mechanism behind their many functions. Astrocytes encircle synapses with their distal processes, which express two potassium pumps (Na-K and NKCC) and an inward rectifying potassium channel (Kir), whereas the vessel-adjacent endfeet express Kir and BK potassium channels. We provide a detailed model of potassium flow throughout the neurovascular unit (synaptic region, astrocytes, and arteriole) for the cortex of the young brain. Our model reproduces several phenomena observed experimentally: functional hyperemia, in which neural activity triggers astrocytic potassium release at the perivascular endfoot, inducing arteriole dilation; K+ undershoot in the synaptic space after periods of neural activity; neurally induced astrocyte hyperpolarization during Kir blockade. Our results suggest that the dynamics of the vascular response during functional hyperemia are governed by astrocytic Kir for the fast onset and astrocytic BK for maintaining dilation. The model supports the hypothesis that K+ undershoot is caused by excessive astrocytic uptake through Na-K and NKCC pumps, whereas the effect is balanced by Kir. We address parametric uncertainty using high-dimensional stochastic sensitivity analysis and identify possible model limitations. PMID:24209849

  3. APOE Stabilization by Exercise Prevents Aging Neurovascular Dysfunction and Complement Induction

    PubMed Central

    Soto, Ileana; Graham, Leah C.; Richter, Hannah J.; Simeone, Stephen N.; Radell, Jake E.; Grabowska, Weronika; Funkhouser, W. Keith; Howell, Megan C.; Howell, Gareth R.

    2015-01-01

    Aging is the major risk factor for neurodegenerative diseases such as Alzheimer's disease, but little is known about the processes that lead to age-related decline of brain structures and function. Here we use RNA-seq in combination with high resolution histological analyses to show that aging leads to a significant deterioration of neurovascular structures including basement membrane reduction, pericyte loss, and astrocyte dysfunction. Neurovascular decline was sufficient to cause vascular leakage and correlated strongly with an increase in neuroinflammation including up-regulation of complement component C1QA in microglia/monocytes. Importantly, long-term aerobic exercise from midlife to old age prevented this age-related neurovascular decline, reduced C1QA+ microglia/monocytes, and increased synaptic plasticity and overall behavioral capabilities of aged mice. Concomitant with age-related neurovascular decline and complement activation, astrocytic Apoe dramatically decreased in aged mice, a decrease that was prevented by exercise. Given the role of APOE in maintaining the neurovascular unit and as an anti-inflammatory molecule, this suggests a possible link between astrocytic Apoe, age-related neurovascular dysfunction and microglia/monocyte activation. To test this, Apoe-deficient mice were exercised from midlife to old age and in contrast to wild-type (Apoe-sufficient) mice, exercise had little to no effect on age-related neurovascular decline or microglia/monocyte activation in the absence of APOE. Collectively, our data shows that neurovascular structures decline with age, a process that we propose to be intimately linked to complement activation in microglia/monocytes. Exercise prevents these changes, but not in the absence of APOE, opening up new avenues for understanding the complex interactions between neurovascular and neuroinflammatory responses in aging and neurodegenerative diseases such as Alzheimer’s disease. PMID:26512759

  4. Remembering AB

    NASA Astrophysics Data System (ADS)

    Belyayev, S. T.

    2013-06-01

    In 1947 I became a second-year student at Moscow State University's Physics and Engineering Department, where a part of the week's classes were taught at base organizations. Our group's base was the future Kurchatov Institute, at that time known as the mysterious "Laboratory N^circ 2," and later as LIPAN. . Besides group lectures and practical work at the experimental laboratories, we also had access to the general seminars which Igor Vasilyevich Kurchatov tried to hold, with Leonid Vasilyevich Groshev filling in when he was absent. At the seminar, theorists spoke as welcome co-presenters and commentators. In 1949 I felt ready to approach A. B. Migdal to ask if I could transfer to his theoretical sector. In response, he suggested a number of simple qualitative problems, which I then successfully solved. (Incidentally, AB used the very same "introductory problems" for screening many generations of students.) So I wound up among AB's students. From 1952 on (for 10 years) I also served as an employee of the Migdal Sector. My memoirs here are mainly inspired by these years of constant communication with AB. After my departure for Novosibirsk in 1962, although our meetings still took place, they became occasional....

  5. Vascular endothelial growth factor: a neurovascular target in neurological diseases.

    PubMed

    Lange, Christian; Storkebaum, Erik; de Almodóvar, Carmen Ruiz; Dewerchin, Mieke; Carmeliet, Peter

    2016-08-01

    Brain function critically relies on blood vessels to supply oxygen and nutrients, to establish a barrier for neurotoxic substances, and to clear waste products. The archetypal vascular endothelial growth factor, VEGF, arose in evolution as a signal affecting neural cells, but was later co-opted by blood vessels to regulate vascular function. Consequently, VEGF represents an attractive target to modulate brain function at the neurovascular interface. On the one hand, VEGF is neuroprotective, through direct effects on neural cells and their progenitors and indirect effects on brain perfusion. In accordance, preclinical studies show beneficial effects of VEGF administration in neurodegenerative diseases, peripheral neuropathies and epilepsy. On the other hand, pathologically elevated VEGF levels enhance vessel permeability and leakage, and disrupt blood-brain barrier integrity, as in demyelinating diseases, for which blockade of VEGF may be beneficial. Here, we summarize current knowledge on the role and therapeutic potential of VEGF in neurological diseases. PMID:27364743

  6. [The neurovascular unit in health and ischemic stroke].

    PubMed

    Ago, Tetsuro

    2016-04-01

    The neurovascular unit (NVU), a minimal unit to exert neurological functions, is composed of neurons, astrocytes, endothelial cells, pericytes, and extracellular matrix proteins forming basal membranes. The cell components interact with one another and function cooperatively under both physiological and pathological conditions. Pericytes and astrocytes participate crucially in the formation and maintenance of the blood-brain barrier (BBB), the tight junction formed by endothelial cells, and regulate cerebral blood flow in response to neurological activities. The BBB actively regulate molecular import and export. The concept of the NVU is also useful for understanding pathogenesis and exploring therapeutic targets in various CNS disorders. In this review, recent research advances regarding the NVU and its components in health and ischemic stroke are summarized. PMID:27333744

  7. Neurovascular Interactions in the Neurologically Compromised Neonatal Brain.

    PubMed

    Singh, H; Cooper, R; Lee, C W; Dempsey, L; Brigadoi, S; Edwards, A; Airantzis, D; Everdell, N; Michell, A; Holder, D; Austin, T; Hebden, J

    2016-01-01

    Neurological brain injuries such as hypoxic ischaemic encephalopathy (HIE) and associated conditions such as seizures have been associated with poor developmental outcome in neonates. Our limited knowledge of the neurological and cerebrovascular processes underlying seizures limits their diagnosis and timely treatment. Diffuse optical tomography (DOT) provides haemodynamic information in the form of changes in concentration of de/oxygenated haemoglobin, which can improve our understanding of seizures and the relationship between neural and vascular processes. Using simultaneous EEG-DOT, we observed distinct haemodynamic changes which are temporally correlated with electrographic seizures. Here, we present DOT-EEG data from two neonates clinically diagnosed as HIE. Our results highlight the wealth of mutually-informative data that can be obtained using DOT-EEG techniques to understand neurovascular coupling in HIE neonates. PMID:26782249

  8. The neurovascular unit and combination treatment strategies for stroke

    PubMed Central

    Zhang, Li; Zhang, Zhang Gang; Chopp, Michael

    2012-01-01

    Tissue plasminogen activator (tPA) administered within 4.5 hours of symptom onset restores cerebral blood flow and promotes neurological recovery of stroke patients. However, the narrow therapeutic time window and the risk of intracerebral hemorrhage after tPA treatment pose major hurdles to its clinical usage. In light of the failures of neuroprotective therapies in clinical trials, emerging concepts suggest that neuroprotection alone without restoration of tissue perfusion and vascular integrity may not be adequate for treatment of acute stroke. Here we review evidence of the use of adjuvant pharmacological agents to extend the therapeutic window for tPA via targeting the neurovascular unit and the underlying mechanisms of the combination therapy in experimental stroke. PMID:22595494

  9. Physical exercise training and neurovascular unit in ischemic stroke.

    PubMed

    Wang, X; Zhang, M; Feng, R; Li, W B; Ren, S Q; Zhang, J; Zhang, F

    2014-06-20

    Physical exercise could exert a neuroprotective effect in both clinical studies and animal experiments. A series of related studies have indicated that physical exercise could reduce infarct volume, alleviate neurological deficits, decrease blood-brain barrier dysfunction, promote angiogenesis in cerebral vascular system and increase the survival rate after ischemic stroke. In this review, we summarized the protective effects of physical exercise on neurovascular unit (NVU), including neurons, astrocytes, pericytes and the extracellular matrix. Furthermore, it was demonstrated that exercise training could decrease the blood-brain barrier dysfunction and promote angiogenesis in cerebral vascular system. An awareness of the exercise intervention benefits pre- and post stroke may lead more stroke patients and people with high-risk factors to accept exercise therapy for the prevention and treatment of stroke. PMID:24780769

  10. Intermittent hypoglossal nerve palsy caused by a calcified persistent hypoglossal artery: an uncommon neurovascular compression syndrome.

    PubMed

    Meila, Dan; Wetter, Axel; Brassel, Friedhelm; Nacimiento, Wilhelm

    2012-12-15

    Neurovascular compression is assumed to cause symptoms like trigeminal neuralgia, hemifacial spasm and vestibular paroxysmia. We present a patient with recurrent episodes of transient dysarthria due to isolated right hypoglossal nerve (HN) palsy. We describe the first case of a calcified persistent hypoglossal artery (PHA) as the putative cause of a hypoglossal neurovascular compression syndrome. Our patient received a daily low-dose medication of carbamazepine resulting in complete relief of symptoms. In conclusion, PHA is not only an anatomic variation but also a possible cause of a neurovascular compression syndrome leading to intermittent HN palsy. PMID:23020989

  11. OCT/PS-OCT imaging of brachial plexus neurovascular structures

    NASA Astrophysics Data System (ADS)

    Raphael, David T.; Zhang, Jun; Zhang, Yaoping; Chen, Zhongping; Miller, Carol; Zhou, Li

    2004-07-01

    Introduction: Optical coherence tomography (OCT) allows high-resolution imaging (less than 10 microns) of tissue structures. A pilot study with OCT and polarization-sensitive OCT (PS-OCT) was undertaken to image ex-vivo neurovascular structures (vessels, nerves) of the canine brachial plexus. Methods: OCT is an interferometry-based optical analog of B-mode ultrasound, which can image through non-transparent biological tissues. With approval of the USC Animal Care and Use Committee, segments of the supra- and infraclavicular brachial plexus were excised from euthanized adult dogs, and the ex-vivo specimens were placed in cold pH-buffered physiologic solution. An OCT beam, in micrometer translational steps, scanned the fixed-position bisected specimens in transverse and longitudinal views. Two-dimensional images were obtained from identified arteries and nerves, with specific sections of interest stained with hematoxylin-eosin for later imaging through a surgical microscope. Results: with the beam scan direction transverse to arteries, the resulting OCT images showed an identifiable arterial lumen and arterial wall tissue layers. By comparison, transverse beam OCT images of nerves revealed a multitude of smaller nerve bundles contained within larger circular-shaped fascicles. PS-OCT imaging was helpful in showing the characteristic birefringence exhibited by arrayed neural structures. Discussion: High-resolution OCT imaging may be useful in the optical identification of neurovascular structures during attempted regional nerve blockade. If incorporated into a needle-shaped catheter endoscope, such a technology could prevent intraneural and intravascular injections immediately prior to local anesthetic injection. The major limitation of OCT is that it can form a coherent image of tissue structures only to a depth of 1.5 - 2 mm.

  12. Neurovascular unit on a chip: implications for translational applications

    PubMed Central

    2013-01-01

    The blood-brain barrier (BBB) dynamically controls exchange between the brain and the body, but this interaction cannot be studied directly in the intact human brain or sufficiently represented by animal models. Most existing in vitro BBB models do not include neurons and glia with other BBB elements and do not adequately predict drug efficacy and toxicity. Under the National Institutes of Health Microtissue Initiative, we are developing a three-dimensional, multicompartment, organotypic microphysiological system representative of a neurovascular unit of the brain. The neurovascular unit system will serve as a model to study interactions between the central nervous system neurons and the cerebral spinal fluid (CSF) compartment, all coupled to a realistic blood-surrogate supply and venous return system that also incorporates circulating immune cells and the choroid plexus. Hence all three critical brain barriers will be recapitulated: blood-brain, brain-CSF, and blood-CSF. Primary and stem cell-derived human cells will interact with a variety of agents to produce critical chemical communications across the BBB and between brain regions. Cytomegalovirus, a common herpesvirus, will be used as an initial model of infections regulated by the BBB. This novel technological platform, which combines innovative microfluidics, cell culture, analytical instruments, bioinformatics, control theory, neuroscience, and drug discovery, will replicate chemical communication, molecular trafficking, and inflammation in the brain. The platform will enable targeted and clinically relevant nutritional and pharmacologic interventions for or prevention of such chronic diseases as obesity and acute injury such as stroke, and will uncover potential adverse effects of drugs. If successful, this project will produce clinically useful technologies and reveal new insights into how the brain receives, modifies, and is affected by drugs, other neurotropic agents, and diseases. PMID:24564885

  13. Effect of exosomes derived from multipluripotent mesenchymal stromal cells on functional recovery and neurovascular plasticity in rats after traumatic brain injury

    PubMed Central

    Zhang, Yanlu; Chopp, Michael; Meng, Yuling; Katakowski, Mark; Xin, Hongqi; Mahmood, Asim; Xiong, Ye

    2015-01-01

    Object Transplanted multipotent mesenchymal stromal cells (MSCs) improve functional recovery in rats after traumatic brain injury (TBI). Here, we test a novel hypothesis that systemic administration of cell-free exosomes generated from MSCs promotes functional recovery and neurovascular remodeling in rats after TBI. Methods Wistar rats were subjected to TBI followed by tail vein injection of 100 μg protein of exosomes derived from MSCs or an equal volume of vehicle phosphate-buffered saline (n = 8/group) 24 hours later. To evaluate cognitive and sensorimotor functional recovery, the modified Morris water maze, neurological severity score and footfault tests were performed. Animals were sacrificed at 35 days after TBI. Histopathological and immunohistochemical analyses were performed for measurements of lesion volume, neurovascular remodeling (angiogenesis and neurogenesis), and neuroinflammation. Results Compared with saline-treated controls, exosome-treated TBI rats showed significant improvement in spatial learning at 34-35 days measured by the Morris water maze test (p < 0.05), and sensorimotor functional recovery, i.e., reduced neurological deficits and footfault frequency, observed at 14-35 days post injury (p < 0.05). Exosome treatment significantly increased the number of newborn endothelial cells in the lesion boundary zone and dentate gyrus, and significantly increased the number of newborn immature and mature neurons in the dentate gyrus as well as reduced neuroinflammation. Conclusions We, for the first time, demonstrate that MSC-generated exosomes effectively improve functional recovery, at least in part, by promoting endogenous angiogenesis and neurogenesis and reducing inflammation in rats after TBI. Thus, MSC-generated exosomes may provide a novel cell-free therapy for TBI and possibly other neurological diseases. PMID:25594326

  14. Neurovascular unit impairment in early Alzheimer's disease measured with magnetic resonance imaging.

    PubMed

    van de Haar, Harm J; Jansen, Jacobus F A; van Osch, Matthias J P; van Buchem, Mark A; Muller, Majon; Wong, Sau May; Hofman, Paul A M; Burgmans, Saartje; Verhey, Frans R J; Backes, Walter H

    2016-09-01

    The neurovascular unit, which protects neuronal cells and supplies them with essential molecules, plays an important role in the pathophysiology of Alzheimer's Disease (AD). The aim of this study was to noninvasively investigate 2 linked functional elements of the neurovascular unit, blood-brain barrier (BBB) permeability and cerebral blood flow (CBF), in patients with early AD and healthy controls. Therefore, both dynamic contrast-enhanced magnetic resonance imaging and arterial spin labeling magnetic resonance imaging were applied to measure BBB permeability and CBF, respectively. The patients with early AD showed significantly lower CBF and local blood volume in the gray matter, compared with controls. In the patients, we also found that a reduction in CBF is correlated with an increase in leakage rate. This finding supports the hypothesis that neurovascular damage, and in particular impairment of the neurovascular unit constitutes the pathophysiological link between CBF reduction and BBB impairment in AD. PMID:27459939

  15. Fstl1 Promotes Asthmatic Airway Remodeling by Inducing Oncostatin M.

    PubMed

    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

    2015-10-15

    Chronic asthma is associated with airway remodeling and decline in lung function. In this article, we show that follistatin-like 1 (Fstl1), a mediator not previously associated with asthma, is highly expressed by macrophages in the lungs of humans with severe asthma. Chronic allergen-challenged Lys-Cre(tg) /Fstl1(Δ/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, whereas administration of an anti-OSM Ab 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/OSM pathway may be a novel pathway to inhibit airway remodeling in severe human asthma. PMID:26355153

  16. Neurovascular Coupling is Impaired in Slow Walkers: The MOBILIZE Boston Study

    PubMed Central

    Sorond, Farzaneh A.; Kiely, Dan K.; Galica, Andrew; Moscufo, Nicola; Serrador, Jorge M.; Iloputaife, Ike; Egorova, Svetlana; Dell'Oglio, Elisa; Meier, Dominik; Newton, Elizabeth; Milberg, William P.; Guttmann, Charles; Lipsitz, Lewis A.

    2011-01-01

    Objective Neurovascular coupling may be involved in compensatory mechanisms responsible for preservation of gait speed in elderly people with cerebrovascular disease. Our study examines the association between neurovascular coupling in the middle cerebral artery and gait speed in elderly individuals with impaired cerebral vasoreactivity. Methods Twenty-two fast and 20 slow walkers in the lowest quartile of cerebral vasoreactivity were recruited from the MOBILIZE Boston Study. Neurovascular coupling was assessed in bilateral middle cerebral arteries by measuring cerebral blood flow during the N-Back Task. Cerebral white matter hyperintensities were measured for each group using magnetic resonance imaging. Results Neurovascular coupling was attenuated in slow compared to fast walkers (2.8% [CI95%: −0.9–6.6] vs. 8.2% [CI95%: 4.7–11.8]; p=0.02). The odds of being a slow walker were 6.4 (CI95%: 1.7–24.9, p=0.007) if there was a high burden of white matter hyperintensity, however, this risk increased to 14.5 (CI95%: 2.3–91.1, p=0.004) if neurovascular coupling was also attenuated. Interpretation Our results suggest that intact neurovascular coupling may help preserve mobility in elderly people with cerebral microvascular disease. PMID:21674588

  17. Blood Pressure Increases in OSA due to Maintained Neurovascular Sympathetic Transduction: Impact of CPAP

    PubMed Central

    Tamisier, Renaud; Tan, Can Ozan; Pepin, Jean-Louis; Levy, Patrick; Taylor, J. Andrew

    2015-01-01

    Study Objectives: To test the hypothesis that greater resting sympathetic activity in obstructive sleep apnea (OSA) syndrome would not induce a lesser sympathetic neurovascular transduction. Design: Case-controlled cohort study. Participants: 33 patients with newly diagnosed OSA without comorbidities and 14 healthy controls. Interventions: 6 months of continuous positive airway pressure (CPAP) treatment for OSA patients and follow-up for 9 healthy controls. Measurements and Results: We assessed resting sympathetic outflow and sympathetic neurovascular transduction. Sympathetic activity was directly measured (microneurography) at rest and in response to sustained isometric handgrip exercise. Neurovascular transduction was derived from the relationship of sympathetic activity and blood pressure to leg blood flow during exercise. Despite an elevated sympathetic activity of ∼50% in OSA compared to controls, neurovascular transduction was not different (i.e., absence of tachyphylaxis). After six months of CPAP, there were significant declines in diastolic pressure, averaging ∼4 mm Hg, and in sympathetic activity, averaging ∼20% with no change in transduction. Conclusions: Greater sympathetic activity in obstructive sleep apnea does not appear to be associated with lesser neurovascular transduction. Hence, elevated sympathetic outflow without lesser transduction may underlie the prevalent development of hypertension in this population that is well controlled by continuous positive airway pressure treatment. Citation: Tamisier R, Tan CO, Pepin JL, Levy P, Taylor JA. Blood pressure increases in OSA due to maintained neurovascular sympathetic transduction: impact of CPAP. SLEEP 2015;38(12):1973–1980. PMID:26039959

  18. Immunoregulation of bone remodelling

    PubMed Central

    Singh, Ajai; Mehdi, Abbass A; Srivastava, Rajeshwer N; Verma, Nar Singh

    2012-01-01

    Remodeling, a continuous physiological process maintains the strength of the bones, which maintains a delicate balance between bone formation and resorption process. This review gives an insight to the complex interaction and correlation between the bone remodeling and the corresponding changes in host immunological environment and also summarises the most recent developments occuring in the understanding of this complex field. T cells, both directly and indirectly increase the expression of receptor activator of nuclear factor kB ligand (RANKL); a vital step in the activation of osteoclasts, thus positively regulates the osteoclastogenesis. Though various cytokines, chemikines, transcription factors and co-stimulatory molecules are shared by both skeletal and immune systems, but researches are being conducted to establish and analyse their role and / or control on this complex but vital process. The understanding of this part of research may open new horizons in the management of inflammatory and autoimmune diseases, resulting into bone loss and that of osteoporosis also. PMID:22837895

  19. Advanced and standardized evaluation of neurovascular compression syndromes

    NASA Astrophysics Data System (ADS)

    Hastreiter, Peter; Vega Higuera, Fernando; Tomandl, Bernd; Fahlbusch, Rudolf; Naraghi, Ramin

    2004-05-01

    Caused by a contact between vascular structures and the root entry or exit zone of cranial nerves neurovascular compression syndromes are combined with different neurological diseases (trigeminal neurolagia, hemifacial spasm, vertigo, glossopharyngeal neuralgia) and show a relation with essential arterial hypertension. As presented previously, the semi-automatic segmentation and 3D visualization of strongly T2 weighted MR volumes has proven to be an effective strategy for a better spatial understanding prior to operative microvascular decompression. After explicit segmentation of coarse structures, the tiny target nerves and vessels contained in the area of cerebrospinal fluid are segmented implicitly using direct volume rendering. However, based on this strategy the delineation of vessels in the vicinity of the brainstem and those at the border of the segmented CSF subvolume are critical. Therefore, we suggest registration with MR angiography and introduce consecutive fusion after semi-automatic labeling of the vascular information. Additionally, we present an approach of automatic 3D visualization and video generation based on predefined flight paths. Thereby, a standardized evaluation of the fused image data is supported and the visualization results are optimally prepared for intraoperative application. Overall, our new strategy contributes to a significantly improved 3D representation and evaluation of vascular compression syndromes. Its value for diagnosis and surgery is demonstrated with various clinical examples.

  20. Microstructured Thin Film Nitinol for a Neurovascular Flow-Diverter

    PubMed Central

    Chen, Yanfei; Howe, Connor; Lee, Yongkuk; Cheon, Seongsik; Yeo, Woon-Hong; Chun, Youngjae

    2016-01-01

    A cerebral aneurysm occurs as a result of a weakened blood vessel, which allows blood to flow into a sac or a ballooned section. Recent advancement shows that a new device, ‘flow-diverter’, can divert blood flow away from the aneurysm sac. People found that a flow-diverter based on thin film nitinol (TFN), works very effectively, however there are no studies proving the mechanical safety in irregular, curved blood vessels. Here, we study the mechanical behaviors and structural safety of a novel microstructured TFN membrane through the computational and experimental studies, which establish the fundamental aspects of stretching and bending mechanics of the structure. The result shows a hyper-elastic behavior of the TFN with a negligible strain change up to 180° in bending and over 500% in radial stretching, which is ideal in the use in neurovascular curved arteries. The simulation determines the optimal joint locations between the TFN and stent frame. In vitro experimental test qualitatively demonstrates the mechanical flexibility of the flow-diverter with multi-modal bending. In vivo micro X-ray and histopathology study demonstrate that the TFN can be conformally deployed in the curved blood vessel of a swine model without any significant complications or abnormalities. PMID:27009500

  1. Pathogenesis of diabetic neuropathy: focus on neurovascular mechanisms.

    PubMed

    Sytze Van Dam, P; Cotter, Mary A; Bravenboer, Bert; Cameron, Norman E

    2013-11-01

    Neuropathies of the peripheral and autonomic nervous systems affect up to half of all people with diabetes, and are major risk factors for foot ulceration and amputation. The aetiology is multifactorial: metabolic changes in diabetes may directly affect neural tissue, but importantly, neurodegenerative changes are precipitated by compromised nerve vascular supply. Experiments in animal models of diabetic neuropathy suggest that similar metabolic sequelae affect neurons and vasa nervorum endothelium. These include elevated polyol pathway activity, oxidative stress, the formation of advanced glycation and lipoxidation end products, and various pro-inflammatory changes such as elevated protein kinase C, nuclear factor κB and p38 mitogen activated protein kinase signalling. These mechanisms do not work in isolation but strongly interact in a mutually facilitatory fashion. Nitrosative stress and the induction of the enzyme poly (ADP-ribose) polymerase form one important link between physiological stressors such as reactive oxygen species and the pro-inflammatory mechanisms. Recently, evidence points to endoplasmic stress and the unfolded protein response as forming another crucial link. This review focuses on the aetiopathogenesis of neurovascular changes in diabetic neuropathy, elucidated in animal studies, and on putative therapeutic targets the majority of which have yet to be tested for efficacy in clinical trials. PMID:23872412

  2. Neuro-vascular link: from genetic insights to therapeutic perspectives.

    PubMed

    Carmeliet, P

    2008-01-01

    Understanding the molecular basis of the formation of blood vessels (angiogenesis) and nerves (neurogenesis) is of great medical relevance. It is well known that dysregulation of angiogenesis leads to tissue ischemia, cancer, inflammation and other disorders, while a dysfunction of the nerve system contributes to motorneuron disorders like amyotrophic lateral sclerosis (ALs) and other neurodegenerative diseases. The observations of Andreas Vesalius--Belgian anatomist of the 16th century--that patterning ofvessels and nerves show more than remarkable similarities, are currently revisited in exciting studies. Indeed, often, vessels and nerves even track alongside each other. Recent genetic studies revealed that vessels and nerves share many more common principles and signals for navigation, proliferation and survival than previously suspected. For instance, gene inactivation studies in mice and zebrafish showed that axon guidance signals regulate vessel navigation. Conversely, prototypic angiogenic factors such as VEGF control neurogenesis and regulate axon and neuron guidance, independently of their angiogenic activity. The next coming years promise to become an exciting journey to further unravel the molecular basis and explore the therapeutic potential of the neurovascular link. PMID:20120252

  3. Gaining Surgical Access for Repositioning the Inferior Alveolar Neurovascular Bundle

    PubMed Central

    Al-Siweedi, Saif Yousif Abdullah; Nambiar, P.; Shanmuhasuntharam, P.; Ngeow, W. C.

    2014-01-01

    This study is aimed at determining anatomical landmarks that can be used to gain access to the inferior alveolar neurovascular (IAN) bundle. Scanned CBCT (i-CAT machine) data of sixty patients and reconstructions performed using the SimPlant dental implant software were reviewed. Outcome variables were the linear distances of the mandibular canal to the inferior border and the buccal cortex of the mandible, measured immediately at the mental foramen (D1) and at 10, 20, 30, and 40 mm (D2–D5) distal to it. Predictor variables were age, ethnicity, and gender of subjects. Apicobasal assessment of the canal reveals that it is curving downward towards the inferior mandibular border until 20 mm (D3) distal to the mental foramen where it then curves upwards, making an elliptic-arc curve. The mandibular canal also forms a buccolingually oriented elliptic arc in relation to the buccal cortex. Variations due to age, ethnicity, and gender were evident and this study provides an accurate anatomic zone for gaining surgical access to the IAN bundle. The findings indicate that the buccal cortex-IAN distance was greatest at D3. Therefore, sites between D2 and D5 can be used as favorable landmarks to access the IAN bundle with the least complications to the patient. PMID:24892077

  4. Microstructured Thin Film Nitinol for a Neurovascular Flow-Diverter

    NASA Astrophysics Data System (ADS)

    Chen, Yanfei; Howe, Connor; Lee, Yongkuk; Cheon, Seongsik; Yeo, Woon-Hong; Chun, Youngjae

    2016-03-01

    A cerebral aneurysm occurs as a result of a weakened blood vessel, which allows blood to flow into a sac or a ballooned section. Recent advancement shows that a new device, ‘flow-diverter’, can divert blood flow away from the aneurysm sac. People found that a flow-diverter based on thin film nitinol (TFN), works very effectively, however there are no studies proving the mechanical safety in irregular, curved blood vessels. Here, we study the mechanical behaviors and structural safety of a novel microstructured TFN membrane through the computational and experimental studies, which establish the fundamental aspects of stretching and bending mechanics of the structure. The result shows a hyper-elastic behavior of the TFN with a negligible strain change up to 180° in bending and over 500% in radial stretching, which is ideal in the use in neurovascular curved arteries. The simulation determines the optimal joint locations between the TFN and stent frame. In vitro experimental test qualitatively demonstrates the mechanical flexibility of the flow-diverter with multi-modal bending. In vivo micro X-ray and histopathology study demonstrate that the TFN can be conformally deployed in the curved blood vessel of a swine model without any significant complications or abnormalities.

  5. Microstructured Thin Film Nitinol for a Neurovascular Flow-Diverter.

    PubMed

    Chen, Yanfei; Howe, Connor; Lee, Yongkuk; Cheon, Seongsik; Yeo, Woon-Hong; Chun, Youngjae

    2016-01-01

    A cerebral aneurysm occurs as a result of a weakened blood vessel, which allows blood to flow into a sac or a ballooned section. Recent advancement shows that a new device, 'flow-diverter', can divert blood flow away from the aneurysm sac. People found that a flow-diverter based on thin film nitinol (TFN), works very effectively, however there are no studies proving the mechanical safety in irregular, curved blood vessels. Here, we study the mechanical behaviors and structural safety of a novel microstructured TFN membrane through the computational and experimental studies, which establish the fundamental aspects of stretching and bending mechanics of the structure. The result shows a hyper-elastic behavior of the TFN with a negligible strain change up to 180° in bending and over 500% in radial stretching, which is ideal in the use in neurovascular curved arteries. The simulation determines the optimal joint locations between the TFN and stent frame. In vitro experimental test qualitatively demonstrates the mechanical flexibility of the flow-diverter with multi-modal bending. In vivo micro X-ray and histopathology study demonstrate that the TFN can be conformally deployed in the curved blood vessel of a swine model without any significant complications or abnormalities. PMID:27009500

  6. Neurovascular factors in resting-state functional MRI

    PubMed Central

    Liu, Thomas T.

    2013-01-01

    There has been growing interest in the use of resting-state functional magnetic resonance imaging (rsfMRI) for the assessment of disease and treatment, and a number of studies have reported significant diseaserelated changes in resting-state blood oxygenation level dependent (BOLD) signal amplitude and functional connectivity. rsfMRI is particularly suitable for clinical applications because the approach does not require the patient to perform a task and scans can be obtained in a relatively short amount of time. However, the mechanisms underlying resting-state BOLD activity are not well understood and thus the interpretation of changes in resting state activity is not always straightforward. The BOLD signal represents the hemodynamic response to neural activity, and changes in resting-state activity can reflect a complex combination of neural, vascular, and metabolic factors. This paper examines the role of neurovascular factors in rsfMRI and reviews approaches for the interpretation and analysis of resting state measures in the presence of confounding factors. PMID:23644003

  7. Targeting the neurovascular unit for treatment of neurological disorders

    PubMed Central

    VanGilder, Reyna L.; Rosen, Charles L.; Barr, Taura L.; Huber, Jason D.

    2011-01-01

    Drug discovery for CNS disorders has been restricted by the inability for therapeutic agents to cross the blood-brain barrier (BBB). Moreover, current drugs aim to correct neuron cell signaling, thereby neglecting pathophysiological changes affecting other cell types of the neurovascular unit (NVU). Components of the NVU (pericytes, microglia, astrocytes, and neurons, and basal lamina) act as an intricate network to maintain the neuronal homeostatic microenvironment. Consequently, disruptions to this intricate cell network lead to neuron malfunction and symptoms characteristic of CNS diseases. A lack of understanding in NVU signaling cascades may explain why current treatments for CNS diseases are not curative. Current therapies treat symptoms by maintaining neuron function. Refocusing drug discovery to sustain NVU function may provide a better method of treatment by promoting neuron survival. In this review, we will examine current therapeutics for common CNS diseases, describe the importance of the NVU in cerebral homeostasis and discuss new possible drug targets and technologies that aim to improve treatment and drug delivery to the diseased brain. PMID:21172386

  8. Remodeling and Shuttling

    PubMed Central

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

    2016-01-01

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

  9. Vestibular paroxysmia: a treatable neurovascular cross-compression syndrome.

    PubMed

    Brandt, Thomas; Strupp, Michael; Dieterich, Marianne

    2016-04-01

    The leading symptoms of vestibular paroxysmia (VP) are recurrent, spontaneous, short attacks of spinning or non-spinning vertigo that generally last less than one minute and occur in a series of up to 30 or more per day. VP may manifest when arteries in the cerebellar pontine angle cause a segmental, pressure-induced dysfunction of the eighth nerve. The symptoms are usually triggered by direct pulsatile compression with ephaptic discharges, less often by conduction blocks. MR imaging reveals the neurovascular compression of the eighth nerve (3D constructive interference in steady state and 3D time-of-flight sequences) in more than 95 % of cases. A loop of the anterior inferior cerebellar artery seems to be most often involved, less so the posterior inferior cerebellar artery, the vertebral artery, or a vein. The frequent attacks of vertigo respond to carbamazepine or oxcarbazepine, even in low dosages (200-600 mg/d or 300-900 mg/d, respectively), which have been shown to also be effective in children. Alternative drugs to try are lamotrigine, phenytoin, gabapentin, topiramate or baclofen or other non-antiepileptic drugs used in trigeminal neuralgia. The results of ongoing randomized placebo-controlled treatment studies, however, are not yet available. Surgical microvascular decompression of the eighth nerve is the "ultima ratio" for medically intractable cases or in exceptional cases of non-vascular compression of the eighth nerve by a tumor or cyst. The International Barany Society for Neuro-Otology is currently working on a consensus document on the clinical criteria for establishing a diagnosis of VP as a clinical entity. PMID:27083889

  10. Adult Neurogenesis: Ultrastructure of a Neurogenic Niche and Neurovascular Relationships

    PubMed Central

    Chaves da Silva, Paula Grazielle; Benton, Jeanne L.; Beltz, Barbara S.; Allodi, Silvana

    2012-01-01

    neurovascular relationships in the brain of P. clarkii by characterizing the organization and ultrastructure of the neurogenic niche and associated vascular tissues. PMID:22723980

  11. 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.

  12. 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.

  13. Technetium 99m-methylene diphosphonate bone scans in children with reflex neurovascular dystrophy

    SciTech Connect

    Laxer, R.M.; Allen, R.C.; Malleson, P.N.; Morrison, R.T.; Petty, R.E.

    1985-03-01

    Eleven children with reflex neurovascular dystrophy were investigated by technetium-labeled methylene diphosphonate bone scanning. Eight of 12 scans demonstrated abnormal findings, four showing diffusely decreased uptake and four diffusely increased uptake of the radionuclide in the affected site. Three scans showed normal findings initially, as did one previously abnormal scan when repeated in the asymptomatic patient 6 months later. Diffusely abnormal findings can be helpful in the diagnosis of childhood reflex neurovascular dystrophy, but a normal scan does not exclude the diagnosis.

  14. 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.

  15. Preliminary methods for wearable neuro-vascular assessment with non-invasive, active sensing.

    PubMed

    Carek, Andrew M; Töreyin, Hakan; Hersek, Sinan; Inan, Omer T

    2015-01-01

    In this study, a non-invasive and active sensing scheme that is ultimately aimed to be integrated in a wearable system for neuro-vascular health assessment is presented with preliminary results. With this system, vascular tone is modulated by local heating and cooling of the palm, and the resulting changes in local hemodynamics are monitored via impedance plethysmography (IPG) and photoplethysmography (PPG) sensors interfaced with custom analog electronics. Proof-of-concept measurements were conducted on three subjects using hot packs/ice bags to modulate the palmar skin temperature. From ensemble averaged and smoothed versions of pulsatile IPG and PPG signals, the effects of local changes in skin temperature on a series of parameters associated with neuro-vascular mechanisms (heart rate, blood volume, blood flow rate, blood volume pulse inflection point area ratio, and local pulse transit time) have been observed. The promising experimental results suggest that, with different active temperature modulation schemes (consisting of heating/cooling cycles covering different temperature ranges at different rates), it would be possible to enhance the depth and specificity of the information associated with neuro-vascular health by using biosensors that can fit inside a wearable device (such as a sleeve). This study sets the foundation for future studies on designing and testing such a wearable neuro-vascular health assessment system employing active sensing. PMID:26736951

  16. Control of the neurovascular coupling by nitric oxide-dependent regulation of astrocytic Ca2+ signaling

    PubMed Central

    Muñoz, Manuel F.; Puebla, Mariela; Figueroa, Xavier F.

    2015-01-01

    Neuronal activity must be tightly coordinated with blood flow to keep proper brain function, which is achieved by a mechanism known as neurovascular coupling. Then, an increase in synaptic activity leads to a dilation of local parenchymal arterioles that matches the enhanced metabolic demand. Neurovascular coupling is orchestrated by astrocytes. These glial cells are located between neurons and the microvasculature, with the astrocytic endfeet ensheathing the vessels, which allows fine intercellular communication. The neurotransmitters released during neuronal activity reach astrocytic receptors and trigger a Ca2+ signaling that propagates to the endfeet, activating the release of vasoactive factors and arteriolar dilation. The astrocyte Ca2+ signaling is coordinated by gap junction channels and hemichannels formed by connexins (Cx43 and Cx30) and channels formed by pannexins (Panx-1). The neuronal activity-initiated Ca2+ waves are propagated among neighboring astrocytes directly via gap junctions or through ATP release via connexin hemichannels or pannexin channels. In addition, Ca2+ entry via connexin hemichannels or pannexin channels may participate in the regulation of the astrocyte signaling-mediated neurovascular coupling. Interestingly, nitric oxide (NO) can activate connexin hemichannel by S-nitrosylation and the Ca2+-dependent NO-synthesizing enzymes endothelial NO synthase (eNOS) and neuronal NOS (nNOS) are expressed in astrocytes. Therefore, the astrocytic Ca2+ signaling triggered in neurovascular coupling may activate NO production, which, in turn, may lead to Ca2+ influx through hemichannel activation. Furthermore, NO release from the hemichannels located at astrocytic endfeet may contribute to the vasodilation of parenchymal arterioles. In this review, we discuss the mechanisms involved in the regulation of the astrocytic Ca2+ signaling that mediates neurovascular coupling, with a special emphasis in the possible participation of NO in this process

  17. Redox regulation of vascular remodeling.

    PubMed

    Karimi Galougahi, Keyvan; Ashley, Euan A; Ali, Ziad A

    2016-01-01

    Vascular remodeling is a dynamic process of structural and functional changes in response to biochemical and biomechanical signals in a complex in vivo milieu. While inherently adaptive, dysregulation leads to maladaptive remodeling. Reactive oxygen species participate in homeostatic cell signaling in tightly regulated- and compartmentalized cellular circuits. It is well established that perturbations in oxidation-reduction (redox) homeostasis can lead to a state of oxidative-, and more recently, reductive stress. We provide an overview of the redox signaling in the vasculature and review the role of oxidative- and reductive stress in maladaptive vascular remodeling. Particular emphasis has been placed on essential processes that determine phenotype modulation, migration and fate of the main cell types in the vessel wall. Recent advances in systems biology and the translational opportunities they may provide to specifically target the redox pathways driving pathological vascular remodeling are discussed. PMID:26483132

  18. Plant cell remodeling by autophagy

    PubMed Central

    Kim, Jimi; Lee, Han Nim; Chung, Taijoon

    2014-01-01

    Plant seedlings are not photoautotrophs until they are equipped with photosynthetic machinery. Some plant cells are remodeled after being exposed to light, and a group of peroxisomal proteins are degraded during the remodeling. Autophagy was proposed as one of the mechanisms for the degradation of peroxisomal proteins. We recently showed that ATG7-dependent autophagy is partially responsible for the degradation of obsolete peroxisomal proteins during Arabidopsis seedling growth. PMID:24492493

  19. Anti-Siglec-F Antibody Reduces Allergen-Induced Eosinophilic Inflammation and Airway Remodeling1

    PubMed Central

    Song, Dae Jin; Cho, Jae Youn; Lee, Sang Yeub; Miller, Marina; Rosenthal, Peter; Soroosh, Pejman; Croft, Michael; Zhang, Mai; Varki, Ajit; Broide, David H.

    2009-01-01

    Siglec-F is a sialic acid-binding Ig superfamily receptor that is highly expressed on eosinophils. We have investigated whether administration of an anti-Siglec-F Ab to OVA-challenged wild-type mice would reduce levels of eosinophilic inflammation and levels of airway remodeling. Mice sensitized to OVA and challenged repetitively with OVA for 1 mo who were administered an anti-Siglec-F Ab had significantly reduced levels of peribronchial eosinophilic inflammation and significantly reduced levels of subepithelial fibrosis as assessed by either trichrome staining or lung collagen levels. The anti-Siglec-F Ab reduced the number of bone marrow, blood, and tissue eosinophils, suggesting that the anti-Siglec-F Ab was reducing the production of eosinophils. Administration of a F(ab′)2 fragment of an anti-Siglec-F Ab also significantly reduced levels of eosinophilic inflammation in the lung and blood. FACS analysis demonstrated increased numbers of apoptotic cells (annexin V+/CCR3+ bronchoalveolar lavage and bone marrow cells) in anti-Siglec-F Ab-treated mice challenged with OVA. The anti-Siglec-F Ab significantly reduced the number of peribronchial major basic protein+/TGF-β+ cells, suggesting that reduced levels of eosinophil-derived TGF-β in anti-Siglec-F Ab-treated mice contributed to reduced levels of peribronchial fibrosis. Administration of the anti-Siglec-F Ab modestly reduced levels of periodic acid-Schiff-positive mucus cells and the thickness of the smooth muscle layer. Overall, these studies suggest that administration of an anti-Siglec-F Ab can significantly reduce levels of allergen-induced eosinophilic airway inflammation and features of airway remodeling, in particular subepithelial fibrosis, by reducing the production of eosinophils and increasing the number of apoptotic eosinophils in lung and bone marrow. PMID:19783675

  20. Neurovascular pathways to neurodegeneration in Alzheimer’s disease and other disorders

    PubMed Central

    Zlokovic, Berislav V.

    2014-01-01

    The neurovascular unit (NVU) comprises brain endothelial cells, pericytes or vascular smooth muscle cells, glia and neurons. The NVU controls blood–brain barrier (BBB) permeability and cerebral blood flow, and maintains the chemical composition of the neuronal ‘milieu’, which is required for proper functioning of neuronal circuits. Recent evidence indicates that BBB dysfunction is associated with the accumulation of several vasculotoxic and neurotoxic molecules within brain parenchyma, a reduction in cerebral blood flow, and hypoxia. Together, these vascular-derived insults might initiate and/or contribute to neuronal degeneration. This article examines mechanisms of BBB dysfunction in neurodegenerative disorders, notably Alzheimer’s disease, and highlights therapeutic opportunities relating to these neurovascular deficits. PMID:22048062

  1. Cerebellopontine angle and internal auditory canal: neurovascular anatomy on gas CT cisternograms

    SciTech Connect

    Bird, C.R.; Hasso, A.N.; Drayer, B.P.; Hinshaw, D.B. Jr.; Thompson, J.R.

    1985-03-01

    The authors reviewed 103 normal gas CT cisternograms to delineate the appearance of normal neurovascular structures in the cerebellopontine angle (CPA) and internal auditory canal (IAC). Cranial nerves VII and VIII were identified in the CPA in 97% of cases, either separately (53%) or as a bundle (44%). Intracanalicular branches of the VIIIth cranial nerve were identified in 20% of cases, and cranial nerve V was visualized in the CPA in 14%. The characteristic vascular loop, usually the anterior inferior cerebellar artery, was visible in 35% of cases, and, in 22% of visualized cases, was in an intracanalicular location. In 10% of cases, greater than 66% of the IAC was occupied by the neurovascular bundle. Familiarity with the normal anatomy and variations seen on gas CT cisternograms is necessary to prevent false-positive interpretations.

  2. Neurovascular and Immuno-Imaging: From Mechanisms to Therapies. Proceedings of the Inaugural Symposium

    PubMed Central

    Akassoglou, Katerina; Agalliu, Dritan; Chang, Christopher J.; Davalos, Dimitrios; Grutzendler, Jaime; Hillman, Elizabeth M. C.; Khakh, Baljit S.; Kleinfeld, David; McGavern, Dorian B.; Nelson, Sarah J.; Zlokovic, Berislav V.

    2016-01-01

    Breakthrough advances in intravital imaging have launched a new era for the study of dynamic interactions at the neurovascular interface in health and disease. The first Neurovascular and Immuno-Imaging Symposium was held at the Gladstone Institutes, University of California, San Francisco in March, 2015. This highly interactive symposium brought together a group of leading researchers who discussed how recent studies have unraveled fundamental biological mechanisms in diverse scientific fields such as neuroscience, immunology, and vascular biology, both under physiological and pathological conditions. These Proceedings highlight how advances in imaging technologies and their applications revolutionized our understanding of the communication between brain, immune, and vascular systems and identified novel targets for therapeutic intervention in neurological diseases. PMID:26941593

  3. EMCCD-Based High Resolution Dynamic X-Ray Detector for Neurovascular Interventions

    PubMed Central

    Sharma, P.; Vasan, S.N. Swetadri; Jain, A.; Panse, A.; Titus, A.H.; Cartwright, A. N.; Bednarek, D. R; Rudin, S.

    2012-01-01

    We have designed and developed from the discrete component level a high resolution dynamic detector for neurovascular interventions. The heart of the detector is a 1024 × 1024 pixel electron multiplying charge coupled device (EMCCD) with a pixel size of 13 × 13 μm2, bonded to a fiber optic plate (FOP), and optically coupled to a 350 μm micro-columnar CsI(TI) scintillator via a 3.3:1 fiber optic taper (FOT). The detector provides x-ray images of 9 cycles/mm resolution at 15 frames/sec and real time live video at 30 frames/sec with binning at a lower resolution, both independent of gain applied to EMCCD, as needed for region-of-interest (ROI) image guidance during neurovascular interventions. PMID:22256144

  4. Neurovascular and Immuno-Imaging: From Mechanisms to Therapies. Proceedings of the Inaugural Symposium.

    PubMed

    Akassoglou, Katerina; Agalliu, Dritan; Chang, Christopher J; Davalos, Dimitrios; Grutzendler, Jaime; Hillman, Elizabeth M C; Khakh, Baljit S; Kleinfeld, David; McGavern, Dorian B; Nelson, Sarah J; Zlokovic, Berislav V

    2016-01-01

    Breakthrough advances in intravital imaging have launched a new era for the study of dynamic interactions at the neurovascular interface in health and disease. The first Neurovascular and Immuno-Imaging Symposium was held at the Gladstone Institutes, University of California, San Francisco in March, 2015. This highly interactive symposium brought together a group of leading researchers who discussed how recent studies have unraveled fundamental biological mechanisms in diverse scientific fields such as neuroscience, immunology, and vascular biology, both under physiological and pathological conditions. These Proceedings highlight how advances in imaging technologies and their applications revolutionized our understanding of the communication between brain, immune, and vascular systems and identified novel targets for therapeutic intervention in neurological diseases. PMID:26941593

  5. New horizons in neurometabolic and neurovascular coupling from calibrated fMRI.

    PubMed

    Shu, C Y; Sanganahalli, B G; Coman, D; Herman, P; Hyder, F

    2016-01-01

    Neurovascular coupling relates changes in neuronal activity to constriction/dilation of microvessels. However neurometabolic coupling, which is less well known, relates alterations in neuronal activity with metabolic demands. The link between the blood oxygenation level dependent (BOLD) signal and neural activity opened doors for functional MRI (fMRI) to be a powerful neuroimaging tool in the neurosciences. But due to the complex makeup of BOLD contrast, researchers began to investigate the relationship between BOLD signal and blood flow and/or volume changes during functional brain activation, which together provided the tools to measure oxygen consumption on the basis of the biophysical model of BOLD. This field is called calibrated fMRI, thereby allowed probing of both neurometabolic and neurovascular couplings for a variety of health conditions in animals and humans. Calibrated fMRI may provide brain disorder biomarkers that could be used for monitoring effective therapies. PMID:27130413

  6. Neurovascular coupling during nociceptive processing in the primary somatosensory cortex of the rat.

    PubMed

    Jeffrey-Gauthier, Renaud; Guillemot, Jean-Paul; Piché, Mathieu

    2013-08-01

    Neuroimaging methods such as functional magnetic resonance imaging (fMRI) have been used extensively to investigate pain-related cerebral mechanisms. However, these methods rely on a tight coupling of neuronal activity to hemodynamic changes. Because pain may be associated with hemodynamic changes unrelated to local neuronal activity (eg, increased mean arterial pressure [MAP]), it is essential to determine whether the neurovascular coupling is maintained during nociceptive processing. In this study, local field potentials (LFP) and cortical blood flow (CBF) changes evoked by electrical stimulation of the left hind paw were recorded concomitantly in the right primary somatosensory cortex (SI) in 15 rats. LFP, CBF, and MAP changes were examined in response to stimulus intensities ranging from 3 to 30 mA. In addition, LFP, CBF, and MAP changes evoked by a 10-mA stimulation were examined during immersion of the tail in non-nociceptive or nociceptive hot water (counter-stimulation). SI neurovascular coupling was altered for stimuli of nociceptive intensities (P<0.001). This alteration was intensity-dependent and was strongly associated with MAP changes (r=0.98, P<0.001). However, when the stimulus intensity was kept constant, SI neurovascular coupling was not significantly affected by nociceptive counter-stimulation (P=0.4), which similarly affected the amplitude of shock-evoked LFP and CBF changes. It remains to be determined whether such neurovascular uncoupling occurs in humans, and whether it also affects other regions usually activated by painful stimuli. These results should be taken into account for accurate interpretation of fMRI studies that involve nociceptive stimuli associated with MAP changes. PMID:23707276

  7. Classification of neurovascular compression in glossopharyngeal neuralgia: Three-dimensional visualization of the glossopharyngeal nerve

    PubMed Central

    Tanrikulu, Levent; Hastreiter, Peter; Dörfler, Arnd; Buchfelder, Michael; Naraghi, Ramin

    2015-01-01

    Background: We introduce a method of noninvasive topographical analysis of the neurovascular relationships of the glossopharyngeal nerve (CN IX) by three-dimensional (3D) visualization. Patients with glossopharyngeal neuralgia (GN) resulting from neurovascular compression (NVC) were studied. Methods: 15 patients with GN were prospectively examined with 3D visualization using high-resolution magnetic resonance imaging with constructive interference in steady state (MR-CISS). The datasets were segmented and visualized with the real, individual neurovascular relationships by direct volume rendering. Segmentation and 3D visualization of the CN IX and corresponding blood vessels were performed. The 3D visualizations were interactively compared with the intraoperative setup during microvascular decompression (MVD) in order to verify the results by the observed surgical-anatomical findings. Results: 15 patients (female/male: 5/10) were examined. All of them underwent MVD (100%). Microvascular details were documented. The posterior inferior cerebellar artery (PICA) was the most common causative vessel in 12 of 15 patients (80%), the vertebral artery (VA) alone in one case (6.7%), and the combination of compression by the VA and PICA in 3 patients (13.3%). We identified three distinct types of NVC within the root entry zone of CN IX. Conclusion: 3D visualization by direct volume rendering of MR-CISS data offers the opportunity of noninvasive exploration and anatomical categorization of the CN IX. It proves to be advantageous in supporting to establish the diagnosis and microneurosurgical interventions by representing original, individual patient data in a 3D fashion. It provides an excellent global individual view over the entire neurovascular relationships of the brainstem and corresponding nerves in each case. PMID:26759734

  8. Early effects of high-fat diet on neurovascular function and focal ischemic brain injury.

    PubMed

    Li, Weiguo; Prakash, Roshini; Chawla, Dhruv; Du, Wenting; Didion, Sean P; Filosa, Jessica A; Zhang, Quanguang; Brann, Darrell W; Lima, Victor V; Tostes, Rita C; Ergul, Adviye

    2013-06-01

    Obesity is a risk factor for stroke, but the early effects of high-fat diet (HFD) on neurovascular function and ischemic stroke outcomes remain unclear. The goal of this study was to test the hypotheses that HFD beginning early in life 1) impairs neurovascular coupling, 2) causes cerebrovascular dysfunction, and 3) worsens short-term outcomes after cerebral ischemia. Functional hyperemia and parenchymal arteriole (PA) reactivity were measured in rats after 8 wk of HFD. The effect of HFD on basilar artery function after middle cerebral artery occlusion (MCAO) and associated O-GlcNAcylation were assessed. Neuronal cell death, infarct size, hemorrhagic transformation (HT) frequency/severity, and neurological deficit were evaluated after global ischemia and transient MCAO. HFD caused a 10% increase in body weight and doubled adiposity without a change in lipid profile, blood glucose, and blood pressure. Functional hyperemia and PA relaxation were decreased with HFD. Basilar arteries from stroked HFD rats were more sensitive to contractile factors, and acetylcholine-mediated relaxation was impaired. Vascular O-GlcNAcylated protein content was increased with HFD. This group also showed greater mortality rate, infarct volume, HT occurrence rate, and HT severity and poor functional outcome compared with the control diet group. These results indicate that HFD negatively affects neurovascular coupling and cerebrovascular function even in the absence of dyslipidemia. These early cerebrovascular changes may be the cause of greater cerebral injury and poor outcomes of stroke in these animals. PMID:23576615

  9. Glial cells dilate and constrict blood vessels: a mechanism of neurovascular coupling.

    PubMed

    Metea, Monica R; Newman, Eric A

    2006-03-15

    Neuronal activity evokes localized changes in blood flow. Although this response, termed neurovascular coupling, is widely used to monitor human brain function and diagnose pathology, the cellular mechanisms that mediate the response remain unclear. We investigated the contribution of glial cells to neurovascular coupling in the acutely isolated mammalian retina. We found that light stimulation and glial cell stimulation can both evoke dilation or constriction of arterioles. Light-evoked and glial-evoked vasodilations were blocked by inhibitors of cytochrome P450 epoxygenase, the synthetic enzyme for epoxyeicosatrienoic acids. Vasoconstrictions, in contrast, were blocked by an inhibitor of omega-hydroxylase, which synthesizes 20-hydroxyeicosatetraenoic acid. Nitric oxide influenced whether vasodilations or vasoconstrictions were produced in response to light and glial stimulation. Light-evoked vasoactivity was blocked when neuron-to-glia signaling was interrupted by a purinergic antagonist. These results indicate that glial cells contribute to neurovascular coupling and suggest that regulation of blood flow may involve both vasodilating and vasoconstricting components. PMID:16540563

  10. Early effects of high-fat diet on neurovascular function and focal ischemic brain injury

    PubMed Central

    Li, Weiguo; Prakash, Roshini; Chawla, Dhruv; Du, Wenting; Didion, Sean P.; Filosa, Jessica A.; Zhang, Quanguang; Brann, Darrell W.; Lima, Victor V.; Tostes, Rita C.

    2013-01-01

    Obesity is a risk factor for stroke, but the early effects of high-fat diet (HFD) on neurovascular function and ischemic stroke outcomes remain unclear. The goal of this study was to test the hypotheses that HFD beginning early in life 1) impairs neurovascular coupling, 2) causes cerebrovascular dysfunction, and 3) worsens short-term outcomes after cerebral ischemia. Functional hyperemia and parenchymal arteriole (PA) reactivity were measured in rats after 8 wk of HFD. The effect of HFD on basilar artery function after middle cerebral artery occlusion (MCAO) and associated O-GlcNAcylation were assessed. Neuronal cell death, infarct size, hemorrhagic transformation (HT) frequency/severity, and neurological deficit were evaluated after global ischemia and transient MCAO. HFD caused a 10% increase in body weight and doubled adiposity without a change in lipid profile, blood glucose, and blood pressure. Functional hyperemia and PA relaxation were decreased with HFD. Basilar arteries from stroked HFD rats were more sensitive to contractile factors, and acetylcholine-mediated relaxation was impaired. Vascular O-GlcNAcylated protein content was increased with HFD. This group also showed greater mortality rate, infarct volume, HT occurrence rate, and HT severity and poor functional outcome compared with the control diet group. These results indicate that HFD negatively affects neurovascular coupling and cerebrovascular function even in the absence of dyslipidemia. These early cerebrovascular changes may be the cause of greater cerebral injury and poor outcomes of stroke in these animals. PMID:23576615

  11. The sectional anatomy of the carpal tunnel and its related neurovascular structures studied by using plastination.

    PubMed

    Sora, M-C; Genser-Strobl, B

    2005-05-01

    The aim of this study was to evaluate the morphology of the carpal tunnel and its related neurovascular structures. A slice anatomy study was performed on 12 right wrists of unfixed human cadavers by using the plastination technique. The measurements were performed at the level of the pisiform, hook of the hamate and in the middle between these structures. The diameters of the carpal tunnel and the median nerve were measured at the level of the hook of the hamate. The median nerve can be predicted to be 18 +/- 1.6 mm radial to the pisiform and the ulnar neurovascular bundle 6.8 +/- 1.4 mm radial to the pisiform. Between those structures there will be at least a 9-mm area, localized 8 mm radial to the pisiform, where the incision of the transverse carpal ligament could be performed risk-free. At the hamate hook the median nerve can be predicted at 9.24 +/- 1.18 mm and the ulnar artery lies usually 1.26 +/- 2.5 mm radial to the hook. An understanding of the contents and their positions, and relationships to each other allows an accurate identification of neurovascular structures in the carpal tunnel. Our findings can be used as anatomic landmarks of the carpal tunnel and could be helpful to physicians performing carpal tunnel investigations. PMID:15804269

  12. Modeling Neurovascular Coupling from Clustered Parameter Sets for Multimodal EEG-NIRS

    PubMed Central

    Talukdar, M. Tanveer; Frost, H. Robert; Diamond, Solomon G.

    2015-01-01

    Despite significant improvements in neuroimaging technologies and analysis methods, the fundamental relationship between local changes in cerebral hemodynamics and the underlying neural activity remains largely unknown. In this study, a data driven approach is proposed for modeling this neurovascular coupling relationship from simultaneously acquired electroencephalographic (EEG) and near-infrared spectroscopic (NIRS) data. The approach uses gamma transfer functions to map EEG spectral envelopes that reflect time-varying power variations in neural rhythms to hemodynamics measured with NIRS during median nerve stimulation. The approach is evaluated first with simulated EEG-NIRS data and then by applying the method to experimental EEG-NIRS data measured from 3 human subjects. Results from the experimental data indicate that the neurovascular coupling relationship can be modeled using multiple sets of gamma transfer functions. By applying cluster analysis, statistically significant parameter sets were found to predict NIRS hemodynamics from EEG spectral envelopes. All subjects were found to have significant clustered parameters (P < 0.05) for EEG-NIRS data fitted using gamma transfer functions. These results suggest that the use of gamma transfer functions followed by cluster analysis of the resulting parameter sets may provide insights into neurovascular coupling in human neuroimaging data. PMID:26089979

  13. Memories of AB

    NASA Astrophysics Data System (ADS)

    Vaks, V. G.

    2013-06-01

    I had the good fortune to be a student of A. B. Migdal - AB, as we called him in person or in his absence - and to work in the sector he headed at the Kurchatov Institute, along with his other students and my friends, including Vitya Galitsky, Spartak Belyayev and Tolya Larkin. I was especially close with AB in the second half of the 1950s, the years most important for my formation, and AB's contribution to this formation was very great. To this day, I've often quoted AB on various occasions, as it's hard to put things better or more precisely than he did; I tell friends stories heard from AB, because these stories enhance life as AB himself enhanced it; my daughter is named Tanya after AB's wife Tatyana Lvovna, and so on. In what follows, I'll recount a few episodes in my life in which AB played an important or decisive role, and then will share some other memories of AB...

  14. Rho Kinases and Cardiac Remodeling.

    PubMed

    Shimizu, Toru; Liao, James K

    2016-06-24

    Hypertensive cardiac remodeling is characterized by left ventricular hypertrophy and interstitial fibrosis, which can lead to heart failure with preserved ejection fraction. The Rho-associated coiled-coil containing kinases (ROCKs) are members of the serine/threonine protein kinase family, which mediates the downstream effects of the small GTP-binding protein RhoA. There are 2 isoforms: ROCK1 and ROCK2. They have different functions in different types of cells and tissues. There is growing evidence that ROCKs contribute to the development of cardiovascular diseases, including cardiac fibrosis, hypertrophy, and subsequent heart failure. Recent experimental studies using ROCK inhibitors, such as fasudil, have shown the benefits of ROCK inhibition in cardiac remodeling. Mice lacking each ROCK isoform also exhibit reduced myocardial fibrosis in a variety of pathological models of cardiac remodeling. Indeed, clinical studies with fasudil have suggested that ROCKs could be potential novel therapeutic targets for cardiovascular diseases. In this review, we summarize the current understanding of the roles of ROCKs in the development of cardiac fibrosis and hypertrophy and discuss their therapeutic potential for deleterious cardiac remodeling. (Circ J 2016; 80: 1491-1498). PMID:27251065

  15. Aerobic exercise training promotes physiological cardiac remodeling involving a set of microRNAs

    PubMed Central

    Fernandes, Tiago; Baraúna, Valério G.; Negrão, Carlos E.; Phillips, M. Ian

    2015-01-01

    Left ventricular (LV) hypertrophy is an important physiological compensatory mechanism in response to chronic increase in hemodynamic overload. There are two different forms of LV hypertrophy, one physiological and another pathological. Aerobic exercise induces beneficial physiological LV remodeling. The molecular/cellular mechanisms for this effect are not totally known, and here we review various mechanisms including the role of microRNA (miRNA). Studies in the heart, have identified antihypertrophic miRNA-1, -133, -26, -9, -98, -29, -378, and -145 and prohypertrophic miRNA-143, -103, -130a, -146a, -21, -210, -221, -222, -27a/b, -199a/b, -208, -195, -499, -34a/b/c, -497, -23a, and -15a/b. Four miRNAs are recognized as cardiac-specific: miRNA-1, -133a/b, -208a/b, and -499 and called myomiRs. In our studies we have shown that miRNAs respond to swimming aerobic exercise by 1) decreasing cardiac fibrosis through miRNA-29 increasing and inhibiting collagen, 2) increasing angiogenesis through miRNA-126 by inhibiting negative regulators of the VEGF pathway, and 3) modulating the renin-angiotensin system through the miRNAs-27a/b and -143. Exercise training also increases cardiomyocyte growth and survival by swimming-regulated miRNA-1, -21, -27a/b, -29a/c, -30e, -99b, -100, -124, -126, -133a/b, -143, -144, -145, -208a, and -222 and running-regulated miRNA-1, -26, -27a, -133, -143, -150, and -222, which influence genes associated with the heart remodeling and angiogenesis. We conclude that there is a potential role of these miRNAs in promoting cardioprotective effects on physiological growth. PMID:26071549

  16. The Brain’s Heart – Therapeutic Opportunities for Patent Foramen Ovale (PFO) and Neurovascular Disease

    PubMed Central

    Ning, MingMing; Lo, Eng H.; Ning, Pei-Chen; Xu, Su-Yu; McMullin, David; Demirjian, Zareh; Inglessis, Ignacio; Dec, G William; Palacios, Igor; Buonanno, Ferdinando S.

    2013-01-01

    Patent foramen ovale (PFO), a common congenital cardiac abnormality, is a connection between the right and left atria in the heart. As a “back door to the brain”, PFO can serve as a conduit for paradoxical embolism, allowing venous thrombi to enter the arterial circulation, avoiding filtration by the lungs, and causing ischemic stroke. PFO-related strokes affect more than 150,000 people per year in the US, and PFO is present in up to 60% of migraine patients with aura, and in one out of four normal individuals. So, in such a highly prevalent condition, what are the best treatment and prevention strategies? Emerging studies show PFO-related neurovascular disease to be a multi-organ condition with varying individual risk factors that may require individualized therapeutic approaches – opening the field for new pharmacologic and therapeutic targets. The anatomy of PFO suggests that, in addition to thrombi, it can also allow harmful circulatory factors to travel directly from the venous to the arterial circulation, a concept important in finding novel therapeutic targets for PFO-related neurovascular injury. Here, we: 1) review emerging data on PFO-related injuries and clinical trials; 2) discuss potential mechanisms of PFO-related neurovascular disease in the context of multi-organ interaction and heart-brain signaling; and 3) discuss novel therapeutic targets and research frontiers. Clinical studies and molecular mapping of the circulatory landscape of this multi-organ disease will both be necessary in order to better individualize clinical treatment for a condition affecting more than a quarter of the world’s population. PMID:23528225

  17. Neurovascular and neuroimaging effects of the hallucinogenic serotonin receptor agonist psilocin in the rat brain.

    PubMed

    Spain, Aisling; Howarth, Clare; Khrapitchev, Alexandre A; Sharp, Trevor; Sibson, Nicola R; Martin, Chris

    2015-12-01

    The development of pharmacological magnetic resonance imaging (phMRI) has presented the opportunity for investigation of the neurophysiological effects of drugs in vivo. Psilocin, a hallucinogen metabolised from psilocybin, was recently reported to evoke brain region-specific, phMRI signal changes in humans. The present study investigated the effects of psilocin in a rat model using phMRI and then probed the relationship between neuronal and haemodynamic responses using a multimodal measurement preparation. Psilocin (2 mg/kg or 0.03 mg/kg i.v.) or vehicle was administered to rats (N=6/group) during either phMRI scanning or concurrent imaging of cortical blood flow and recording of local field potentials. Compared to vehicle controls psilocin (2 mg/kg) evoked phMRI signal increases in a number of regions including olfactory and limbic areas and elements of the visual system. PhMRI signal decreases were seen in other regions including somatosensory and motor cortices. Investigation of neurovascular coupling revealed that whilst neuronal responses (local field potentials) to sensory stimuli were decreased in amplitude by psilocin administration, concurrently measured haemodynamic responses (cerebral blood flow) were enhanced. The present findings show that psilocin evoked region-specific changes in phMRI signals in the rat, confirming recent human data. However, the results also suggest that the haemodynamic signal changes underlying phMRI responses reflect changes in both neuronal activity and neurovascular coupling. This highlights the importance of understanding the neurovascular effects of pharmacological manipulations for interpreting haemodynamic neuroimaging data. PMID:26192543

  18. Neurovascular and neuroimaging effects of the hallucinogenic serotonin receptor agonist psilocin in the rat brain

    PubMed Central

    Spain, Aisling; Howarth, Clare; Khrapitchev, Alexandre A.; Sharp, Trevor; Sibson, Nicola R.; Martin, Chris

    2015-01-01

    The development of pharmacological magnetic resonance imaging (phMRI) has presented the opportunity for investigation of the neurophysiological effects of drugs in vivo. Psilocin, a hallucinogen metabolised from psilocybin, was recently reported to evoke brain region-specific, phMRI signal changes in humans. The present study investigated the effects of psilocin in a rat model using phMRI and then probed the relationship between neuronal and haemodynamic responses using a multimodal measurement preparation. Psilocin (2 mg/kg or 0.03 mg/kg i.v.) or vehicle was administered to rats (N = 6/group) during either phMRI scanning or concurrent imaging of cortical blood flow and recording of local field potentials. Compared to vehicle controls psilocin (2 mg/kg) evoked phMRI signal increases in a number of regions including olfactory and limbic areas and elements of the visual system. PhMRI signal decreases were seen in other regions including somatosensory and motor cortices. Investigation of neurovascular coupling revealed that whilst neuronal responses (local field potentials) to sensory stimuli were decreased in amplitude by psilocin administration, concurrently measured haemodynamic responses (cerebral blood flow) were enhanced. The present findings show that psilocin evoked region-specific changes in phMRI signals in the rat, confirming recent human data. However, the results also suggest that the haemodynamic signal changes underlying phMRI responses reflect changes in both neuronal activity and neurovascular coupling. This highlights the importance of understanding the neurovascular effects of pharmacological manipulations for interpreting haemodynamic neuroimaging data. PMID:26192543

  19. Regional differences in neurovascular coupling in rat brain as determined by fMRI and electrophysiology.

    PubMed

    Sloan, H L; Austin, V C; Blamire, A M; Schnupp, J W H; Lowe, A S; Allers, K A; Matthews, P M; Sibson, N R

    2010-11-01

    Increases in neuronal activity induce local increases in cerebral perfusion. However, our understanding of the processes underlying this neurovascular coupling remains incomplete and, particularly, how these vary across the brain. Recent work supports an important role for astrocytes in neurovascular coupling, in large part via activation of their metabotropic glutamate receptors (mGluR). Here, using a combination of functional magnetic resonance imaging (fMRI) and electrophysiology we demonstrate regional heterogeneity in the mechanisms underlying neurovascular coupling. Direct electrical stimulation of the rat hindpaw sensorimotor cortex induces blood oxygenation level dependent (BOLD) and cerebral blood volume (CBV) fMRI responses in several anatomically distinct cortical and subcortical structures. Following intraperitoneal administration of the type 5 mGluR antagonist, MPEP, both BOLD and CBV responses to cortical stimulation were significantly reduced, whilst the local field potential (LFP) responses remained largely constant. Spatially, the degree of reduction in fMRI responses varied between cortical and subcortical regions (primary cortex approximately 18% vs. striatum approximately 66%), and also between primary and secondary cortical areas ( approximately 18% vs. approximately 55%). Similarly, greater decreases in response amplitude were seen in the contralateral secondary cortex ( approximately 91%) and ipsilateral striatum (approximately 70%), compared to the primary cortex (approximately 44%). Following MPEP, a negative component of the BOLD and CBV responses became more apparent, suggesting that different mechanisms mediate vasodilatory and vasoconstrictory responses. Interestingly, under baseline conditions the quantitative relationship between fMRI and LFP responses in cortical and subcortical regions was markedly different. Our data indicate that coupling between neuronal and fMRI responses is neither empirically nor mechanistically consistent

  20. Acute Resveratrol Consumption Improves Neurovascular Coupling Capacity in Adults with Type 2 Diabetes Mellitus

    PubMed Central

    Wong, Rachel H.X.; Raederstorff, Daniel; Howe, Peter R.C.

    2016-01-01

    Background: Poor cerebral perfusion may contribute to cognitive impairment in type 2 diabetes mellitus (T2DM). We conducted a randomized controlled trial to test the hypothesis that resveratrol can enhance cerebral vasodilator function and thereby alleviate the cognitive deficits in T2DM. We have already reported that acute resveratrol consumption improved cerebrovascular responsiveness (CVR) to hypercapnia. We now report the effects of resveratrol on neurovascular coupling capacity (CVR to cognitive stimuli), cognitive performance and correlations with plasma resveratrol concentrations. Methods: Thirty-six T2DM adults aged 40–80 years were randomized to consume single doses of resveratrol (0, 75, 150 and 300 mg) at weekly intervals. Transcranial Doppler ultrasound was used to monitor changes in blood flow velocity (BFV) during a cognitive test battery. The battery consisted of dual-tasking (finger tapping with both Trail Making task and Serial Subtraction 3 task) and a computerized multi-tasking test that required attending to four tasks simultaneously. CVR to cognitive tasks was calculated as the per cent increase in BFV from pre-test basal to peak mean blood flow velocity and also as the area under the curve for BFV. Results: Compared to placebo, 75 mg resveratrol significantly improved neurovascular coupling capacity, which correlated with plasma total resveratrol levels. Enhanced performance on the multi-tasking test battery was also evident following 75 mg and 300 mg of resveratrol. Conclusion: a single 75 mg dose of resveratrol was able to improve neurovascular coupling and cognitive performance in T2DM. Evaluation of benefits of chronic resveratrol supplementation is now warranted. PMID:27420093

  1. Frontiers in growth and remodeling.

    PubMed

    Menzel, Andreas; Kuhl, Ellen

    2012-06-01

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

  2. 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

  3. Advances in understanding cartilage remodeling

    PubMed Central

    Li, Yefu; Xu, Lin

    2015-01-01

    Cartilage remodeling is currently among the most popular topics in osteoarthritis research. Remodeling includes removal of the existing cartilage and replacement by neo-cartilage. As a loss of balance between removal and replacement of articular cartilage develops (particularly, the rate of removal surpasses the rate of replacement), joints will begin to degrade. In the last few years, significant progress in molecular understanding of the cartilage remodeling process has been made. In this brief review, we focus on the discussion of some current “controversial” observations in articular cartilage degeneration: (1) the biological effect of transforming growth factor-beta 1 on developing and mature articular cartilages, (2) the question of whether aggrecanase 1 (ADAMTS4) and aggrecanase 2 (ADAMTS5) are key enzymes in articular cartilage destruction, and (3) chondrocytes versus chondron in the development of osteoarthritis. It is hoped that continued discussion and investigation will follow to better clarify these topics. Clarification will be critical for those in search of novel therapeutic targets for the treatment of osteoarthritis. PMID:26380073

  4. Cocaine attenuates blood flow but not neuronal responses to stimulation while preserving neurovascular coupling for resting brain activity

    PubMed Central

    Chen, Wei; Liu, Peng; Volkow, Nora D.; Pan, Yingtian; Du, Congwu

    2016-01-01

    Cocaine affects neuronal activity and constricts cerebral blood vessels, making it difficult to determine whether cocaine-induced changes in cerebral blood flow (CBF) reflect neuronal activation or its vasoactive effects. Here we assessed the effects of acute cocaine on both resting-state and stimulation responses to investigate cocaine’s effects on neurovascular coupling and to differentiate its effects on neuronal activity from its vasoactive actions. We concurrently measured cortical field potentials via thinned skull EEG recordings and CBF with laser Doppler flowmetry in the rat’s somatosensory cortex for both resting state and forepaw stimulation prior to and following cocaine administration (1mg/kg, i.v.). Results show both resting-state field potentials and CBF were depressed after cocaine administration (19.8±4.7% and 52.1±13.4%, respectively) and these changes were strongly correlated with each other (r=0.81, p<0.001) indicating that cocaine did not affect neurovascular coupling at rest and that the reduction in resting CBF reflected reduction in synchronized spontaneous neuronal activity rather than vasoconstriction. In contrast, the forepaw-stimulation-evoked neuronal activity was not changed by cocaine (p=0.244) whereas the CBF to the stimulation was reduced 49.9±2.6% (p=0.028) gradually recovering ~20min post cocaine injection, indicating that neurovascular coupling during stimulation was temporarily disrupted by cocaine. Neurovascular uncoupling by cocaine during stimulation but not during rest indicates that distinct processes might underlie regulation of neurovascular coupling for spontaneous than for stimulation-induced activity. The greater reductions by cocaine to the stimulation-induced CBF increases than to the background CBF should be considered when interpreting fMRI studies comparing activation responses between controls and cocaine abusers. Neurovascular uncoupling could contribute to cocaine’s neurotoxicity particularly for

  5. 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.

  6. A modular approach to create a neurovascular unit-on-a-chip.

    PubMed

    Achyuta, Anil Kumar H; Conway, Amy J; Crouse, Richard B; Bannister, Emilee C; Lee, Robin N; Katnik, Christopher P; Behensky, Adam A; Cuevas, Javier; Sundaram, Shivshankar S

    2013-02-21

    In this work, we describe the fabrication and working of a modular microsystem that recapitulates the functions of the "Neurovascular Unit". The microdevice comprised a vertical stack of a poly(dimethylsiloxane) (PDMS) neural parenchymal chamber separated by a vascular channel via a microporous polycarbonate (PC) membrane. The neural chamber housed a mixture of neurons (~4%), astrocytes (~95%), and microglia (~1%). The vascular channel was lined with a layer of rat brain microvascular endothelial cell line (RBE4). Cellular components in the neural chamber and vascular channel showed viability (>90%). The neural cells fired inhibitory as well as excitatory potentials following 10 days of culture. The endothelial cells showed diluted-acetylated low density lipoprotein (dil-a-LDL) uptake, expressed von Willebrand factor (vWF) and zonula occludens (ZO-1) tight junctions, and showed decreased Alexafluor™-conjugated dextran leakage across their barriers significantly compared with controls (p < 0.05). When the vascular layer was stimulated with TNF-α for 6 h, about 75% of resident microglia and astrocytes on the neural side were activated significantly (p < 0.05 compared to controls) recapitulating tissue-mimetic responses resembling neuroinflammation. The impact of this microsystem lies in the fact that this biomimetic neurovascular platform might not only be harnessed for obtaining mechanistic insights for neurodegenerative disorders, but could also serve as a potential screening tool for central nervous system (CNS) therapeutics in toxicology and neuroinfectious diseases. PMID:23108480

  7. Modified Bilateral Neurovascular Cheek Flap: Functional Reconstruction of Extensive Lower Lip Defects

    PubMed Central

    2016-01-01

    Background: Reconstruction of extensive lower lip defects is challenging, and functional outcomes are difficult to achieve. Methods: A modified bilateral neurovascular cheek (MBNC) flap has been described. The data of patients with cancer of the lower lip treated with wide excision and reconstructed with the MBNC flap in the Plastic Surgery Unit, Srinagarind Hospital, Khon Kaen University, from 1966 to 2012 were reviewed. Results: Of the total of 143 patients included, 90.91% were women, and their age ranged from 32 to 100 years. All defects involved 70% or greater of the lower lip, which included oral commissure, buccal mucosa, or cheek skin and upper lip. All 20 patients who were followed up demonstrated good outcomes of intercommissural distance, interlabial distance, sulcus depth, and 2-point discrimination compared with normal lip parameters according to age group and satisfaction with treatment. Conclusions: Reconstruction of extensive lower lip defects with the MBNC flap provided good oral competence and functional outcomes. The flap provided adequate lip height and width, with proper position of oral commissure and vermilion reconstruction. The awareness about neurovascular anatomy of the lip and cheek and gentle dissection preserve the lip function. The flap overcomes the drawbacks of Karapandzic technique, which is microstomia, and of Bernard technique, which is a tight adynamic lower lip. It can be used in defects of more than two-thirds of the lip, extending to the cheek, commissural reconstruction, and secondary reconstruction.

  8. Neurophysiological, metabolic and cellular compartments that drive neurovascular coupling and neuroimaging signals.

    PubMed

    Moreno, Andrea; Jego, Pierrick; de la Cruz, Feliberto; Canals, Santiago

    2013-01-01

    Complete understanding of the mechanisms that coordinate work and energy supply of the brain, the so called neurovascular coupling, is fundamental to interpreting brain energetics and their influence on neuronal coding strategies, but also to interpreting signals obtained from brain imaging techniques such as functional magnetic resonance imaging. Interactions between neuronal activity and cerebral blood flow regulation are largely compartmentalized. First, there exists a functional compartmentalization in which glutamatergic peri-synaptic activity and its electrophysiological events occur in close proximity to vascular responses. Second, the metabolic processes that fuel peri-synaptic activity are partially segregated between glycolytic and oxidative compartments. Finally, there is cellular segregation between astrocytic and neuronal compartments, which has potentially important implications on neurovascular coupling. Experimental data is progressively showing a tight interaction between the products of energy consumption and neurotransmission-driven signaling molecules that regulate blood flow. Here, we review some of these issues in light of recent findings with special attention to the neuron-glia interplay on the generation of neuroimaging signals. PMID:23543907

  9. Neurovascular coupling to D2/D3 dopamine receptor occupancy using simultaneous PET/functional MRI

    PubMed Central

    Sander, Christin Y.; Hooker, Jacob M.; Catana, Ciprian; Normandin, Marc D.; Alpert, Nathaniel M.; Knudsen, Gitte M.; Vanduffel, Wim; Rosen, Bruce R.; Mandeville, Joseph B.

    2013-01-01

    This study employed simultaneous neuroimaging with positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) to demonstrate the relationship between changes in receptor occupancy measured by PET and changes in brain activity inferred by fMRI. By administering the D2/D3 dopamine receptor antagonist [11C]raclopride at varying specific activities to anesthetized nonhuman primates, we mapped associations between changes in receptor occupancy and hemodynamics [cerebral blood volume (CBV)] in the domains of space, time, and dose. Mass doses of raclopride above tracer levels caused increases in CBV and reductions in binding potential that were localized to the dopamine-rich striatum. Moreover, similar temporal profiles were observed for specific binding estimates and changes in CBV. Injection of graded raclopride mass doses revealed a monotonic coupling between neurovascular responses and receptor occupancies. The distinct CBV magnitudes between putamen and caudate at matched occupancies approximately matched literature differences in basal dopamine levels, suggesting that the relative fMRI measurements reflect basal D2/D3 dopamine receptor occupancy. These results can provide a basis for models that relate dopaminergic occupancies to hemodynamic changes in the basal ganglia. Overall, these data demonstrate the utility of simultaneous PET/fMRI for investigations of neurovascular coupling that correlate neurochemistry with hemodynamic changes in vivo for any receptor system with an available PET tracer. PMID:23723346

  10. A Novel In Vitro Model to Study Pericytes in the Neurovascular Unit of the Developing Cortex

    PubMed Central

    Zehendner, Christoph M.; Wedler, Hannah E.; Luhmann, Heiko J.

    2013-01-01

    Cortical function is impaired in various disorders of the central nervous system including Alzheimer’s disease, autism and schizophrenia. Some of these disorders are speculated to be associated with insults in early brain development. Pericytes have been shown to regulate neurovascular integrity in development, health and disease. Hence, precisely controlled mechanisms must have evolved in evolution to operate pericyte proliferation, repair and cell fate within the neurovascular unit (NVU). It is well established that pericyte deficiency leads to NVU injury resulting in cognitive decline and neuroinflammation in cortical layers. However, little is known about the role of pericytes in pathophysiological processes of the developing cortex. Here we introduce an in vitro model that enables to precisely study pericytes in the immature cortex and show that moderate inflammation and hypoxia result in caspase-3 mediated pericyte loss. Using heterozygous EYFP-NG2 mouse mutants we performed live imaging of pericytes for several days in vitro. In addition we show that pericytes maintain their capacity to proliferate which may allow cell-based therapies like reprogramming of pericytes into induced neuronal cells in the presented approach. PMID:24278454

  11. Pharmacologically-induced neurovascular uncoupling is associated with cognitive impairment in mice.

    PubMed

    Tarantini, Stefano; Hertelendy, Peter; Tucsek, Zsuzsanna; Valcarcel-Ares, M Noa; Smith, Nataliya; Menyhart, Akos; Farkas, Eszter; Hodges, Erik L; Towner, Rheal; Deak, Ferenc; Sonntag, William E; Csiszar, Anna; Ungvari, Zoltan; Toth, Peter

    2015-11-01

    There is increasing evidence that vascular risk factors, including aging, hypertension, diabetes mellitus, and obesity, promote cognitive impairment; however, the underlying mechanisms remain obscure. Cerebral blood flow (CBF) is adjusted to neuronal activity via neurovascular coupling (NVC) and this mechanism is known to be impaired in the aforementioned pathophysiologic conditions. To establish a direct relationship between impaired NVC and cognitive decline, we induced neurovascular uncoupling pharmacologically in mice by inhibiting the synthesis of vasodilator mediators involved in NVC. Treatment of mice with the epoxygenase inhibitor N-(methylsulfonyl)-2-(2-propynyloxy)-benzenehexanamide (MSPPOH), the NO synthase inhibitor l-NG-Nitroarginine methyl ester (L-NAME), and the COX inhibitor indomethacin decreased NVC by over 60% mimicking the aging phenotype, which was associated with significantly impaired spatial working memory (Y-maze), recognition memory (Novel object recognition), and impairment in motor coordination (Rotarod). Blood pressure (tail cuff) and basal cerebral perfusion (arterial spin labeling perfusion MRI) were unaffected. Thus, selective experimental disruption of NVC is associated with significant impairment of cognitive and sensorimotor function, recapitulating neurologic symptoms and signs observed in brain aging and pathophysiologic conditions associated with accelerated cerebromicrovascular aging. PMID:26174328

  12. Neurovascular coupling in normal aging: A combined optical, ERP and fMRI study

    PubMed Central

    Fabiani, Monica; Gordon, Brian A.; Maclin, Edward L.; Pearson, Melanie A.; Brumback-Peltz, Carrie R.; Low, Kathy A.; McAuley, Edward; Sutton, Bradley P.; Kramer, Arthur F.; Gratton, Gabriele

    2013-01-01

    Brain aging is characterized by changes in both hemodynamic and neuronal responses, which may be influenced by the cardiorespiratory fitness of the individual. To investigate the relationship between neuronal and hemodynamic changes, we studied the brain activity elicited by visual stimulation (checkerboard reversals at different frequencies) in younger adults and in older adults varying in physical fitness. Four functional brain measures were used to compare neuronal and hemodynamic responses obtained from BA17: two reflecting neuronal activity (the event-related optical signal, EROS, and the C1 response of the ERP), and two reflecting functional hemodynamic changes (functional magnetic resonance imaging, fMRI, and near-infrared spectroscopy, NIRS). The results indicated that both younger and older adults exhibited a quadratic relationship between neuronal and hemodynamic effects, with reduced increases of the hemodynamic response at high levels of neuronal activity. Although older adults showed reduced activation, similar neurovascular coupling functions were observed in the two age groups when fMRI and deoxy-hemoglobin measures were used. However, the coupling between oxy-and deoxy-hemoglobin changes decreased with age and increased with increasing fitness. These data indicate that departures from linearity in neurovascular coupling may be present when using hemodynamic measures to study neuronal function. PMID:23664952

  13. Neurovascular coupling and the influence of luminal agonists via the endothelium.

    PubMed

    Dormanns, K; van Disseldorp, E M J; Brown, R G; David, T

    2015-01-01

    A numerical model of neurovascular coupling (NVC) is presented based on neuronal activity coupled to vasodilation/contraction models via the astrocytic mediated perivascular K(+) and the smooth muscle cell Ca(2+) pathway. Luminal agonists acting on P2Y receptors on the endothelial cell surface provide a flux of IP3 into the endothelial cytosol. This concentration of IP3 is transported via gap junctions between endothelial and smooth muscle cells providing a source of sacroplasmic derived Ca(2+) in the smooth muscle cell. The model is able to relate a neuronal input signal to the corresponding vessel reaction. Results indicate that blood flow mediated IP3 production via the agonist ATP has a substantial effect on the contraction/dilation dynamics of the SMC. The resulting variation in cytosolic Ca(2+) can enhance and inhibit the flow of blood to the cortical tissue. IP3 coupling between endothelial and smooth muscle cells seems to be important in the dynamics of the smooth muscle cell. The VOCC channels are, due to the hyperpolarisation from K(+) SMC efflux, almost entirely closed and do not seem to play a significant role during neuronal activity. The current model shows that astrocytic Ca(2+) is not necessary for neurovascular coupling to occur in contrast to a number of experiments outlining the importance of astrocytic Ca(2+) in NVC, however this Ca(2+) pathway is not the only one mediating NVC. Importantly agonists in flowing blood have a significant influence on the endothelial and smooth muscle cell dynamics. PMID:25167790

  14. Neurophysiological, metabolic and cellular compartments that drive neurovascular coupling and neuroimaging signals

    PubMed Central

    Moreno, Andrea; Jego, Pierrick; de la Cruz, Feliberto; Canals, Santiago

    2013-01-01

    Complete understanding of the mechanisms that coordinate work and energy supply of the brain, the so called neurovascular coupling, is fundamental to interpreting brain energetics and their influence on neuronal coding strategies, but also to interpreting signals obtained from brain imaging techniques such as functional magnetic resonance imaging. Interactions between neuronal activity and cerebral blood flow regulation are largely compartmentalized. First, there exists a functional compartmentalization in which glutamatergic peri-synaptic activity and its electrophysiological events occur in close proximity to vascular responses. Second, the metabolic processes that fuel peri-synaptic activity are partially segregated between glycolytic and oxidative compartments. Finally, there is cellular segregation between astrocytic and neuronal compartments, which has potentially important implications on neurovascular coupling. Experimental data is progressively showing a tight interaction between the products of energy consumption and neurotransmission-driven signaling molecules that regulate blood flow. Here, we review some of these issues in light of recent findings with special attention to the neuron-glia interplay on the generation of neuroimaging signals. PMID:23543907

  15. Role of Inflammasome Activation in the Pathophysiology of Vascular Diseases of the Neurovascular Unit

    PubMed Central

    Mohamed, Islam N.; Ishrat, Tauheed; Fagan, Susan C.

    2015-01-01

    Abstract Significance: Inflammation is the standard double-edged defense mechanism that aims at protecting the human physiological homeostasis from devastating threats. Both acute and chronic inflammation have been implicated in the occurrence and progression of vascular diseases. Interference with components of the immune system to improve patient outcome after ischemic injury has been uniformly unsuccessful. There is a need for a deeper understanding of the innate immune response to injury in order to modulate, rather than to block inflammation and improve the outcome for vascular diseases. Recent Advances: Nucleotide-binding oligomerization domain-like receptors or NOD-like receptor proteins (NLRPs) can be activated by sterile and microbial inflammation. NLR family plays a major role in activating the inflammasome. Critical Issues: The aim of this work is to review recent findings that provided insights into key inflammatory mechanisms and define the place of the inflammasome, a multi-protein complex involved in instigating inflammation in neurovascular diseases, including retinopathy, neurodegenerative diseases, and stroke. Future Directions: The significant contribution of NLRP-inflammasome activation to vascular disease of the neurovascular unit in the brain and retina suggests that therapeutic strategies focused on specific targeting of inflammasome components could significantly improve the outcomes of these diseases. Antioxid. Redox Signal. 22, 1188–1206. PMID:25275222

  16. Role of CXCR2/CXCR2 ligands in vascular remodeling during bronchiolitis obliterans syndrome

    PubMed Central

    Belperio, John A.; Keane, Michael P.; Burdick, Marie D.; Gomperts, Brigitte; Xue, Ying Ying; Hong, Kurt; Mestas, Javier; Ardehali, Abbas; Mehrad, Borna; Saggar, Rajan; Lynch, Joseph P.; Ross, David J.; Strieter, Robert M.

    2005-01-01

    Angiogenesis and vascular remodeling support fibroproliferative processes; however, no study has addressed the importance of angiogenesis during fibro-obliteration of the allograft airway during bronchiolitis obliterans syndrome (BOS) that occurs after lung transplantation. The ELR+ CXC chemokines both mediate neutrophil recruitment and promote angiogenesis. Their shared endothelial cell receptor is the G-coupled protein receptor CXC chemokine receptor 2 (CXCR2). We found that elevated levels of multiple ELR+ CXC chemokines correlated with the presence of BOS. Proof-of-concept studies using a murine model of BOS not only demonstrated an early neutrophil infiltration but also marked vascular remodeling in the tracheal allografts. In addition, tracheal allograft ELR+ CXC chemokines were persistently expressed even in the absence of significant neutrophil infiltration and were temporally associated with vascular remodeling during fibro-obliteration of the tracheal allograft. Furthermore, in neutralizing studies, treatment with anti-CXCR2 Abs inhibited early neutrophil infiltration and later vascular remodeling, which resulted in the attenuation of murine BOS. A more profound attenuation of fibro-obliteration was seen when CXCR2–/– mice received cyclosporin A. This supports the notion that the CXCR2/CXCR2 ligand biological axis has a bimodal function during the course of BOS: early, it is important for neutrophil recruitment and later, during fibro-obliteration, it is important for vascular remodeling independent of neutrophil recruitment. PMID:15864347

  17. Role of CXCR2/CXCR2 ligands in vascular remodeling during bronchiolitis obliterans syndrome.

    PubMed

    Belperio, John A; Keane, Michael P; Burdick, Marie D; Gomperts, Brigitte; Xue, Ying Ying; Hong, Kurt; Mestas, Javier; Ardehali, Abbas; Mehrad, Borna; Saggar, Rajan; Lynch, Joseph P; Ross, David J; Strieter, Robert M

    2005-05-01

    Angiogenesis and vascular remodeling support fibroproliferative processes; however, no study has addressed the importance of angiogenesis during fibro-obliteration of the allograft airway during bronchiolitis obliterans syndrome (BOS) that occurs after lung transplantation. The ELR(+) CXC chemokines both mediate neutrophil recruitment and promote angiogenesis. Their shared endothelial cell receptor is the G-coupled protein receptor CXC chemokine receptor 2 (CXCR2). We found that elevated levels of multiple ELR(+) CXC chemokines correlated with the presence of BOS. Proof-of-concept studies using a murine model of BOS not only demonstrated an early neutrophil infiltration but also marked vascular remodeling in the tracheal allografts. In addition, tracheal allograft ELR(+) CXC chemokines were persistently expressed even in the absence of significant neutrophil infiltration and were temporally associated with vascular remodeling during fibro-obliteration of the tracheal allograft. Furthermore, in neutralizing studies, treatment with anti-CXCR2 Abs inhibited early neutrophil infiltration and later vascular remodeling, which resulted in the attenuation of murine BOS. A more profound attenuation of fibro-obliteration was seen when CXCR2(-/-) mice received cyclosporin A. This supports the notion that the CXCR2/CXCR2 ligand biological axis has a bimodal function during the course of BOS: early, it is important for neutrophil recruitment and later, during fibro-obliteration, it is important for vascular remodeling independent of neutrophil recruitment. PMID:15864347

  18. Dynamin, a membrane remodelling GTPase

    PubMed Central

    Ferguson, Shawn M.; De Camilli, Pietro

    2012-01-01

    Dynamin, the founding member of a family of dynamin-like GTPases (DLPs) implicated in membrane remodelling, has a critical role in endocytic membrane fission events. The use of complementary approaches, including live cell imaging, cell free-studies, X-ray crystallography and genetic studies in mice has greatly advanced our understanding of the mechanisms by which dynamin acts, its essential roles in cell physiology and the specific function of different dynamin isoforms. In addition, several connections between dynamin and human disease have also emerged that highlight specific contributions of this GTPase to the physiology of different tissues. PMID:22233676

  19. Osteocyte-Driven Bone Remodeling

    PubMed Central

    Bellido, Teresita

    2013-01-01

    Osteocytes, the most abundant cells in bone, have been long postulated to detect and respond to mechanical and hormonal stimuli and to coordinate the function of osteoblasts and osteoclasts. The discovery that the inhibitor of bone formation sclerostin is primarily expressed in osteocytes in bone and it is downregulated by anabolic stimuli provided a mechanism by which osteocytes influence the activity of osteoblasts. Advances of the last few years provided experimental evidence demonstrating that osteocytes also participate in the recruitment of osteoclasts and the initiation of bone remodeling. Apoptotic osteocytes trigger yet to be identified signals that attract osteoclast precursors to specific areas of bone, which in turn differentiate to mature, bone resorbing osteoclasts. Osteocytes are also the source of molecules that regulate generation and activity of osteoclasts, such as OPG and RANKL; and genetic manipulations of the mouse genome leading to loss or gain of function, or to altered expression of either molecule in osteocytes, markedly affect bone resorption. This review highlights these investigations and discusses how the novel concept of osteocyte-driven bone resorption and formation impacts our understanding of the mechanisms by which current therapies control bone remodeling. PMID:24002178

  20. HDL biogenesis, remodeling, and catabolism.

    PubMed

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

    2015-01-01

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

  1. Intracranial pressure and skull remodeling

    PubMed Central

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

    2014-01-01

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

  2. Anatomy of Mandibular Vital Structures. Part I: Mandibular Canal and Inferior Alveolar Neurovascular Bundle in Relation with Dental Implantology

    PubMed Central

    Wang, Hom-Lay; Sabalys, Gintautas

    2010-01-01

    ABSTRACT Objectives It is critical to determine the location and configuration of the mandibular canal and related vital structures during the implant treatment. The purpose of the present study was to review the literature concerning the mandibular canal and inferior alveolar neurovascular bundle anatomical variations related to the implant surgery. Material and Methods Literature was selected through the search of PubMed, Embase and Cochrane electronic databases. The keywords used for search were mandibular canal, inferior alveolar nerve, and inferior alveolar neurovascular bundle. The search was restricted to English language articles, published from 1973 to November 2009. Additionally, a manual search in the major anatomy, dental implant, prosthetic and periodontal journals and books were performed. Results In total, 46 literature sources were obtained and morphological aspects and variations of the anatomy related to implant treatment in posterior mandible were presented as two entities: intraosseous mandibular canal and associated inferior alveolar neurovascular bundle. Conclusions A review of morphological aspects and variations of the anatomy related to mandibular canal and mandibular vital structures are very important especially in implant therapy since inferior alveolar neurovascular bundle exists in different locations and possesses many variations. Individual, gender, age, race, assessing technique used and degree of edentulous alveolar bone atrophy largely influence these variations. It suggests that osteotomies in implant dentistry should not be developed in the posterior mandible until the position of the mandibular canal is established. PMID:24421958

  3. An Analysis of the Residential Remodeling Occupation.

    ERIC Educational Resources Information Center

    Scruggs, Kenneth

    The general purpose of the occupational analysis is to provide workable, basic information dealing with the many and varied duties performed in the residential remodeling occupation. The analysis only briefly covers the many areas of residential remodeling. The document opens with a brief introduction followed by a job description. The bulk of the…

  4. Bone remodeling and silicon deficiency in rats

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

  5. Chromatin Remodelers: From Function to Dysfunction

    PubMed Central

    Längst, Gernot; Manelyte, Laura

    2015-01-01

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

  6. Multiscale Simulation of Protein Mediated Membrane Remodeling

    PubMed Central

    Ayton, Gary S.; Voth, Gregory A.

    2009-01-01

    Proteins interacting with membranes can result in substantial membrane deformations and curvatures. This effect is known in its broadest terms as membrane remodeling. This review article will survey current multiscale simulation methodologies that have been employed to examine protein-mediated membrane remodeling. PMID:19922811

  7. Omega-AB

    2007-05-01

    A hierarchical, modular modeling environment for hybrid simulations of sequential-modular, systems dynamics, discrete-event, and agent-based paradigms Omega-AB models contain a hierarchically-defined module tree that specifies the execution logic for the simulation, and a multi-network graph that defines the environment within which the simulation occurs. Modules are the fundamental buildinig blocks of an Omega-AB model and can define anything from a basic mathematical operation to a complex behavioral response model. Modules rely on the "plug-in" conceptmore » which allows developers to build independent module libraries that are gathered, linked, and instantiated by the Omega-AB engine at run time. Inter-module communication occurs through two complimentary systems: pull-based "ports" for general computation patterns and push-based "plugs" for event processing. The simulation environment is an abstract graph of nodes and links. Agents (module sub-trees headed up by an Agent module) reside at nodes and relate to their neighbors through typed links. To facilitate the construction and visualization of complex, interacting networks with dramatically different structure, Omega-AB provides a system for organizing the nodes into hierarchica trees that describe "slices" of the overall network.« less

  8. Nucleosome dynamics during chromatin remodeling in vivo

    PubMed Central

    Ramachandran, Srinivas; Henikoff, Steven

    2016-01-01

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

  9. Lipid Acyl Chain Remodeling in Yeast

    PubMed Central

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

    2015-01-01

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

  10. 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. PMID:26933790

  11. Computational and Pharmacological Target of Neurovascular Unit for Drug Design and Delivery

    PubMed Central

    Islam, Md. Mirazul; Mohamed, Zahurin

    2015-01-01

    The blood-brain barrier (BBB) is a dynamic and highly selective permeable interface between central nervous system (CNS) and periphery that regulates the brain homeostasis. Increasing evidences of neurological disorders and restricted drug delivery process in brain make BBB as special target for further study. At present, neurovascular unit (NVU) is a great interest and highlighted topic of pharmaceutical companies for CNS drug design and delivery approaches. Some recent advancement of pharmacology and computational biology makes it convenient to develop drugs within limited time and affordable cost. In this review, we briefly introduce current understanding of the NVU, including molecular and cellular composition, physiology, and regulatory function. We also discuss the recent technology and interaction of pharmacogenomics and bioinformatics for drug design and step towards personalized medicine. Additionally, we develop gene network due to understand NVU associated transporter proteins interactions that might be effective for understanding aetiology of neurological disorders and new target base protective therapies development and delivery. PMID:26579539

  12. A Neurovascular Perspective for Long-Term Changes After Brain Trauma

    PubMed Central

    Pop, V.; Badaut, J.

    2012-01-01

    Traumatic brain injury (TBI) affects all age groups in a population and is an injury generating scientific interest not only as an acute event, but also as a complex brain disease with several underlying neurobehavioral and neuropathological characteristics. We review early and long-term alterations after juvenile and adult TBI with a focus on changes in the neurovascular unit (NVU), including neuronal interactions with glia and blood vessels at the blood-brain barrier (BBB). Post-traumatic changes in cerebral blood-flow, BBB structures and function, as well as mechanistic pathways associated with brain aging and neurodegeneration are presented from clinical and experimental reports. Based on the literature, increased attention on BBB changes should be integrated in studies characterizing TBI outcome and may provide a meaningful therapeutic target to resolve detrimental post-traumatic dysfunction. PMID:22350620

  13. Development and pathological changes of neurovascular unit regulated by hypoxia response in the retina.

    PubMed

    Kurihara, T

    2016-01-01

    Retina is a highly vascularized tissue with a high oxygen and metabolic demand receiving light located in the back of the eye. The development and the maintenance of the retinal vasculature are important to regulate the homeostasis in the tissue. α Subunits of hypoxia-inducible factor (HIF) are key molecules in hypoxia response inducing genes required for cell survival such as vascular endothelial growth factor under hypoxia. Neurons, glia, and vascular endothelium cells interdependently form neurovascular unit in the retina tightly regulated by hypoxia response via HIF expression. A corruption of the precise hypoxia response in the developmental or matured retinal tissue may lead congenital vascular anomalies or adult neovascular ocular diseases. To regulate hypoxia response through HIF activity would be an ideal therapeutic target for these vision-threatening eye diseases. PMID:27130417

  14. Investigating Human Neurovascular Coupling Using Functional Neuroimaging: A Critical Review of Dynamic Models

    PubMed Central

    Huneau, Clément; Benali, Habib; Chabriat, Hugues

    2015-01-01

    The mechanisms that link a transient neural activity to the corresponding increase of cerebral blood flow (CBF) are termed neurovascular coupling (NVC). They are possibly impaired at early stages of small vessel or neurodegenerative diseases. Investigation of NVC in humans has been made possible with the development of various neuroimaging techniques based on variations of local hemodynamics during neural activity. Specific dynamic models are currently used for interpreting these data that can include biophysical parameters related to NVC. After a brief review of the current knowledge about possible mechanisms acting in NVC we selected seven models with explicit integration of NVC found in the literature. All these models were described using the same procedure. We compared their physiological assumptions, mathematical formalism, and validation. In particular, we pointed out their strong differences in terms of complexity. Finally, we discussed their validity and their potential applications. These models may provide key information to investigate various aspects of NVC in human pathology. PMID:26733782

  15. Hemostatic hydrodissection of the neurovascular bundles during robotic assisted laparoscopic radical prostatectomy: safety and efficacy trial

    NASA Astrophysics Data System (ADS)

    Parekattil, Sijo J.; Dahm, Philipp; Vieweg, Johannes W.

    2009-02-01

    Preservation of continence and potency after Robotic Assisted Laparoscopic Radical Prostatectomy (RALP) are two key outcome measures that patients consider when comparing different treatment options for localized prostate cancer. Ensuring that positive surgical margins are as low as possible provides oncologic control. Various techniques to optimize these outcomes have been employed. This study presents the early outcomes for Hemostatic Hydrodissection of the Neurovascular Bundles during 86 consecutive RALPs. Positive margin rates were 12.5% overall (9% for pT2 and 28.6% for pT3); continence at 6 months was 100%, at 3 months 90% and at 1 month 66%. In patients with no preoperative erectile dysfunction (preoperative SHIM of 25), 79% had return of erections sufficient for intercourse by 6 months. 2 of these patients were able to have intercourse 2 weeks after surgery. These preliminary findings appear promising.

  16. Sensitivity evaluation of DSA-based parametric imaging using Doppler ultrasound in neurovascular phantoms

    NASA Astrophysics Data System (ADS)

    Balasubramoniam, A.; Bednarek, D. R.; Rudin, S.; Ionita, C. N.

    2016-03-01

    An evaluation of the relation between parametric imaging results obtained from Digital Subtraction Angiography (DSA) images and blood-flow velocity measured using Doppler ultrasound in patient-specific neurovascular phantoms is provided. A silicone neurovascular phantom containing internal carotid artery, middle cerebral artery and anterior communicating artery was embedded in a tissue equivalent gel. The gel prevented movement of the vessels when blood mimicking fluid was pumped through it to obtain Colour Doppler images. The phantom was connected to a peristaltic pump, simulating physiological flow conditions. To obtain the parametric images, water was pumped through the phantom at various flow rates (100, 120 and 160 ml/min) and 10 ml contrast boluses were injected. DSA images were obtained at 10 frames/sec from the Toshiba C-arm and DSA image sequences were input into LabVIEW software to get parametric maps from time-density curves. The parametric maps were compared with velocities determined by Doppler ultrasound at the internal carotid artery. The velocities measured by the Doppler ultrasound were 38, 48 and 65 cm/s for flow rates of 100, 120 and 160 ml/min, respectively. For the 20% increase in flow rate, the percentage change of blood velocity measured by Doppler ultrasound was 26.3%. Correspondingly, there was a 20% decrease of Bolus Arrival Time (BAT) and 14.3% decrease of Mean Transit Time (MTT), showing strong inverse correlation with Doppler measured velocity. The parametric imaging parameters are quite sensitive to velocity changes and are well correlated to the velocities measured by Doppler ultrasound.

  17. Correlation of histomorphologic findings and partial neurovascular bundle preservation during laparoscopic and robotic radical prostatectomy.

    PubMed

    Andino, Lizmarie; Davis, John W; Wei, Wei; Prokhorova, Ina N; Troncoso, Patricia; Matin, Surena F

    2013-03-01

    The objective of this work was to compare the amount of residual periprostatic tissue for radical prostatectomy performed by the partial NS (PNS) technique with that performed by the nerve-sparing (NS) or wide-resection (WR) techniques. Retrospective histomorphologic evaluation of radical prostatectomy specimens (RPSs) from patients undergoing laparoscopic radical prostatectomy (LRP) or robot-assisted radical prostatectomy (RARP) was performed. The posterolateral regions corresponding to the neurovascular bundle in RPSs from 48 patients who had undergone NS, PNS, or WR during LRP (n = 30) or RARP (n = 18) were examined by two pathologists unaware of the technique used. The RPSs were evaluated at the base, mid-gland, and apex. The amount of periprostatic tissue at each site was recorded. Measurements were analyzed by use of a linear mixed model. For both LRP and RARP, each gradation of nerve-preservation was associated with periprostatic tissue, except PNS and WR did not differ for LRP at the apex and base or for RARP at the apex, mid-gland, and base. For LRP, a greater amount of tissue was on the left side of the prostate than on the right at the mid-gland level (P = 0.004) whereas for RARP the opposite was found (P = 0.024). Of 18 separate analyses, 13 were significantly associated. The study is limited by its retrospective design. The amount of periprostatic tissue in the neurovascular bundle area correlates well with the nerve-preservation approach used during LRP and RARP, providing anatomic evidence supporting the PNS approach. We also describe a novel finding of laterality bias at the mid-gland level in LRP and RARP specimens. PMID:27000885

  18. Mechanistic Mathematical Modeling Tests Hypotheses of the Neurovascular Coupling in fMRI

    PubMed Central

    Lundengård, Karin; Cedersund, Gunnar; Sten, Sebastian; Leong, Felix; Smedberg, Alexander; Elinder, Fredrik

    2016-01-01

    Functional magnetic resonance imaging (fMRI) measures brain activity by detecting the blood-oxygen-level dependent (BOLD) response to neural activity. The BOLD response depends on the neurovascular coupling, which connects cerebral blood flow, cerebral blood volume, and deoxyhemoglobin level to neuronal activity. The exact mechanisms behind this neurovascular coupling are not yet fully investigated. There are at least three different ways in which these mechanisms are being discussed. Firstly, mathematical models involving the so-called Balloon model describes the relation between oxygen metabolism, cerebral blood volume, and cerebral blood flow. However, the Balloon model does not describe cellular and biochemical mechanisms. Secondly, the metabolic feedback hypothesis, which is based on experimental findings on metabolism associated with brain activation, and thirdly, the neurotransmitter feed-forward hypothesis which describes intracellular pathways leading to vasoactive substance release. Both the metabolic feedback and the neurotransmitter feed-forward hypotheses have been extensively studied, but only experimentally. These two hypotheses have never been implemented as mathematical models. Here we investigate these two hypotheses by mechanistic mathematical modeling using a systems biology approach; these methods have been used in biological research for many years but never been applied to the BOLD response in fMRI. In the current work, model structures describing the metabolic feedback and the neurotransmitter feed-forward hypotheses were applied to measured BOLD responses in the visual cortex of 12 healthy volunteers. Evaluating each hypothesis separately shows that neither hypothesis alone can describe the data in a biologically plausible way. However, by adding metabolism to the neurotransmitter feed-forward model structure, we obtained a new model structure which is able to fit the estimation data and successfully predict new, independent validation data

  19. Morroniside Improves Microvascular Functional Integrity of the Neurovascular Unit after Cerebral Ischemia

    PubMed Central

    Sun, Fang-Ling; Cheng, Hua; Wang, Ying; Li, Lei; Xue, Jin-Long; Wang, Xiao-feng; Ai, Hou-Xi; Zhang, Li; Xu, Jing-dong

    2014-01-01

    Treating the vascular elements within the neurovascular unit is essential for protecting and repairing the brain after stroke. Acute injury on endothelial systems results in the disruption of blood-brain barrier (BBB), while post-ischemic angiogenesis plays an important role in delayed functional recovery. Here, we considered alterations in microvessel integrity to be targets for brain recovery, and tested the natural compound morroniside as a therapeutic approach to restore the vascular elements of injured tissue in a rat model of focal cerebral ischemia. Sprague-Dawley rats were subjected to middle cerebral artery occlusion (MCAO) model, and morroniside was then administered intragastrically once a day at doses of 30, 90, and 270 mg/kg. BBB integrity and associated factors were analyzed to identify cerebrovascular permeability 3 days after MCAO. The recruitment of endothelial progenitor cells (EPCs), the expression of angiogenic factors and the new vessel formation in the peri-infarct cortex of rats were examined 7 days after MCAO to identify the angiogenesis. We demonstrated that at 3 days post-ischemia, morroniside preserved neurovascular unit function by ameliorating BBB injury. By 7 days post-ischemia, morroniside amplified angiogenesis, in part by enhancing endothelial progenitor cell proliferation and expression of angiogenic factors. Morever, the increase in the amount of vWF+ vessels induced by ischemia could be extended to 28 days after administration of morroniside, indicating the crucial role of morroniside in angiogenesis during the chronic phase. Taken together, our findings suggested that morroniside might offer a novel therapeutic approach for promoting microvascular integrity recovery and provide a thoroughly new direction for stroke therapy. PMID:24979385

  20. Developmental Switch in Neurovascular Coupling in the Immature Rodent Barrel Cortex

    PubMed Central

    Zehendner, Christoph M.; Tsohataridis, Simeon; Luhmann, Heiko J.; Yang, Jenq-Wei

    2013-01-01

    Neurovascular coupling (NVC) in the adult central nervous system (CNS) is a mechanism that provides regions of the brain with more oxygen and glucose upon increased levels of neural activation. Hemodynamic changes that go along with neural activation evoke a blood oxygen level-dependent (BOLD) signal in functional magnetic resonance imaging (fMRI) that can be used to study brain activity non-invasively. A correct correlation of the BOLD signal to neural activity is pivotal to understand this signal in neuronal development, health and disease. However, the function of NVC during development is largely unknown. The rodent whisker-to-barrel cortex is an experimentally well established model to study neurovascular interdependences. Using extracellular multi-electrode recordings and laser-Doppler-flowmetry (LDF) we show in the murine barrel cortex of postnatal day 7 (P7) and P30 mice in vivo that NVC undergoes a physiological shift during the first month of life. In the mature CNS it is well accepted that cortical sensory processing results in a rise in regional cerebral blood flow (rCBF). We show in P7 animals that rCBF decreases during prolonged multi-whisker stimulation and goes along with multi unit activity (MUA) fatigue. In contrast at P30, MUA remains stable during repetitive stimulation and is associated with an increase in rCBF. Further we characterize in both age groups the responses in NVC to single sensory stimuli. We suggest that the observed shift in NVC is an important process in cortical development that may be of high relevance for the correct interpretation of brain activity e.g. in fMRI studies of the immature central nervous system (CNS). PMID:24224059

  1. Mechanistic Mathematical Modeling Tests Hypotheses of the Neurovascular Coupling in fMRI.

    PubMed

    Lundengård, Karin; Cedersund, Gunnar; Sten, Sebastian; Leong, Felix; Smedberg, Alexander; Elinder, Fredrik; Engström, Maria

    2016-06-01

    Functional magnetic resonance imaging (fMRI) measures brain activity by detecting the blood-oxygen-level dependent (BOLD) response to neural activity. The BOLD response depends on the neurovascular coupling, which connects cerebral blood flow, cerebral blood volume, and deoxyhemoglobin level to neuronal activity. The exact mechanisms behind this neurovascular coupling are not yet fully investigated. There are at least three different ways in which these mechanisms are being discussed. Firstly, mathematical models involving the so-called Balloon model describes the relation between oxygen metabolism, cerebral blood volume, and cerebral blood flow. However, the Balloon model does not describe cellular and biochemical mechanisms. Secondly, the metabolic feedback hypothesis, which is based on experimental findings on metabolism associated with brain activation, and thirdly, the neurotransmitter feed-forward hypothesis which describes intracellular pathways leading to vasoactive substance release. Both the metabolic feedback and the neurotransmitter feed-forward hypotheses have been extensively studied, but only experimentally. These two hypotheses have never been implemented as mathematical models. Here we investigate these two hypotheses by mechanistic mathematical modeling using a systems biology approach; these methods have been used in biological research for many years but never been applied to the BOLD response in fMRI. In the current work, model structures describing the metabolic feedback and the neurotransmitter feed-forward hypotheses were applied to measured BOLD responses in the visual cortex of 12 healthy volunteers. Evaluating each hypothesis separately shows that neither hypothesis alone can describe the data in a biologically plausible way. However, by adding metabolism to the neurotransmitter feed-forward model structure, we obtained a new model structure which is able to fit the estimation data and successfully predict new, independent validation data

  2. Effects of natural free radical scavengers on peripheral nerve and neurovascular function in diabetic rats.

    PubMed

    Cotter, M A; Love, A; Watt, M J; Cameron, N E; Dines, K C

    1995-11-01

    Increased generation of reactive oxygen species, coupled with impaired endogenous scavenging mechanisms, plays a prominent role in the aetiology of neurovascular abnormalities in experimental diabetes mellitus. We examined the efficacy of the natural anti-oxidants vitamins C, E and beta-carotene in preventing nerve conduction and nutritive blood flow deficits in streptozotocin-diabetic rats. One month of diabetes caused a 19.1% reduction in sciatic motor conduction velocity (p < 0.001). This was approximately prevented 80-90% by high-dose (1000 mg.kg-1.day-1) vitamin E and beta-carotene treatments (p < 0.001). Vitamin C had lesser effects; the maximum protection found for motor conduction velocity was 36% using a dose of 150 mg.kg-1.day-1 (p < 0.001). High dose (500 mg.kg-1.day-1 (p < 0.001). High dose (500 mg.kg-1.day-1) vitamin C had a lesser effect on conduction than intermediate doses. Joint vitamin C and lower dose (500 mg.kg-1.day-1) vitamin E treatment had a predominantly additive preventive effect against nerve dysfunction. Resistance to hypoxic conduction failure for sciatic nerve in vitro was markedly increased by diabetes and this remained relatively unaffected by treatment. Sciatic nutritive endoneurial blood flow, measured using microelectrode polarography and hydrogen clearance, was reduced 46.1% by 1 month of diabetes (p < 0.001). This was prevented to the extent of 87%, 36% and 98% by vitamins E, C and beta-carotene, respectively (p < 0.01). These data emphasize the role of oxidative stress in the development of early neurovascular changes in experimental diabetes and show that naturally available scavengers have a neuroprotective action. PMID:8582537

  3. Acute two-photon imaging of the neurovascular unit in the cortex of active mice

    PubMed Central

    Tran, Cam Ha T.; Gordon, Grant R.

    2015-01-01

    In vivo two-photon scanning fluorescence imaging is a powerful technique to observe physiological processes from the millimeter to the micron scale in the intact animal. In neuroscience research, a common approach is to install an acute cranial window and head bar to explore neocortical function under anesthesia before inflammation peaks from the surgery. However, there are few detailed acute protocols for head-restrained and fully awake animal imaging of the neurovascular unit during activity. This is because acutely performed awake experiments are typically untenable when the animal is naïve to the imaging apparatus. Here we detail a method that achieves acute, deep-tissue two-photon imaging of neocortical astrocytes and microvasculature in behaving mice. A week prior to experimentation, implantation of the head bar alone allows mice to train for head-immobilization on an easy-to-learn air-supported ball treadmill. Following just two brief familiarization sessions to the treadmill on separate days, an acute cranial window can subsequently be installed for immediate imaging. We demonstrate how running and whisking data can be captured simultaneously with two-photon fluorescence signals with acceptable movement artifacts during active motion. We also show possible applications of this technique by (1) monitoring dynamic changes to microvascular diameter and red blood cells in response to vibrissa sensory stimulation, (2) examining responses of the cerebral microcirculation to the systemic delivery of pharmacological agents using a tail artery cannula during awake imaging, and (3) measuring Ca2+ signals from synthetic and genetically encoded Ca2+ indicators in astrocytes. This method will facilitate acute two-photon fluorescence imaging in awake, active mice and help link cellular events within the neurovascular unit to behavior. PMID:25698926

  4. Hydrogen sulfide mitigates matrix metalloproteinase-9 activity and neurovascular permeability in hyperhomocysteinemic mice*

    PubMed Central

    Tyagi, Neetu; Givvimani, Srikanth; Qipshidze, Natia; Kundu, Soumi; Kapoor, Shray; Vacek, Jonathan C.; Tyagi, Suresh C.

    2010-01-01

    An elevated level of homocysteine (Hcy), known as hyperhomocysteinmia (HHcy), was associated with neurovascular diseases. At physiological levels, hydrogen sulfide (H2S) protected the neurovascular system. Because Hcy was also a precursor of hydrogen sulfide (H2S), we sought to test whether the H2S protected the brain during HHcy. Cystathionine-β-synthase heterozygous (CBS+/−) and wild type (WT) mice were supplemented with or without NaHS (30 µM/L, H2S donor) in drinking water. Blood flow and cerebral microvascular permeability in pial vessels were measured by intravital microscopy in WT, WT+NaHS, CBS−/+ and CBS−/+ + NaHS treated mice. The brain tissues were analyzed for matrix metalloproteinase (MMP) and tissue inhibitor of metalloproteinase (TIMP) by Western blot and RT-PCR. The mRNA levels of CBS and cystathionine gamma lyase (CSE, enzyme responsible for conversion of Hcy to H2S) genes were measured by RT-PCR. The results showed a significant increase in MMP-2, MMP-9, TIMP-3 protein and mRNA in CBS (−/+) mice, while H2S treatment mitigated this increase. Interstitial localization of MMPs was also apparent through Immunohistochemistry. A decrease in protein and mRNA expression of TIMP-4 was observed in CBS (−/+) mice. Microscopy data revealed increase in permeability in CBS (−/+) mice. These effects were ameliorated by H2S and suggested that physiological levels of H2S supplementation may have therapeutic potential against HHcy-induced microvascular permeability, in part, by normalizing the MMP/TIMP ratio in the brain. PMID:19913585

  5. Thyroid Hormone and Vascular Remodeling.

    PubMed

    Ichiki, Toshihiro

    2016-01-01

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

  6. 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. PMID:22435804

  7. Lung morphometry changes in prevention of airway remodeling by protocatechuic aldehyde in asthmatic mice.

    PubMed

    Zhang, Jiankai; Ma, Mulan; Qin, Dongyun; Huang, Jianping; Cui, Xiaojun; Wu, Yongfu; Yang, Huiling; Fu, Hui; Liao, Cui

    2015-01-01

    Airway remodeling can lead to irreversible airflow obstruction and persistent airway hyper-responsiveness, which is the pathological basis of refractory asthma. To investigate the preventive effect of protocatechuic aldehyde on airway remodeling in asthmatic mice by lung morphometry methods. BALB/c mice were used to establish model of airway remodeling by ovalbumin (OVA) inhalation. Bronchoalveolar lavage fluid (BALF) were collected for eosinophils (EOS) count and detection of interleukin 4 (IL-4), interleukin-13 (IL-13) and interferon (IFN-γ) content. The left lung pathological sections were performed HE, AB-PAS and Masson staining. The epithelial lamina thickness of the left main bronchus (Re), the smooth muscle layer thickness (Rm), the number of goblet cells and goblet cell area percentage (%Ac) and gas side of the road and vascular collagen deposition (%Aco, %Avc) situation were measured. Protocatechuic aldehyde gavage made the reduction of BALF EOS count. IL-4 and IL-13 levels also decreased, while the IFN-γ level increased. The left main bronchus Re, Rm, goblet cell count, Ac% and Aco% and Avc% reduced. Protocatechuic aldehyde can significantly control airway inflammation and prevent airway remodeling. PMID:26221226

  8. Lung morphometry changes in prevention of airway remodeling by protocatechuic aldehyde in asthmatic mice

    PubMed Central

    Zhang, Jiankai; Ma, Mulan; Qin, Dongyun; Huang, Jianping; Cui, Xiaojun; Wu, Yongfu; Yang, Huiling; Fu, Hui; Liao, Cui

    2015-01-01

    Airway remodeling can lead to irreversible airflow obstruction and persistent airway hyper-responsiveness, which is the pathological basis of refractory asthma. To investigate the preventive effect of protocatechuic aldehyde on airway remodeling in asthmatic mice by lung morphometry methods. BALB/c mice were used to establish model of airway remodeling by ovalbumin (OVA) inhalation. Bronchoalveolar lavage fluid (BALF) were collected for eosinophils (EOS) count and detection of interleukin 4 (IL-4), interleukin-13 (IL-13) and interferon (IFN-γ) content. The left lung pathological sections were performed HE, AB-PAS and Masson staining. The epithelial lamina thickness of the left main bronchus (Re), the smooth muscle layer thickness (Rm), the number of goblet cells and goblet cell area percentage (%Ac) and gas side of the road and vascular collagen deposition (%Aco, %Avc) situation were measured. Protocatechuic aldehyde gavage made the reduction of BALF EOS count. IL-4 and IL-13 levels also decreased, while the IFN-γ level increased. The left main bronchus Re, Rm, goblet cell count, Ac% and Aco% and Avc% reduced. Protocatechuic aldehyde can significantly control airway inflammation and prevent airway remodeling. PMID:26221226

  9. 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)

  10. Bone Remodeling Under Pathological Conditions.

    PubMed

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

    2016-01-01

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

  11. Stimulation of UvrD helicase by UvrAB.

    PubMed

    Atkinson, John; Guy, Colin P; Cadman, Chris J; Moolenaar, Geri F; Goosen, Nora; McGlynn, Peter

    2009-04-01

    Helicases play critical roles in all aspects of nucleic acid metabolism by catalyzing the remodeling of DNA and RNA structures. UvrD is an abundant helicase in Escherichia coli with well characterized functions in mismatch and nucleotide excision repair and a possible role in displacement of proteins such as RecA from single-stranded DNA. The mismatch repair protein MutL is known to stimulate UvrD. Here we show that the nucleotide excision repair proteins UvrA and UvrB can together stimulate UvrD-catalyzed unwinding of a range of DNA substrates containing strand discontinuities, including forked DNA substrates. The stimulation is specific for UvrD, as UvrAB failed to stimulate Rep helicase, a UvrD homologue. Moreover, although UvrAB can promote limited strand displacement, stimulation of UvrD did not require the strand displacement function of UvrAB. We conclude that UvrAB, like MutL, modulate UvrD helicase activity. This stimulation likely plays a role in DNA strand and protein displacement by UvrD in nucleotide excision repair. Promotion of UvrD-catalyzed unwinding of nicked duplexes by UvrAB may also explain the need for UvrAB and UvrD in Okazaki fragment processing in cells lacking DNA polymerase I. More generally, these data support the idea that helicase activity is regulated in vivo, with helicases acting as part of multisubunit complexes rather than in isolation. PMID:19208629

  12. Remodeling kitchens: A smorgasbord of energy savings

    SciTech Connect

    Sullivan, B.

    1995-09-01

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

  13. Effect of material damping on bone remodelling.

    PubMed

    Misra, J C; Samanta, S

    1987-01-01

    This paper considers the effect of internal material damping on the stresses, strains, and surface and internal remodelling behaviour in a section of axisymmetrical bone with a force-fitted axially oriented medullary pin. The bone response to several loading situations is modelled using visco-elastic equations. An approximate method is developed to analyse the proposed mathematical model. By considering a numerical example, the effect of material damping on the remodelling stresses is quantified. PMID:3584150

  14. Chromatin remodeling by nucleosome disassembly in vitro.

    PubMed

    Lorch, Yahli; Maier-Davis, Barbara; Kornberg, Roger D

    2006-02-28

    The RSC chromatin-remodeling complex completely disassembles a nucleosome in the presence of the histone chaperone Nap1 and ATP. Disassembly occurs in a stepwise manner, with the removal of H2A/H2B dimers, followed by the rest of the histones and the release of naked DNA. RSC and related chromatin-remodeling complexes may be responsible for the removal of promoter nucleosomes during transcriptional activation in vivo. PMID:16492771

  15. Biomechanics of vascular mechanosensation and remodeling

    PubMed Central

    Baeyens, Nicolas; Schwartz, Martin A.

    2016-01-01

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

  16. Microstructural abnormalities of the trigeminal nerve by diffusion-tensor imaging in trigeminal neuralgia without neurovascular compression.

    PubMed

    Neetu, Soni; Sunil, Kumar; Ashish, Awasthi; Jayantee, Kalita; Usha Kant, Misra

    2016-02-01

    Microstructural changes of the trigeminal nerve in trigeminal neuralgia due to neurovascular compression have been reported by using diffusion tensor imaging. Other aetiologies such as primary demyelinating lesions, brain stem infarction and nerve root infiltration by tumour affecting the trigeminal pathway may also present as trigeminal neuralgia. The aim of this study was to evaluate the microstructural tissue abnormalities in the trigeminal nerve in symptomatic trigeminal neuralgia not related to neurovascular compression using diffusion tensor imaging. Mean values of the quantitative diffusion parameters of trigeminal nerve, fractional anisotropy and apparent diffusion coefficient, were measured in a group of four symptomatic trigeminal neuralgia patients without neurovascular compression who showed focal non-enhancing T2-hyperintense lesions in the pontine trigeminal pathway. These diffusion parameters were compared between the affected and unaffected sides in the same patient and with four age-matched healthy controls. Cranial magnetic resonance imaging revealed hyperintense lesions in the dorsolateral part of the pons along the central trigeminal pathway on T2-fluid-attenuated inversion recovery sequences. The mean fractional anisotropy value on the affected side was significantly decreased (P = 0.001) compared to the unaffected side and healthy controls. Similarly, the mean apparent diffusion coefficient value was significantly higher (P = 0.001) on the affected side compared to the unaffected side and healthy controls. The cause of trigeminal neuralgia in our patients was abnormal pontine lesions affecting the central trigeminal pathway. The diffusion tensor imaging results suggest that microstructural tissue abnormalities of the trigeminal nerve also exist even in non-neurovascular compression-related trigeminal neuralgia. PMID:26678753

  17. Dynamics of the Ethanolamine Glycerophospholipid Remodeling Network

    PubMed Central

    Hermansson, Martin; Somerharju, Pentti; Chuang, Jeffrey

    2012-01-01

    Acyl chain remodeling in lipids is a critical biochemical process that plays a central role in disease. However, remodeling remains poorly understood, despite massive increases in lipidomic data. In this work, we determine the dynamic network of ethanolamine glycerophospholipid (PE) remodeling, using data from pulse-chase experiments and a novel bioinformatic network inference approach. The model uses a set of ordinary differential equations based on the assumptions that (1) sn1 and sn2 acyl positions are independently remodeled; (2) remodeling reaction rates are constant over time; and (3) acyl donor concentrations are constant. We use a novel fast and accurate two-step algorithm to automatically infer model parameters and their values. This is the first such method applicable to dynamic phospholipid lipidomic data. Our inference procedure closely fits experimental measurements and shows strong cross-validation across six independent experiments with distinct deuterium-labeled PE precursors, demonstrating the validity of our assumptions. In constrast, fits of randomized data or fits using random model parameters are worse. A key outcome is that we are able to robustly distinguish deacylation and reacylation kinetics of individual acyl chain types at the sn1 and sn2 positions, explaining the established prevalence of saturated and unsaturated chains in the respective positions. The present study thus demonstrates that dynamic acyl chain remodeling processes can be reliably determined from dynamic lipidomic data. PMID:23251394

  18. Mitochondria, myocardial remodeling, and cardiovascular disease.

    PubMed

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

    2012-12-01

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

  19. Epigenomic regulation of oncogenesis by chromatin remodeling.

    PubMed

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

    2016-08-25

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

  20. Astrocyte Ca2+ Signaling Drives Inversion of Neurovascular Coupling after Subarachnoid Hemorrhage.

    PubMed

    Pappas, Anthony C; Koide, Masayo; Wellman, George C

    2015-09-30

    Physiologically, neurovascular coupling (NVC) matches focal increases in neuronal activity with local arteriolar dilation. Astrocytes participate in NVC by sensing increased neurotransmission and releasing vasoactive agents (e.g., K(+)) from perivascular endfeet surrounding parenchymal arterioles. Previously, we demonstrated an increase in the amplitude of spontaneous Ca(2+) events in astrocyte endfeet and inversion of NVC from vasodilation to vasoconstriction in brain slices obtained from subarachnoid hemorrhage (SAH) model rats. However, the role of spontaneous astrocyte Ca(2+) signaling in determining the polarity of the NVC response remains unclear. Here, we used two-photon imaging of Fluo-4-loaded rat brain slices to determine whether altered endfoot Ca(2+) signaling underlies SAH-induced inversion of NVC. We report a time-dependent emergence of endfoot high-amplitude Ca(2+) signals (eHACSs) after SAH that were not observed in endfeet from unoperated animals. Furthermore, the percentage of endfeet with eHACSs varied with time and paralleled the development of inversion of NVC. Endfeet with eHACSs were present only around arterioles exhibiting inversion of NVC. Importantly, depletion of intracellular Ca(2+) stores using cyclopiazonic acid abolished SAH-induced eHACSs and restored arteriolar dilation in SAH brain slices to two mediators of NVC (a rise in endfoot Ca(2+) and elevation of extracellular K(+)). These data indicate a causal link between SAH-induced eHACSs and inversion of NVC. Ultrastructural examination using transmission electron microscopy indicated that a similar proportion of endfeet exhibiting eHACSs also exhibited asymmetrical enlargement. Our results demonstrate that subarachnoid blood causes a delayed increase in the amplitude of spontaneous intracellular Ca(2+) release events leading to inversion of NVC. Significance statement: Aneurysmal subarachnoid hemorrhage (SAH)--strokes involving cerebral aneurysm rupture and release of blood onto the

  1. Neurovascular risks of sacral screws with bicortical purchase: an anatomical study

    PubMed Central

    Ergur, Ipek; Kiray, Amac; Kosay, Can; Tayefi, Hamid

    2007-01-01

    The aim of this cadaver study is to define the anatomic structures on anterior sacrum, which are under the risk of injury during bicortical screw application to the S1 and S2 pedicles. Thirty formaldehyde-preserved human male cadavers were studied. Posterior midline incision was performed, and soft tissues and muscles were dissected from the posterior part of the lumbosacral region. A 6 mm pedicle screw was inserted between the superior facet of S1 and the S1 foramen. The entry point of the S2 pedicle screw was located between S1 and S2 foramina. S1 and S2 screws were placed on both right and the left sides of all cadavers. Then, all cadavers were turned into supine position. All abdominal and pelvic organs were moved away and carefully observed for any injury. The tips of the sacral screws were marked and the relations with the anatomic structures were defined. The position of the sacral screws relative to the middle and lateral sacral arteries and veins, and the sacral sympathetic trunk were measured. There was no injury to the visceral organs. In four cases, S1 screw tip was in direct contact with middle sacral artery. In two cases, S1 screw tip was in direct contact with middle sacral vein. It was observed that the S1 screw tips were in close proximity to sacral sympathetic trunk on both right and the left sides. The tip of the S2 screw was in contact with middle sacral artery on the left side only in one case. It is found that the tip of the S2 screw was closely located with the middle sacral vein in two cases. The tip of the S2 pedicle screw was in contact with the sacral sympathetic trunk in eight cases on the right side and seven cases on the left side. Lateral sacral vein was also observed to be disturbed by the S1 and S2 screws. As a conclusion, anterior cortical penetration during sacral screw insertion carries a risk of neurovascular injury. The risk of sacral sympathetic trunk and minor vascular structures together with the major neurovascular

  2. The absolute CBF response to activation is preserved during elevated perfusion: Implications for neurovascular coupling measures

    PubMed Central

    Whittaker, Joseph R.; Driver, Ian D.; Bright, Molly G.; Murphy, Kevin

    2016-01-01

    Functional magnetic resonance imaging (fMRI) techniques in which the blood oxygenation level dependent (BOLD) and cerebral blood flow (CBF) response to a neural stimulus are measured, can be used to estimate the fractional increase in the cerebral metabolic rate of oxygen consumption (CMRO2) that accompanies evoked neural activity. A measure of neurovascular coupling is obtained from the ratio of fractional CBF and CMRO2 responses, defined as n, with the implicit assumption that relative rather than absolute changes in CBF and CMRO2 adequately characterise the flow-metabolism response to neural activity. The coupling parameter n is important in terms of its effect on the BOLD response, and as potential insight into the flow-metabolism relationship in both normal and pathological brain function. In 10 healthy human subjects, BOLD and CBF responses were measured to test the effect of baseline perfusion (modulated by a hypercapnia challenge) on the coupling parameter n during graded visual stimulation. A dual-echo pulsed arterial spin labelling (PASL) sequence provided absolute quantification of CBF in baseline and active states as well as relative BOLD signal changes, which were used to estimate CMRO2 responses to the graded visual stimulus. The absolute CBF response to the visual stimuli were constant across different baseline CBF levels, meaning the fractional CBF responses were reduced at the hyperperfused baseline state. For the graded visual stimuli, values of n were significantly reduced during hypercapnia induced hyperperfusion. Assuming the evoked neural responses to the visual stimuli are the same for both baseline CBF states, this result has implications for fMRI studies that aim to measure neurovascular coupling using relative changes in CBF. The coupling parameter n is sensitive to baseline CBF, which would confound its interpretation in fMRI studies where there may be significant differences in baseline perfusion between groups. The absolute change in

  3. Astrocyte Ca2+ Signaling Drives Inversion of Neurovascular Coupling after Subarachnoid Hemorrhage

    PubMed Central

    Pappas, Anthony C.; Koide, Masayo

    2015-01-01

    Physiologically, neurovascular coupling (NVC) matches focal increases in neuronal activity with local arteriolar dilation. Astrocytes participate in NVC by sensing increased neurotransmission and releasing vasoactive agents (e.g., K+) from perivascular endfeet surrounding parenchymal arterioles. Previously, we demonstrated an increase in the amplitude of spontaneous Ca2+ events in astrocyte endfeet and inversion of NVC from vasodilation to vasoconstriction in brain slices obtained from subarachnoid hemorrhage (SAH) model rats. However, the role of spontaneous astrocyte Ca2+ signaling in determining the polarity of the NVC response remains unclear. Here, we used two-photon imaging of Fluo-4-loaded rat brain slices to determine whether altered endfoot Ca2+ signaling underlies SAH-induced inversion of NVC. We report a time-dependent emergence of endfoot high-amplitude Ca2+ signals (eHACSs) after SAH that were not observed in endfeet from unoperated animals. Furthermore, the percentage of endfeet with eHACSs varied with time and paralleled the development of inversion of NVC. Endfeet with eHACSs were present only around arterioles exhibiting inversion of NVC. Importantly, depletion of intracellular Ca2+ stores using cyclopiazonic acid abolished SAH-induced eHACSs and restored arteriolar dilation in SAH brain slices to two mediators of NVC (a rise in endfoot Ca2+ and elevation of extracellular K+). These data indicate a causal link between SAH-induced eHACSs and inversion of NVC. Ultrastructural examination using transmission electron microscopy indicated that a similar proportion of endfeet exhibiting eHACSs also exhibited asymmetrical enlargement. Our results demonstrate that subarachnoid blood causes a delayed increase in the amplitude of spontaneous intracellular Ca2+ release events leading to inversion of NVC. SIGNIFICANCE STATEMENT Aneurysmal subarachnoid hemorrhage (SAH)—strokes involving cerebral aneurysm rupture and release of blood onto the brain surface

  4. New aspects of the topographical anatomy of the mammary gland regarding its neurovascular supply along a regular ligamentous suspension.

    PubMed

    Wueringer, Elisabeth; Tschabitscher, Manfred

    2002-07-01

    The exact location of the main nerves and vessels to the breast and the nipple-areola complex has always been obscure. We found that the course of the rich neurovascular supply to the nipple runs along a regularly-located, suspensory apparatus and can therefore be predicted exactly. It consists of a horizontal fibrous septum originating at the pectoral fascia along the 5th rib, merging into vertical ligaments along the sternum medially and along the lateral border of pectoralis minor laterally. Cranially, and in an anterior direction, the vertical ligaments are connected by the superficial fascia. In the current anatomical study, we seek to demonstrate the vascular supply provided by these structures more impressively. For this purpose we dissected the ligamentous suspension after intraarterial injection with colored latex in both breasts of 10 female cadavers. The large vessels, guided by this circle of fibrous attachments could then be seen clearly. In a further 4 female cadavers, a similar procedure was performed after intraarterial injection of surgical ink. This stained the vascular layers even more intensely. This topographical knowledge has clinical relevance. The rich and constant neurovascular supply to the nipple areola complex may be maintained in a new breast-reduction technique, which allows safe postoperative viability and sensibility of the nipple. The clinical results act as a striking evidence of our anatomical findings. Further procedures taking advantage of the easy determination and access to the neurovascular supply may be seen in future. PMID:14566611

  5. Simultaneous real-time 3D photoacoustic tomography and EEG for neurovascular coupling study in an animal model of epilepsy

    NASA Astrophysics Data System (ADS)

    Wang, Bo; Xiao, Jiaying; Jiang, Huabei

    2014-08-01

    Objective. Neurovascular coupling in epilepsy is poorly understood; its study requires simultaneous monitoring of hemodynamic changes and neural activity in the brain. Approach. Here for the first time we present a combined real-time 3D photoacoustic tomography (PAT) and electrophysiology/electroencephalography (EEG) system for the study of neurovascular coupling in epilepsy, whose ability was demonstrated with a pentylenetetrazol (PTZ) induced generalized seizure model in rats. Two groups of experiments were carried out with different wavelengths to detect the changes of oxy-hemoglobin (HbO2) and deoxy-hemoglobin (HbR) signals in the rat brain. We extracted the average PAT signals of the superior sagittal sinus (SSS), and compared them with the EEG signal. Main results. Results showed that the seizure process can be divided into three stages. A ‘dip’ lasting for 1-2 min in the first stage and the following hyperfusion in the second stage were observed. The HbO2 signal and the HbR signal were generally negatively correlated. The change of blood flow was also estimated. All the acquired results here were in accordance with other published results. Significance. Compared to other existing functional neuroimaging tools, the method proposed here enables reliable tracking of hemodynamic signal with both high spatial and high temporal resolution in 3D, so it is more suitable for neurovascular coupling study of epilepsy.

  6. Toward the Era of a One-Stop Imaging Service Using an Angiography Suite for Neurovascular Disorders

    PubMed Central

    Hung, Sheng-Che; Lin, Chung-Jung; Chang, Feng-Chi; Luo, Chao-Bao; Teng, Michael Mu-Huo; Chang, Cheng-Yen

    2013-01-01

    Transportation of patients requiring multiple diagnostic and imaging-guided therapeutic modalities is unavoidable in current radiological practice. This clinical scenario causes time delays and increased risk in the management of stroke and other neurovascular emergencies. Since the emergence of flat-detector technology in imaging practice in recent decades, studies have proven that flat-detector X-ray angiography in conjunction with contrast medium injection and specialized reconstruction algorithms can provide not only high-quality and high-resolution CT-like images but also functional information. This improvement in imaging technology allows quantitative assessment of intracranial hemodynamics and, subsequently in the same imaging session, provides treatment guidance for patients with neurovascular disorders by using only a flat-detector angiographic suite—a so-called one-stop quantitative imaging service (OSIS). In this paper, we review the recent developments in the field of flat-detector imaging and share our experience of applying this technology in neurovascular disorders such as acute ischemic stroke, cerebral aneurysm, and stenoocclusive carotid diseases. PMID:23762863

  7. Early and late stimulus-evoked cortical hemodynamic responses provide insight into the neurogenic nature of neurovascular coupling

    PubMed Central

    Kennerley, Aneurin J; Harris, Sam; Bruyns-Haylett, Michael; Boorman, Luke; Zheng, Ying; Jones, Myles; Berwick, Jason

    2012-01-01

    Understanding neurovascular coupling is a prerequisite for the interpretation of results obtained from modern neuroimaging techniques. This study investigated the hemodynamic and neural responses in rat somatosensory cortex elicited by 16 seconds electrical whisker stimuli. Hemodynamics were measured by optical imaging spectroscopy and neural activity by multichannel electrophysiology. Previous studies have suggested that the whisker-evoked hemodynamic response contains two mechanisms, a transient ‘backwards' dilation of the middle cerebral artery, followed by an increase in blood volume localized to the site of neural activity. To distinguish between the mechanisms responsible for these aspects of the response, we presented whisker stimuli during normocapnia (‘control'), and during a high level of hypercapnia. Hypercapnia was used to ‘predilate' arteries and thus possibly ‘inhibit' aspects of the response related to the ‘early' mechanism. Indeed, hemodynamic data suggested that the transient stimulus-evoked response was absent under hypercapnia. However, evoked neural responses were also altered during hypercapnia and convolution of the neural responses from both the normocapnic and hypercapnic conditions with a canonical impulse response function, suggested that neurovascular coupling was similar in both conditions. Although data did not clearly dissociate early and late vascular responses, they suggest that the neurovascular coupling relationship is neurogenic in origin. PMID:22126914

  8. ABS plastic RPCs

    SciTech Connect

    Ables, E.; Bionta, R.; Olson, H.; Ott, L.; Parker, E.; Wright, D.; Wuest, C

    1996-02-01

    After investigating a number of materials, we discovered that an ABS plastic doped with a conducting polymer performs well as the resistive electrode in a narrow gap RPC (resistive plate chamber). Operating in the streamer mode, we find efficiencies of 90-96% with low noise and low strip multiplicities. We have also studied a variety of operating gases and found that a mixture containing SF{sub 6}, a non-ozone depleting gas, argon and isobutane gives good streamer mode performance, even with isobutane concentrations of 20% or less.

  9. Cardiac remodelling and RAS inhibition.

    PubMed

    Ferrario, Carlos M

    2016-06-01

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

  10. Model of the transient neurovascular response based on prompt arterial dilation.

    PubMed

    Kim, Jung Hwan; Khan, Reswanul; Thompson, Jeffrey K; Ress, David

    2013-09-01

    Brief neural stimulation results in a stereotypical pattern of vascular and metabolic response that is the basis for popular brain-imaging methods such as functional magnetic resonance imagine. However, the mechanisms of transient oxygen transport and its coupling to cerebral blood flow (CBF) and oxygen metabolism (CMRO2) are poorly understood. Recent experiments show that brief stimulation produces prompt arterial vasodilation rather than venous vasodilation. This work provides a neurovascular response model for brief stimulation based on transient arterial effects using one-dimensional convection-diffusion transport. Hemoglobin oxygen dissociation is included to enable predictions of absolute oxygen concentrations. Arterial CBF response is modeled using a lumped linear flow model, and CMRO2 response is modeled using a gamma function. Using six parameters, the model successfully fit 161/166 measured extravascular oxygen time courses obtained for brief visual stimulation in cat cerebral cortex. Results show how CBF and CMRO2 responses compete to produce the observed features of the hemodynamic response: initial dip, hyperoxic peak, undershoot, and ringing. Predicted CBF and CMRO2 response amplitudes are consistent with experimental measurements. This model provides a powerful framework to quantitatively interpret oxygen transport in the brain; in particular, its intravascular oxygen concentration predictions provide a new model for fMRI responses. PMID:23756690

  11. Regulation of cerebrospinal fluid (CSF) flow in neurodegenerative, neurovascular and neuroinflammatory disease.

    PubMed

    Simon, Matthew J; Iliff, Jeffrey J

    2016-03-01

    Cerebrospinal fluid (CSF) circulation and turnover provides a sink for the elimination of solutes from the brain interstitium, serving an important homeostatic role for the function of the central nervous system. Disruption of normal CSF circulation and turnover is believed to contribute to the development of many diseases, including neurodegenerative conditions such as Alzheimer's disease, ischemic and traumatic brain injury, and neuroinflammatory conditions such as multiple sclerosis. Recent insights into CSF biology suggesting that CSF and interstitial fluid exchange along a brain-wide network of perivascular spaces termed the 'glymphatic' system suggest that CSF circulation may interact intimately with glial and vascular function to regulate basic aspects of brain function. Dysfunction within this glial vascular network, which is a feature of the aging and injured brain, is a potentially critical link between brain injury, neuroinflammation and the development of chronic neurodegeneration. Ongoing research within this field may provide a powerful new framework for understanding the common links between neurodegenerative, neurovascular and neuroinflammatory disease, in addition to providing potentially novel therapeutic targets for these conditions. This article is part of a Special Issue entitled: Neuro Inflammation edited by Helga E. de Vries and Markus Schwaninger. PMID:26499397

  12. Emerging roles of pericytes in the regulation of the neurovascular unit in health and disease

    PubMed Central

    Hill, Jeremy; Rom, Slava; Ramirez, Servio H.; Persidsky, Yuri

    2014-01-01

    Pericytes of the central nervous system (CNS) are uniquely positioned within a multicellular structure termed the neurovascular unit (NVU) to provide crucial support to blood brain barrier (BBB) formation, maintenance, and stability. Numerous CNS diseases are associated with some aspect of BBB dysfunction. A dysfunction can manifest as one or multiple disruptions to any of the following barriers: physical, metabolic, immunological and transport barrier. A breach in the BBB can notably result in BBB hyper-permeability, endothelial activation and enhanced immune-endothelial interaction. How the BBB is regulated within this integrated unit remains largely unknown, especially as it relates to pericyte-endothelial interaction. We summarize the latest findings on pericyte origin, possible marker expression, and availability within different organ systems. We highlight pericyte-endothelial cell interactions, concentrating on extra- and intra- cellular signaling mechanisms linked to platelet derived growth factor-B, transforming growth factor -β, angiopoietins, Notch, and gap junctions. We discuss the role of pericytes in the NVU under inflammatory insult, focusing on how pericytes may indirectly affect leukocyte CNS infiltration, the direct role of pericyte-mediated basement membrane modifications, and immune responses. We review new findings of pericyte actions in CNS pathologies including Alzheimer’s disease, stroke, multiple sclerosis, diabetic retinopathy, and HIV-1 infection. The uncovering of the regulatory role of pericytes on the BBB will provide key insight into how barrier integrity can be re-established during neuroinflammation. PMID:25119834

  13. Three-Dimensional Blood-Brain Barrier Model for in vitro Studies of Neurovascular Pathology.

    PubMed

    Cho, Hansang; Seo, Ji Hae; Wong, Keith H K; Terasaki, Yasukazu; Park, Joseph; Bong, Kiwan; Arai, Ken; Lo, Eng H; Irimia, Daniel

    2015-01-01

    Blood-brain barrier (BBB) pathology leads to neurovascular disorders and is an important target for therapies. However, the study of BBB pathology is difficult in the absence of models that are simple and relevant. In vivo animal models are highly relevant, however they are hampered by complex, multi-cellular interactions that are difficult to decouple. In vitro models of BBB are simpler, however they have limited functionality and relevance to disease processes. To address these limitations, we developed a 3-dimensional (3D) model of BBB on a microfluidic platform. We verified the tightness of the BBB by showing its ability to reduce the leakage of dyes and to block the transmigration of immune cells towards chemoattractants. Moreover, we verified the localization at endothelial cell boundaries of ZO-1 and VE-Cadherin, two components of tight and adherens junctions. To validate the functionality of the BBB model, we probed its disruption by neuro-inflammation mediators and ischemic conditions and measured the protective function of antioxidant and ROCK-inhibitor treatments. Overall, our 3D BBB model provides a robust platform, adequate for detailed functional studies of BBB and for the screening of BBB-targeting drugs in neurological diseases. PMID:26503597

  14. Iron transport across the blood-brain barrier; Development, neurovascular regulation and cerebral amyloid angiopathy

    PubMed Central

    McCarthy, Ryan C; Kosman, Daniel J

    2014-01-01

    There are two barriers for iron entry into the brain: 1) the brain-cerebrospinal fluid (CSF) barrier and 2) the blood-brain barrier (BBB). Here, we review the literature on developmental iron accumulation by the brain, focusing on the transport of iron through the brain microvascular endothelial cells (BMVEC) of the BBB. We review the iron trafficking proteins which may be involved in the iron flux across BMVEC and discuss the plausible mechanisms of BMVEC iron uptake and efflux. We suggest a model for how BMVEC iron uptake and efflux are regulated and a mechanism by which the majority of iron is trafficked across the developing BBB under the direct guidance of neighboring astrocytes. Thus, we place brain iron uptake in the context of the neurovascular unit of the adult brain. Last, we propose that BMVEC iron is involved in the aggregation of amyloid-β peptides leading to the progression of cerebral amyloid angiopathy which often occurs prior to dementia and the onset of Alzheimer's disease. PMID:25355056

  15. Three-Dimensional Blood-Brain Barrier Model for in vitro Studies of Neurovascular Pathology

    NASA Astrophysics Data System (ADS)

    Cho, Hansang; Seo, Ji Hae; Wong, Keith H. K.; Terasaki, Yasukazu; Park, Joseph; Bong, Kiwan; Arai, Ken; Lo, Eng H.; Irimia, Daniel

    2015-10-01

    Blood-brain barrier (BBB) pathology leads to neurovascular disorders and is an important target for therapies. However, the study of BBB pathology is difficult in the absence of models that are simple and relevant. In vivo animal models are highly relevant, however they are hampered by complex, multi-cellular interactions that are difficult to decouple. In vitro models of BBB are simpler, however they have limited functionality and relevance to disease processes. To address these limitations, we developed a 3-dimensional (3D) model of BBB on a microfluidic platform. We verified the tightness of the BBB by showing its ability to reduce the leakage of dyes and to block the transmigration of immune cells towards chemoattractants. Moreover, we verified the localization at endothelial cell boundaries of ZO-1 and VE-Cadherin, two components of tight and adherens junctions. To validate the functionality of the BBB model, we probed its disruption by neuro-inflammation mediators and ischemic conditions and measured the protective function of antioxidant and ROCK-inhibitor treatments. Overall, our 3D BBB model provides a robust platform, adequate for detailed functional studies of BBB and for the screening of BBB-targeting drugs in neurological diseases.

  16. Brain regional angiogenic potential at the neurovascular unit during normal aging

    PubMed Central

    Murugesan, Nivetha; Demarest, Tyler G.; Madri, Joseph A.; Pachter, Joel S.

    2011-01-01

    Given strong regional specialization of the brain, cerebral angiogenesis may be regionally modified during normal aging. To test this hypothesis, expression of a broad cadre of angiogenesis-associated genes was assayed at the neurovascular unit (NVU) in discrete brain regions of young vs. aged mice by laser capture microdissection coupled to quantitative real-time PCR. Complementary quantitative capillary density/branching studies were performed as well. Effects of physical exercise were also assayed to determine if age-related trends could be reversed. Additionally, gene response to hypoxia was probed to highlight age-associated weaknesses in adapting to this angiogenic stress. Aging impacted resting expression of angiogenesis-associated genes at the NVU in a region-dependent manner. Physical exercise reversed some of these age-associated gene trends, as well as positively influenced cerebral capillary density/branching in a region-dependent way. Lastly, hypoxia revealed a weaker angiogenic response in aged brain. These results suggest heterogeneous changes in angiogenic capacity of the brain during normal aging, and imply a therapeutic benefit of physical exercise that acts at the level of the NVU. PMID:22019053

  17. A 3D neurovascular bundles segmentation method based on MR-TRUS deformable registration

    NASA Astrophysics Data System (ADS)

    Yang, Xiaofeng; Rossi, Peter; Jani, Ashesh B.; Mao, Hui; Ogunleye, Tomi; Curran, Walter J.; Liu, Tian

    2015-03-01

    In this paper, we propose a 3D neurovascular bundles (NVB) segmentation method for ultrasound (US) image by integrating MR and transrectal ultrasound (TRUS) images through MR-TRUS deformable registration. First, 3D NVB was contoured by a physician in MR images, and the 3D MRdefined NVB was then transformed into US images using a MR-TRUS registration method, which models the prostate tissue as an elastic material, and jointly estimates the boundary deformation and the volumetric deformations under the elastic constraint. This technique was validated with a clinical study of 6 patients undergoing radiation therapy (RT) treatment for prostate cancer. The accuracy of our approach was assessed through the locations of landmarks, as well as previous ultrasound Doppler images of patients. MR-TRUS registration was successfully performed for all patients. The mean displacement of the landmarks between the post-registration MR and TRUS images was less than 2 mm, and the average NVB volume Dice Overlap Coefficient was over 89%. This NVB segmentation technique could be a useful tool as we try to spare the NVB in prostate RT, monitor NVB response to RT, and potentially improve post-RT potency outcomes.

  18. Free neurovascular flap from the first web of the foot in hand reconstruction.

    PubMed

    May, J W; Chait, L A; Cohen, B E; O'Brien, B M

    1977-09-01

    To identify an anatomically reliable and functionally acceptable neurovascular free flap for use in hand reconstruction, 50 fresh cadaver feet were dissected under the operating microscope, with particular attention paid to the anatomy of the first web area. A distal communicating artery was seen in 100% of dissections, allowing either dorsal or plantar donor artery inflow to nourish the entire flap area. Because of the ease of dissection, the first dorsal metatarsal or dorsalis pedis is suggested as the donor artery, and a dorsal branch of the greater saphenous venous system is suggested as the donor vein. The deep peroneal nerve was seen to consistently innervate the first web and, along with the plantar digital nerves, is suggested as an anatomically identifiable donor nerve. Either part of the foot first web may be used alone or together as a free flap. When indicated further dorsal skin may be incorporated into the web flap to expand its application. Two-point discrimination studies of the lateral plantar surface of the great toe in 50 normal individuals showed an average of 11.2 mm. This was significantly better as a potential donor flap than the medial dorsum of the foot where the average was 32 mm. A single case demonstrating the application of this flap in hand reconstruction is presented. PMID:332757

  19. Neuronal networks and mediators of cortical neurovascular coupling responses in normal and altered brain states.

    PubMed

    Lecrux, C; Hamel, E

    2016-10-01

    Brain imaging techniques that use vascular signals to map changes in neuronal activity, such as blood oxygenation level-dependent functional magnetic resonance imaging, rely on the spatial and temporal coupling between changes in neurophysiology and haemodynamics, known as 'neurovascular coupling (NVC)'. Accordingly, NVC responses, mapped by changes in brain haemodynamics, have been validated for different stimuli under physiological conditions. In the cerebral cortex, the networks of excitatory pyramidal cells and inhibitory interneurons generating the changes in neural activity and the key mediators that signal to the vascular unit have been identified for some incoming afferent pathways. The neural circuits recruited by whisker glutamatergic-, basal forebrain cholinergic- or locus coeruleus noradrenergic pathway stimulation were found to be highly specific and discriminative, particularly when comparing the two modulatory systems to the sensory response. However, it is largely unknown whether or not NVC is still reliable when brain states are altered or in disease conditions. This lack of knowledge is surprising since brain imaging is broadly used in humans and, ultimately, in conditions that deviate from baseline brain function. Using the whisker-to-barrel pathway as a model of NVC, we can interrogate the reliability of NVC under enhanced cholinergic or noradrenergic modulation of cortical circuits that alters brain states.This article is part of the themed issue 'Interpreting BOLD: a dialogue between cognitive and cellular neuroscience'. PMID:27574304

  20. Lipid-lowering drugs prevent neurovascular and cognitive consequences of cardiopulmonary bypass.

    PubMed

    Ouk, Thavarak; Amr, Gilles; Azzaoui, Richard; Delassus, Laëtitia; Fossaert, Emilie; Tailleux, Anne; Bordet, Régis; Modine, Thomas

    2016-05-01

    Inflammatory injury and hypoperfusion following cardiopulmonary bypass (CPB) are associated with potential brain injury in relationship between CPB, memory impairment, changes in cerebral vascular reactivity and both systemic and cerebral inflammatory reaction. The objective of this study was to assess the preventive effect of a pretreatment with simvastatin or fenofibrate on neurovascular and cognitive consequences of CPB. Male Sprague-Dawley rats were treated by control diet, simvastatin 10mg/kg/day or fenofibrate 200mg/kg/day for 14days before CPB surgery and were sacrificed immediately after surgery or 24h later. Cognitive function, vascular reactivity, neuronal counts in CA1 and CA3 hippocampal regions, and inflammatory markers were assessed. CPB induced memory impairment and endothelial dysfunction 24h after surgery associated with neuronal loss. Neuronal loss was reduced by simvastatin or fenofibrate treatment in parallel to memory alteration prevention. Pretreatment by simvastatin and fenofibrate prevented CPB-induced endothelial dysfunction. CPB led to early and marked release of TNFα and overexpression of ICAM-1. Both inflammatory marker expression was decreased in the pretreated groups by lipid-lowering drugs. In a rat model of CPB, we demonstrated that simvastatin and fenofibrate protected against CPB-induced endothelial dysfunction, cerebral and systemic inflammation in parallel to memory impairment prevention. PMID:26779598

  1. Reconstruction of fingertip defects with the neurovascular tranquilli-leali flap.

    PubMed

    Loréa, P; Chahidi, N; Marchesi, S; Ezzedine, R; Marin Braun, F; Dury, M

    2006-06-01

    For many years, bipedicled palmar advancement flaps were used rarely in fingers because they sacrificed the dorsal branches of the digital arteries, risking dorsal skin necrosis. In 1995, a short bipedicled neurovascular VY advancement flap raised distally to the PIP flexion crease, which spared the dorsal blood supply, was described by Elliot et al. (1995). This paper includes an anatomical study on 28 fresh cadaver fingers to evaluate the advancement potential of this flap. It also reviews 22 fingertip reconstructions in 22 patients using this flap. The mean advancement of the flap in the cadaver study was 14 (range 10-16) mm. This procedure gave good clinical results in respect of healing, sensibility, bone cover and appearance. Complications occurred in four fingers (18%), viz. two infections, one neuroma and one stiff proximal interphalangeal joint. Our study suggests that this flap can be used to treat fingertip defects of a size of approximately half of the pulp of the distal phalangeal segment of the finger. PMID:16403425

  2. Imaging the Perivascular Space as a Potential Biomarker of Neurovascular and Neurodegenerative Diseases.

    PubMed

    Ramirez, Joel; Berezuk, Courtney; McNeely, Alicia A; Gao, Fuqiang; McLaurin, JoAnne; Black, Sandra E

    2016-03-01

    Although the brain lacks conventional lymphatic vessels found in peripheral tissue, evidence suggests that the space surrounding the vasculature serves a similar role in the clearance of fluid and metabolic waste from the brain. With aging, neurodegeneration, and cerebrovascular disease, these microscopic perivascular spaces can become enlarged, allowing for visualization and quantification on structural MRI. The purpose of this review is to: (i) describe some of the recent pre-clinical findings from basic science that shed light on the potential neurophysiological mechanisms driving glymphatic and perivascular waste clearance, (ii) review some of the pathobiological etiologies that may lead to MRI-visible enlarged perivascular spaces (ePVS), (iii) describe the possible clinical implications of ePVS, (iv) evaluate existing qualitative and quantitative techniques used for measuring ePVS burden, and (v) propose future avenues of research that may improve our understanding of this potential clinical neuroimaging biomarker for fluid and metabolic waste clearance dysfunction in neurodegenerative and neurovascular diseases. PMID:26993511

  3. Advancing Cardiovascular, Neurovascular, and Renal Magnetic Resonance Imaging in Small Rodents Using Cryogenic Radiofrequency Coil Technology

    PubMed Central

    Niendorf, Thoralf; Pohlmann, Andreas; Reimann, Henning M.; Waiczies, Helmar; Peper, Eva; Huelnhagen, Till; Seeliger, Erdmann; Schreiber, Adrian; Kettritz, Ralph; Strobel, Klaus; Ku, Min-Chi; Waiczies, Sonia

    2015-01-01

    Research in pathologies of the brain, heart and kidney have gained immensely from the plethora of studies that have helped shape new methods in magnetic resonance (MR) for characterizing preclinical disease models. Methodical probing into preclinical animal models by MR is invaluable since it allows a careful interpretation and extrapolation of data derived from these models to human disease. In this review we will focus on the applications of cryogenic radiofrequency (RF) coils in small animal MR as a means of boosting image quality (e.g., by supporting MR microscopy) and making data acquisition more efficient (e.g., by reducing measuring time); both being important constituents for thorough investigational studies on animal models of disease. This review attempts to make the (bio)medical imaging, molecular medicine, and pharmaceutical communities aware of this productive ferment and its outstanding significance for anatomical and functional MR in small rodents. The goal is to inspire a more intense interdisciplinary collaboration across the fields to further advance and progress non-invasive MR methods that ultimately support thorough (patho)physiological characterization of animal disease models. In this review, current and potential future applications for the RF coil technology in cardiovascular, neurovascular, and renal disease will be discussed. PMID:26617515

  4. SIV-induced impairment of neurovascular repair: a potential role for VEGF

    PubMed Central

    Ebenezer, Gigi J.; McArthur, Justin C.; Polydefkis, Michael; Dorsey, Jamie L.; O'Donnell, Ryan; Hauer, Peter; Adams, Robert J.

    2013-01-01

    Peripheral nerves and blood vessels travel together closely during development but little is known about their interactions post-injury. The SIV-infected pigtailed macaque model of human immunodeficiency virus (HIV) recapitulates peripheral nervous system pathology of HIV infection. In this study, we assessed the effect of SIV infection on neurovascular regrowth using a validated excisional axotomy model. Six uninfected and five SIV-infected macaques were studied 14 and 70 days after axotomy to characterize regenerating vessels and axons. Blood vessel extension preceded the appearance of regenerating nerve fibers suggesting that vessels serve as scaffolding to guide regenerating axons through extracellular matrix. Vascular endothelial growth factor (VEGF) was expressed along vascular silhouettes by endothelial cells, pericytes, and perivascular cells. VEGF expression correlated with dermal nerve (r=0.68, p= 0.01) and epidermal nerve fiber regrowth (r=0.63, p=0.02). No difference in blood vessel growth was observed between SIV-infected and control macaques. In contrast, SIV-infected animals demonstrated altered length, pruning and arborization of nerve fibers as well as alteration of VEGF expression. These results reinforce earlier human primate findings that vessel growth precedes and influences axonal regeneration. The consistency of these observations across human and non-human primates validates the use of the pigtailed-macaque as a preclinical model. PMID:22549763

  5. Aging exacerbates obesity-induced cerebromicrovascular rarefaction, neurovascular uncoupling, and cognitive decline in mice.

    PubMed

    Tucsek, Zsuzsanna; Toth, Peter; Tarantini, Stefano; Sosnowska, Danuta; Gautam, Tripti; Warrington, Junie P; Giles, Cory B; Wren, Jonathan D; Koller, Akos; Ballabh, Praveen; Sonntag, William E; Ungvari, Zoltan; Csiszar, Anna

    2014-11-01

    Epidemiological studies show that obesity has deleterious effects on the brain and cognitive function in the elderly population. However, the specific mechanisms through which aging and obesity interact to promote cognitive decline remain unclear. To test the hypothesis that aging exacerbates obesity-induced cerebromicrovascular impairment, we compared young (7 months) and aged (24 months) high-fat diet-fed obese C57BL/6 mice. We found that aging exacerbates the obesity-induced decline in microvascular density both in the hippocampus and in the cortex. The extent of hippocampal microvascular rarefaction and the extent of impairment of hippocampal-dependent cognitive function positively correlate. Aging exacerbates obesity-induced loss of pericyte coverage on cerebral microvessels and alters hippocampal angiogenic gene expression signature, which likely contributes to microvascular rarefaction. Aging also exacerbates obesity-induced oxidative stress and induction of NADPH oxidase and impairs cerebral blood flow responses to whisker stimulation. Collectively, obesity exerts deleterious cerebrovascular effects in aged mice, promoting cerebromicrovascular rarefaction and neurovascular uncoupling. The morphological and functional impairment of the cerebral microvasculature in association with increased blood-brain barrier disruption and neuroinflammation (Tucsek Z, Toth P, Sosnowsk D, et al. Obesity in aging exacerbates blood-brain barrier disruption, neuroinflammation and oxidative stress in the mouse hippocampus: effects on expression of genes involved in beta-amyloid generation and Alzheimer's disease. J Gerontol Biol Med Sci. 2013. In press, PMID: 24269929) likely contribute to obesity-induced cognitive decline in aging. PMID:24895269

  6. The neurovascular protection afforded by delayed local hypothermia after transient middle cerebral artery occlusion.

    PubMed

    Kim, Jong-Heon; Seo, Minchul; Han, Hyung Soo; Park, Jaechan; Suk, Kyoungho

    2013-05-01

    Therapeutic hypothermia is a robust therapeutic tool in experimental stroke models but its clinical applications are limited. Furthermore, optimal conditions for therapeutic hypothermia, such as, temperature and the initiation and duration of cooling must be individualized. Here, we evaluated the therapeutic effects of delayed local hypothermia, administered for 44 hr after 4 hr of reperfusion in a rat model of transient middle cerebral artery occlusion (tMCAo), using a cooling device that allowed controlled local hypothermia (31 °C) in brain. Histological data revealed that local hypothermia significantly reduced infarct volumes and glial hypertrophic activation. Brain water contents, IgG leakage, and Evans Blue extravasation were notably reduced by local hypothermia. Furthermore, local hypothermia had strong vasculoprotective effects, as determined by immunohistochemistry and Western blot analyses for endothelial barrier antigen (EBA), laminin, aquaporin-4, and tight junction proteins in brain. Our data indicate that delayed/prolonged local hypothermia confers neurovascular protection, reduces brain edema, and inhibits inflammatory glial activation, and suggest that hypothermic conservation of vascular structures and functions account for the therapeutic effects of local hypothermia observed in this model of experimental stroke. PMID:23469955

  7. Testing methodologies for the nonlinear analysis of causal relationships in neurovascular coupling.

    PubMed

    Lüdtke, Niklas; Logothetis, Nikos K; Panzeri, Stefano

    2010-10-01

    We investigated the use and implementation of a nonlinear methodology for establishing which changes in neurophysiological signals cause changes in the blood oxygenation level-dependent (BOLD) contrast measured in functional magnetic resonance imaging. Unlike previous analytical approaches, which used linear correlation to establish covariations between neural activity and BOLD, we propose a directed information-theoretic measure, the transfer entropy, which can elucidate even highly nonlinear causal relationships between neural activity and BOLD signal. In this study we investigated the practicality of such an analysis given the limited data samples that can be collected experimentally due to the low temporal resolution of BOLD signals. We implemented several algorithms for the estimation of transfer entropy and we tested their effectiveness using simulated local field potentials (LFPs) and BOLD data constructed to match the main statistical properties of real LFP and BOLD signals measured simultaneously in monkey primary visual cortex. We found that using the advanced methods of entropy estimation implemented and described here, a transfer entropy analysis of neurovascular coupling based on experimentally attainable data sets is feasible. PMID:20409664

  8. Three-Dimensional Blood-Brain Barrier Model for in vitro Studies of Neurovascular Pathology

    PubMed Central

    Cho, Hansang; Seo, Ji Hae; Wong, Keith H. K.; Terasaki, Yasukazu; Park, Joseph; Bong, Kiwan; Arai, Ken; Lo, Eng H.; Irimia, Daniel

    2015-01-01

    Blood–brain barrier (BBB) pathology leads to neurovascular disorders and is an important target for therapies. However, the study of BBB pathology is difficult in the absence of models that are simple and relevant. In vivo animal models are highly relevant, however they are hampered by complex, multi-cellular interactions that are difficult to decouple. In vitro models of BBB are simpler, however they have limited functionality and relevance to disease processes. To address these limitations, we developed a 3-dimensional (3D) model of BBB on a microfluidic platform. We verified the tightness of the BBB by showing its ability to reduce the leakage of dyes and to block the transmigration of immune cells towards chemoattractants. Moreover, we verified the localization at endothelial cell boundaries of ZO-1 and VE-Cadherin, two components of tight and adherens junctions. To validate the functionality of the BBB model, we probed its disruption by neuro-inflammation mediators and ischemic conditions and measured the protective function of antioxidant and ROCK-inhibitor treatments. Overall, our 3D BBB model provides a robust platform, adequate for detailed functional studies of BBB and for the screening of BBB-targeting drugs in neurological diseases. PMID:26503597

  9. 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

  10. A fly's view of neuronal remodeling.

    PubMed

    Yaniv, Shiri P; Schuldiner, Oren

    2016-09-01

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

  11. The role of midkine in skeletal remodelling

    PubMed Central

    Liedert, A; Schinke, T; Ignatius, A; Amling, M

    2014-01-01

    Bone tissue is subjected to continuous remodelling, replacing old or damaged bone throughout life. In bone remodelling, the coordinated activities of bone-forming osteoblasts and bone-resorbing osteoclasts ensure the maintenance of bone mass and strength. In early life, the balance of these cellular activities is tightly regulated by various factors, including systemic hormones, the mechanical environment and locally released growth factors. Age-related changes in the activity of these factors in bone remodelling can result in diseases with low bone mass, such as osteoporosis. Osteoporosis is a systemic and age-related skeletal disease characterized by low bone mass and structural degeneration of bone tissue, predisposing the patient to an increased fracture risk. The growth factor midkine (Mdk) plays a key role in bone remodelling and it is expressed during bone formation and fracture repair. Using a mouse deficient in Mdk, our group have identified this protein as a negative regulator of bone formation and mechanically induced bone remodelling. Thus, specific Mdk antagonists might represent a therapeutic option for diseases characterized by low bone mass, such as osteoporosis. Linked Articles This article is part of a themed section on Midkine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-4 PMID:24102259

  12. 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

  13. NADPH-diaphorase activity and neurovascular coupling in the rat cerebral cortex.

    PubMed

    Vlasenko, O V; Maisky, V A; Maznychenko, A V; Pilyavskii, A I

    2008-01-01

    The distribution of NADPH-diaphorase-reactive (NADPH-dr) neurons and neuronal processes in the cerebral cortex and basal forebrain and their association with parenchymal vessels were studied in normal adult rats using NADPH-d histochemical protocol. The intensely stained cortical interneurons and reactive subcortically originating afferents, and stained microvessels were examined through a light microscope at law (x250) and high (x630) magnifications. NADPH-dr interneurons were concentrated in layers 2-6 of the M1 and M2 areas. However, clear predominance in their concentration (14 +/- 0.8 P < 0.05 per section) was found in layer 6. A mean number of labeled neurons in auditory (AuV), granular and agranular (GI, AIP) areas of the insular cortex was calculated to reach 12.3 +/- 0.7, 18.5 +/- 1.0 and 23.3 +/- 1.7 units per section, respectively (P < 0.05). The distinct apposition of labelled neurons to intracortical vessels was found in the M1, M2. The order of frequency of neurovascular coupling in different zones of the cerebral cortex was as following sequence: AuV (31.2%, n = 1040) > GI (18.0%, n = 640) > S1 (13.3%, n = 720) > M1 (6.3%, n = 1360). A large number of structural associations between labeled cells and vessels in the temporal and insular cortex indicate that NADPH-d-reactive interneurons can contribute to regulation of the cerebral regional blood flow in these areas. PMID:18416183

  14. Recreating blood-brain barrier physiology and structure on chip: A novel neurovascular microfluidic bioreactor

    PubMed Central

    Brown, Jacquelyn A.; Pensabene, Virginia; Markov, Dmitry A.; Allwardt, Vanessa; Neely, M. Diana; Shi, Mingjian; Britt, Clayton M.; Hoilett, Orlando S.; Yang, Qing; Brewer, Bryson M.; Samson, Philip C.; McCawley, Lisa J.; May, James M.; Webb, Donna J.; Li, Deyu; Bowman, Aaron B.; Reiserer, Ronald S.; Wikswo, John P.

    2015-01-01

    The blood-brain barrier (BBB) is a critical structure that serves as the gatekeeper between the central nervous system and the rest of the body. It is the responsibility of the BBB to facilitate the entry of required nutrients into the brain and to exclude potentially harmful compounds; however, this complex structure has remained difficult to model faithfully in vitro. Accurate in vitro models are necessary for understanding how the BBB forms and functions, as well as for evaluating drug and toxin penetration across the barrier. Many previous models have failed to support all the cell types involved in the BBB formation and/or lacked the flow-created shear forces needed for mature tight junction formation. To address these issues and to help establish a more faithful in vitro model of the BBB, we have designed and fabricated a microfluidic device that is comprised of both a vascular chamber and a brain chamber separated by a porous membrane. This design allows for cell-to-cell communication between endothelial cells, astrocytes, and pericytes and independent perfusion of both compartments separated by the membrane. This NeuroVascular Unit (NVU) represents approximately one-millionth of the human brain, and hence, has sufficient cell mass to support a breadth of analytical measurements. The NVU has been validated with both fluorescein isothiocyanate (FITC)-dextran diffusion and transendothelial electrical resistance. The NVU has enabled in vitro modeling of the BBB using all human cell types and sampling effluent from both sides of the barrier. PMID:26576206

  15. Citalopram Enhances Neurovascular Regeneration and Sensorimotor Functional Recovery after Ischemic Stroke in Mice

    PubMed Central

    Espinera, Alyssa R.; Ogle, Molly E.; Gu, Xiaohuan; Wei, Ling

    2013-01-01

    Recent clinical trials have demonstrated that treatment with selective serotonin reuptake inhibitors (SSRIs) after stroke enhances motor functional recovery; however, the underlying mechanisms remain to be further elucidated. We hypothesized that daily administration of the clinical drug citalopram would produce these functional benefits via enhancing neurovascular repair in the ischemic peri-infarct region. To test this hypothesis, focal ischemic stroke was induced in male C57/B6 mice by permanent ligation of distal branches of the middle cerebral artery to the barrel cortex and 7-min occlusion of the bilateral common carotid arteries. Citalopram (10 mg/kg, i.p.) was injected 24 hrs after stroke and daily thereafter. To label proliferating cells, bromo-deoxyuridine was injected daily beginning 3 days after stroke. Immunohistochemical and functional assays were performed to elucidate citalopram-mediated cellular and sensorimotor changes after stroke. Citalopram treatment had no significant effect on infarct formation or edema 3 days after stroke; however, citalopram-treated mice had better functional recovery than saline-treated controls 3 and 14 days after stroke in the adhesive removal test. Increased expression of brain derived neurotrophic factor was detected in the peri-infarct region 7 days after stroke in citalopram-treated animals. The number of proliferating neural progenitor cells and the distance of neuroblast migration from the sub-ventricular zone towards the ischemic cortex were significantly greater in citalopram-treated mice at 7 days after stroke. Immunohistochemical staining and co-localization analysis showed that citalopram-treated animals generated more new neurons and microvessels in the peri-infarct region 21 and 28 days after stroke. Taken together, these results suggest that citalopram promotes post-stroke sensorimotor recovery likely via enhancing neurogenesis, neural cell migration and the microvessel support in the peri-infarct region of

  16. Neurovascular bundle dissection for Nesbit procedure in congenital penile curvature patients: medial or lateral?

    PubMed

    Akbulut, Fatih; Akman, Tolga; Salabas, Emre; Dincer, Murat; Ortac, Mazhar; Kadioglu, Ates

    2014-01-01

    The objective of this study was to compare the outcomes of the modified Nesbit procedure using different techniques for dissecting the neurovascular bundle (NVB) to correct ventral congenital penile curvatures (CPCs). The bundle was mobilized using the medial and lateral dissection technique in 21 (Group 1) and 13 (Group 2) patients, respectively. In the medial technique, Buck's fascia is opened at the dorsal side of the penis, the deep dorsal vein is removed at the most prominent site of the curvature and a diamond-shaped tunica albuginea (TA) is excised from the midline of the penis. In the lateral technique, the bundle is mobilized using a longitudinal lateral incision of the Buck's fascia above the urethra at the 5 and 7 o'clock positions via a bilateral approach. The localization and degree of curvature was evaluated using the combined intracavernous injection stimulation test or from the patients' photographs. The mean patient age and degree of curvature were similar between groups. The mean operation time was longer for Group 2 (P = 0.01). In Group 1, nine patients (42.8%) required one diamond excision, 10 (47.6%) required two diamond excisions and two (9.5%) required more than two excisions; in Group 2, six patients (46.2%) required two diamond excisions and seven patients (53.8%) required more than two diamond excisions (P = 0.019). The differences in penile shortening, penile straightening and numbness of the glans penis were not statistically significant. Medial dissection of the bundle for the modified Nesbit procedure reduces the number of diamond-shaped removals of TA and thus shortens operation time in comparison with its lateral counterpart. PMID:24625879

  17. Effect of acute nitrate supplementation on neurovascular coupling and cognitive performance in hypoxia.

    PubMed

    Lefferts, Wesley K; Hughes, William E; White, Corey N; Brutsaert, Tom D; Heffernan, Kevin S

    2016-02-01

    The matching of oxygen supply to neural demand (i.e., neurovascular coupling (NVC)) is an important determinant of cognitive performance. The impact of hypoxia on NVC remains poorly characterized. NVC is partially modulated by nitric oxide (NO), which may initially decrease in hypoxia. This study investigated the effect of acute NO-donor (nitrate) supplementation on NVC and cognitive function in hypoxia. Twenty healthy men participated in this randomized, double-blind, crossover design study. Following normoxic cognitive/NVC testing, participants consumed either nitrate (NIT) or a NIT-depleted placebo (PLA). Participants then underwent 120 min of hypoxia (11.6% ± 0.1% O2) and all cognitive/NVC testing was repeated. NVC was assessed as change in middle cerebral artery (MCA) blood flow during a cognitive task (incongruent Stroop) using transcranial Doppler. Additional computerized cognitive testing was conducted separately to assess memory, executive function, attention, sensorimotor, and social cognition domains. Salivary nitrite significantly increased following supplementation in hypoxia for NIT (+2.6 ± 1.0 arbitrary units (AU)) compared with PLA (+0.2 ± 0.3 AU; p < 0.05). Memory performance (-6 ± 13 correct) significantly decreased (p < 0.05) in hypoxia while all other cognitive domains were unchanged in hypoxia for both PLA and NIT conditions (p > 0.05). MCA flow increased during Stroop similarly in normoxia (PLA +5 ± 6 cm·s(-1), NIT +7 ± 7 cm·s(-1)) and hypoxia (PLA +5 ± 9 cm·s(-1), NIT +6 ± 7 cm·s(-1)) (p < 0.05) and this increase was not altered by PLA or NIT (p > 0.05). In conclusion, acute hypoxia resulted in significant reductions in memory concomitant with preservation of executive function, attention, and sensorimotor function. Hypoxia had no effect on NVC. Acute NIT supplementation had no effect on NVC or cognitive performance in hypoxia. PMID:26751937

  18. Failed microvascular decompression surgery for hemifacial spasm due to persistent neurovascular compression: an analysis of reoperations.

    PubMed

    Bigder, Mark Gregory; Kaufmann, Anthony M

    2016-01-01

    OBJECT Microvascular decompression (MVD) surgery for hemifacial spasm (HFS) is potentially curative. The findings at repeat MVD in patients with persistent or recurrent HFS were analyzed with the aim to identify factors that may improve surgical outcomes. METHODS Intraoperative findings were determined from review of dictated operative reports and operative diagrams for patients who underwent repeat MVD after prior surgery elsewhere. Clinical follow-up was obtained from the hospital and clinic records, as well as telephone questionnaires. RESULTS Among 845 patients who underwent MVD performed by the senior author, 12 had been referred after prior MVD for HFS performed elsewhere. Following repeat MVD, all patients improved and complete spasm resolution was described by 11 of 12 patients after a mean follow-up of 91 ± 55 months (range 28-193). Complications were limited to 1 patient with aggravation of preexisting hearing loss and mild facial weakness and 1 patient with aseptic meningitis without sequelae. Significant factors that may have contributed to the failure of the first surgery included retromastoid craniectomies that did not extend laterally to the sigmoid sinus or inferiorly to the posterior fossa floor in 11 of 12 patients and a prior surgical approach that focused on the cisternal portion of the facial nerve in 9 of 12 patients. In all cases, significant persistent neurovascular compression (NVC) was evident and alleviated more proximally on the facial root exit zone (fREZ). CONCLUSIONS Most HFS patients will achieve spasm relief with thorough alleviation of NVC of the fREZ, which extends from the pontomedullary sulcus root exit point to the Obersteiner-Redlich transition zone. PMID:26295916

  19. 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.

  20. Subdural hygroma after craniosynostosis remodeling surgery.

    PubMed

    Ganesh, Praveen; Nagarjuna, Muralidhara; Shetty, Samarth; Salins, Paul C

    2015-01-01

    Craniosynostosis is defined as the premature fusion of the cranial sutures and can cause functional impairment or cosmetic deformity. Surgical techniques for the correction of craniosynostosis have changed overtime, as so have the intraoperative and postoperative complications. Extensive surgeries involving fronto-orbital unit repositioning and cranial vault remodeling are associated with various complications. Intraoperative and postoperative hemorrhage, venous infarct, air embolism, hydrocephalus, cerebrospinal fluid leak, as well as meningitis are a few complications associated with cranial vault remodeling surgery. Postoperative complications can increase the morbidity and mortality associated with these procedures. Identification of the complications and their timely management should be a part of every craniofacial reconstruction team's training program.In this article, we report a case of subdural hygroma in an infant after cranial vault remodeling procedure. Subdural hygroma is a known complication following head injuries and represents 5% to 20% of posttraumatic intracranial mass lesions. However, subdural hygroma developing after a cranial procedure is rare and has not been reported in the literature. Identification of the complication, close monitoring of the change in subdural fluid volume, and tapping of the fluid through the craniotomy site if indicated form the mainstay of management of subdural hygroma that develops after cranial vault remodeling surgery. PMID:25469899

  1. Interleukin-20 promotes airway remodeling in asthma.

    PubMed

    Gong, Wenbin; Wang, Xin; Zhang, Yuguo; Hao, Junqing; Xing, Chunyan; Chu, Qi; Wang, Guicheng; Zhao, Jiping; Wang, Junfei; Dong, Qian; Liu, Tian; Zhang, Yuanyuan; Dong, Liang

    2014-12-01

    Previous studies have demonstrated that interleukin-20 (IL-20) is a pro-inflammatory cytokine, and it has been implicated in psoriasis, lupus nephritis, rheumatoid arthritis, atherosclerosis, and ulcerative colitis. Little is known about the effects of IL-20 in airway remodeling in asthma. The aim of our study was to demonstrate the function of IL-20 in airway remodeling in asthma. To identify the expression of IL-20 and its receptor, IL-20R1/IL-20R2, in the airway epithelium in bronchial tissues, bronchial biopsy specimens were collected from patients and mice with asthma and healthy subjects and stained with specific antibodies. To characterize the effects of IL-20 in asthmatic airway remodeling, we silenced and stimulated IL-20 in cell lines isolated from mice by shRNA and recombinant protein approaches, respectively, and detected the expression of α-SMA and FN-1 by Western blot analysis. First, overexpression of IL-20 and its receptor, IL-20R1/IL-20R2, was detected in the airway epithelium collected from patients and mice with asthma. Second, IL-20 increased the expression of fibronectin-1 and α-SMA, and silencing of IL-20 in mouse lung epithelial (MLE)-12 cells decreased the expression of fibronectin-1 and α-SMA. IL-20 may be a critical cytokine in airway remodeling in asthma. This study indicates that targeting IL-20 and/or its receptors may be a new therapeutic strategy for asthma. PMID:25028099

  2. Chromatin-modifying and -remodeling complexes.

    PubMed

    Kornberg, R D; Lorch, Y

    1999-04-01

    Nucleosomes have long been known to inhibit DNA transactions on chromosomes and a remarkable abundance of multiprotein complexes that either enhance or relieve this inhibition have been described. Most is known about chromatin-remodeling complexes that perturb nucleosome structure. PMID:10322131

  3. 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…

  4. 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…

  5. Arterial Remodeling Associates with CKD Progression

    PubMed Central

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

    2011-01-01

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

  6. Revealing remodeler function: Varied and unique

    NASA Astrophysics Data System (ADS)

    Eastlund, Allen

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

  7. Effects of cerebral ischemia on human neurovascular coupling, CO2 reactivity, and dynamic cerebral autoregulation.

    PubMed

    Salinet, Angela S M; Robinson, Thompson G; Panerai, Ronney B

    2015-01-15

    Cerebral blood flow (CBF) regulation can be impaired in acute ischemic stroke but the combined effects of dynamic cerebral autoregulation (CA), CO2 cerebrovascular reactivity (CVR), and neurovascular coupling (NVC), obtained from simultaneous measurements, have not been described. CBF velocity in the middle cerebral artery (MCA) (CBFv, transcranial Doppler), blood pressure (BP, Finometer), and end-tidal Pco2 (PetCO2 , infrared capnography) were recorded during a 1-min passive movement of the arm in 27 healthy controls [mean age (SD) 61.4 (6.0) yr] and 27 acute stroke patients [age 63 (11.7) yr]. A multivariate autoregressive-moving average model was used to separate the contributions of BP, arterial Pco2 (PaCO2 ), and the neural activation to the CBFv responses. CBFv step responses for the BP, CO2, and stimulus inputs were also obtained. The contribution of the stimulus to the CBFv response was highly significant for the difference between the affected side [area under the curve (AUC) 104.5 (4.5)%] and controls [AUC 106.9 (4.3)%; P = 0.008]. CBFv step responses to CO2 [affected hemisphere 0.39 (0.7), unaffected 0.55 (0.8), controls 1.39 (0.9)%/mmHg; P = 0.01, affected vs. controls; P = 0.025, unaffected vs. controls] and motor stimulus inputs [affected hemisphere 0.20 (0.1), unaffected 0.22 (0.2), controls 0.37 (0.2) arbitrary units; P = 0.009, affected vs. controls; P = 0.02, unaffected vs. controls] were reduced in the stroke group compared with controls. The CBFv step responses to the BP input at baseline and during the paradigm were not different between groups (P = 0.07), but PetCO2 was lower in the stroke group (P < 0.05). These results provide new insights into the interaction of CA, CVR, and NVC in both health and disease states. PMID:25593216

  8. Neurovascular changes in acute, sub-acute and chronic mouse models of Parkinson's disease.

    PubMed

    Sarkar, Sumit; Raymick, James; Mann, Dushyant; Bowyer, John F; Hanig, Joseph P; Schmued, Larry C; Paule, Merle G; Chigurupati, Srinivasulu

    2014-02-01

    Although selective neurodegeneration of nigro-striatal dopaminergic neurons is widely accepted as a cause of Parkinson's disease (PD), the role of vascular components in the brain in PD pathology is not well understood. However, the neurodegeneration seen in PD is known to be associated with neuroinflammatory-like changes that can affect or be associated with brain vascular function. Thus, dysfunction of the capillary endothelial cell component of neurovascular units present in the brain may contribute to the damage to dopaminergic neurons that occurs in PD. An animal model of PD employing acute, sub-acute and chronic exposures of mice to methyl-phenyl-tetrahydropyridine (MPTP) was used to determine the extent to which brain vasculature may be damaged in PD. Fluoro-Turquoise gelatin labeling of microvessels and endothelial cells was used to determine the extent of vascular damage produced by MPTP. In addition, tyrosine hydroxylase (TH) and NeuN were employed to detect and quantify dopaminergic neuron damage in the striatum (CPu) and substantia nigra (SNc). Gliosis was evaluated through GFAP immunohistochemistry. MPTP treatment drastically reduced TH immunoreactive neurons in the SNc (20.68 ± 2.83 in acute; 22.98 ± 2.14 in sub-acute; 10.20 ± 2.24 in chronic vs 34.88 ± 2.91 in controls; p<0.001). Similarly, TH immunoreactive terminals were dramatically reduced in the CPu of MPTP treated mice. Additionally, all three MPTP exposures resulted in a decrease in the intensity, length, and number of vessels in both CPu and SNc. Degenerative vascular changes such as endothelial cell 'clusters' were also observed after MPTP suggesting that vasculature damage may be modifying the availability of nutrients and exposing blood cells and/or toxic substances to neurons and glia. In summary, vascular damage and degeneration could be an additional exacerbating factor in the progression of PD, and therapeutics that protect and insure vascular integrity may be novel treatments for

  9. The effects of sodium-2-mercaptoethanesulfonate application on the neural and neurovascular tissues: An experimental animal study

    PubMed Central

    Ant, Ayca; Karamert, Recep; Kulduk, Gamze; Ekinci, Özgür; Tutar, Hakan; Göksu, Nebil

    2015-01-01

    Background: Sodium-2-mercaptoethanesulfonate (MESNA) is a protective agent that is also used as “a chemical dissector” in various surgical fields. The aim of this study is to evaluate the toxic effects of MESNA on neural and neurovascular structures based on a morphological analysis and examine its safety in neurotological applications. Methods: Three groups of guinea pigs were used as subjects. MESNA solution (50 and 100%) and saline solution were applied to the subarachnoid space over the brain tissue via a middle fossa approach of study and control groups, respectively. Effects of MESNA were assessed by means of light microscope. McNemar Chi-square test was used to evaluate the histopathological findings. Statistical significance of P < 0.05 was taken as criterion. Results: No morphological changes were observed on vascular and neural structures in the study groups in both concentrations, compared to the control group. Conclusions: On a morphological basis, a single application of MESNA does not cause any morphological changes that indicate a toxicity in neural and neurovascular structures. PMID:26487975

  10. Positive Outcome After a Small-Caliber Gunshot Fracture of the Upper Cervical Spine without Neurovascular Damage

    PubMed Central

    Walter, Thula; Schwabe, Philipp; Schaser, Klaus-Dieter; Maurer, Martin

    2016-01-01

    Summary Background Gunshot wounds to the cervical spine most frequently concur with serious injuries to the spinal cord and cervical vessels and often have a fatal outcome. Case Report We describe the case of a 35-year-old male with a complex fracture of the C2 vertebra body and a mandibular fracture after a penetration gunshot to the cervical spine. Computed tomography (CT) at admission revealed the exact extent of the fractures and the small caliber bullet lodged next to the C2 vertebra. In this rare and extremely lucky case no collateral vascular or neurological damage was detected. Eighteen months after surgical bullet removal and posterior C1–C3 fusion complete bone healing of the C2 vertebra was achieved and there were no secondary neurovascular deficits. Conclusions Immediate surgical C1–C3 fixation resulted in an excellent outcome without secondary neurovascular deficits in this rare case of traumatic complex C2 vertebral fracture caused by a gunshot injury. PMID:27081417

  11. 3-D Imaging Reveals Participation of Donor Islet Schwann Cells and Pericytes in Islet Transplantation and Graft Neurovascular Regeneration

    PubMed Central

    Juang, Jyuhn-Huarng; Kuo, Chien-Hung; Peng, Shih-Jung; Tang, Shiue-Cheng

    2015-01-01

    The primary cells that participate in islet transplantation are the endocrine cells. However, in the islet microenvironment, the endocrine cells are closely associated with the neurovascular tissues consisting of the Schwann cells and pericytes, which form sheaths/barriers at the islet exterior and interior borders. The two cell types have shown their plasticity in islet injury, but their roles in transplantation remain unclear. In this research, we applied 3-dimensional neurovascular histology with cell tracing to reveal the participation of Schwann cells and pericytes in mouse islet transplantation. Longitudinal studies of the grafts under the kidney capsule identify that the donor Schwann cells and pericytes re-associate with the engrafted islets at the peri-graft and perivascular domains, respectively, indicating their adaptability in transplantation. Based on the morphological proximity and cellular reactivity, we propose that the new islet microenvironment should include the peri-graft Schwann cell sheath and perivascular pericytes as an integral part of the new tissue. PMID:26137552

  12. 3-D Imaging Reveals Participation of Donor Islet Schwann Cells and Pericytes in Islet Transplantation and Graft Neurovascular Regeneration.

    PubMed

    Juang, Jyuhn-Huarng; Kuo, Chien-Hung; Peng, Shih-Jung; Tang, Shiue-Cheng

    2015-02-01

    The primary cells that participate in islet transplantation are the endocrine cells. However, in the islet microenvironment, the endocrine cells are closely associated with the neurovascular tissues consisting of the Schwann cells and pericytes, which form sheaths/barriers at the islet exterior and interior borders. The two cell types have shown their plasticity in islet injury, but their roles in transplantation remain unclear. In this research, we applied 3-dimensional neurovascular histology with cell tracing to reveal the participation of Schwann cells and pericytes in mouse islet transplantation. Longitudinal studies of the grafts under the kidney capsule identify that the donor Schwann cells and pericytes re-associate with the engrafted islets at the peri-graft and perivascular domains, respectively, indicating their adaptability in transplantation. Based on the morphological proximity and cellular reactivity, we propose that the new islet microenvironment should include the peri-graft Schwann cell sheath and perivascular pericytes as an integral part of the new tissue. PMID:26137552

  13. Caspase-3 Contributes to ZO-1 and Cl-5 Tight-Junction Disruption in Rapid Anoxic Neurovascular Unit Damage

    PubMed Central

    de Curtis, Marco; Kuhlmann, Christoph R. W.; Luhmann, Heiko J.

    2011-01-01

    Background Tight-junction (TJ) protein degradation is a decisive step in hypoxic blood-brain barrier (BBB) breakdown in stroke. In this study we elucidated the impact of acute cerebral ischemia on TJ protein arrangement and the role of the apoptotic effector protease caspase-3 in this context. Methodology/Principal Findings We used an in vitro model of the neurovascular unit and the guinea pig whole brain preparation to analyze with immunohistochemical methods the BBB properties and neurovascular integrity. In both methodological approaches we observed rapid TJ protein disruptions after 30 min of oxygen and glucose deprivation or middle cerebral artery occlusion, which were accompanied by strong caspase-3 activation in brain endothelial cells (BEC). Surprisingly only few DNA-fragmentations were detected with TUNEL stainings in BEC. Z-DEVD-fmk, an irreversible caspase-3 inhibitor, partly blocked TJ disruptions and was protective on trans-endothelial electrical resistance. Conclusions/Significance Our data provide evidence that caspase-3 is rapidly activated during acute cerebral ischemia predominantly without triggering DNA-fragmentation in BEC. Further we detected fast TJ protein disruptions which could be partly blocked by caspase-3 inhibition with Z-DEVD-fmk. We suggest that the basis for clinically relevant BBB breakdown in form of TJ disruptions is initiated within minutes during ischemia and that caspase-3 contributes to this process. PMID:21364989

  14. Role of reactive oxygen species in myocardial remodeling.

    PubMed

    Zhang, Min; Shah, Ajay M

    2007-03-01

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

  15. Interleukin-2/Anti-Interleukin-2 Immune Complex Attenuates Cardiac Remodeling after Myocardial Infarction through Expansion of Regulatory T Cells

    PubMed Central

    Zeng, Zhipeng; Yu, Kunwu; Chen, Long; Li, Weihua; Xiao, Hong; Huang, Zhengrong

    2016-01-01

    CD4+CD25+Foxp3+ regulatory T cells (Treg cells) have protective effects in wound healing and adverse ventricular remodeling after myocardial infarction (MI). We hypothesize that the interleukin- (IL-) 2 complex comprising the recombinant mouse IL-2/anti-IL-2 mAb (JES6-1) attenuates cardiac remodeling after MI through the expansion of Treg. Mice were subjected to surgical left anterior descending coronary artery ligation and treated with either PBS or IL-2 complex. The IL-2 complex significantly attenuates ventricular remodeling, as demonstrated by reduced infarct size, improved left ventricular (LV) function, and attenuated cardiomyocyte apoptosis. The IL-2 complex increased the percentage of CD4+CD25+Foxp3+ Treg cells, which may be recruited to the infarcted heart, and decreased the frequencies of IFN-γ- and IL-17-producing CD4+ T helper (Th) cells among the CD4+Foxp3− T cells in the spleen. Furthermore, the IL-2 complex inhibited the gene expression of proinflammatory cytokines as well as macrophage infiltrates in the infarcted myocardium and induced the differentiation of macrophages from M1 to M2 phenotype in border zone of infarcted myocardium. Our studies indicate that the IL-2 complex may serve as a promising therapeutic approach to attenuate adverse remodeling after MI through expanding Treg cells specifically. PMID:27144181

  16. Remodeling of Calcium Entry Pathways in Cancer.

    PubMed

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

    2016-01-01

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

  17. 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

  18. 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

  19. Perspectives on biological growth and remodeling

    PubMed Central

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

    2011-01-01

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

  20. Link between vitamin D and airway remodeling

    PubMed Central

    Berraies, Anissa; Hamzaoui, Kamel; Hamzaoui, Agnes

    2014-01-01

    In the last decade, many epidemiologic studies have investigated the link between vitamin D deficiency and asthma. Most studies have shown that vitamin D deficiency increases the risk of asthma and allergies. Low levels of vitamin D have been associated with asthma severity and loss of control, together with recurrent exacerbations. Remodeling is an early event in asthma described as a consequence of production of mediators and growth factors by inflammatory and resident bronchial cells. Consequently, lung function is altered, with a decrease in forced expiratory volume in one second and exacerbated airway hyperresponsiveness. Subepithelial fibrosis and airway smooth muscle cell hypertrophy are typical features of structural changes in the airways. In animal models, vitamin D deficiency enhances inflammation and bronchial anomalies. In severe asthma of childhood, major remodeling is observed in patients with low vitamin D levels. Conversely, the antifibrotic and antiproliferative effects of vitamin D in smooth muscle cells have been described in several experiments. In this review, we briefly summarize the current knowledge regarding the relationship between vitamin D and asthma, and focus on its effect on airway remodeling and its potential therapeutic impact for asthma. PMID:24729717

  1. Tissue Remodelling following Resection of Porcine Liver

    PubMed Central

    Nygård, Ingvild Engdal; Mortensen, Kim Erlend; Hedegaard, Jakob; Conley, Lene Nagstrup; Bendixen, Christian; Sveinbjørnsson, Baldur; Revhaug, Arthur

    2015-01-01

    Aim. To study genes regulating the extracellular matrix (ECM) and investigate the tissue remodelling following liver resection in porcine. Methods. Four pigs with 60% partial hepatectomy- (PHx-) induced liver regeneration were studied over six weeks. Four pigs underwent sham surgery and another four pigs were used as controls of the normal liver growth. Liver biopsies were taken upon laparotomy, after three and six weeks. Gene expression profiles were obtained using porcine-specific oligonucleotide microarrays. Immunohistochemical staining was performed and a proliferative index was assessed. Results. More differentially expressed genes were associated with the regulation of ECM in the resection group compared to the sham and control groups. Secreted protein acidic and rich in cysteine (SPARC) and collagen 1, alpha 2 (COL1A2) were both upregulated in the early phase of liver regeneration, validated by immunopositive cells during the remodelling phase of liver regeneration. A broadened connective tissue was demonstrated by Masson's Trichrome staining, and an immunohistochemical staining against pan-Cytokeratin (pan-CK) demonstrated a distinct pattern of migrating cells, followed by proliferating cell nuclear antigen (PCNA) positive nuclei. Conclusions. The present study demonstrates both a distinct pattern of PCNA positive nuclei and a deposition of ECM proteins in the remodelling phase of liver regeneration. PMID:26240819

  2. Stepwise nucleosome translocation by RSC remodeling complexes.

    PubMed

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

    2016-01-01

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

  3. Stepwise nucleosome translocation by RSC remodeling complexes

    PubMed Central

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

    2016-01-01

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

  4. MicroRNA and vascular remodelling in acute vascular injury and pulmonary vascular remodelling

    PubMed Central

    McDonald, Robert A.; Hata, Akiko; MacLean, Margaret R.; Morrell, Nicholas W.; Baker, Andrew H.

    2012-01-01

    Vascular remodelling is an integral pathological process central to a number of cardiovascular diseases. The complex interplay between distinct cell populations in the vessel wall following vascular injury leads to inflammation, cellular dysfunction, pro-growth signals in the smooth muscle cell (SMC) compartment, and the acquisition of a synthetic phenotype. Although the signals for vascular remodelling are diverse in different pathological contexts, SMC proliferation and migration are consistently observed. It is therefore critical to elucidate key mechanisms central to these processes. MicroRNAs (miRNAs) are small non-coding sequences of RNA that have the capacity to regulate many genes, pathways, and complex biological networks within cells, acting either alone or in concert with one another. In diseases such as cancer and cardiac disease, the role of miRNA in disease pathogenesis has been documented in detail. In contrast, despite a great deal of interest in miRNA, relatively few studies have directly assessed the role of miRNA in vascular remodelling. The potential for modulation of miRNA to achieve therapeutic benefits in this setting is attractive. Here, we focus on the role of miRNA in vascular inflammation and remodelling associated with acute vascular injury (vein graft disease, angioplasty restenosis, and in-stent restenosis) as well as in vascular remodelling associated with the development of pulmonary arterial hypertension. PMID:22065733

  5. PI3K/Akt Pathway Contributes to Neurovascular Unit Protection of Xiao-Xu-Ming Decoction against Focal Cerebral Ischemia and Reperfusion Injury in Rats

    PubMed Central

    Xiang, Jun; Zhang, Yong; Wang, Guo-Hua; Bao, Jie; Li, Wen-Wei; Zhang, Wen; Xu, Li-Li; Cai, Ding-Fang

    2013-01-01

    In the present study, we used a focal cerebral ischemia and reperfusion rat model to investigate the protective effects of Xiao-Xu-Ming decoction (XXMD) on neurovascular unit and to examine the role of PI3K (phosphatidylinositol 3-kinase)/Akt pathway in this protection. The cerebral ischemia was induced by 90 min of middle cerebral artery occlusion. Cerebral infarct area was measured by tetrazolium staining, and neurological function was observed at 24 h after reperfusion. DNA fragmentation assay, combined with immunofluorescence, was performed to evaluate apoptosis of neuron, astrocyte, and vascular endothelial cell which constitute neurovascular unit. The expression levels of proteins involved in PI3K/Akt pathway were detected by Western blot. The results showed that XXMD improved neurological function, decreased cerebral infarct area and neuronal damage, and attenuated cellular apoptosis in neurovascular unit, while these effects were abolished by inhibition of PI3K/Akt with LY294002. We also found that XXMD upregulated p-PDKl, p-Akt, and p-GSK3β expression levels, which were partly reversed by LY294002. In addition, the increases of p-PTEN and p-c-Raf expression levels on which LY294002 had no effect were also observed in response to XXMD treatment. The data indicated the protective effects of XXMD on neurovascular unit partly through the activation of PI3K/Akt pathway. PMID:23781261

  6. Arterial remodeling of basilar atherosclerosis in isolated pontine infarction.

    PubMed

    Feng, Chao; Hua, Ting; Xu, Yu; Liu, Xue-Yuan; Huang, Jing

    2015-04-01

    Isolated pontine infarctions are usually classified as paramedian pontine infarction (PPI) and lacunar pontine infarction (LPI). Although they have different shapes and locations, some recent studies proved that they might both be associated with basilar artery atherosclerosis in pathogenesis. This study aimed to explore the difference of basilar artery remodeling between two subtypes of pontine infarctions. Patients with PPI or LPI were scanned by High-resolution MRI (HR-MRI). The MR images of patients with basilar artery atherosclerosis were further analyzed to measure the vessel, lumen and wall areas at different segments of basilar arteries. Stenosis rate and remodeling index were calculated according to which arterial remodeling was divided into positive, intermediate and negative remodeling. Vascular risk factors and remodeling-related features were compared between PPI and LPI, and also between patients with and without positive remodeling. 34 patients with PPI and 21 patients with LPI had basilar artery atherosclerosis identified by HR-MRI. Positive remodeling was dominant in LPI group while in PPI group, three subtypes of remodeling were equal. Patients with positive remodeling had higher levels of low-density lipoprotein and homocysteine. Positive remodeling of basilar artery might reflect the low stability of basilar atherosclerotic plaques, which was more closely associated with LPI than PPI. PMID:25367406

  7. Immunologic and inflammatory mechanisms that drive asthma progression to remodeling

    PubMed Central

    Broide, David H.

    2008-01-01

    Although histologic features of airway remodeling have been well characterized in asthma, the immunologic and inflammatory mechanisms that drive progression of asthma to remodeling are still incompletely understood. Conceptually, airway remodeling may be due to persistent inflammation and/or aberrant tissue repair mechanisms. It is likely that several immune and inflammatory cell types and mediators are involved in mediating airway remodeling. In addition, different features of airway remodeling are likely mediated by different inflammatory pathways. Several important candidate mediators of remodeling have been identified including TGF-β and Th2 cytokines (including IL-5 and IL-13), as well as VEGF, ADAM-33, and MMP-9. Mouse models of airway remodeling have provided important insight into potential mechanisms by which TGF-β activation of the Smad 2/3 signaling pathway may contribute to airway remodeling. Human studies have demonstrated that anti-IL-5 reduces levels of airway eosinophils expressing TGF-β, as well as levels of airway remodeling as assessed by bronchial biopsies. Further such studies confirming these observations, as well as alternate studies targeting additional individual cell types, cytokines, and mediators are needed in human subjects with asthma to determine the role of candidate mediators of inflammation on the development and progression of airway remodeling. PMID:18328887

  8. Neurovascular free-muscle transfer for the treatment of established facial paralysis following ablative surgery in the parotid region.

    PubMed

    Takushima, Akihiko; Harii, Kiyonori; Asato, Hirotaka; Ueda, Kazuki; Yamada, Atsushi

    2004-05-01

    Neurovascular free-muscle transfer for facial reanimation was performed as a secondary reconstructive procedure for 45 patients with facial paralysis resulting from ablative surgery in the parotid region. This intervention differs from neurovascular free-muscle transfer for treatment of established facial paralysis resulting from conditions such as congenital dysfunction, unresolved Bell palsy, Hunt syndrome, or intracranial morbidity, with difficulties including selection of recipient vessels and nerves, and requirements for soft-tissue augmentation. This article describes the authors' operative procedure for neurovascular free-muscle transfer after ablative surgery in the parotid region. Gracilis muscle (n = 24) or latissimus dorsi muscle (n = 21) was used for transfer. With gracilis transfer, recipient vessels comprised the superficial temporal vessels in 12 patients and the facial vessels in 12. For latissimus dorsi transfer, recipient vessels comprised the facial vessels in 16 patients and the superior thyroid artery and superior thyroid or internal jugular vein in four. Facial vessels on the contralateral side were used with interpositional graft of radial vessels in the remaining patient with latissimus dorsi transfer. Cross-face nerve grafting was performed before muscle transfer in 22 patients undergoing gracilis transfer. In the remaining two gracilis patients, the ipsilateral facial nerve stump was used as the primary recipient nerve. Dermal fat flap overlying the gracilis muscle was used for cheek augmentation in one patient. In the other 23 patients, only the gracilis muscle was used. With latissimus dorsi transfer, the ipsilateral facial nerve stump was used as the recipient nerve in three patients, and a cross-face nerve graft was selected as the recipient nerve in six. The contralateral facial nerve was selected as the recipient nerve in 12 patients, and a thoracodorsal nerve from the latissimus dorsi muscle segment was crossed through the upper lip

  9. Exposure of the superior gluteal neurovascular bundle for the safe application of acetabular reinforcement cages in complex revisions.

    PubMed

    Smitham, Peter J; Kosuge, Dennis; Howie, Donald W; Solomon, Lucian B

    2016-05-16

    The posterior approach to the hip is the most common extensile approach used, however exposure is limited superiorly by the superior gluteal neurovascular bundle (SGNB). The extra-pelvic course of the SGNB demonstrates variability between individuals, occasionally located only 1 cm from the acetabular rim. In complex acetabular reconstructions where the application of a reinforcement cage maybe required protecting the SGNB is challenging. The flanges of these cages are designed to sit on the ilium superior to the acetabular rim and to receive screws for fixation. The application of such cages may result in iatrogenic injury to the SGNB by way of forceful retraction or entrapment. We describe a technique that involves exposure and release of the SGNB such that the flanges of cage constructs may be safely applied. PMID:27079287

  10. Two-photon microscopy as a tool to study blood flow and neurovascular coupling in the rodent brain

    PubMed Central

    Shih, Andy Y; Driscoll, Jonathan D; Drew, Patrick J; Nishimura, Nozomi; Schaffer, Chris B; Kleinfeld, David

    2012-01-01

    The cerebral vascular system services the constant demand for energy during neuronal activity in the brain. Attempts to delineate the logic of neurovascular coupling have been greatly aided by the advent of two-photon laser scanning microscopy to image both blood flow and the activity of individual cells below the surface of the brain. Here we provide a technical guide to imaging cerebral blood flow in rodents. We describe in detail the surgical procedures required to generate cranial windows for optical access to the cortex of both rats and mice and the use of two-photon microscopy to accurately measure blood flow in individual cortical vessels concurrent with local cellular activity. We further provide examples on how these techniques can be applied to the study of local blood flow regulation and vascular pathologies such as small-scale stroke. PMID:22293983

  11. Neurovascular pathophysiology in cerebral ischemia, dementia and the ageing brain – current trends in basic, translational and clinical research

    PubMed Central

    2012-01-01

    The 7th International Symposium on Neuroprotection and Neurorepair was held from May 2nd to May 5th, 2012 in Potsdam, Germany. The symposium, which directly continues the successful Magdeburg meeting series, attracted over 330 colleagues from 29 countries to discuss recent findings and advances in the field. The focus of the 2012 symposium was widened from stroke and traumatic brain injury to neurodegenerative diseases, notably dementia, and more generally the ageing brain. Thereby, emphasis was given on neurovascular aspects of neurodegeneration and stroke including the blood–brain barrier, recent findings regarding the pathomechanism of Alzheimer’s disease, and brain imaging approaches. In addition, neurobiochemical aspects of neuroprotection, the role of astrogliosis, the clinical progress of cell-based approaches as well as translational hurdles and opportunities were discussed in-depth. This review summarizes some of the most stimulating discussions and reports from the meeting. PMID:22883324

  12. A dynamic zone defines interneuron remodeling in the adult neocortex

    PubMed Central

    Lee, Wei-Chung Allen; Chen, Jerry L.; Huang, Hayden; Leslie, Jennifer H.; Amitai, Yael; So, Peter T.; Nedivi, Elly

    2008-01-01

    The contribution of structural remodeling to long-term adult brain plasticity is unclear. Here, we investigate features of GABAergic interneuron dendrite dynamics and extract clues regarding its potential role in cortical function and circuit plasticity. We show that remodeling interneurons are contained within a “dynamic zone” corresponding to a superficial strip of layers 2/3, and remodeling dendrites respect the lower border of this zone. Remodeling occurs primarily at the periphery of dendritic fields with addition and retraction of new branch tips. We further show that dendrite remodeling is not intrinsic to a specific interneuron class. These data suggest that interneuron remodeling is not a feature predetermined by genetic lineage, but rather, it is imposed by cortical laminar circuitry. Our findings are consistent with dynamic GABAergic modulation of feedforward and recurrent connections in response to top-down feedback and suggest a structural component to functional plasticity of supragranular neocortical laminae. PMID:19066223

  13. The temporo-spatial localization of polymorphonuclear cells related to the neurovascular unit after transient focal cerebral ischemia.

    PubMed

    Ullrich, Nora; Strecker, Jan-Kolja; Minnerup, Jens; Schilling, Matthias

    2014-10-24

    Inflammatory responses after cerebral ischemia are important for the development of final infarct size but the role of polymorphonuclear cells (PMN) is still a matter of debate, since previously used antibodies were recently declared as non-specific. In the present study, we investigated the temporo-spatial localization of PMN related to the neurovascular unit using specific antibodies, 7/4 and Ly6G, and application of G-CSF to induce proliferation and mobilization of PMN precursors after transient focal cerebral ischemia in mice. Infarct volumes, sensorimotor function, neurological outcome and immunohistochemical analysis of PMN were performed after G-CSF administration or placebo treatment. G-CSF-treated mice showed reduced infarct size (51.15±15.68 mm(2) vs. 39.31±16.13 mm(2) at day 1; 50.11±16.68 mm(2) vs. 33.16±4.86 mm(2) at day 4; p<0.05). They showed improved motor-function recovery and had a significantly better outcome compared to placebo-treated animals. Comparison of the two PMN detecting antibodies showed no difference in saturation plots or cell quantification. Studying the basement membrane-associated localization revealed ca. 60% extravascular PMN, independent of G-CSF administration. Extravascular PMNs were without any connection to laminin, but all near to the vessels. We conclude that 7/4 is a suitable marker to investigate PMN compared to Ly6G, which confirms results from former studies using the 7/4-antibody. Furthermore we report the observation that PMN were detected outside the laminin barrier but almost exclusively in close vicinity to the neurovascular unit. PMID:25152468

  14. Helium preconditioning protects the brain against hypoxia/ischemia injury via improving the neurovascular niche in a neonatal rat model.

    PubMed

    Li, Yi; Zhang, Peixi; Liu, Ying; Liu, Wenwu; Yin, Na

    2016-11-01

    This study aimed to investigate whether helium preconditioning (He-PC) is able to exert neuroprotective effects via improving focal neurovascular niche in a neonatal rat hypoxia/ischemia (HI) brain injury model. Seven day old rat pups were divided into control group, HI group and He-PC group. HI was induced by exposure to 8% oxygen for 90min one day after preconditioning with 70% helium-30% oxygen for three 5-min periods. At 3 and 7 days, the brain was collected for the detection of inflammation related factors (tumor necrosis factor α [TNF-α], interleukin-1β [IL-1β], IL-10) and growth/neurotrophic factors (brain-derived neurotrophic factor [BDNF], basic fibroblast growth factor [bFGF] and nerve growth factor [NGF]); at 7 days, neurobehaviors were evaluated, and the brain was collected for the detection of mRNA expression of vascular endothelial growth factor (VEGF) and angiopoietin-1 (Ang-1) by PCR, protein expression of angiogenesis related molecules (VEGF, Ang-1, Tie-2 and Flt-1) by Western blotting and microvessel density (MCD) by immunohistochemistry for vWF. Results showed He-PC was able to reduce TNF-α and IL-1β, further increase IL-10, BDNF, bFGF and NGF, elevate the mRNA expression of VEGF and Ang-1, increase the protein expression of VEGF, Ang-1, Tie-2 and Flt-1, promote angiogenesis and improve neurobehaviors as compared to HI group. These findings suggest that He-PC may improve the post-stroke neurovascular niche to exert neuroprotective effects on neonatal HI brain injury. PMID:27515290

  15. Functional MRI during hyperbaric oxygen: Effects of oxygen on neurovascular coupling and BOLD fMRI signals.

    PubMed

    Cardenas, Damon P; Muir, Eric R; Huang, Shiliang; Boley, Angela; Lodge, Daniel; Duong, Timothy Q

    2015-10-01

    Hyperbaric oxygen (HBO) therapy is used to treat a number of ailments. Improved understanding of how HBO affects neuronal activity, cerebral blood flow (CBF) and blood-oxygenation-level dependent (BOLD) changes could shed light on the role of oxygen in neurovascular coupling and help guide HBO treatments. The goal of this study was to test two hypotheses: i) activation-induced CBF fMRI response is not dependent on hemoglobin deoxygenation, and ii) activation-induced BOLD fMRI is markedly attenuated under HBO. CBF and BOLD fMRI of forepaw stimulation in anesthetized rats under HBO at 3 atmospheres absolute (ATA) were compared with normobaric air. Robust BOLD and CBF fMRI were detected under HBO. Inflow effects and spin-density changes did not contribute significantly to the BOLD fMRI signal under HBO. Analysis of the T2(⁎)-weighted signal at normobaric air and 1, 2 and 3ATA oxygen in the tissue and the superior sagittal sinus showed a strong dependence on increasing inhaled [O2]. Spontaneous electrophysiological activity and evoked local-field potentials were reduced under HBO. The differences between normobaric air and HBO in basal and evoked electrical activity could not fully account for the strong BOLD responses under HBO. We concluded that activation-induced CBF regulation in the brain does not operate through an oxygen-sensing mechanism and that stimulus-evoked BOLD responses and the venous T2(⁎)-weighted signals still have room to increase under 3ATA HBO. To our knowledge, this is the first fMRI study under HBO, providing insights into the effects of HBO on neural activity, neurovascular coupling, tissue oxygenation, and the BOLD signal. PMID:26143203

  16. Dietary supplementation with omega-3 polyunsaturated fatty acids robustly promotes neurovascular restorative dynamics and improves neurological functions after stroke.

    PubMed

    Zhang, Wenting; Wang, Hailian; Zhang, Hui; Leak, Rehana K; Shi, Yejie; Hu, Xiaoming; Gao, Yanqin; Chen, Jun

    2015-10-01

    Stroke is a devastating neurological disease with no satisfactory therapies to preserve long-term neurological function, perhaps due to the sole emphasis on neuronal survival in most preclinical studies. Recent studies have revealed the importance of protecting multiple cell types in the injured brain, such as oligodendrocytes and components of the neurovascular unit, before long-lasting recovery of function can be achieved. For example, revascularization in the ischemic penumbra is critical to provide various neurotrophic factors that enhance the survival and activity of neurons and other progenitor cells, such as oligodendrocyte precursor cells. In the present study, we hypothesized that chronic dietary supplementation with fish oil promotes post-stroke angiogenesis, neurogenesis, and oligodendrogenesis, thereby leading to long-term functional improvements. Mice received dietary supplementation with n-3 PUFA-enriched fish oil for three months before and up to one month after stroke. As expected, dietary n-3 PUFAs significantly increased levels of n-3 PUFAs in the brain and improved long-term behavioral outcomes after cerebral ischemia. n-3 PUFAs also robustly improved revascularization and angiogenesis and boosted the survival of NeuN/BrdU labeled newborn neurons up to 35days after stroke injury. Furthermore, these pro-neurogenic effects were accompanied by robust oligodendrogenesis. Thus, this is the first study to demonstrate that chronic dietary intake of n-3 PUFAs is an effective prophylactic measure not only to protect against ischemic injury for the long term but also to actively promote neurovascular restorative dynamics and brain repair. PMID:25771800

  17. In Brief: Picturing the complex world of chromatin remodelling families.

    PubMed

    Witkowski, Leora; Foulkes, William D

    2015-12-01

    Over the past decade, chromatin remodelling emerged as one of the most important causes of both abnormal development and cancer. Although much has been written about one or another of the complexes, no recent concise summary of the chromatin remodelling families as a whole is available. In this short review, we introduce the family members, briefly summarize their role in developmental abnormalities and neoplasia, and outline the different ways in which these families remodel chromatin. PMID:26174723

  18. 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.

  19. AB 1725: A Comprehensive Analysis.

    ERIC Educational Resources Information Center

    California Community Colleges, Sacramento. Board of Governors.

    A summary and analysis is provided of California Assembly Bill (AB) 1725, a reform bill that provides new direction and support for the state's community colleges. The analysis addresses each of the eight sections of the bill: (1) mission, highlighting reforms related to mission statements, transfer core curriculum, remedial limits, articulation…

  20. Pregnancy-induced remodeling of heart valves.

    PubMed

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

    2015-11-01

    Recent studies have demonstrated remodeling of aortic and mitral valves leaflets under the volume loading and cardiac expansion of pregnancy. Those valves' leaflets enlarge with altered collagen fiber architecture, content, and cross-linking and biphasic changes (decreases, then increases) in extensibility during gestation. This study extends our analyses to right-sided valves, with additional compositional measurements for all valves. Valve leaflets were harvested from nonpregnant heifers and pregnant cows. Leaflet structure was characterized by leaflet dimensions, and ECM composition was determined using standard biochemical assays. Histological studies assessed changes in cellular and ECM components. Leaflet mechanical properties were assessed using equibiaxial mechanical testing. Collagen thermal stability and cross-linking were assessed using denaturation and hydrothermal isometric tension tests. Pulmonary and tricuspid leaflet areas increased during pregnancy by 35 and 55%, respectively. Leaflet thickness increased by 20% only in the pulmonary valve and largely in the fibrosa (30% thickening). Collagen crimp length was reduced in both the tricuspid (61%) and pulmonary (42%) valves, with loss of crimped area in the pulmonary valve. Thermomechanics showed decreased collagen thermal stability with surprisingly maintained cross-link maturity. The pulmonary leaflet exhibited the biphasic change in extensibility seen in left side valves, whereas the tricuspid leaflet mechanics remained largely unchanged throughout pregnancy. The tricuspid valve exhibits a remodeling response during pregnancy that is significantly diminished from the other three valves. All valves of the heart remodel in pregnancy in a manner distinct from cardiac pathology, with much similarity valve to valve, but with interesting valve-specific responses in the aortic and tricuspid valves. PMID:26371175

  1. Bacterial genome remodeling through bacteriophage recombination.

    PubMed

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

    2015-01-01

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

  2. [Histamine in regulation of bone remodeling processes].

    PubMed

    Wiercigroch, Marek; Folwarczna, Joanna

    2013-01-01

    Bone remodeling is under autocrine, paracrine, endocrine and central nervous system control. One of the potential endogenous factors affecting bone remodeling is histamine, an endogenous amine which acts as a mediator of allergic reactions and neuromediator, and induces production of gastric acid. Histamine H₁ receptor antagonists are widely used in the treatment of allergic conditions, H₂ receptor antagonists in peptic ulcer disease, and betahistine (an H₃ receptor antagonist and H₁ receptor agonist) is used in the treatment of Ménière's disease. Excess histamine release in mastocytosis and allergic diseases may lead to development of osteoporosis. Clinical and population-based studies on the effects of histamine receptor antagonists on the skeletal system have not delivered unequivocal results. Expression of mRNA of histamine receptors has been discovered in bone cells (osteoblasts and osteoclasts). Histamine synthesis has been demonstrated in osteoclast precursors. Histamine increases bone resorption both by direct effects on osteoclast precursors and osteoclasts, and indirectly, by increasing the expression of RANKL in osteoblasts. In in vivo studies, H₁ and H₂ receptor antagonists exerted protective effects on the bone tissue, although not in all experimental models. In the present article, in vitro and in vivo studies conducted so far, concerning the effects of histamine and drugs modifying its activity on the skeletal system, have been reviewed. PMID:24018454

  3. 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

  4. PARP inhibition and postinfarction myocardial remodeling.

    PubMed

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

    2016-08-01

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

  5. Remodeling of the Fetal Collecting Duct Epithelium

    PubMed Central

    Hiatt, Michael J.; Ivanova, Larissa; Toran, Nuria; Tarantal, Alice F.; Matsell, Douglas G.

    2010-01-01

    Congenital urinary tract obstruction induces changes to the renal collecting duct epithelium, including alteration and depletion of intercalated cells. To study the effects of obstruction on the ontogeny of intercalated cell development, we examined normal and obstructed human fetal and postnatal kidneys. In the normal human fetal kidney, intercalated cells originated in the medullary collecting duct at 8 weeks gestation and remained most abundant in the inner medulla throughout gestation. In the cortex, intercalated cells were rare at 18 and 26 weeks gestation and observed at low abundance at 36 weeks gestation. Although early intercalated cells exhibit an immature phenotype, Type A intercalated cells predominated in the inner and outer medullae at 26 and 36 weeks gestation with other intercalated cell subtypes observed rarely. Postnatally, the collecting duct epithelium underwent a remodeling whereby intercalated cells become abundant in the cortex yet absent from the inner medulla. In 18-week obstructed kidneys with mild to moderate injury, the intercalated cells became more abundant and differentiated than the equivalent age-matched normal kidney. In contrast, more severely injured ducts of the late obstructed kidney exhibited a significant reduction in intercalated cells. These studies characterize the normal ontogeny of human intercalated cell development and suggest that obstruction induces premature remodeling and differentiation of the fetal collecting duct epithelium. PMID:20035053

  6. Abnormal bone remodelling in inflammatory arthritis

    PubMed Central

    Bogoch, Earl R.; Moran, Erica

    1998-01-01

    Osteopenia is responsible for substantial comorbidity in patients suffering from rheumatoid arthritis and is an important factor in the surgical management of joint disease. In animal models of bone loss stimulated by inflammatory arthritis, increased bone remodelling and altered microstructure of bone have been documented. The subchondral bone plate near the joint surface is narrow and perforated by vascular inflammatory invasion, and in the shaft the thin cortices are weakened by giant resorption defects. Biomechanical tests and a mathematical model of bone strength suggest that cortical defects, much larger than those found in normal osteonal remodelling, are principally responsible for the experimentally observed loss of strength. Similarly, these defects may explain the increased femoral fracture risk in rheumatoid arthritis. The osteoclast, the cell resorbing bone, is demonstrated in increased number and activity in rheumatoid arthritis and in animal models. Bisphosphonates, drugs that inhibit osteoclast function, have been shown experimentally to reduce both focal and generalized osteopenia and to prevent loss of bone strength. Bisphosphonates also protect articular cartilage from damage characteristic of inflammatory arthritis. The mechanism of chondroprotection may be prevention of subchondral bone resorption by the osteoclast and also an altered distribution of bone marrow cells. Thus, bisphosphonates, currently in clinical use for other bone metabolic diseases, appear to have potential as prophylaxis and treatment for osteopenia and joint damage in inflammatory arthritis. PMID:9711159

  7. Hard tissue remodeling using biofabricated coralline biomaterials.

    PubMed

    Vago, Razi; Plotquin, Daniel; Bunin, Alex; Sinelnikov, Igor; Atar, Dan; Itzhak, David

    2002-01-01

    Biotechnical and biomedical approaches were combined in an attempt to identify potential uses of biofabricated marine carbonate materials in biomedical applications, particularly as biomatrices for remodeling bone and cartilage tissue. After grafting, it is desirable for bone ingrowth to proceed as quickly as possible because the strength of the implanted region depends on a good mechanical bond forming between the implant and surrounding regions in the body. Ingrowth can take place as a result of growth of tissue and cells into the implanted porous material, or it may be promoted by transplanting cells seeded onto such a material. The rate at which ingrowth occurs is dependent on many factors, including pore size and the interconnectivity of the implanted structure. In vivo graftings into osteochondral defects demonstrated that our biofabricated porous material is highly biocompatible with cartilage and bone tissue. The biofabricated matrix was well incorporated into the biphasic osteochondral area. Resorption was followed by bone and cartilage formation, and after 4 months, the biomaterial had been replaced by new tissue. Ossification was induced and enhanced without introduction of additional factors. We believe that this is the first time that such biofabricated materials have been used for biomedical purposes. In face of the obvious environmental disadvantages of harvesting from limited natural resources, we propose the use of bioengineered coralline and other materials such as those cultured by our group under field and laboratory conditions as a possible biomatrix for hard tissue remodeling. PMID:11741712

  8. Chromatin remodeling in cardiovascular development and physiology

    PubMed Central

    Han, Pei; Hang, Calvin T.; Yang, Jin; Chang, Ching-Pin

    2010-01-01

    Chromatin regulation provides an important means of controlling cardiac gene expression under different physiological and pathological conditions. Processes that direct the development of normal embryonic hearts and pathology of stressed adult hearts may share general mechanisms that govern cardiac gene expression by chromatin-regulating factors. These common mechanisms may provide a framework for us to investigate the interactions among diverse chromatin remodelers/modifiers and various transcription factors in the fine regulation of gene expression, essential for all aspects of cardiovascular biology. Aberrant cardiac gene expression, triggered by a variety of pathological insults, can cause heart diseases in both animals and humans. The severity of cardiomyopathy and heart failure correlates strongly with abnormal cardiac gene expression. Therefore, controlling cardiac gene expression presents a promising approach to the treatment of human cardiomyopathy. This review focuses on the roles of ATP-dependent chromatin-remodeling factors and chromatin-modifying enzymes in the control of gene expression during cardiovascular development and disease. PMID:21293009

  9. Atrial remodeling, fibrosis, and atrial fibrillation.

    PubMed

    Jalife, José; Kaur, Kuljeet

    2015-08-01

    The fundamental mechanisms governing the perpetuation of atrial fibrillation (AF), the most common arrhythmia seen in clinical practice, are poorly understood, which explains in part why AF prevention and treatment remain suboptimal. Although some clinical parameters have been identified as predicting a transition from paroxysmal to persistent AF in some patients, the molecular, electrophysiological, and inflammation changes leading to such a progression have not been described in detail. Oxidative stress, atrial dilatation, calcium overload, inflammation, microRNAs, and myofibroblast activation are all thought to be involved in AF-induced atrial remodeling. However, it is unknown to what extent and at which time points such alterations influence the remodeling process that perpetuates AF. Here we postulate a working model that might open new pathways for future investigation into mechanisms of AF perpetuation. We start from the premise that the progression to AF perpetuation is the result of interplay among manifold signaling pathways with differing kinetics. Some such pathways have relatively fast kinetics (e.g., oxidative stress-mediated shortening of refractory period); others likely depend on molecular processes with slower kinetics (e.g., transcriptional changes in myocyte ion channel protein expression mediated through inflammation and fibroblast activation). We stress the need to fully understand the relationships among such pathways should one hope to identify novel, truly effective targets for AF therapy and prevention. PMID:25661032

  10. Temporally tuned neuronal differentiation supports the functional remodeling of a neuronal network in Drosophila.

    PubMed

    Veverytsa, Lyubov; Allan, Douglas W

    2012-03-27

    During insect metamorphosis, neuronal networks undergo extensive remodeling by restructuring their connectivity and recruiting newborn neurons from postembryonic lineages. The neuronal network that directs the essential behavior, ecdysis, generates a distinct behavioral sequence at each developmental transition. Larval ecdysis replaces the cuticle between larval stages, and pupal ecdysis externalizes and expands the head and appendages to their adult position. However, the network changes that support these differences are unknown. Crustacean cardioactive peptide (CCAP) neurons and the peptide hormones they secrete are critical for ecdysis; their targeted ablation alters larval ecdysis progression and results in a failure of pupal ecdysis. In this study, we demonstrate that the CCAP neuron network is remodeled immediately before pupal ecdysis by the emergence of 12 late CCAP neurons. All 12 are CCAP efferents that exit the central nervous system. Importantly, these late CCAP neurons were found to be entirely sufficient for wild-type pupal ecdysis, even after targeted ablation of all other 42 CCAP neurons. Our evidence indicates that late CCAP neurons are derived from early, likely embryonic, lineages. However, they do not differentiate to express their peptide hormone battery, nor do they project an axon via lateral nerve trunks until pupariation, both of which are believed to be critical for the function of CCAP efferent neurons in ecdysis. Further analysis implicated ecdysone signaling via ecdysone receptors A/B1 and the nuclear receptor ftz-f1 as the differentiation trigger. These results demonstrate the utility of temporally tuned neuronal differentiation as a hard-wired developmental mechanism to remodel a neuronal network to generate a scheduled change in behavior. PMID:22393011

  11. National Remodelling Team: Evaluation Study (Year 2). Final Report

    ERIC Educational Resources Information Center

    Easton, Claire; Wilson, Rebekah; Sharp, Caroline

    2005-01-01

    This report sets out to provide the National Remodelling Team (NRT) with comprehensive details on stakeholders' views about the second year of the remodelling programme. This report is divided into nine chapters: (1) Introduction; (2) outlines the aims of the evaluation and the methodology used; (3) describes the findings from the survey of local…

  12. Chromatin-remodeling and the initiation of transcription.

    PubMed

    Lorch, Yahli; Kornberg, Roger D

    2015-11-01

    The nucleosome serves as a general gene repressor by the occlusion of regulatory and promoter DNA sequences. Repression is relieved by the SWI/SNF-RSC family of chromatin-remodeling complexes. Research reviewed here has revealed the essential features of the remodeling process. PMID:26537406

  13. Macrophage plasticity and polarization in tissue repair and remodelling.

    PubMed

    Mantovani, Alberto; Biswas, Subhra K; Galdiero, Maria Rosaria; Sica, Antonio; Locati, Massimo

    2013-01-01

    Mononuclear phagocyte plasticity includes the expression of functions related to the resolution of inflammation, tissue repair and remodelling, particularly when these cells are set in an M2 or an M2-like activation mode. Macrophages are credited with an essential role in remodelling during ontogenesis. In extraembryonic life, under homeostatic conditions, the macrophage trophic and remodelling functions are recapitulated in tissues such as bone, mammary gland, decidua and placenta. In pathology, macrophages are key components of tissue repair and remodelling that occur during wound healing, allergy, parasite infection and cancer. Interaction with cells bearing stem or progenitor cell properties is likely an important component of the role of macrophages in repair and remodelling. These properties of cells of the monocyte-macrophage lineage may represent a tool and a target for therapeutic exploitation. PMID:23096265

  14. The “Neurovascular Unit approach” to Evaluate Mechanisms of Dysfunctional Autoregulation in Asphyxiated Newborns in the era of Hypothermia Therapy

    PubMed Central

    Chalak, Lina F.; Tarumi, Takashi; Zhang, Rong

    2014-01-01

    Despite improvements in obstetrical and neonatal care, and introduction of hypothermia as a neuroprotective therapy, perinatal brain injury remains a frequent cause of cerebral palsy, mental retardation and epilepsy. The recognition of dysfunction of cerebral autoregulation is essential for a real time measure of efficacy to identify those who are at highest risk for brain injury. This article will focus on the “neurovascular unit” approach to the care of asphyxiated neonates to review 1) potential mechanisms of dysfunctional cerebral blood flow (CBF) regulation, 2) optimal monitoring methodology such as NIRS (near infrared spectroscopy), and TCD (transcutaneous Doppler), and 3) clinical implications of monitoring in the neonatal intensive care setting in asphyxiated newborns undergoing hypothermia and rewarming. Critical knowledge of the functional regulation of the neurovascular unit may lead to improved ability to predict outcomes in real time during hypothermia, as well as differentiate nonresponders who might benefit from additional therapies. PMID:25062804

  15. 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. PMID:26741177

  16. 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

  17. Osteocytes: The master cells in bone remodelling.

    PubMed

    Prideaux, Matthew; Findlay, David M; Atkins, Gerald J

    2016-06-01

    Bone remodelling is an essential process for shaping and maintaining bone mass in the mature skeleton. During our lifetime bone is constantly being removed by osteoclasts and new bone is formed by osteoblasts. The activities of osteoclasts and osteoblasts must be regulated under a strict balance to ensure that bone homeostasis is maintained. Osteocytes, which form an extensive, multi-functional syncytium throughout the bone, are increasingly considered to be the cells that maintain this balance. Current research is elucidating key signalling pathways by which the osteocyte exerts control over the other cell types in bone and over its own activities, and potential ways in which these pathways may be exploited therapeutically. PMID:26927500

  18. 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

  19. Distribution of temperature changes and neurovascular coupling in rat brain following 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") exposure.

    PubMed

    Coman, Daniel; Sanganahalli, Basavaraju G; Jiang, Lihong; Hyder, Fahmeed; Behar, Kevin L

    2015-10-01

    (+/-)3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") is an abused psychostimulant that produces strong monoaminergic stimulation and whole-body hyperthermia. MDMA-induced thermogenesis involves activation of uncoupling proteins (UCPs), primarily a type specific to skeletal muscle (UCP-3) and absent from the brain, although other UCP types are expressed in the brain (e.g. thalamus) and might contribute to thermogenesis. Since neuroimaging of brain temperature could provide insights into MDMA action, we measured spatial distributions of systemically administered MDMA-induced temperature changes and dynamics in rat cortex and subcortex using a novel magnetic resonance method, Biosensor Imaging of Redundant Deviation in Shifts (BIRDS), with an exogenous temperature-sensitive probe (thulium ion and macrocyclic chelate 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethyl-1,4,7,10-tetraacetate (DOTMA(4-))). The MDMA-induced temperature rise was greater in the cortex than in the subcortex (1.6 ± 0.4 °C versus 1.3 ± 0.4 °C) and occurred more rapidly (2.0 ± 0.2 °C/h versus 1.5 ± 0.2 °C/h). MDMA-induced temperature changes and dynamics in the cortex and body were correlated, although the body temperature exceeded the cortex temperature before and after MDMA. Temperature, neuronal activity, and blood flow (CBF) were measured simultaneously in the cortex and subcortex (i.e. thalamus) to investigate possible differences of MDMA-induced warming across brain regions. MDMA-induced warming correlated with increases in neuronal activity and blood flow in the cortex, suggesting that the normal neurovascular response to increased neural activity was maintained. In contrast to the cortex, a biphasic relationship was seen in the subcortex (i.e. thalamus), with a decline in CBF as temperature and neural activity rose, transitioning to a rise in CBF for temperature above 37 °C, suggesting that MDMA affected CBF and neurovascular coupling differently in subcortical regions

  20. PNPLA3 mediates hepatocyte triacylglycerol remodeling.

    PubMed

    Ruhanen, Hanna; Perttilä, Julia; Hölttä-Vuori, Maarit; Zhou, You; Yki-Järvinen, Hannele; Ikonen, Elina; Käkelä, Reijo; Olkkonen, Vesa M

    2014-04-01

    The I148M substitution in patatin-like phospholipase domain containing 3 (PNPLA3(I148M)) determines a genetic form of nonalcoholic fatty liver disease. To elucidate the mode of PNPLA3 action in human hepatocytes, we studied effects of WT PNPLA3 (PNPLA3(WT)) and PNPLA3(I148M) on HuH7 cell lipidome after [(13)C]glycerol labeling, cellular turnover of oleic acid labeled with 17 deuterium atoms ([D17]oleic acid) in triacylglycerols (TAGs), and subcellular distribution of the protein variants. PNPLA3(I148M) induced a net accumulation of unlabeled TAGs, but not newly synthesized total [(13)C]TAGs. Principal component analysis (PCA) revealed that both PNPLA3(WT) and PNPLA3(I148M) induced a relative enrichment of TAGs with saturated FAs or MUFAs, with concurrent enrichment of polyunsaturated phosphatidylcholines. PNPLA3(WT) associated in PCA with newly synthesized [(13)C]TAGs, particularly 52:1 and 50:1, while PNPLA3(I148M) associated with similar preexisting TAGs. PNPLA3(WT) overexpression resulted in increased [D17]oleic acid labeling of TAGs during 24 h, and after longer incubations their turnover was accelerated, effects not detected with PNPLA3(I148M). PNPLA3(I148M) localized more extensively to lipid droplets (LDs) than PNPLA3(WT), suggesting that the substitution alters distribution of PNPLA3 between LDs and endoplasmic reticulum/cytosol. This study reveals a function of PNPLA3 in FA-selective TAG remodeling, resulting in increased TAG saturation. A defect in TAG remodeling activity likely contributes to the TAG accumulation observed in cells expressing PNPLA3(I148M). PMID:24511104

  1. Anatomy of Mandibular Vital Structures. Part II: Mandibular Incisive Canal, Mental Foramen and Associated Neurovascular Bundles in Relation with Dental Implantology

    PubMed Central

    Wang, Hom-Lay; Sabalys, Gintautas

    2010-01-01

    ABSTRACT Objectives The purpose of the present study was to review the literature of how to identify the mental foramen, mandibular incisive canal and associated neurovascular bundles during implant surgery and how to detect and avoid the damage of these vital structures during implant therapy. Material and Methods Literature was selected through a search of PubMed, Embase and Cochrane electronic databases. The keywords used for search were mandibular incisive canal, mental foramen, mental nerve, anterior mental loop. The search was restricted to English language articles, published from 1979 to November 2009. Additionally, a manual search in the major anatomy, dental implant, and periodontal journals and books was performed. Results In total, 47 literature sources were obtained and reviewed. The morphology and variations of the mandibular incisive canal, mental foramen and associated neurovascular bundles were presented as two entities. It suggested that clinicians should carefully assess these vital structures to avoid nerve/artery damage. Conclusions The mandibular incisive canal, mental foramen and associated neurovascular bundles exist in different locations and possess many variations. Individual, gender, age, race, assessing technique used and degree of edentulous alveolar bone atrophy largely influence these variations. It suggests that the clinicians should carefully identify these anatomical landmarks, by analyzing all influencing factors, prior to their implant surgical operation. PMID:24421959

  2. Microstructural alterations in trigeminal neuralgia determined by diffusion tensor imaging are independent of symptom duration, severity, and type of neurovascular conflict.

    PubMed

    Lutz, Juergen; Thon, Niklas; Stahl, Robert; Lummel, Nina; Tonn, Joerg-Christian; Linn, Jennifer; Mehrkens, Jan-Hinnerk

    2016-03-01

    OBJECT In this prospective study diffusion tensor imaging (DTI) was used to evaluate the influence of clinical and anatomical parameters on structural alterations within the fifth cranial nerve in patients with trigeminal neuralgia (TN) due to neurovascular compression. METHODS Overall, 81 patients (40 men and 41 women; mean age 60 ± 5 years) with typical TN were included who underwent microsurgical decompression. Preoperative 3.0-T high-resolution MRI and DTI were analyzed in a blinded fashion. The respective fractional anisotropy (FA) and apparent diffusion coefficient values were compared with the clinical, imaging, and intraoperative data. This study was approved by the institutional review board, and written informed consent was obtained from all patients. RESULTS DTI analyses revealed significantly lower FA values within the vulnerable zone of the affected trigeminal nerve compared with the contralateral side (p = 0.05). The DTI analyses also included 3 patients without clear evidence of neurovascular conflict on preoperative MRI. No differences were seen between arterial and venous compression. Lower FA values were found 5 months after symptom onset; however, no correlation was found with the duration of symptoms or severity of compression. CONCLUSIONS DTI analysis allows the quantification of structural alterations, even in those patients without any discernible neurovascular contact on MRI. Moreover, our findings support the hypothesis that both the arteries and veins can cause structural alterations that lead to TN. These aspects can be useful for making treatment decisions. PMID:26406792

  3. Neurovascular Invasion and Histological Grade Serve as the Risk Factors of Cervical Lymph Node Metastases in Early Tongue Squamous Cell Carcinoma.

    PubMed

    Wu, Kailiu; Yang, Xi; Li, Liwen; Ruan, Min; Liu, Wei; Lu, Wei; Zhang, Chenping; Li, Siyi

    2016-07-01

    The objectives of this study were to analyze the regional characteristics of the cervical lymph node metastasis and to investigate the factors associated with the risk of lymph node involvement. One hundred seventy-one patients suffering from early primary squamous cell carcinoma (SCC) of the tongue (cT1-2N0) were enrolled. Gender, age, growth site, T stage, histological grade, and neurovascular invasion were statistically analyzed by K-M survival analysis and Cox multivariate analysis to evaluate the relationship between the factors and the neck lymph node metastasis. Of the 171 cases divided into the neck dissection group and observation group, 40 ended up with lymph node metastasis, of which 17 were metastasized to level I, 27 to level II, 10 to level III, 2 to level IV, and 1 to level V. Histological grade and neurovascular invasion were significantly associated with lymph node involvement in univariate and multivariate analyses. Age distribution was found to be significantly associated with the lymph node metastasis in multivariate analysis. The metastasis of early tongue SCC has a certain regularity at different sites. Age was not a critical risk factor for cervical lymph node metastasis after surgery. Tumor size was suspected to exert a negative effect on metastasis by influencing tumor invasion. Histological grade and neurovascular invasion were significantly associated with the risk of cervical lymph node metastasis of early tongue SCC. PMID:25911199

  4. Neurovascular unit dysfunction with blood-brain barrier hyperpermeability contributes to major depressive disorder: a review of clinical and experimental evidence

    PubMed Central

    2013-01-01

    About one-third of people with major depressive disorder (MDD) fail at least two antidepressant drug trials at 1 year. Together with clinical and experimental evidence indicating that the pathophysiology of MDD is multifactorial, this observation underscores the importance of elucidating mechanisms beyond monoaminergic dysregulation that can contribute to the genesis and persistence of MDD. Oxidative stress and neuroinflammation are mechanistically linked to the presence of neurovascular dysfunction with blood-brain barrier (BBB) hyperpermeability in selected neurological disorders, such as stroke, epilepsy, multiple sclerosis, traumatic brain injury, and Alzheimer’s disease. In contrast to other major psychiatric disorders, MDD is frequently comorbid with such neurological disorders and constitutes an independent risk factor for morbidity and mortality in disorders characterized by vascular endothelial dysfunction (cardiovascular disease and diabetes mellitus). Oxidative stress and neuroinflammation are implicated in the neurobiology of MDD. More recent evidence links neurovascular dysfunction with BBB hyperpermeability to MDD without neurological comorbidity. We review this emerging literature and present a theoretical integration between these abnormalities to those involving oxidative stress and neuroinflammation in MDD. We discuss our hypothesis that alterations in endothelial nitric oxide levels and endothelial nitric oxide synthase uncoupling are central mechanistic links in this regard. Understanding the contribution of neurovascular dysfunction with BBB hyperpermeability to the pathophysiology of MDD may help to identify novel therapeutic and preventative approaches. PMID:24289502

  5. An extended posterior approach to the hip and pelvis for complex acetabular reconstruction that preserves the gluteal muscles and their neurovascular supply.

    PubMed

    Solomon, L B; Hofstaetter, J G; Bolt, M J; Howie, D W

    2014-01-01

    We investigated the detailed anatomy of the gluteus maximus, gluteus medius and gluteus minimus and their neurovascular supply in 22 hips in 11 embalmed adult Caucasian human cadavers. This led to the development of a surgical technique for an extended posterior approach to the hip and pelvis that exposes the supra-acetabular ilium and preserves the glutei during revision hip surgery. Proximal to distal mobilisation of the gluteus medius from the posterior gluteal line permits exposure and mobilisation of the superior gluteal neurovascular bundle between the sciatic notch and the entrance to the gluteus medius, enabling a wider exposure of the supra-acetabular ilium. This technique was subsequently used in nine patients undergoing revision total hip replacement involving the reconstruction of nine Paprosky 3B acetabular defects, five of which had pelvic discontinuity. Intra-operative electromyography showed that the innervation of the gluteal muscles was not affected by surgery. Clinical follow-up demonstrated good hip abduction function in all patients. These results were compared with those of a matched cohort treated through a Kocher-Langenbeck approach. Our modified approach maximises the exposure of the ilium above the sciatic notch while protecting the gluteal muscles and their neurovascular bundle. PMID:24395310

  6. The Redox State of Transglutaminase 2 Controls Arterial Remodeling

    PubMed Central

    van den Akker, Jeroen; VanBavel, Ed; van Geel, Remon; Matlung, Hanke L.; Guvenc Tuna, Bilge; Janssen, George M. C.; van Veelen, Peter A.; Boelens, Wilbert C.; De Mey, Jo G. R.; Bakker, Erik N. T. P.

    2011-01-01

    While inward remodeling of small arteries in response to low blood flow, hypertension, and chronic vasoconstriction depends on type 2 transglutaminase (TG2), the mechanisms of action have remained unresolved. We studied the regulation of TG2 activity, its (sub) cellular localization, substrates, and its specific mode of action during small artery inward remodeling. We found that inward remodeling of isolated mouse mesenteric arteries by exogenous TG2 required the presence of a reducing agent. The effect of TG2 depended on its cross-linking activity, as indicated by the lack of effect of mutant TG2. The cell-permeable reducing agent DTT, but not the cell-impermeable reducing agent TCEP, induced translocation of endogenous TG2 and high membrane-bound transglutaminase activity. This coincided with inward remodeling, characterized by a stiffening of the artery. The remodeling could be inhibited by a TG2 inhibitor and by the nitric oxide donor, SNAP. Using a pull-down assay and mass spectrometry, 21 proteins were identified as TG2 cross-linking substrates, including fibronectin, collagen and nidogen. Inward remodeling induced by low blood flow was associated with the upregulation of several anti-oxidant proteins, notably glutathione-S-transferase, and selenoprotein P. In conclusion, these results show that a reduced state induces smooth muscle membrane-bound TG2 activity. Inward remodeling results from the cross-linking of vicinal matrix proteins, causing a stiffening of the arterial wall. PMID:21901120

  7. A simple bracing technique to correct kinking of arterial branches to avoid ischemic sequelae during neurovascular surgery

    PubMed Central

    Motoyama, Yasushi; Tanaka, Yoshitaka; Gurung, Pritam; Nakagawa, Ichiro; Park, Young-Soo; Nakase, Hiroyuki

    2016-01-01

    Background: During microscopic procedures for neurovascular disease, we sometimes encounter kinking of arterial branches resulting in ischemic sequelae. A simple and useful technique that involves inserting a small, ball-like prosthesis made of oxidized cellulose or shredded Teflon with fibrin glue that corrects the arterial branch kinking and avoids subsequent compromise is reported. Methods: Between January and December 2014, three patients developed arterial kinking during microscopic procedures, including two in the caudal loop of the posterior inferior cerebellar artery during microvascular decompression for glossopharyngeal neuralgia and one in a branch of the middle cerebral artery (MCA) during clipping for an unruptured MCA aneurysm. Blood flow insufficiency was confirmed by microvascular Doppler ultrasonography (MDU) and indocyanine green (ICG) videoangiography. The prosthesis, which was made of shredded Teflon in two cases and oxidized cellulose in one case, was inserted into the crotch of the kinked arteries to correct the kinking of the arteries and restore the proper vascular shape and normal blood flow. Results: The small, ball-shaped prosthesis corrected the kinked arteries and maintained the proper shape, which was confirmed by ICG videoangiography and MDU during the operation and three-dimensional computerized tomography angiography postoperatively. Postoperatively, the patients did not manifest any ischemic sequelae related to the kinked arteries. Conclusion: The insertion of prostheses with fibrin glue into the crotch of a kinked artery for repair is considered a simple and useful method for correcting a kinked artery that avoids ischemic sequelae. PMID:26862447

  8. A brain microvasculature endothelial cell-specific viral vector with the potential to treat neurovascular and neurological diseases.

    PubMed

    Körbelin, Jakob; Dogbevia, Godwin; Michelfelder, Stefan; Ridder, Dirk A; Hunger, Agnes; Wenzel, Jan; Seismann, Henning; Lampe, Melanie; Bannach, Jacqueline; Pasparakis, Manolis; Kleinschmidt, Jürgen A; Schwaninger, Markus; Trepel, Martin

    2016-01-01

    Gene therapy critically relies on vectors that combine high transduction efficiency with a high degree of target specificity and that can be administered through a safe intravenous route. The lack of suitable vectors, especially for gene therapy of brain disorders, represents a major obstacle. Therefore, we applied an in vivo screening system of random ligand libraries displayed on adeno-associated viral capsids to select brain-targeted vectors for the treatment of neurovascular diseases. We identified a capsid variant showing an unprecedented degree of specificity and long-lasting transduction efficiency for brain microvasculature endothelial cells as the primary target of selection. A therapeutic vector based on this selected viral capsid was used to markedly attenuate the severe cerebrovascular pathology of mice with incontinentia pigmenti after a single intravenous injection. Furthermore, the versatility of this selection system will make it possible to select ligands for additional in vivo targets without requiring previous identification of potential target-specific receptors. PMID:27137490

  9. Mechanism of Mitochondrial Connexin43′s Protection of the Neurovascular Unit under Acute Cerebral Ischemia-Reperfusion Injury

    PubMed Central

    Hou, Shuai; Shen, Ping-Ping; Zhao, Ming-Ming; Liu, Xiu-Ping; Xie, Hong-Yan; Deng, Fang; Feng, Jia-Chun

    2016-01-01

    We observed mitochondrial connexin43 (mtCx43) expression under cerebral ischemia-reperfusion (I/R) injury, analyzed its regulation, and explored its protective mechanisms. Wistar rats were divided into groups based on injections received before middle cerebral artery occlusion (MCAO). Cerebral infarction volume was detected by 2,3,5-triphenyltetrazolim chloride staining, and cell apoptosis was observed by transferase dUTP nick end labeling. We used transmission electron microscopy to observe mitochondrial morphology and determined superoxide dismutase (SOD) activity and malondialdehyde (MDA) content. MtCx43, p-mtCx43, protein kinase C (PKC), and p-PKC expression were detected by Western blot. Compared with those in the IR group, cerebral infarction volumes in the carbenoxolone (CBX) and diazoxide (DZX) groups were obviously smaller, and the apoptosis indices were down-regulated. Mitochondrial morphology was damaged after I/R, especially in the IR and 5-hydroxydecanoic acid (5-HD) groups. Similarly, decreased SOD activity and increased MDA were observed after MCAO; CBX, DZX, and phorbol-12-myristate-13-acetate (PMA) reduced mitochondrial functional injury. Expression of mtCx43 and p-mtCx43 and the p-Cx43/Cx43 ratio were significantly lower in the IR group than in the sham group. These abnormalities were ameliorated by CBX, DZX, and PMA. MtCx43 may protect the neurovascular unit from acute cerebral IR injury via PKC activation induced by mitoKATP channel agonists. PMID:27164087

  10. Intravitreal AAV2.COMP-Ang1 Prevents Neurovascular Degeneration in a Murine Model of Diabetic Retinopathy.

    PubMed

    Cahoon, Judd M; Rai, Ruju R; Carroll, Lara S; Uehara, Hironori; Zhang, Xiaohui; O'Neil, Christina L; Medina, Reinhold J; Das, Subtrata K; Muddana, Santosh K; Olson, Paul R; Nielson, Spencer; Walker, Kortnie; Flood, Maggie M; Messenger, Wyatt B; Archer, Bonnie J; Barabas, Peter; Krizaj, David; Gibson, Christopher C; Li, Dean Y; Koh, Gou Y; Gao, Guangping; Stitt, Alan W; Ambati, Balamurali K

    2015-12-01

    Diabetic retinopathy (DR) is the leading cause of blindness in the working-age population in the U.S. The vision-threatening processes of neuroglial and vascular dysfunction in DR occur in concert, driven by hyperglycemia and propelled by a pathway of inflammation, ischemia, vasodegeneration, and breakdown of the blood retinal barrier. Currently, no therapies exist for normalizing the vasculature in DR. Here, we show that a single intravitreal dose of adeno-associated virus serotype 2 encoding a more stable, soluble, and potent form of angiopoietin 1 (AAV2.COMP-Ang1) can ameliorate the structural and functional hallmarks of DR in Ins2Akita mice, with sustained effects observed through six months. In early DR, AAV2.COMP-Ang1 restored leukocyte-endothelial interaction, retinal oxygenation, vascular density, vascular marker expression, vessel permeability, retinal thickness, inner retinal cellularity, and retinal neurophysiological response to levels comparable with nondiabetic controls. In late DR, AAV2.COMP-Ang1 enhanced the therapeutic benefit of intravitreally delivered endothelial colony-forming cells by promoting their integration into the vasculature and thereby stemming further visual decline. AAV2.COMP-Ang1 single-dose gene therapy can prevent neurovascular pathology, support vascular regeneration, and stabilize vision in DR. PMID:26340930

  11. Virtual stenting workflow with vessel-specific initialization and adaptive expansion for neurovascular stents and flow diverters.

    PubMed

    Paliwal, Nikhil; Yu, Hongyu; Xu, Jinhui; Xiang, Jianping; Siddiqui, Adnan H; Yang, Xinjian; Li, Haiyun; Meng, Hui

    2016-10-01

    Endovascular intervention using traditional neurovascular stents and densely braided flow diverters (FDs) have become the preferred treatment strategies for traditionally challenging intracranial aneurysms. Modeling stent and FD deployment in patient-specific aneurysms and its flow modification results prior to the actual intervention can potentially predict the patient outcome and treatment optimization. We present a clinically focused, streamlined virtual stenting workflow that efficiently simulates stent and FD treatment in patient-specific aneurysms based on expanding a simplex mesh structure. The simplex mesh is generated using an innovative vessel-specific initialization technique, which uses the patient's parent artery diameter to identify the initial position of the simplex mesh inside the artery. A novel adaptive expansion algorithm enables the acceleration of deployment process by adjusting the expansion forces based on the distance of the simplex mesh from the parent vessel. The virtual stenting workflow was tested by modeling the treatment of two patient-specific aneurysms using the Enterprise stent and the Pipeline Embolization Device (commercial FD). Both devices were deployed in the aneurysm models in a few seconds. Computational fluid dynamics analyses of pre- and post-treatment aneurysmal hemodynamics show flow reduction in the aneurysmal sac in treated aneurysms, with the FD diverting more flow than the Enterprise stent. The test results show that this workflow can rapidly simulate clinical deployment of stents and FDs, hence paving the way for its future clinical implementation. PMID:26899135

  12. The multifactorial nature of microRNAs in vascular remodelling.

    PubMed

    Welten, S M J; Goossens, E A C; Quax, P H A; Nossent, A Y

    2016-05-01

    Vascular remodelling is a multifactorial process that involves both adaptive and maladaptive changes of the vessel wall through, among others, cell proliferation and migration, but also apoptosis and necrosis of the various cell types in the vessel wall. Vascular remodelling can be beneficial, e.g. during neovascularization after ischaemia, as well as pathological, e.g. during atherosclerosis and aneurysm formation. In recent years, it has become clear that microRNAs are able to target many genes that are involved in vascular remodelling processes and either can promote or inhibit structural changes of the vessel wall. Since many different processes of vascular remodelling are regulated by similar mechanisms and factors, both positive and negative vascular remodelling can be affected by the same microRNAs. A large number of microRNAs has been linked to various aspects of vascular remodelling and indeed, several of these microRNAs regulate multiple vascular remodelling processes, including both the adaptive processes angiogenesis and arteriogenesis as well as maladaptive processes of atherosclerosis, restenosis and aneurysm formation. Here, we discuss the multifactorial role of microRNAs and microRNA clusters that were reported to play a role in multiple forms of vascular remodelling and are clearly linked to cardiovascular disease (CVD). The microRNAs reviewed are miR-126, miR-155 and the microRNA gene clusters 17-92, 23/24/27, 143/145 and 14q32. Understanding the contribution of these microRNAs to the entire spectrum of vascular remodelling processes is important, especially as these microRNAs may have great potential as therapeutic targets for treatment of various CVDs. PMID:26912672

  13. Intratracheal Bleomycin Causes Airway Remodeling and Airflow Obstruction in Mice

    PubMed Central

    Polosukhin, Vasiliy V.; Degryse, Amber L.; Newcomb, Dawn C.; Jones, Brittany R.; Ware, Lorraine B.; Lee, Jae Woo; Loyd, James E.; Blackwell, Timothy S.; Lawson, William E.

    2014-01-01

    Introduction In addition to parenchymal fibrosis, fibrotic remodeling of the distal airways has been reported in interstitial lung diseases. Mechanisms of airway wall remodeling, which occurs in a variety of chronic lung diseases, are not well defined and current animal models are limited. Methods We quantified airway remodeling in lung sections from subjects with idiopathic pulmonary fibrosis (IPF) and controls. To investigate intratracheal bleomycin as a potential animal model for fibrotic airway remodeling, we evaluated lungs from C57BL/6 mice after bleomycin treatment by histologic scoring for fibrosis and peribronchial inflammation, morphometric evaluation of subepithelial connective tissue volume density, TUNEL assay, and immunohistochemistry for transforming growth factor β1 (TGFβ1), TGFβ2, and the fibroblast marker S100A4. Lung mechanics were determined at 3 weeks post-bleomycin. Results IPF lungs had small airway remodeling with increased bronchial wall thickness compared to controls. Similarly, bleomycin treated mice developed dose-dependent airway wall inflammation and fibrosis and greater airflow resistance after high dose bleomycin. Increased TUNEL+ bronchial epithelial cells and peribronchial inflammation were noted by 1 week, and expression of TGFβ1 and TGFβ2 and accumulation of S100A4+ fibroblasts correlated with airway remodeling in a bleomycin dose-dependent fashion. Conclusions IPF is characterized by small airway remodeling in addition to parenchymal fibrosis, a pattern also seen with intratracheal bleomycin. Bronchial remodeling from intratracheal bleomycin follows a cascade of events including epithelial cell injury, airway inflammation, pro-fibrotic cytokine expression, fibroblast accumulation, and peribronchial fibrosis. Thus, this model can be utilized to investigate mechanisms of airway remodeling. PMID:22394287

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed

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

    2012-10-01

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

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

    PubMed Central

    2016-01-01

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

  17. 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

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

    PubMed

    Genovese, Luca; Brendolan, Andrea

    2016-01-01

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

  19. AB INITIO AND CALPHAD THERMODYNAMICS OF MATERIALS

    SciTech Connect

    Turchi, P A

    2004-04-14

    Ab initio electronic structure methods can supplement CALPHAD in two major ways for subsequent applications to stability in complex alloys. The first one is rather immediate and concerns the direct input of ab initio energetics in CALPHAD databases. The other way, more involved, is the assessment of ab initio thermodynamics {acute a} la CALPHAD. It will be shown how these results can be used within CALPHAD to predict the equilibrium properties of multi-component alloys.

  20. 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

  1. 65. (Credit JTL) Filter room looking WSW across remodelled New ...

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

    65. (Credit JTL) Filter room looking WSW across remodelled New York horizontal pressure filters (in foreground). - McNeil Street Pumping Station, McNeil Street & Cross Bayou, Shreveport, Caddo Parish, LA

  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. Emerging mechanisms of mRNP remodeling regulation

    PubMed Central

    Chen, Chyi-Ying A.

    2015-01-01

    The assembly and remodeling of the components of messenger ribonucleoprotein particles (mRNPs) are important in determining the fate of an mRNA. A combination of biochemical and cell biology research, recently complemented by genome-wide high-throughput approaches, has led to significant progress on understanding the formation, dynamics and function of mRNPs. These studies also advanced the challenging process of identifying the evolving constituents of individual mRNPs at various stages during an mRNA’s lifetime. While research on mRNP remodeling in general has been gaining momentum, there has been relatively little attention paid to the regulatory aspect of mRNP remodeling. Here, we discuss the results of some new studies and potential mechanisms for regulation of mRNP remodeling. PMID:24923990

  4. Remodeled second floor with stairs and stacks. This was formerly ...

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

    Remodeled second floor with stairs and stacks. This was formerly the upper part of the original two story reading room. View to southwest. - San Bernardino Valley College, Library, 701 South Mount Vernon Avenue, San Bernardino, San Bernardino County, CA

  5. Restricting Fermentative Potential by Proteome Remodeling

    PubMed Central

    Clair, Gérémy; Armengaud, Jean; Duport, Catherine

    2012-01-01

    Pathogenesis hinges on successful colonization of the gastrointestinal (GI) tract by pathogenic facultative anaerobes. The GI tract is a carbohydrate-limited environment with varying oxygen availability and oxidoreduction potential (ORP). How pathogenic bacteria are able to adapt and grow in these varying conditions remains a key fundamental question. Here, we designed a system biology-inspired approach to pinpoint the key regulators allowing Bacillus cereus to survive and grow efficiently under low ORP anoxic conditions mimicking those encountered in the intestinal lumen. We assessed the proteome components using high throughput nanoLC-MS/MS techniques, reconstituted the main metabolic circuits, constructed ΔohrA and ΔohrR mutants, and analyzed the impacts of ohrA and ohrR disruptions by a novel round of shotgun proteomics. Our study revealed that OhrR and OhrA are crucial to the successful adaptation of B. cereus to the GI tract environment. Specifically, we showed that B. cereus restricts its fermentative growth under low ORP anaerobiosis and sustains efficient aerobic respiratory metabolism, motility, and stress response via OhrRA-dependent proteome remodeling. Finally, our results introduced a new adaptive strategy where facultative anaerobes prefer to restrict their fermentative potential for a long term benefit. PMID:22232490

  6. Chromatin remodeling effects on enhancer activity.

    PubMed

    García-González, Estela; Escamilla-Del-Arenal, Martín; Arzate-Mejía, Rodrigo; Recillas-Targa, Félix

    2016-08-01

    During organism development, a diversity of cell types emerges with disparate, yet stable profiles of gene expression with distinctive cellular functions. In addition to gene promoters, the genome contains enhancer regulatory sequences, which are implicated in cellular specialization by facilitating cell-type and tissue-specific gene expression. Enhancers are DNA binding elements characterized by highly sophisticated and various mechanisms of action allowing for the specific interaction of general and tissue-specific transcription factors (TFs). However, eukaryotic organisms package their genetic material into chromatin, generating a physical barrier for TFs to interact with their cognate sequences. The ability of TFs to bind DNA regulatory elements is also modulated by changes in the chromatin structure, including histone modifications, histone variants, ATP-dependent chromatin remodeling, and the methylation status of DNA. Furthermore, it has recently been revealed that enhancer sequences are also transcribed into a set of enhancer RNAs with regulatory potential. These interdependent processes act in the context of a complex network of chromatin interactions, which together contributes to a renewed vision of how gene activation is coordinated in a cell-type-dependent manner. In this review, we describe the interplay between genetic and epigenetic aspects associated with enhancers and discuss their possible roles on enhancer function. PMID:27026300

  7. Remodeling of the bone material containing microcracks: A theoretical analysis

    NASA Astrophysics Data System (ADS)

    Ramtani, S.; Zidi, M.

    1999-12-01

    The question is, what happens when the bone loses its ability for load-driven adaptation, when damage is no longer repaired as it seems to be the case for bone loss associated with age, medication or disease? In this study, we tempt to show how damage can influence the remodeling process. A thermodynamic theoretical framework is therefore provided as a basis for a consistent formulation of bone remodeling involving a chemical reaction and mass transfer between two constituents in presence of microcracks.

  8. The role of the epithelium in airway remodeling in asthma.

    PubMed

    Davies, Donna E

    2009-12-01

    The bronchial epithelium is the barrier to the external environment and plays a vital role in protection of the internal milieu of the lung. It functions within the epithelial-mesenchymal trophic unit to control the local microenvironment and help maintain tissue homeostasis. However, in asthma, chronic perturbation of these homeostatic mechanisms leads to alterations in the structure of the airways, termed remodeling. Damage to the epithelium is now recognized to play a key role in driving airway remodeling. We have postulated that epithelial susceptibility to environmental stress and injury together with impaired repair responses results in generation of signals that act on the underlying mesenchyme to propagate and amplify inflammatory and remodeling responses in the submucosa. Many types of challenges to the epithelium, including pathogens, allergens, environmental pollutants, cigarette smoke, and even mechanical forces, can elicit production of mediators by the epithelium, which can be translated into remodeling responses by the mesenchyme. Several important mediators of remodeling have been identified, most notably transforming growth factor-beta, which is released from damaged/repairing epithelium or in response to inflammatory mediators, such as IL-13. The cross talk between the epithelium and the underlying mesenchyme to drive remodeling responses is considered in the context of subepithelial fibrosis and potential pathogenetic mechanisms linked to the asthma susceptibility gene, a disintegrin and metalloprotease (ADAM)33. PMID:20008875

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

    PubMed Central

    Hirano, Ikuo; Aceves, Seema S.

    2014-01-01

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

  10. Ultrasound Biomicroscopy Comparison of Ab Interno and Ab Externo Intraocular Lens Scleral Fixation.

    PubMed

    Horiguchi, Lie; Garcia, Patricia Novita; Malavazzi, Gustavo Ricci; Allemann, Norma; Gomes, Rachel L R

    2016-01-01

    Purpose. To compare ab interno and ab externo scleral fixation of posterior chamber intraocular lenses (PCIOL) using ultrasound biomicroscopy (UBM). Methods. Randomized patients underwent ab externo or ab interno scleral fixation of a PCIOL. Ultrasound biomicroscopy was performed 3 to 6 months postoperatively, to determine PCIOL centration, IOL distance to the iris at 12, 3, 6, and 9 hours, and haptics placement in relation to the ciliary sulcus. Results. Fifteen patients were enrolled in the study. The ab externo technique was used in 7 eyes (46.6%) and the ab interno in 8 eyes (53.3%). In the ab externo technique, 14 haptics were located: 4 (28.57%) in the ciliary sulcus; 2 (14.28%) anterior to the sulcus; and 8 (57.14%) posterior to the sulcus, 6 in the ciliary body and 2 posterior to the ciliary body. In the ab interno group, 4 haptics (25.0%) were in the ciliary sulcus, 2 (12.50%) anterior to the sulcus, and 10 (75.0%) posterior to the sulcus, 4 in the ciliary body and 6 posterior to the ciliary body. Conclusions. Ab externo and ab interno scleral fixation techniques presented similar results in haptic placement. Ab externo technique presented higher vertical tilt when compared to the ab interno. PMID:27293878

  11. Ultrasound Biomicroscopy Comparison of Ab Interno and Ab Externo Intraocular Lens Scleral Fixation

    PubMed Central

    Horiguchi, Lie; Garcia, Patricia Novita; Malavazzi, Gustavo Ricci; Allemann, Norma

    2016-01-01

    Purpose. To compare ab interno and ab externo scleral fixation of posterior chamber intraocular lenses (PCIOL) using ultrasound biomicroscopy (UBM). Methods. Randomized patients underwent ab externo or ab interno scleral fixation of a PCIOL. Ultrasound biomicroscopy was performed 3 to 6 months postoperatively, to determine PCIOL centration, IOL distance to the iris at 12, 3, 6, and 9 hours, and haptics placement in relation to the ciliary sulcus. Results. Fifteen patients were enrolled in the study. The ab externo technique was used in 7 eyes (46.6%) and the ab interno in 8 eyes (53.3%). In the ab externo technique, 14 haptics were located: 4 (28.57%) in the ciliary sulcus; 2 (14.28%) anterior to the sulcus; and 8 (57.14%) posterior to the sulcus, 6 in the ciliary body and 2 posterior to the ciliary body. In the ab interno group, 4 haptics (25.0%) were in the ciliary sulcus, 2 (12.50%) anterior to the sulcus, and 10 (75.0%) posterior to the sulcus, 4 in the ciliary body and 6 posterior to the ciliary body. Conclusions. Ab externo and ab interno scleral fixation techniques presented similar results in haptic placement. Ab externo technique presented higher vertical tilt when compared to the ab interno. PMID:27293878

  12. Cytomembrane ATP-sensitive K+ channels in neurovascular unit targets of ischemic stroke in the recovery period

    PubMed Central

    Zhang, Yang; Pan, Sipei; Zheng, Xiaolu; Wan, Qi

    2016-01-01

    The present study was to analyze the mechanism of cytomembrane ATP-sensitive K+ channels (KATP) in the neurovascular unit treatment of ischemic stroke in the recovery period. A total of 24 healthy adult male Wistar rats of 5–8 weeks age, weighing 160–200 g were randomly divided into the control (sham-operation group), model, KATP blocker and KATP opener groups (n=6 rats per group). Nylon cerebral artery occlusion was conducted using nylon monofilament coated with Poly-L-lysine, which was used to produce a cerebral infarction model. After feeding normally for 3 days, 5-hydroxydecanoate (40 mg/Kg), and diazoxide (40 mg/Kg) were injected to the abdominal cavity in the blocker, and opener groups, respectively. The control received an equivalent normal saline that was injected into the sham-operation and model groups. The animals were mutilated and samples were collected after 3 days. RT-PCR was used to detect the expression levels of the three subunits of KATP, i.e., kir6.1, and sulfonylurea receptor (SUR) 1 and SUR2 mRNA, as well as to calculate infarct size in tetrazolium chloride staining. The expression level of mRNA in the opener group were significantly higher, followed by the model and blocker groups, with the control group being the lowest (P<0.05). Infarct size in the opener group was markedly smaller than the model and blocker groups, and infarct size in the blocker group was significantly larger (P<0.05). Thus, the target treatment on KATP may improve the prognosis of ischemic stroke during the recovery period. PMID:27446320

  13. Interaction of mechanisms involving epoxyeicosatrienoic acids, adenosine receptors, and metabotropic glutamate receptors in neurovascular coupling in rat whisker barrel cortex

    PubMed Central

    Shi, Yanrong; Liu, Xiaoguang; Gebremedhin, Debebe; Falck, John R; Harder, David R; Koehler, Raymond C

    2008-01-01

    Adenosine, astrocyte metabotropic glutamate receptors (mGluRs), and epoxyeicosatrienoic acids (EETs) have been implicated in neurovascular coupling. Although A2A and A2B receptors mediate cerebral vasodilation to adenosine, the role of each receptor in the cerebral blood flow (CBF) response to neural activation remains to be fully elucidated. In addition, adenosine can amplify astrocyte calcium, which may increase arachidonic acid metabolites such as EETs. The interaction of these pathways was investigated by determining if combined treatment with antagonists exerted an additive inhibitory effect on the CBF response. During whisker stimulation of anesthetized rats, the increase in cortical CBF was reduced by approximately half after individual administration of A2B, mGluR and EET antagonists and EET synthesis inhibitors. Combining treatment of either a mGluR antagonist, an EET antagonist, or an EET synthesis inhibitor with an A2B receptor antagonist did not produce an additional decrement in the CBF response. Likewise, the CBF response also remained reduced by ~50% when an EET antagonist was combined with an mGluR antagonist or an mGluR antagonist plus an A2B receptor antagonist. In contrast, A2A and A3 receptor antagonists had no effect on the CBF response to whisker stimulation. We conclude that (1) adenosine A2B receptors, rather than A2A or A3 receptors, play a significant role in coupling cortical CBF to neuronal activity, and (2) the adenosine A2B receptor, mGluR, and EETs signaling pathways are not functionally additive, consistent with the possibility of astrocytic mGluR and adenosine A2B receptor linkage to the synthesis and release of vasodilatory EETs. PMID:17519974

  14. Simultaneous epidural functional near-infrared spectroscopy and cortical electrophysiology as a tool for studying local neurovascular coupling in primates.

    PubMed

    Zaidi, Ali Danish; Munk, Matthias H J; Schmidt, Andreas; Risueno-Segovia, Cristina; Bernard, Rebekka; Fetz, Eberhard; Logothetis, Nikos; Birbaumer, Niels; Sitaram, Ranganatha

    2015-10-15

    Simultaneous measurements of intra-cortical electrophysiology and hemodynamic signals in primates are essential for relating human neuroimaging studies with intra-cortical electrophysiology in monkeys. Previously, technically challenging and resourcefully demanding techniques such as fMRI and intrinsic-signal optical imaging have been used for such studies. Functional near-infrared spectroscopy is a relatively less cumbersome neuroimaging method that uses near-infrared light to detect small changes in concentrations of oxy-hemoglobin (HbO), deoxy-hemoglobin (HbR) and total hemoglobin (HbT) in a volume of tissue with high specificity and temporal resolution. FNIRS is thus a good candidate for hemodynamic measurements in primates to acquire local hemodynamic signals during electrophysiological recordings. To test the feasibility of using epidural fNIRS with concomitant extracellular electrophysiology, we recorded neuronal and hemodynamic activity from the primary visual cortex of two anesthetized monkeys during visual stimulation. We recorded fNIRS epidurally, using one emitter and two detectors. We performed simultaneous cortical electrophysiology using tetrodes placed between the fNIRS sensors. We observed robust and reliable responses to the visual stimulation in both [HbO] and [HbR] signals, and quantified the signal-to-noise ratio of the epidurally measured signals. We also observed a positive correlation between stimulus-induced modulation of [HbO] and [HbR] signals and strength of neural modulation. Briefly, our results show that epidural fNIRS detects single-trial responses to visual stimuli on a trial-by-trial basis, and when coupled with cortical electrophysiology, is a promising tool for studying local hemodynamic signals and neurovascular coupling. PMID:26169323

  15. 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

  16. 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

  17. Obstruction-induced pulmonary vascular remodeling.

    PubMed

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

    2011-11-01

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

  18. PTH signaling mediates perilacunar remodeling during exercise.

    PubMed

    Gardinier, Joseph D; Al-Omaishi, Salam; Morris, Michael D; Kohn, David H

    2016-01-01

    Mechanical loading and release of endogenous parathyroid hormone (PTH) during exercise facilitate the adaptation of bone. However, it remains unclear how exercise and PTH influence the composition of bone and how exercise and PTH-mediated compositional changes influence the mechanical properties of bone. Thus, the primary purpose of this study was to establish compositional changes within osteocytes' perilacunar region of cortical bone following exercise, and evaluate the influence of endogenous PTH signaling on this perilacunar adaptation. Raman spectroscopy, scanning electron microscopy (SEM), and energy dispersive X-ray spectroscopy (EDS) were used to evaluate tissue composition surrounding individual lacuna within the tibia of 19week old male mice exposed to treadmill running for 3weeks. As a result of exercise, tissue within the perilacunar region (within 0-5μm of the lacuna wall) had a lower mineral-to-matrix ratio (MMR) compared to sedentary controls. In addition, exercise also increased the carbonate-to-phosphate ratio (CPR) across both perilacunar and non-perilacunar regions (5-10μm and 10-15μm from the lacuna walls). Tibial post-yield work had a significant negative correlation with perilacunar MMR. Inhibition of PTH activity with PTH(7-34) demonstrated that perilacunar remodeling during exercise was dependent on the cellular response to endogenous PTH. The osteocytes' response to endogenous PTH during exercise was characterized by a significant reduction in SOST expression and significant increase in FGF-23 expression. The potential reduction in phosphate levels due to FGF-23 expression may explain the increase in carbonate substitution. Overall, this is the first study to demonstrate that adaptation in tissue composition is localized around individual osteocytes, may contribute to the changes in whole bone mechanics during exercise, and that PTH signaling during exercise contributes to these adaptations. PMID:26924474

  19. Remodeling of alveolar septa after murine pneumonectomy.

    PubMed

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

    2015-06-15

    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

  20. Mechanisms of Cardiovascular Remodeling in Hyperhomocysteinemia

    PubMed Central

    Steed, Mesia M.

    2011-01-01

    Abstract In hypertension, an increase in arterial wall thickness and loss of elasticity over time result in an increase in pulse wave velocity, a direct measure of arterial stiffness. This change is reflected in gradual fragmentation and loss of elastin fibers and accumulation of stiffer collagen fibers in the media that occurs independently of atherosclerosis. Similar results are seen with an elevated level of homocysteine (Hcy), known as hyperhomocysteinemia (HHcy), which increases vascular thickness, elastin fragmentation, and arterial blood pressure. Studies from our laboratory have demonstrated a decrease in elasticity and an increase in pulse wave velocity in HHcy cystathionine β synthase heterozygote knockout (CBS−/+) mice. Nitric oxide (NO) is a potential regulator of matrix metalloproteinase (MMP) activity in MMP-NO-TIMP (tissue inhibitor of metalloproteinase) inhibitory tertiary complex. We have demonstrated the contribustion of the NO synthase (NOS) isoforms, endothelial NOS and inducible NOS, in the activation of latent MMP. The differential production of NO contributes to oxidative stress and increased oxidative/nitrative activation of MMP resulting in vascular remodeling in response to HHcy. The contribution of the NOS isoforms, endothelial and inducible in the collagen/elastin switch, has been demonstrated. We have showed that an increase in inducible NOS activity is a key contributor to HHcy-mediated collagen/elastin switch and resulting decline in aortic compliance. In addition, increased levels of Hcy compete and suppress the γ-amino butyric acid-receptor, N-methyl-d-aspartame-receptor, and peroxisome proliferator-activated receptor. The HHcy causes oxidative stress by generating nitrotyrosine, activating the latent MMPs and decreasing the endothelial NO concentration. The HHcy causes elastinolysis and decrease elastic complicance of the vessel wall. The treatment with γ-amino butyric acid-receptor agonist (muscimol), N

  1. The role of microRNAs in arterial remodelling.

    PubMed

    Nazari-Jahantigh, M; Wei, Y; Schober, A

    2012-04-01

    Adaptive alterations of the vessel wall architecture, called vascular remodelling, can be found in arterial hypertension, during the formation of aneurysms, in restenosis after vascular interventions, and in atherosclerosis. MicroRNAs (miR) critically affect the main cellular players in arterial remodelling and may either promote or inhibit the structural changes in the vessel wall. They regulate the phenotype of smooth muscle cells (SMCs) and control the inflammatory response in endothelial cells and macrophages. In SMCs, different sets of miRs induce either a synthetic or contractile phenotype, respectively. The conversion into a synthetic SMC phenotype is a crucial event in arterial remodelling. Therefore, reprogramming of the SMC phenotype by miR targeting can modulate the remodelling process. Furthermore, the effects of stimuli that induce remodelling, such as shear stress, angiotensin II, oxidised low-density lipoprotein, or apoptosis, on endothelial cells are mediated by miRs. The endothelial cell-specific miR-126, for example, is transferred in microvesicles from apoptotic endothelial cells and plays a protective role in atherogenesis. The inflammatory response of the innate immune system, especially through macrophages, promotes arterial remodelling. miR-155 induces the expression of inflammatory cytokines, whereas miR-146a and miR-147 are involved in the resolution phase of inflammation. However, in vivo data on the role of miRs in vascular remodelling are still scarce, which are required to test the therapeutic potential of the available, highly effective miR inhibitors. PMID:22371089

  2. Klotho and phosphate are modulators of pathologic uremic cardiac remodeling.

    PubMed

    Hu, Ming Chang; 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; Moe, Orson W

    2015-06-01

    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

  3. Ab initio nuclear structure theory

    NASA Astrophysics Data System (ADS)

    Negoita, Gianina Alina

    Ab initio no core methods have become major tools for understanding the properties of light nuclei based on realistic nucleon-nucleon (NN) and three-nucleon (NNN) interactions. A brief description is provided for the inter-nucleon interactions that fit two-body scattering and bound state data, as well as NNN interactions. Major new progress, including the goal of applying these interactions to solve for properties of nuclei, is limited by convergence issues. That is, with the goal of obtaining high precision solutions of the nuclear many-body Hamiltonian with no core methods (all nucleons treated on the same footing), one needs to proceed to very large basis spaces to achieve a convergence pattern suitable for extrapolation to the exact result. This thesis investigates (1) the similarity renormalization group (SRG) approach to soften the interaction, while preserving its phase shift properties, and (2) adoption of a realistic basis space using Woods-Saxon (WS) single-particle wavefunctions. Both have their advantages and limitations, discussed here. For (1), SRG was demonstrated by applying it to a realistic NN interaction, JISP16, in a harmonic oscillator (HO) representation. The degree of interaction softening achieved through a regulator parameter is examined. For (2), new results are obtained with the realistic JISP16 NN interaction in ab initio calculations of light nuclei 4He, 6He and 12C, using a WS basis optimized to minimize the ground-state energy within the truncated no core shell model. These are numerically-intensive many-body calculations. Finally, to gain insight into the potential for no core investigations of heavier nuclei, an initial investigation was obtained for the odd mass A = 47 - 49 region nuclei straddling 48Ca. The motivation for selecting these nuclei stems from the aim of preparing for nuclear double beta-decay studies of 48Ca. In these heavier systems, phenomenological additions to the realistic NN interaction determined by previous

  4. Ab initio phonon limited transport

    NASA Astrophysics Data System (ADS)

    Verstraete, Matthieu

    We revisit the thermoelectric (TE) transport properties of two champion materials, PbTe and SnSe, using fully first principles methods. In both cases the performance of the material is due to subtle combinations of structural effects, scattering, and phase space reduction. In PbTe anharmonic effects are completely opposite to the predicted quasiharmonic evolution of phonon frequencies and to frequently (and incorrectly) cited extrapolations of experiments. This stabilizes the material at high T, but also tends to enhance its thermal conductivity, in a non linear manner, above 600 Kelvin. This explains why PbTe is in practice limited to room temperature applications. SnSe has recently been shown to be the most efficient TE material in bulk form. This is mainly due to a strongly enhanced carrier concentration and electrical conductivity, after going through a phase transition from 600 to 800 K. We calculate the transport coefficients as well as the defect concentrations ab initio, showing excellent agreement with experiment, and elucidating the origin of the double phase transition as well as the new charge carriers. AH Romero, EKU Gross, MJ Verstraete, and O Hellman PRB 91, 214310 (2015) O. Hellman, IA Abrikosov, and SI Simak, PRB 84 180301 (2011)

  5. A spinor boson AB chain

    NASA Astrophysics Data System (ADS)

    Cruz Reyes, Greis Julieth; Franco, Roberto; Silva Valencia, Jereson; Universidad Santo Tomas Collaboration; Universidad Nacional de Colombia Collaboration

    Recent research is focused on superlattices arising from optical lattices, which allow a tunable environment. Experimentally bosons present transitions from superfluid to Mott insulator by changing the energy offset in the unit cell [Nat. Commun. 5:5735 (2014)]. Many studies displayed that ground state of spinless boson systems on superlattices present superfluid, Mott insulator and an additional CDW phase created by the energy shift between the sites into the unit cell [Phys. Rev. A 83, 053621 (2011)]. The first confinement methods were magnetic traps, which freezes the spin; with optical lattices the grade of freedom of spin plays an important role. We consider bosons with spin S =1 on a superlattice made by two sites with energy offset per unit cell (AB chain). The Hamiltonian that describes the system is the Bose-Hubbard model with the superlattice potential (W) and the exchange interaction (V) parameters. This model supports CDW, Mott insulator and superfluid phases. For W near to U, with V =0, Mott phase disappears, but for V increasing, a new CDW appears due to the spin interaction, while the half-integer CDW decrease. These results are widely different from spinless boson, where the CDW phases are stables.

  6. Ab inito investigation of hydrodesulferization

    SciTech Connect

    Tilson, J.L.; Marshall, C.L.; Brenner, J.R.

    1997-12-31

    We utilize MPP and vector computers to model the interaction of large sulfur-containing species bonded with hydrodesulfurization (HDS) catalysts. This work is made possible by the availability large aggregate memory, parallel computers. The ability of modern non-traditional computers to solve large-scale scientific problems has been demonstrated. This success is accomplished, in part, by access to portable low- and user-level software tools which exhibit good control over NUMA. ab initio SCF methods are used to characterize the energies of adsorption of poly-aromatic, sulfur-containing hydrocarbons onto a series of molecular-based models of MoS2. These hydrocarbon include thiophene (TP), benzothiophene (BT) and dibenzothiophene (DBT) which are representative of heavy crude feedstocks. Our work attempts to ascertain if a consistent model of adsorption onto a MoS2 surface exists and to determine how the electronic and steric configuration of each species affect their energies of interaction with the metal surface.

  7. GINGA Observations of AB Doradus

    NASA Astrophysics Data System (ADS)

    Vilhu, O.; Tsuru, T.; Collier Cameron, A.

    We report GINGA observations of the pre main sequence star AB Doradus (HD 36705), performed during 8 - 12 January, 1990. Some rotational modulation might be present. four X-ray flares were detected. Three of these events were similar to the EINSTEIN HRI-flare (Vilhu and Linsky, 1987), with decay times around 25 min. The last flare had long rise and decay times (100 min), resembling the EXOSAT flares observed by Collier Cameron et.al. (1988). The mean flare spectrum can be fitted by a thermal bremstrahlung with temperature 5.0 keV, or by a power-law model with photon index 2.2. The 3 upper limit of the Iron line equivalent width in the flare spectrum is 1 keV, weaker than predicted by thermal models. This Iron line anomaly was first discussed in the case of UX Ari by Tsuru et. al. (1989). However, normal equivalent widths can be derived from several EXOSAT spectra of active cool stars (Pallavicini and Tagliaferri, 1990). We discuss the possibility that the continuum from non-thermal electrons (producing also the microwave emission) could occasionally lower the apparent equivalent width. The mechanism works for reasonably low magnetic field strengths and electon power-law indexes. However, a large population of non-thermal electrons is needed (comparable to the thermal one). Stronger magnetic fields could explain the radio emission with less electrons, but then the non-thermal X-ray continuum remains small.

  8. The B AB AR detector

    NASA Astrophysics Data System (ADS)

    Aubert, B.; Bazan, A.; Boucham, A.; Boutigny, D.; De Bonis, I.; Favier, J.; Gaillard, J.-M.; Jeremie, A.; Karyotakis, Y.; Le Flour, T.; Lees, J. P.; Lieunard, S.; Petitpas, P.; Robbe, P.; Tisserand, V.; Zachariadou, K.; Palano, A.; Chen, G. P.; Chen, J. C.; Qi, N. D.; Rong, G.; Wang, P.; Zhu, Y. S.; Eigen, G.; Reinertsen, P. L.; Stugu, B.; Abbott, B.; Abrams, G. S.; Amerman, L.; Borgland, A. W.; Breon, A. B.; Brown, D. N.; Button-Shafer, J.; Clark, A. R.; Dardin, S.; Day, C.; Dow, S. F.; Fan, Q.; Gaponenko, I.; Gill, M. S.; Goozen, F. R.; Gowdy, S. J.; Gritsan, A.; Groysman, Y.; Hernikl, C.; Jacobsen, R. G.; Jared, R. C.; Kadel, R. W.; Kadyk, J.; Karcher, A.; Kerth, L. T.; Kipnis, I.; Kluth, S.; Kral, J. F.; Lafever, R.; LeClerc, C.; Levi, M. E.; Lewis, S. A.; Lionberger, C.; Liu, T.; Long, M.; Luo, L.; Lynch, G.; Luft, P.; Mandelli, E.; Marino, M.; Marks, K.; Matuk, C.; Meyer, A. B.; Minor, R.; Mokhtarani, A.; Momayezi, M.; Nyman, M.; Oddone, P. J.; Ohnemus, J.; Oshatz, D.; Patton, S.; Pedrali-Noy, M.; Perazzo, A.; Peters, C.; Pope, W.; Pripstein, M.; Quarrie, D. R.; Rasson, J. E.; Roe, N. A.; Romosan, A.; Ronan, M. T.; Shelkov, V. G.; Stone, R.; Strother, P. D.; Telnov, A. V.; von der Lippe, H.; Weber, T. F.; Wenzel, W. A.; Zizka, G.; Bright-Thomas, P. G.; Hawkes, C. M.; Kirk, A.; Knowles, D. J.; O'Neale, S. W.; Watson, A. T.; Watson, N. K.; Deppermann, T.; Koch, H.; Krug, J.; Kunze, M.; Lewandowski, B.; Peters, K.; Schmuecker, H.; Steinke, M.; Andress, J. C.; Barlow, N. R.; Bhimji, W.; Chevalier, N.; Clark, P. J.; Cottingham, W. N.; De Groot, N.; Dyce, N.; Foster, B.; Mass, A.; McFall, J. D.; Wallom, D.; Wilson, F. F.; Abe, K.; Hearty, C.; McKenna, J. A.; Thiessen, D.; Camanzi, B.; Harrison, T. J.; McKemey, A. K.; Tinslay, J.; Antohin, E. I.; Blinov, V. E.; Bukin, A. D.; Bukin, D. A.; Buzykaev, A. R.; Dubrovin, M. S.; Golubev, V. B.; Ivanchenko, V. N.; Kolachev, G. M.; Korol, A. A.; Kravchenko, E. A.; Mikhailov, S. F.; Onuchin, A. P.; Salnikov, A. A.; Serednyakov, S. I.; Skovpen, Yu. I.; Telnov, V. I.; Yushkov, A. N.; Booth, J.; Lankford, A. J.; Mandelkern, M.; Pier, S.; Stoker, D. P.; Zioulas, G.; Ahsan, A.; Arisaka, K.; Buchanan, C.; Chun, S.; Faccini, R.; MacFarlane, D. B.; Prell, S. A.; Rahatlou, Sh.; Raven, G.; Sharma, V.; Burke, S.; Callahan, D.; Campagnari, C.; Dahmes, B.; Hale, D.; Hart, P. A.; Kuznetsova, N.; Kyre, S.; Levy, S. L.; Long, O.; Lu, A.; May, J.; Richman, J. D.; Verkerke, W.; Witherell, M.; Yellin, S.; Beringer, J.; DeWitt, J.; Dorfan, D. E.; Eisner, A. M.; Frey, A.; Grillo, A. A.; Grothe, M.; Heusch, C. A.; Johnson, R. P.; Kroeger, W.; Lockman, W. S.; Pulliam, T.; Rowe, W.; Sadrozinski, H.; Schalk, T.; Schmitz, R. E.; Schumm, B. A.; Seiden, A.; Spencer, E. N.; Turri, M.; Walkowiak, W.; Wilder, M.; Williams, D. C.; Chen, E.; Dubois-Felsmann, G. P.; Dvoretskii, A.; Hanson, J. E.; Hitlin, D. G.; Kolomensky, Yu. G.; Metzler, S.; Oyang, J.; Porter, F. C.; Ryd, A.; Samuel, A.; Weaver, M.; Yang, S.; Zhu, R. Y.; Devmal, S.; Geld, T. L.; Jayatilleke, S.; Jayatilleke, S. M.; Mancinelli, G.; Meadows, B. T.; Sokoloff, M. D.; Bloom, P.; Broomer, B.; Erdos, E.; Fahey, S.; Ford, W. T.; Gaede, F.; van Hoek, W. C.; Johnson, D. R.; Michael, A. K.; Nauenberg, U.; Olivas, A.; Park, H.; Rankin, P.; Roy, J.; Sen, S.; Smith, J. G.; Wagner, D. L.; Blouw, J.; Harton, J. L.; Krishnamurthy, M.; Soffer, A.; Toki, W. H.; Warner, D. W.; Wilson, R. J.; Zhang, J.; Brandt, T.; Brose, J.; Dahlinger, G.; Dickopp, M.; Dubitzky, R. S.; Eckstein, P.; Futterschneider, H.; Kocian, M. L.; Krause, R.; Müller-Pfefferkorn, R.; Schubert, K. R.; Schwierz, R.; Spaan, B.; Wilden, L.; Behr, L.; Bernard, D.; Bonneaud, G. R.; Brochard, F.; Cohen-Tanugi, J.; Ferrag, S.; Fouque, G.; Gastaldi, F.; Matricon, P.; Mora de Freitas, P.; Renard, C.; Roussot, E.; T'Jampens, S.; Thiebaux, C.; Vasileiadis, G.; Verderi, M.; Anjomshoaa, A.; Bernet, R.; Di Lodovico, F.; Muheim, F.; Playfer, S.; Swain, J. E.; Falbo, M.; Bozzi, C.; Dittongo, S.; Folegani, M.; Piemontese, L.; Ramusino, A. C.; Treadwell, E.; Anulli, F.; Baldini-Ferroli, R.; Calcaterra, A.; de Sangro, R.; Falciai, D.; Finocchiaro, G.; Patteri, P.; Peruzzi, I. M.; Piccolo, M.; Xie, Y.; Zallo, A.; Bagnasco, S.; Buzzo, A.; Contri, R.; Crosetti, G.; Fabbricatore, P.; Farinon, S.; Lo Vetere, M.; Macri, M.; Minutoli, S.; Monge, M. R.; Musenich, R.; Pallavicini, M.; Parodi, R.; Passaggio, S.; Pastore, F. C.; Patrignani, C.; Pia, M. G.; Priano, C.; Robutti, E.; Santroni, A.; Bartoldus, R.; Dignan, T.; Hamilton, R.; Mallik, U.; Cochran, J.; Crawley, H. B.; Fischer, P. A.; Lamsa, J.; McKay, R.; Meyer, W. T.; Rosenberg, E. I.; Albert, J. N.; Beigbeder, C.; Benkebil, M.; Breton, D.; Cizeron, R.; Du, S.; Grosdidier, G.; Hast, C.; Höcker, A.; Lacker, H. M.; LePeltier, V.; Lutz, A. M.

    2002-02-01

    B AB AR, the detector for the SLAC PEP-II asymmetric e +e - B Factory operating at the ϒ(4 S) resonance, was designed to allow comprehensive studies of CP-violation in B-meson decays. Charged particle tracks are measured in a multi-layer silicon vertex tracker surrounded by a cylindrical wire drift chamber. Electromagnetic showers from electrons and photons are detected in an array of CsI crystals located just inside the solenoidal coil of a superconducting magnet. Muons and neutral hadrons are identified by arrays of resistive plate chambers inserted into gaps in the steel flux return of the magnet. Charged hadrons are identified by d E/d x measurements in the tracking detectors and by a ring-imaging Cherenkov detector surrounding the drift chamber. The trigger, data acquisition and data-monitoring systems, VME- and network-based, are controlled by custom-designed online software. Details of the layout and performance of the detector components and their associated electronics and software are presented.

  9. Myocardial reverse remodeling: how far can we rewind?

    PubMed

    Rodrigues, Patrícia G; Leite-Moreira, Adelino F; Falcão-Pires, Inês

    2016-06-01

    Heart failure (HF) is a systemic disease that can be divided into HF with reduced ejection fraction (HFrEF) and with preserved ejection fraction (HFpEF). HFpEF accounts for over 50% of all HF patients and is typically associated with high prevalence of several comorbidities, including hypertension, diabetes mellitus, pulmonary hypertension, obesity, and atrial fibrillation. Myocardial remodeling occurs both in HFrEF and HFpEF and it involves changes in cardiac structure, myocardial composition, and myocyte deformation and multiple biochemical and molecular alterations that impact heart function and its reserve capacity. Understanding the features of myocardial remodeling has become a major objective for limiting or reversing its progression, the latter known as reverse remodeling (RR). Research on HFrEF RR process is broader and has delivered effective therapeutic strategies, which have been employed for some decades. However, the RR process in HFpEF is less clear partly due to the lack of information on HFpEF pathophysiology and to the long list of failed standard HF therapeutics strategies in these patient's outcomes. Nevertheless, new proteins, protein-protein interactions, and signaling pathways are being explored as potential new targets for HFpEF remodeling and RR. Here, we review recent translational and clinical research in HFpEF myocardial remodeling to provide an overview on the most important features of RR, comparing HFpEF with HFrEF conditions. PMID:26993225

  10. Myocardial Remodeling: Cellular and Extracellular Events and Targets

    PubMed Central

    Dixon, Jennifer A.; Spinale, Francis G.

    2011-01-01

    The focus of this review is on translational studies utilizing large-animal models and clinical studies that provide fundamental insight into cellular and extracellular pathways contributing to post–myocardial infarction (MI) left ventricle (LV) remodeling. Specifically, both large-animal and clinical studies have examined the potential role of endogenous and exogenous stem cells to alter the course of LV remodeling. Interestingly, there have been alterations in LV remodeling with stem cell treatment despite a lack of long-term cell engraftment. The translation of the full potential of stem cell treatments to clinical studies has yet to be realized. The modulation of proteolytic pathways that contribute to the post-MI remodeling process has also been examined. On the basis of recent large-animal studies, there appears to be a relationship between stem cell treatment post-MI and the modification of proteolytic pathways, generating the hypothesis that stem cells leave an echo effect that moderates LV remodeling. PMID:21314431

  11. 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

  12. Hydrogen sulfide depletion contributes to microvascular remodeling in obesity.

    PubMed

    Candela, Joseph; Velmurugan, Gopal V; White, Carl

    2016-05-01

    Structural remodeling of the microvasculature occurs during obesity. Based on observations that impaired H2S signaling is associated with cardiovascular pathologies, the current study was designed to test the hypothesis that altered H2S homeostasis is involved in driving the remodeling process in a diet-induced mouse model of obesity. The structural and passive mechanical properties of mesenteric resistance arterioles isolated from 30-wk-old lean and obese mice were assessed using pressure myography, and vessel H2S levels were quantified using the H2S indicator sulfidefluor 7-AM. Remodeling gene expression was assessed using quantitative RT-PCR, and histological staining was used to quantify vessel collagen and elastin. Obesity was found to be associated with decreased vessel H2S concentration, inward hypertrophic remodeling, altered collagen-to-elastin ratio, and reduced vessel stiffness. In addition, mRNA levels of fibronectin, collagen types I and III, matrix metalloproteinases 2 and 9, and tissue inhibitor of metalloproteinase 1 were increased and elastin was decreased by obesity. Evidence that decreased H2S was responsible for the genetic changes was provided by experiments in which H2S levels were manipulated, either by inhibition of the H2S-generating enzyme cystathionine γ-lyase with dl-propargylglycine or by incubation with the H2S donor GYY4137. These data suggest that, during obesity, depletion of H2S is involved in orchestrating the genetic changes underpinning inward hypertrophic remodeling in the microvasculature. PMID:26993223

  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. PMID:26923825

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

    PubMed Central

    López, Alberto J.; Wood, Marcelo A.

    2015-01-01

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

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

    PubMed

    López, Alberto J; Wood, Marcelo A

    2015-01-01

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

  16. Unremodeled and remodeled cardiolipin are functionally indistinguishable in yeast.

    PubMed

    Baile, Matthew G; Sathappa, Murugappan; Lu, Ya-Wen; Pryce, Erin; Whited, Kevin; McCaffery, J Michael; Han, Xianlin; Alder, Nathan N; Claypool, Steven M

    2014-01-17

    After biosynthesis, an evolutionarily conserved acyl chain remodeling process generates a final highly homogeneous and yet tissue-specific molecular form of the mitochondrial lipid cardiolipin. Hence, cardiolipin molecules in different organisms, and even different tissues within the same organism, contain a distinct collection of attached acyl chains. This observation is the basis for the widely accepted paradigm that the acyl chain composition of cardiolipin is matched to the unique mitochondrial demands of a tissue. For this hypothesis to be correct, cardiolipin molecules with different acyl chain compositions should have distinct functional capacities, and cardiolipin that has been remodeled should promote cardiolipin-dependent mitochondrial processes better than its unremodeled form. However, functional disparities between different molecular forms of cardiolipin have never been established. Here, we interrogate this simple but crucial prediction utilizing the best available model to do so, Saccharomyces cerevisiae. Specifically, we compare the ability of unremodeled and remodeled cardiolipin, which differ markedly in their acyl chain composition, to support mitochondrial activities known to require cardiolipin. Surprisingly, defined changes in the acyl chain composition of cardiolipin do not alter either mitochondrial morphology or oxidative phosphorylation. Importantly, preventing cardiolipin remodeling initiation in yeast lacking TAZ1, an ortholog of the causative gene in Barth syndrome, ameliorates mitochondrial dysfunction. Thus, our data do not support the prevailing hypothesis that unremodeled cardiolipin is functionally distinct from remodeled cardiolipin, at least for the functions examined, suggesting alternative physiological roles for this conserved pathway. PMID:24285538

  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. Collective rotation from ab initio theory

    NASA Astrophysics Data System (ADS)

    Caprio, M. A.; Maris, P.; Vary, J. P.; Smith, R.

    2015-08-01

    Through ab initio approaches in nuclear theory, we may now seek to quantitatively understand the wealth of nuclear collective phenomena starting from the underlying internucleon interactions. No-core configuration interaction (NCCI) calculations for p-shell nuclei give rise to rotational bands, as evidenced by rotational patterns for excitation energies, electromagnetic moments and electromagnetic transitions. In this review, NCCI calculations of 7-9Be are used to illustrate and explore ab initio rotational structure, and the resulting predictions for rotational band properties are compared with experiment. We highlight the robustness of ab initio rotational predictions across different choices for the internucleon interaction.

  19. SU-D-9A-06: 3D Localization of Neurovascular Bundles Through MR-TRUS Registration in Prostate Radiotherapy

    SciTech Connect

    Yang, X; Rossi, P; Ogunleye, T; Jani, A; Curran, W; Liu, T

    2014-06-01

    Purpose: Erectile dysfunction (ED) is the most common complication of prostate-cancer radiotherapy (RT) and the major mechanism is radiation-induced neurovascular bundle (NVB) damage. However, the localization of the NVB remains challenging. This study's purpose is to accurately localize 3D NVB by integrating MR and transrectal ultrasound (TRUS) images through MR-TRUS fusion. Methods: T1 and T2-weighted MR prostate images were acquired using a Philips 1.5T MR scanner and a pelvic phase-array coil. The 3D TRUS images were captured with a clinical scanner and a 7.5 MHz biplane probe. The TRUS probe was attached to a stepper; the B-mode images were captured from the prostate base to apex at a 1-mm step and the Doppler images were acquired in a 5-mm step. The registration method modeled the prostate tissue as an elastic material, and jointly estimated the boundary condition (surface deformation) and the volumetric deformations under elastic constraint. This technique was validated with a clinical study of 7 patients undergoing RT treatment for prostate cancer. The accuracy of our approach was assessed through the locations of landmarks, as well as previous ultrasound Doppler images of patients. Results: MR-TRUS registration was successfully performed for all patients. The mean displacement of the landmarks between the post-registration MR and TRUS images was 1.37±0.42 mm, which demonstrated the precision of the registration based on the biomechanical model; and the NVB volume Dice Overlap Coefficient was 92.1±3.2%, which demonstrated the accuracy of the NVB localization. Conclusion: We have developed a novel approach to improve 3D NVB localization through MR-TRUS fusion for prostate RT, demonstrated its clinical feasibility, and validated its accuracy with ultrasound Doppler data. This technique could be a useful tool as we try to spare the NVB in prostate RT, monitor NBV response to RT, and potentially improve post-RT potency outcomes.

  20. Demonstration of Brain Tumor-Induced Neurovascular Uncoupling in Resting-State fMRI at Ultrahigh Field.

    PubMed

    Agarwal, Shruti; Sair, Haris I; Airan, Raag; Hua, Jun; Jones, Craig K; Heo, Hye-Young; Olivi, Alessandro; Lindquist, Martin A; Pekar, James J; Pillai, Jay J

    2016-05-01

    To demonstrate in a small case series for the first time the phenomenon of brain tumor-related neurovascular uncoupling (NVU) in resting-state blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) at ultrahigh field (7T). Two de novo (i.e., untreated) brain tumor patients underwent both BOLD resting-state fMRI (rsfMRI) on a 7T MRI system and motor task-based BOLD fMRI at 3T. Ipsilesional (i.e., ipsilateral to tumor or IL) and contralesional (i.e., contralateral to tumor or CL) region of interest (ROI) analysis was performed on both 3T motor task-related general linear model-derived activation maps and on 7T rsfMRI independent component analysis (ICA)-derived sensorimotor network maps for each case. Asymmetry scores (ASs) were computed based on numbers of suprathreshold voxels in the IL and CL ROIs. In each patient, ASs derived from ROI analysis of suprathreshold voxels in IL and CL ROIs in task-related activation maps and rsfMRI ICA-derived sensorimotor component maps indicate greater number of suprathreshold voxels in contralesional than ipsilesional sensorimotor cortex in both maps. In patient 1, an AS of 0.2 was obtained from the suprathreshold Z-score spectrum (voxels with Z-scores >5.0) of the task-based activation map and AS of 1.0 was obtained from the suprathreshold Z-score spectrum (Z-scores >5.0) of the ICA-derived sensorimotor component map. Similarly, in patient 2, an AS of 1.0 was obtained from the suprathreshold Z-score spectrum (Z-scores >5.0) of the task-based activation map and an AS of 1.0 was obtained from the suprathreshold Z-score spectrum (Z-scores >5.0) of the ICA-derived sensorimotor component map. Overall, decreased BOLD signal was noted in IL compared with CL ROIs on both task-based activation maps and ultrahigh field resting-state maps, indicating the presence of NVU. We have demonstrated evidence of NVU on ultrahigh field 7T rsfMRI comparable with the findings on standard 3T motor task-based fMRI in both cases

  1. Dexamethasone Rescues Neurovascular Unit Integrity from Cell Damage Caused by Systemic Administration of Shiga Toxin 2 and Lipopolysaccharide in Mice Motor Cortex

    PubMed Central

    Pinto, Alipio; Jacobsen, Mariana; Geoghegan, Patricia A.; Cangelosi, Adriana; Cejudo, María Laura; Tironi-Farinati, Carla; Goldstein, Jorge

    2013-01-01

    Shiga toxin 2 (Stx2)-producing Escherichia coli (STEC) causes hemorrhagic colitis and hemolytic uremic syndrome (HUS) that can lead to fatal encephalopathies. Neurological abnormalities may occur before or after the onset of systemic pathological symptoms and motor disorders are frequently observed in affected patients and in studies with animal models. As Stx2 succeeds in crossing the blood-brain barrier (BBB) and invading the brain parenchyma, it is highly probable that the observed neurological alterations are based on the possibility that the toxin may trigger the impairment of the neurovascular unit and/or cell damage in the parenchyma. Also, lipopolysaccharide (LPS) produced and secreted by enterohemorrhagic Escherichia coli (EHEC) may aggravate the deleterious effects of Stx2 in the brain. Therefore, this study aimed to determine (i) whether Stx2 affects the neurovascular unit and parenchymal cells, (ii) whether the contribution of LPS aggravates these effects, and (iii) whether an inflammatory event underlies the pathophysiological mechanisms that lead to the observed injury. The administration of a sub-lethal dose of Stx2 was employed to study in detail the motor cortex obtained from a translational murine model of encephalopathy. In the present paper we report that Stx2 damaged microvasculature, caused astrocyte reaction and neuronal degeneration, and that this was aggravated by LPS. Dexamethasone, an anti-inflammatory, reversed the pathologic effects and proved to be an important drug in the treatment of acute encephalopathies. PMID:23894578

  2. P2RX7 sensitizes Mac-1/ICAM-1-dependent leukocyte-endothelial adhesion and promotes neurovascular injury during septic encephalopathy

    PubMed Central

    Wang, Huan; Hong, Ling-Juan; Huang, Ji-Yun; Jiang, Quan; Tao, Rong-Rong; Tan, Chao; Lu, Nan-Nan; Wang, Cheng-Kun; Ahmed, Muhammad M; Lu, Ying-Mei; Liu, Zhi-Rong; Shi, Wei-Xing; Lai, En-Yin; Wilcox, Christopher S; Han, Feng

    2015-01-01

    Septic encephalopathy (SE) is a critical factor determining sepsis mortality. Vascular inflammation is known to be involved in SE, but the molecular events that lead to the development of encephalopathy remain unclear. Using time-lapse in vivo two-photon laser scanning microscopy, we provide the first direct evidence that cecal ligation and puncture in septic mice induces microglial trafficking to sites adjacent to leukocyte adhesion on inflamed cerebral microvessels. Our data further demonstrate that septic injury increased the chemokine CXCL1 level in brain endothelial cells by activating endothelial P2RX7 and eventually enhanced the binding of Mac-1 (CD11b/CD18)-expressing leukocytes to endothelial ICAM-1. In turn, leukocyte adhesion upregulated endothelial CX3CL1, thereby triggering microglia trafficking to the injured site. The sepsis-induced increase in endothelial CX3CL1 was abolished in CD18 hypomorphic mutant mice. Inhibition of the P2RX7 pathway not only decreased endothelial ICAM-1 expression and leukocyte adhesion but also prevented microglia overactivation, reduced brain injury, and consequently doubled the early survival of septic mice. These results demonstrate the role of the P2RX7 pathway in linking neurovascular inflammation to brain damage in vivo and provide a rationale for targeting endothelial P2RX7 for neurovascular protection during SE. PMID:25998681

  3. Assessment of neurovascular dynamics during transient ischemic attack by the novel integration of micro-electrocorticography electrode array with functional photoacoustic microscopy.

    PubMed

    Liu, Yu-Hang; Liao, Lun-De; Tan, Stacey Sze Hui; Kwon, Ki Yong; Ling, Ji Min; Bandla, Aishwarya; Shih, Yen-Yu Ian; Tan, Eddie Tung Wee; Li, Wen; Ng, Wai Hoe; Lai, Hsin-Yi; Chen, You-Yin; Thakor, Nitish V

    2015-10-01

    This study developed a novel system combining a 16-channel micro-electrocorticography (μECoG) electrode array and functional photoacoustic microscopy (fPAM) to examine changes in neurovascular functions following transient ischemic attack (TIA) in rats. To mimic the pathophysiology of TIA, a modified photothrombotic ischemic model was developed by using 3 min illumination of 5 mW continuous-wave (CW) green laser light focusing on a distal branch of the middle cerebral artery (MCA). Cerebral blood volume (CBV), hemoglobin oxygen saturation (SO2), somatosensory evoked potentials (SSEPs) and alpha-to-delta ratio (ADR) were measured pre- and post-ischemia over a focal cortical region (i.e., 1.5×1.5 mm(2)). Unexpectedly, the SO2, peak-to-peak amplitude (PPA) of SSEPs and ADR recovered and achieved levels greater than the baseline values at the 4th hour post-ischemia induction without any intervention, whereas the CBV value only partially recovered. In other words, transient ischemia led to increased neural activity when the relative CBV was reduced, which may further compromise neural integrity or lead to subsequent vascular disease. This novel μECoG-fPAM system complements currently available imaging techniques and represents a promising technology for studying neurovascular coupling in animal models. PMID:26149348

  4. P2RX7 sensitizes Mac-1/ICAM-1-dependent leukocyte-endothelial adhesion and promotes neurovascular injury during septic encephalopathy.

    PubMed

    Wang, Huan; Hong, Ling-Juan; Huang, Ji-Yun; Jiang, Quan; Tao, Rong-Rong; Tan, Chao; Lu, Nan-Nan; Wang, Cheng-Kun; Ahmed, Muhammad M; Lu, Ying-Mei; Liu, Zhi-Rong; Shi, Wei-Xing; Lai, En-Yin; Wilcox, Christopher S; Han, Feng

    2015-06-01

    Septic encephalopathy (SE) is a critical factor determining sepsis mortality. Vascular inflammation is known to be involved in SE, but the molecular events that lead to the development of encephalopathy remain unclear. Using time-lapse in vivo two-photon laser scanning microscopy, we provide the first direct evidence that cecal ligation and puncture in septic mice induces microglial trafficking to sites adjacent to leukocyte adhesion on inflamed cerebral microvessels. Our data further demonstrate that septic injury increased the chemokine CXCL1 level in brain endothelial cells by activating endothelial P2RX7 and eventually enhanced the binding of Mac-1 (CD11b/CD18)-expressing leukocytes to endothelial ICAM-1. In turn, leukocyte adhesion upregulated endothelial CX3CL1, thereby triggering microglia trafficking to the injured site. The sepsis-induced increase in endothelial CX3CL1 was abolished in CD18 hypomorphic mutant mice. Inhibition of the P2RX7 pathway not only decreased endothelial ICAM-1 expression and leukocyte adhesion but also prevented microglia overactivation, reduced brain injury, and consequently doubled the early survival of septic mice. These results demonstrate the role of the P2RX7 pathway in linking neurovascular inflammation to brain damage in vivo and provide a rationale for targeting endothelial P2RX7 for neurovascular protection during SE. PMID:25998681

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

    PubMed Central

    Alford, Patrick W.; Taber, Larry A.

    2009-01-01

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

  6. ATP-dependent chromatin remodeling in T cells

    PubMed Central

    Wurster, Andrea L.; Pazin, Michael J.

    2012-01-01

    One of the best studied systems for mammalian chromatin remodeling is transcriptional regulation during T cell development. The variety of these studies have led to important findings in T cell gene regulation and cell fate determination. Importantly, these findings have also advanced our knowledge of the function of remodeling enzymes in mammalian gene regulation. In this review, first we briefly present biochemical/cell-free analysis of 3 types of ATP dependent remodeling enzymes (SWI/SNF, Mi2, and ISWI), to construct an intellectual framework to understand how these enzymes might be working. Second, we compare and contrast the function of these enzymes, during early (thymic) and late (peripheral) T cell development. Finally, we examine some of the gaps in our present understanding. PMID:21999456

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

    PubMed

    Saito, Mitsuru; Marumo, Keishi

    2016-01-01

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

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

    PubMed

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

    2012-11-01

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

  9. Subject-specific bone remodelling of the scapula.

    PubMed

    Quental, Carlos; Folgado, João; Fernandes, Paulo R; Monteiro, Jacinto

    2014-08-01

    Finite element analyses, with increasing levels of detail and complexity, are becoming effective tools to evaluate the performance of joint replacement prostheses and to predict the behaviour of bone. As a first step towards the study of the complications of shoulder arthroplasty, the aim of this work was the development and validation of a 3D finite element model of an intact scapula for the prediction of the bone remodelling process based on a previously published model that attempts to follow Wolff's law. The boundary conditions applied include full muscle and joint loads taken from a multibody system of the upper limb based on the same subject whose scapula was here analysed. To validate the bone remodelling simulations, qualitative and quantitative comparisons between the predicted and the specimen's bone density distribution were performed. The results showed that the bone remodelling model was able to successfully reproduce the actual bone density distribution of the analysed scapula. PMID:23210487

  10. Anisotropic stress orients remodelling of mammalian limb bud ectoderm.

    PubMed

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

    2015-05-01

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

  11. Anisotropic stress orients remodelling of mammalian limb bud ectoderm

    PubMed Central

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

    2016-01-01

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

  12. Physiological bases of bone regeneration II. The remodeling process.

    PubMed

    Fernández-Tresguerres-Hernández-Gil, Isabel; Alobera-Gracia, Miguel Angel; del-Canto-Pingarrón, Mariano; Blanco-Jerez, Luis

    2006-03-01

    Bone remodeling is the restructuring process of existing bone, which is in constant resorption and formation. Under normal conditions, this balanced process allows the renewal of 5-10% of bone volume per year. At the microscopic level, bone remodeling is produced in basic multicellular units, where osteoclasts resorb a certain quantity of bone and osteoblasts form the osteoid matrix and mineralize it to fill the previously created cavity. These units contain osteoclasts, macrophages, preosteoblasts and osteoblasts, and are controlled by a series of factors, both general and local, allowing normal bone function and maintaining the bone mass. When this process becomes unbalanced then bone pathology appears, either in excess (osteopetrosis) or deficit (osteoporosis). The purpose of this study is to undertake a revision of current knowledge on the physiological and biological mechanisms of the bone remodeling process; highlighting the role played by the regulating factors, in particular that of the growth factors. PMID:16505794

  13. 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

  14. 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.

  15. The Role of Reactive Oxygen Species in Microvascular Remodeling

    PubMed Central

    Staiculescu, Marius C.; Foote, Christopher; Meininger, Gerald A.; Martinez-Lemus, Luis A.

    2014-01-01

    The microcirculation is a portion of the vascular circulatory system that consists of resistance arteries, arterioles, capillaries and venules. It is the place where gases and nutrients are exchanged between blood and tissues. In addition the microcirculation is the major contributor to blood flow resistance and consequently to regulation of blood pressure. Therefore, structural remodeling of this section of the vascular tree has profound implications on cardiovascular pathophysiology. This review is focused on the role that reactive oxygen species (ROS) play on changing the structural characteristics of vessels within the microcirculation. Particular attention is given to the resistance arteries and the functional pathways that are affected by ROS in these vessels and subsequently induce vascular remodeling. The primary sources of ROS in the microcirculation are identified and the effects of ROS on other microcirculatory remodeling phenomena such as rarefaction and collateralization are briefly reviewed. PMID:25535075

  16. Remodelling the extracellular matrix in development and disease

    PubMed Central

    Bonnans, Caroline; Chou, Jonathan; Werb, Zena

    2015-01-01

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

  17. Myocardial repair/remodelling following infarction: roles of local factors

    PubMed Central

    Sun, Yao

    2009-01-01

    Heart failure is a global health problem, appearing most commonly in patients with previous myocardial infarction (MI). Cardiac remodelling, particularly fibrosis, seen in both the infarcted and non-infarcted myocardium is recognized to be a major determinant of the development of impaired ventricular function, leading to a poor prognosis. Elucidating cellular and molecular mechanisms responsible for the accumulation of extracellular matrix is essential for designing cardioprotective and reparative strategies that could regress fibrosis after infarction. Multiple factors contribute to left ventricular remodelling at different stages post-MI. This review will discuss the role of oxidative stress and locally produced angiotensin II in the pathogenesis of myocardial repair/remodelling after MI. PMID:19050008

  18. Uptake and remodeling of exogenous phosphatidylethanolamine in E. coli.

    PubMed

    Kol, Matthijs A; Kuster, Diederik W D; Boumann, Henry A; de Cock, Hans; Heck, Albert J R; de Kruijff, Ben; de Kroon, Anton I P M

    2004-03-22

    The fate of exogenous short-chain analogues of phosphatidylethanolamine and phosphatidylserine was studied in a deep-rough derivative of E. coli mutant strain AD93 that cannot synthesize phosphatidylethanolamine de novo. Using mass spectrometry, it was shown that dicaproyl(di 6:0)-phosphatidylethanolamine is extensively remodeled, eventually adopting the phosphatidylethanolamine species profile of the parental wild-type strain of AD93. Dicaproyl-phosphatidylserine was decarboxylated to form phosphatidylethanolamine, and yielded a species profile, which strongly resembled that of the introduced phosphatidylethanolamine. This demonstrates transport of phosphatidylserine to the cytosolic leaflet of the inner membrane. The changes of the species profile of phosphatidylethanolamine indicate that the short-chain phospholipids are most likely remodeled via two consecutive acyl chain substitutions, and at least part of this remodeling involves transport to the inner membrane. PMID:15164768

  19. Assessment of bone vascularization and its role in bone remodeling

    PubMed Central

    Lafage-Proust, Marie-Hélène; Roche, Bernard; Langer, Max; Cleret, Damien; Vanden Bossche, Arnaud; Olivier, Thomas; Vico, Laurence

    2015-01-01

    Bone is a composite organ that fulfils several interconnected functions, which may conflict with each other in pathological conditions. Bone vascularization is at the interface between these functions. The roles of bone vascularization are better documented in bone development, growth and modeling than in bone remodeling. However, every bone remodeling unit is associated with a capillary in both cortical and trabecular envelopes. Here we summarize the most recent data on vessel involvement in bone remodeling, and we present the characteristics of bone vascularization. Finally, we describe the various techniques used for bone vessel imaging and quantitative assessment, including histology, immunohistochemistry, microtomography and intravital microscopy. Studying the role of vascularization in adult bone should provide benefits for the understanding and treatment of metabolic bone diseases. PMID:25861447

  20. Ab Initio Study of Polonium

    SciTech Connect

    Zabidi, Noriza Ahmad; Kassim, Hasan Abu; Shrivastava, Keshav N.

    2008-05-20

    Polonium is the only element with a simple cubic (sc) crystal structure. Atoms in solid polonium sit at the corners of a simple cubic unit cell and no where else. Polonium has a valence electron configuration 6s{sup 2}6p{sup 4} (Z = 84). The low temperature {alpha}-phase transforms into the rhombohedral (trigonal) {beta} structure at {approx}348 K. The sc {alpha}-Po unit cell constant is a = 3.345 A. The beta form of polonium ({beta}-Po) has the lattice parameters, a{sub R} = 3.359 A and a rhombohedral angle 98 deg. 13'. We have performed an ab initio electronic structure calculation by using the density functional theory. We have performed the calculation with and without spin-orbit (SO) coupling by using both the LDA and the GGA for the exchange-correlations. The k-points in a simple cubic BZ are determined by R (0.5, 0.5, 0.5), {gamma} (0, 0, 0), X (0.5, 0, 0), M (0.5, 0.5, 0) and {gamma} (0, 0, 0). Other directions of k-points are {gamma} (0, 0, 0), X (0.5, 0, 0), R (0.5, 0.5, 0.5) and {gamma} (0, 0, 0). The SO splittings of p states at the {gamma} point in the GGA+SO scheme for {alpha}-Po are 0.04 eV and 0.02 eV while for the {beta}-Po these are 0.03 eV and 0.97 eV. We have also calculated the vibrational spectra for the unit cells in both the structures. We find that exchanging of a Po atom by Pb atom produces several more bands and destabilizes the {beta} phase.

  1. 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

  2. Efficient computational simulation of actin stress fiber remodeling.

    PubMed

    Ristori, T; Obbink-Huizer, C; Oomens, C W J; Baaijens, F P T; Loerakker, S

    2016-09-01

    Understanding collagen and stress fiber remodeling is essential for the development of engineered tissues with good functionality. These processes are complex, highly interrelated, and occur over different time scales. As a result, excessive computational costs are required to computationally predict the final organization of these fibers in response to dynamic mechanical conditions. In this study, an analytical approximation of a stress fiber remodeling evolution law was derived. A comparison of the developed technique with the direct numerical integration of the evolution law showed relatively small differences in results, and the proposed method is one to two orders of magnitude faster. PMID:26823159

  3. Structural remodeling of unweighted soleus myotendinous junction in monkey.

    PubMed

    Roffino, Sandrine; Carnino, Alain; Chopard, Angèle; Mutin, Murielle; Marini, Jean-François

    2006-03-01

    This study describes the morphology of the soleus myotendinous junction (MTJ) in the Rhesus monkey. Ultrastructural observations revealed a structural complexity that probably reflects functional adaptations. We also studied ultrastructural modifications of the MTJ in response to 14 days of hypokinesia and microgravity (Bion 11 mission). The reduced limb mobility of the animals, placed in a safety seat aboard the satellite, induced a sarcolemmal remodeling that was enhanced by the microgravity conditions. Signs of MTJ remodeling such as alterations of contractile apparatus and myofilament-anchoring structures, T-tubule dilation, and autophagic vacuoles could be ascribed to the microgravity. PMID:16545758

  4. 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

  5. Mechanisms of ATP-Dependent Chromatin Remodeling Motors.

    PubMed

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

    2016-07-01

    Chromatin remodeling motors play essential roles in all DNA-based processes. These motors catalyze diverse outcomes ranging from sliding the smallest units of chromatin, known as nucleosomes, to completely disassembling chromatin. The broad range of actions carried out by these motors on the complex template presented by chromatin raises many stimulating mechanistic questions. Other well-studied nucleic acid motors provide examples of the depth of mechanistic understanding that is achievable from detailed biophysical studies. We use these studies as a guiding framework to discuss the current state of knowledge of chromatin remodeling mechanisms and highlight exciting open questions that would continue to benefit from biophysical analyses. PMID:27391925

  6. Synaptic circuit remodelling by matrix metalloproteinases in health and disease

    PubMed Central

    Huntley, George W.

    2016-01-01

    Matrix metalloproteinases (MMPs) are extracellularly acting enzymes that have long been known to have deleterious roles in brain injury and disease. In particular, widespread and protracted MMP activity can contribute to neuronal loss and synaptic dysfunction. However, recent studies show that rapid and focal MMP-mediated proteolysis proactively drives synaptic structural and functional remodelling that is crucial for ongoing cognitive processes. Deficits in synaptic remodelling are associated with psychiatric and neurological disorders, and aberrant MMP expression or function may contribute to the molecular mechanisms underlying these deficits. This Review explores the paradigm shift in our understanding of the contribution of MMPs to normal and abnormal synaptic plasticity and function. PMID:23047773

  7. Mechanisms contributing to myocardial potassium channel diversity, regulation and remodeling.

    PubMed

    Yang, Kai-Chien; Nerbonne, Jeanne M

    2016-04-01

    In the mammalian heart, multiple types of K(+) channels contribute to the control of cardiac electrical and mechanical functioning through the regulation of resting membrane potentials, action potential waveforms and refractoriness. There are similarly vast arrays of K(+) channel pore-forming and accessory subunits that contribute to the generation of functional myocardial K(+) channel diversity. Maladaptive remodeling of K(+) channels associated with cardiac and systemic diseases results in impaired repolarization and increased propensity for arrhythmias. Here, we review the diverse transcriptional, post-transcriptional, post-translational, and epigenetic mechanisms contributing to regulating the expression, distribution, and remodeling of cardiac K(+) channels under physiological and pathological conditions. PMID:26391345

  8. [Bone quality and strength relating with bone remodeling].

    PubMed

    Mori, Satoshi

    2016-01-01

    The bone has the functions of mineral reservoir and mechanical support as skeleton. Bone remodeling is the adult mode of bone metabolism, replacing old bone tissue to new one. Bone strength is determined by bone volume, structure and quality such as micro damage, degree of mineralization and collagen cross linkage, which are all controlled by bone remodeling. Bone strength decreases under high turn-over condition by decreasing bone volume and deterioration of bone structure, which also decreases under low turn-over condition by increased micro damage, increasing mineralization and AGE collagen cross linkage. PMID:26728527

  9. Silent Synapse-Based Circuitry Remodeling in Drug Addiction.

    PubMed

    Dong, Yan

    2016-05-01

    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

  10. MRN1 Implicates Chromatin Remodeling Complexes and Architectural Factors in mRNA Maturation

    PubMed Central

    Düring, Louis; Thorsen, Michael; Petersen, Darima Sophia Njama; Køster, Brian; Jensen, Torben Heick; Holmberg, Steen

    2012-01-01

    A functional relationship between chromatin structure and mRNA processing events has been suggested, however, so far only a few involved factors have been characterized. Here we show that rsc nhp6ΔΔ mutants, deficient for the function of the chromatin remodeling factor RSC and the chromatin architectural proteins Nhp6A/Nhp6B, accumulate intron-containing pre-mRNA at the restrictive temperature. In addition, we demonstrate that rsc8-ts16 nhp6ΔΔ cells contain low levels of U6 snRNA and U4/U6 di-snRNA that is further exacerbated after two hours growth at the restrictive temperature. This change in U6 snRNA and U4/U6 di-snRNA levels in rsc8-ts16 nhp6ΔΔ cells is indicative of splicing deficient conditions. We identify MRN1 (multi-copy suppressor of rsc nhp6ΔΔ) as a growth suppressor of rsc nhp6ΔΔ synthetic sickness. Mrn1 is an RNA binding protein that localizes both to the nucleus and cytoplasm. Genetic interactions are observed between 2 µm-MRN1 and the splicing deficient mutants snt309Δ, prp3, prp4, and prp22, and additional genetic analyses link MRN1, SNT309, NHP6A/B, SWI/SNF, and RSC supporting the notion of a role of chromatin structure in mRNA processing. PMID:23028530

  11. 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

  12. Minor Groove Binder Distamycin Remodels Chromatin but Inhibits Transcription

    PubMed Central

    Majumder, Parijat; Banerjee, Amrita; Shandilya, Jayasha; Senapati, Parijat; Chatterjee, Snehajyoti; Kundu, Tapas K.; Dasgupta, Dipak

    2013-01-01

    The condensed structure of chromatin limits access of cellular machinery towards template DNA. This in turn represses essential processes like transcription, replication, repair and recombination. The repression is alleviated by a variety of energy dependent processes, collectively known as “chromatin remodeling”. In a eukaryotic cell, a fine balance between condensed and de-condensed states of chromatin helps to maintain an optimum level of gene expression. DNA binding small molecules have the potential to perturb such equilibrium. We present herein the study of an oligopeptide antibiotic distamycin, which binds to the minor groove of B-DNA. Chromatin mobility assays and circular dichroism spectroscopy have been employed to study the effect of distamycin on chromatosomes, isolated from the liver of Sprague-Dawley rats. Our results show that distamycin is capable of remodeling both chromatosomes and reconstituted nucleosomes, and the remodeling takes place in an ATP-independent manner. Binding of distamycin to the linker and nucleosomal DNA culminates in eviction of the linker histone and the formation of a population of off-centered nucleosomes. This hints at a possible corkscrew type motion of the DNA with respect to the histone octamer. Our results indicate that distamycin in spite of remodeling chromatin, inhibits transcription from both DNA and chromatin templates. Therefore, the DNA that is made accessible due to remodeling is either structurally incompetent for transcription, or bound distamycin poses a roadblock for the transcription machinery to advance. PMID:23460895

  13. "New Professionalism," Workforce Remodeling and the Restructuring of Teachers' Work

    ERIC Educational Resources Information Center

    Stevenson, Howard; Carter, Bob; Passy, Rowena

    2007-01-01

    Since its election in 1997 the Labour government's policy has sought to promote a "new professionalism" amongst teachers. First mooted at the time when new performance management arrangements were introduced, the discourse of new professionalism has now become closely associated with the "workforce remodeling" agenda in which teachers' work is…

  14. Remodeling of University of Minnesota President's House and Office.

    ERIC Educational Resources Information Center

    Minnesota State Office of the Legislative Auditor, St. Paul. Program Evaluation Div.

    A report on the remodeling projects at the University of Minnesota president's house and office is presented, noting significant shortcomings in the way the projects were managed and in the reporting relationship that existed between the Board of Regents and the university's administration. Recommendations are offered to the university on how…

  15. Role of microRNAs in Vascular Remodeling.

    PubMed

    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

  16. 19. 'Southern Pacific Company, Pacific Lines, Remodeling of Piers For ...

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

    19. 'Southern Pacific Company, Pacific Lines, Remodeling of Piers For Renewal of Br. 210-C Near Tehama, Sac. Division, Scale 1' = 40' & 1/4' = 1'-0', Sept. 1927, M.W.D., Drawing 5935, Sheet 2.' - Southern Pacific Railroad Shasta Route, Bridge No. 210.52, Milepost 210.52, Tehama, Tehama County, CA

  17. 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.

  18. Differential remodeling of extracellular matrices by breast cancer initiating cells.

    PubMed

    Raja, Anju M; Xu, Shuoyu; Zhuo, Shuangmu; Tai, Dean C S; Sun, Wanxin; So, Peter T C; Welsch, Roy E; Chen, Chien-Shing; Yu, Hanry

    2015-10-01

    Cancer initiating cells (CICs) have been the focus of recent anti-cancer therapies, exhibiting strong invasion capability via potentially enhanced ability to remodel extracellular matrices (ECM). We have identified CICs in a human breast cancer cell line, MX-1, and developed a xenograft model in SCID mice. We investigated the CICs' matrix-remodeling effects using Second Harmonic Generation (SHG) microscopy to identify potential phenotypic signatures of the CIC-rich tumors. The isolated CICs exhibit higher proliferation, drug efflux and drug resistant properties in vitro; were more tumorigenic than non-CICs, resulting in more and larger tumors in the xenograft model. The CIC-rich tumors have less collagen in the tumor interior than in the CIC-poor tumors supporting the idea that the CICs can remodel the collagen more effectively. The collagen fibers were preferentially aligned perpendicular to the CIC-rich tumor boundary while parallel to the CIC-poor tumor boundary suggesting more invasive behavior of the CIC-rich tumors. These findings would provide potential translational values in quantifying and monitoring CIC-rich tumors in future anti-cancer therapies. CIC-rich tumors remodel the collagen matrix more than CIC-poor tumors. PMID:25597396

  19. Using Extracellular Matrix Proteomics: To Understand Left Ventricular Remodeling

    PubMed Central

    Lindsey, Merry L.; Weintraub, Susan T.; Lange, Richard A.

    2011-01-01

    Survival following myocardial infarction (MI) has improved substantially over the last 40 years; however, the incidence of subsequent congestive heart failure has dramatically increased as a consequence. Discovering plasma markers that signify adverse cardiac remodeling may allow high-risk patients to be recognized earlier and may provide an improved way to assess treatment efficacy. Alterations in extracellular matrix (ECM) regulate cardiac remodeling following MI and potentially provide a large array of candidate indicators. The field of cardiac proteomics has progressed rapidly over the past 20 years, since publication of the first two-dimensional electrophoretic gels of left ventricle proteins. Proteomic approaches are now routinely utilized to better understand how the left ventricle responds to injury. In this review, we will discuss how methods have developed to allow comprehensive evaluation of the ECM proteome. We will explain how ECM proteomic data can be used to predict adverse remodeling for an individual patient and highlight future directions. Although this review will focus on the use of ECM proteomics to better understand post-MI remodeling responses, these approaches have applicability to a wide-range of cardiac pathologies, including pressure overload hypertrophy, viral myocarditis, and non-ischemic heart failure. PMID:22337931

  20. Bioresorbable vascular scaffolds: Biodegradation, drug delivery and vascular remodeling.

    PubMed

    Tesfamariam, Belay

    2016-05-01

    The metallic stents with durable polymers have been effective in reducing the need for revascularization, but the permanent presence of the metal and polymer have been associated with persistent inflammation, hypersensitivity reactions and incidence of thrombosis. Recent innovations of bioresorbable polymers are in development which could serve as temporary scaffolds that degrade into molecules and eventually resorb overtime, and leave the artery free of any permanent prosthetic constraints. The transient scaffolding has the advantages of restoring blood vessel to natural state, improve vasomotor tone and increase lumen enlargement because of expansive remodeling following completion of polymer resorption. The success of bioresorbable vascular scaffolds will depend on the degradation timeline, such that the elastic recoil of the blood vessel and negative remodeling which could potentially lead to restenosis are prevented. Bioresorbable scaffolds with bulky backbone and thick struts could lead to prolonged biodegradation, alter blood flow dynamics and increase thrombogenicity. The development of bioresorbable scaffolds is challenging because of the complexity of finding an ideal balance of polymer biodegradation and controlled drug release over time, such that the fractional drug released achieves optimal inhibitory concentration until the blood vessel remodels to a stable set point. This review discusses the various types of biodegradable materials, factors affecting biodegradation, drug release kinetics, vascular biocompatibility, adaptive vascular remodeling, and challenges in the development of bioresorbable scaffolds to treat vascular restenosis. PMID:27001225

  1. Energy Efficiency Measures to Incorporate into Remodeling Projects

    SciTech Connect

    Liaukus, C.

    2014-12-01

    Energy improvements in a home are often approached as one concerted effort, beginning with a simple walk-through assessment or more in-depth energy audit and followed by the installation of recommended energy measures. While this approach allows for systems thinking to guide the efforts, comprehensive energy improvements of this nature are undertaken by a relatively small number of the households in our nation compared to more piecemeal remodeling efforts. Even when programs like the Weatherization Assistance Program and Home Performance with ENERGY STAR are considered, homes that have had a comprehensive energy makeover still represent a small fraction of the 111.1 million households. In this report, the U.S Department of Energy Building America Retrofit Alliance research team looks at the improvement of a home's energy performance in an opportunistic way: it examines what can be done to incorporate energy efficiency measures into general remodeling work and home repair projects. This allows for the possibility for people who would not normally pursue energy efficiency but will remodel their kitchen or re-side their home to improve their home's performance at the same time. There are challenges to this approach, not the least of which being that the work will take place over time in potentially many separate projects. The opportunity to improve a home's energy efficiency at one time expands or contracts with the scope of the remodel. As such, guidance on how to do each piece thoughtfully and with consideration for potential future projects, is critical.

  2. DNA Looping Facilitates Targeting of a Chromatin Remodeling Enzyme

    PubMed Central

    Yadon, Adam N; Singh, Badri Nath; Hampsey, Michael; Tsukiyama, Toshio

    2013-01-01

    Summary ATP-dependent chromatin remodeling enzymes are highly abundant and play pivotal roles regulating DNA-dependent processes. The mechanisms by which they are targeted to specific loci have not been well understood on a genome-wide scale. Here we present evidence that a major targeting mechanism for the Isw2 chromatin remodeling enzyme to specific genomic loci is through sequence-specific transcription factor (TF)-dependent recruitment. Unexpectedly, Isw2 is recruited in a TF-dependent fashion to a large number of loci without TF binding sites. Using the 3C assay, we show that Isw2 can be targeted by Ume6- and TFIIB-dependent DNA looping. These results identify DNA looping as a previously unknown mechanism for the recruitment of a chromatin remodeling enzyme and defines a novel function for DNA looping. We also present evidence suggesting that Ume6-dependent DNA looping is involved in chromatin remodeling and transcriptional repression, revealing a mechanism by which the three-dimensional folding of chromatin affects DNA-dependent processes. PMID:23478442

  3. School Buildings: Remodeling; Rehabilitation; Modernization; Repair. Bulletin, 1950, No. 17

    ERIC Educational Resources Information Center

    Yiles, Nelson E.

    1950-01-01

    Adequate school plants are essential to a modern educational program. The school plant that is not properly maintained soon fails to provide the service for which it was intended. The total program of maintenance, including repairs, renovation, remodeling, rehabilitation, and modernization should be carefully planned. Some tasks will recur at…

  4. 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…

  5. 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.

  6. Pentoxifylline Attenuates Cardiac Remodeling Induced by Tobacco Smoke Exposure

    PubMed Central

    Minicucci, Marcos; Oliveira, Fernando; Santos, Priscila; Polegato, Bertha; Roscani, Meliza; Fernandes, Ana Angelica; Lustosa, Beatriz; Paiva, Sergio; Zornoff, Leonardo; Azevedo, Paula

    2016-01-01

    Background Tobacco smoke exposure is an important risk factor for cardiac remodeling. Under this condition, inflammation, oxidative stress, energy metabolism abnormalities, apoptosis, and hypertrophy are present. Pentoxifylline has anti‑inflammatory, anti-apoptotic, anti-thrombotic and anti-proliferative properties. Objective The present study tested the hypothesis that pentoxifylline would attenuate cardiac remodeling induced by smoking. Methods Wistar rats were distributed in four groups: Control (C), Pentoxifylline (PX), Tobacco Smoke (TS), and PX-TS. After two months, echocardiography, invasive blood pressure measurement, biochemical, and histological studies were performed. The groups were compared by two-way ANOVA with a significance level of 5%. Results TS increased left atrium diameter and area, which was attenuated by PX. In the isolated heart study, TS lowered the positive derivate (+dp/dt), and this was attenuated by PX. The antioxidants enzyme superoxide dismutase and glutathione peroxidase were decreased in the TS group; PX recovered these activities. TS increased lactate dehydrogenase (LDH) and decreased 3-hydroxyacyl Coenzyme A dehydrogenases (OH-DHA) and citrate synthase (CS). PX attenuated LDH, 3-OH-DHA and CS alterations in TS-PX group. TS increased IL-10, ICAM-1, and caspase-3. PX did not influence these variables. Conclusion TS induced cardiac remodeling, associated with increased inflammation, oxidative stress, apoptosis, and changed energy metabolism. PX attenuated cardiac remodeling by reducing oxidative stress and improving cardiac bioenergetics, but did not act upon cardiac cytokines and apoptosis. PMID:27096523

  7. 18. Photographic copy of original remodeling drawings dated July 8, ...

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

    18. Photographic copy of original remodeling drawings dated July 8, 1988 (original sepia in plan room of Base Civil Engineer, Scott AFB) First and second floor demolition and framing plan - Scott Air Force Base, General Officer Quarters, 229 Birchard Street, O'Fallon, St. Clair County, IL

  8. 17. Photographic copy of original remodeling drawings dated July 8, ...

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

    17. Photographic copy of original remodeling drawings dated July 8, 1988 (original sepia in plan room of Base Civil Engineer, Scott AFB) First and second floor plans - Scott Air Force Base, General Officer Quarters, 229 Birchard Street, O'Fallon, St. Clair County, IL

  9. Effects of Electrical and Structural Remodeling on Atrial Fibrillation Maintenance: A Simulation Study

    PubMed Central

    Krogh-Madsen, Trine; Abbott, Geoffrey W.; Christini, David J.

    2012-01-01

    Atrial fibrillation, a common cardiac arrhythmia, often progresses unfavourably: in patients with long-term atrial fibrillation, fibrillatory episodes are typically of increased duration and frequency of occurrence relative to healthy controls. This is due to electrical, structural, and contractile remodeling processes. We investigated mechanisms of how electrical and structural remodeling contribute to perpetuation of simulated atrial fibrillation, using a mathematical model of the human atrial action potential incorporated into an anatomically realistic three-dimensional structural model of the human atria. Electrical and structural remodeling both shortened the atrial wavelength - electrical remodeling primarily through a decrease in action potential duration, while structural remodeling primarily slowed conduction. The decrease in wavelength correlates with an increase in the average duration of atrial fibrillation/flutter episodes. The dependence of reentry duration on wavelength was the same for electrical vs. structural remodeling. However, the dynamics during atrial reentry varied between electrical, structural, and combined electrical and structural remodeling in several ways, including: (i) with structural remodeling there were more occurrences of fragmented wavefronts and hence more filaments than during electrical remodeling; (ii) dominant waves anchored around different anatomical obstacles in electrical vs. structural remodeling; (iii) dominant waves were often not anchored in combined electrical and structural remodeling. We conclude that, in simulated atrial fibrillation, the wavelength dependence of reentry duration is similar for electrical and structural remodeling, despite major differences in overall dynamics, including maximal number of filaments, wave fragmentation, restitution properties, and whether dominant waves are anchored to anatomical obstacles or spiralling freely. PMID:22383869

  10. Obliterative airway remodelling in transplanted and non-transplanted lungs.

    PubMed

    Jonigk, Danny; Theophile, Katharina; Hussein, Kais; Bock, Oliver; Lehmann, Ulrich; Bockmeyer, Clemens L; Gottlieb, Jens; Fischer, Stefan; Simon, Andre; Welte, Tobias; Maegel, Lavinia; Kreipe, Hans; Laenger, Florian

    2010-09-01

    Obliterative airway remodelling is a morphological sequence in a variety of pulmonary diseases. Notably, bronchiolitis obliterans represents one of the key complications of lung transplantation, induced by (immigrating) myofibroblasts. A comparative expression analysis of obliterative airway remodelling in transplanted and non-transplanted patients has not been reported so far. Obliterated and unremodelled airways from explanted lungs (n = 19) from patients suffering from chronic allograft dysfunction, infection, graft-versus-host disease and toxic exposure were isolated by laser-assisted microdissection. Airways from lung allografts harvested shortly before and after transplantation (n = 4) as well as fibroblastic foci from lungs with interstitial pulmonary fibrosis (n = 4) served as references. Pre-amplified cDNA was analysed by quantitative real-time RT-PCR for expression of fibrosis, inflammation and apoptosis-associated genes. Composition of infiltrating cells and protein expression were assessed by conventional histology and immunohistochemistry. Bronchiolitis obliterans in transplanted patients showed a significant increase of BMP-7 expression (p = 0.0141 compared with controls), while TGF-beta1 and FGF-2 as well as BMP-4 and BMP-7 were up-regulated in fibroblastic foci in interstitial pulmonary fibrosis (p < 0.0424 compared with controls). Regarding other fibrosis-associated genes (BMP-6, SMAD-3, CASP-3 and CASP-9, FASLG, NF-KB1, IL-1 and IL-2) as well as cellularity and cellular composition, no significant differences between obliterative airway remodelling in transplanted and non-transplanted patients could be shown. Obliterative airway remodelling in lung allografts and in non-transplanted patients share many morphological and genetic traits. BMPs, especially BMP-7, warrant further investigation as possible markers for the aggravation of airway remodelling. PMID:20632031

  11. Urokinase plasminogen activator gene deficiency inhibits fracture cartilage remodeling.

    PubMed

    Popa, Nicoleta L; Wergedal, Jon E; Lau, K-H William; Mohan, Subburaman; Rundle, Charles H

    2014-03-01

    Urokinase plasminogen activator (uPA) regulates a proteolytic cascade of extracellular matrix degradation that functions in tissue development and tissue repair. The development and remodeling of the skeletal extracellular matrix during wound healing suggests that uPA might regulate bone development and repair. To determine whether uPA functions regulate bone development and repair, we examined the basal skeletal phenotype and endochondral bone fracture repair in uPA-deficient mice. The skeletal phenotype of uPA knockout mice was compared with that of control mice under basal conditions by dual-energy X-ray absorptiometry and micro-CT analysis, and during femur fracture repair by micro-CT and histological examination of the fracture callus. No effects of uPA gene deficiency were observed in the basal skeletal phenotype of the whole body or the femur. However, uPA gene deficiency resulted in increased fracture callus cartilage abundance during femur fracture repair at 14 days healing. The increase in cartilage corresponded to reduced tartrate-resistant acid phosphatase (TRAP) staining for osteoclasts in the uPA knockout fracture callus at this time, consistent with impaired osteoclast-mediated remodeling of the fracture cartilage. CD31 staining was reduced in the knockout fracture tissues at this time, suggesting that angiogenesis was also reduced. Osteoclasts also colocalized with CD31 expression in the endothelial cells of the fracture tissues during callus remodeling. These results indicate that uPA promotes remodeling of the fracture cartilage by osteoclasts that are associated with angiogenesis and suggest that uPA promotes angiogenesis and remodeling of the fracture cartilage at this time of bone fracture repair. PMID:23700285

  12. Protective role of heme oxygenase-1 in atrial remodeling.

    PubMed

    Yeh, Yung-Hsin; Hsu, Lung-An; Chen, Ying-Hwa; Kuo, Chi-Tai; Chang, Gwo-Jyh; Chen, Wei-Jan

    2016-09-01

    Structural and electrical remodeling in the atrium constitutes the main feature of atrial fibrillation (AF), which is characterized by increased oxidative stress. Heme oxygenase-1 (HO-1) is a potent anti-oxidant system that may provide protection against various oxidative stress-related diseases. The aim of this study is to investigate whether HO-1 has a protective effect on AF-related remodeling. Cultured atrium-derived myocytes (HL-1 cell line) were used to evaluate tachypacing-induced oxidative stress, structural, and electrical remodeling. Transforming growth factor-β (TGF-β) was utilized to assess collagen (a main fibrosis-related protein) expression in atrial fibroblasts. Tachypacing in HL-1 myocytes and treatment of atrial fibroblasts with TGF-β enhanced the expression of HO-1, both of which were mediated by the activation of nuclear factor erythroid-2-related factor 2. Over-expression of HO-1 in HL-1 cells attenuated tachypacing-induced oxidative stress, myofibril degradation, down-regulation of L-type calcium channel, and shortening of action potential duration. Furthermore, HO-1 over-expression in atrial fibroblasts blocked the up-regulation of collagen by TGF-β, implicating a protective role of HO-1 in structural and electrical remodeling in the atrium. In vivo, HO-1(-/-) mice exhibited a higher degree of oxidative stress, myofibril degradation, and collagen deposit in their atria than wild-type mice. Moreover, burst atrial pacing induced a greater susceptibility to AF in HO-1(-/-) mice than in wild-type mice. In conclusion, a negative-feedback regulation of HO-1 in activated atrial myocytes and fibroblasts may provide protection against AF-related remodeling and AF development. PMID:27562817

  13. Characterizing matrix remodeling in collagen gels using optical coherence tomography

    NASA Astrophysics Data System (ADS)

    Levitz, David; Hinds, Monica T.; Hanson, Stephen R.; Jacques, Steven L.

    2010-02-01

    Optical coherence tomography (OCT) has shown promise at non-destructively characterizing engineered tissues such as collagen gels. However, as the collagen gels develop, the OCT images lose contrast of structures as the gels develop, making visual assessment difficult. Our group proposed quantitatively characterizing these gels by fitting the optical properties from the OCT signals. In this paper, we imaged collagen gels seeded with smooth muscle cells (SMCs) over a 5-day period and used the data to measure their optical properties. Our results showed that over time, the reflectivity of the samples increased 10-fold, corresponding to a decrease in anisotropy factor g, without much change in the scattering coefficient μs. Overall, the optical properties appeared to be dominated by scattering from the collagen matrix, not the cells. However, SMCs remodeled the collagen matrix, and this collagen remodeling by the cells is what causes the observed changes in optical properties. Moreover, the data showed that the optical properties were sensitive to the activity of matrix metalloproteinases (MMPs), enzymes that break down local collagen fibrils into smaller fragments. Blocking MMPs in the SMC gels greatly impeded both the remodeling process and change in optical properties at day 5. Treating day 1 acellular gels with MMP-8 for 3 hr managed to partially reproduce the remodeling observed in SMC gels at day 5. Altogether, we conclude that matrix remodeling in general, and MMPs specifically, greatly affect the local optical properties of the sample, and OCT is a unique tool that can assess MMP activity in collagen gels both non-destructively and label free.

  14. Ab interno trabeculectomy: patient selection and perspectives.

    PubMed

    Vinod, Kateki; Gedde, Steven J

    2016-01-01

    Ab interno trabeculectomy is one among several recently introduced minimally invasive glaucoma surgeries that avoid a conjunctival incision and full-thickness sclerostomy involved in traditional glaucoma surgery. Ablation of the trabecular meshwork and inner wall of Schlemm's canal is performed in an arcuate fashion via a clear corneal incision, alone or in combination with phacoemulsification cataract surgery. Intraocular pressure reduction following ab interno trabeculectomy is limited by resistance in distal outflow pathways and generally stabilizes in the mid-to-high teens. Relief of medication burden has been demonstrated by some studies. A very low rate of complications, most commonly transient hyphema and intraocular pressure elevations in the immediate postoperative period, have been reported. However, available data are derived from small retrospective and prospective case series. Randomized, controlled trials are needed to better elucidate the potential merits of ab interno trabeculectomy in the combined setting versus phacoemulsification cataract surgery alone and to compare it with other minimally invasive glaucoma surgeries. PMID:27574396

  15. Prefrontal white matter pathology in air pollution exposed Mexico City young urbanites and their potential impact on neurovascular unit dysfunction and the development of Alzheimer's disease.

    PubMed

    Calderón-Garcidueñas, Lilian; Reynoso-Robles, Rafael; Vargas-Martínez, Javier; Gómez-Maqueo-Chew, Aline; Pérez-Guillé, Beatriz; Mukherjee, Partha S; Torres-Jardón, Ricardo; Perry, George; Gónzalez-Maciel, Angélica

    2016-04-01

    Millions of urban children are chronically exposed to high concentrations of air pollutants, i.e., fine particulate matter (PM2.5) and ozone, associated with increased risk for Alzheimer's disease. Compared with children living with clear air those in Mexico City (MC) exhibit systemic, brain and intrathecal inflammation, low CSF Aβ42, breakdown of the BBB, attention and short-term memory deficits, prefrontal white matter hyperintensities, damage to epithelial and endothelial barriers, tight junction and neural autoantibodies, and Alzheimer and Parkinson's hallmarks. The prefrontal white matter is a target of air pollution. We examined by light and electron microscopy the prefrontal white matter of MC dogs (n: 15, age 3.17±0.74 years), children and teens (n: 34, age: 12.64±4.2 years) versus controls. Major findings in MC residents included leaking capillaries and small arterioles with extravascular lipids and erythrocytes, lipofuscin in pericytes, smooth muscle and endothelial cells (EC), thickening of cerebrovascular basement membranes with small deposits of amyloid, patchy absence of the perivascular glial sheet, enlarged Virchow-Robin spaces and nanosize particles (20-48nm) in EC, basement membranes, axons and dendrites. Tight junctions, a key component of the neurovascular unit (NVU) were abnormal in MC versus control dogs (χ(2)<0.0001), and white matter perivascular damage was significantly worse in MC dogs (p=0.002). The integrity of the NVU, an interactive network of vascular, glial and neuronal cells is compromised in MC young residents. Characterizing the early NVU damage and identifying biomarkers of neurovascular dysfunction may provide a fresh insight into Alzheimer pathogenesis and open opportunities for pediatric neuroprotection. PMID:26829765

  16. Impaired neurovascular coupling to ictal epileptic activity and spreading depolarization in a patient with subarachnoid hemorrhage: possible link to blood-brain barrier dysfunction.

    PubMed

    Winkler, Maren K L; Chassidim, Yoash; Lublinsky, Svetlana; Revankar, Gajanan S; Major, Sebastian; Kang, Eun-Jeung; Oliveira-Ferreira, Ana I; Woitzik, Johannes; Sandow, Nora; Scheel, Michael; Friedman, Alon; Dreier, Jens P

    2012-11-01

    Spreading depolarization describes a sustained neuronal and astroglial depolarization with abrupt ion translocation between intraneuronal and extracellular space leading to a cytotoxic edema and silencing of spontaneous activity. Spreading depolarizations occur abundantly in acutely injured human brain and are assumed to facilitate neuronal death through toxic effects, increased metabolic demand, and inverse neurovascular coupling. Inverse coupling describes severe hypoperfusion in response to spreading depolarization. Ictal epileptic events are less frequent than spreading depolarizations in acutely injured human brain but may also contribute to lesion progression through increased metabolic demand. Whether abnormal neurovascular coupling can occur with ictal epileptic events is unknown. Herein we describe a patient with aneurysmal subarachnoid hemorrhage in whom spreading depolarizations and ictal epileptic events were measured using subdural opto-electrodes for direct current electrocorticography and regional cerebral blood flow recordings with laser-Doppler flowmetry. Simultaneously, changes in tissue partial pressure of oxygen were recorded with an intraparenchymal oxygen sensor. Isolated spreading depolarizations and clusters of recurrent spreading depolarizations with persistent depression of spontaneous activity were recorded over several days followed by a status epilepticus. Both spreading depolarizations and ictal epileptic events where accompanied by hyperemic blood flow responses at one optode but mildly hypoemic blood flow responses at another. Of note, quantitative analysis of Gadolinium-diethylene-triamine-pentaacetic acid (DTPA)-enhanced magnetic resonance imaging detected impaired blood-brain barrier integrity in the region where the optode had recorded the mildly hypoemic flow responses. The data suggest that abnormal flow responses to spreading depolarizations and ictal epileptic events, respectively, may be associated with blood-brain barrier

  17. MELCOR 1.8.2 assessment: Aerosol experiments ABCOVE AB5, AB6, AB7, and LACE LA2

    SciTech Connect

    Souto, F.J.; Haskin, F.E.; Kmetyk, L.N.

    1994-10-01

    The MELCOR computer code has been used to model four of the large-scale aerosol behavior experiments conducted in the Containment System Test Facility (CSTF) vessel. Tests AB5, AB6 and AB7 of the ABCOVE program simulate the dry aerosol conditions during a hypothetical severe accident in an LMFBR. Test LA2 of the LACE program simulates aerosol behavior in a condensing steam environment during a postulated severe accident in an LWR with failure to isolate the containment. The comparison of code results to experimental data show that MELCOR is able to correctly predict most of the thermal-hydraulic results in the four tests. MELCOR predicts reasonably well the dry aerosol behavior of the ABCOVE tests, but significant disagreements are found in the aerosol behavior modelling for the LA2 experiment. These results tend to support some of the concerns about the MELCOR modelling of steam condensation onto aerosols expressed in previous works. During these analyses, a limitation in the MELCOR input was detected for the specification of the aerosol parameters for more than one component. A Latin Hypercube Sampling (LHS) sensitivity study of the aerosol dynamic constants is presented for test AB6. The study shows the importance of the aerosol shape factors in the aerosol deposition behavior, and reveals that MELCOR input/output processing is highly labor intensive for uncertainty and sensitivity analyses based on LHS.

  18. Characterization of mAb dimers reveals predominant dimer forms common in therapeutic mAbs.

    PubMed

    Plath, Friederike; Ringler, Philippe; Graff-Meyer, Alexandra; Stahlberg, Henning; Lauer, Matthias E; Rufer, Arne C; Graewert, Melissa A; Svergun, Dmitri; Gellermann, Gerald; Finkler, Christof; Stracke, Jan O; Koulov, Atanas; Schnaible, Volker

    2016-07-01

    The formation of undesired high molecular weight species such as dimers is an important quality attribute for therapeutic monoclonal antibody formulations. Therefore, the thorough understanding of mAb dimerization and the detailed characterization mAb dimers is of great interest for future pharmaceutical development of therapeutic antibodies. In this work, we focused on the analyses of different mAb dimers regarding size, surface properties, chemical identity, overall structure and localization of possible dimerization sites. Dimer fractions of different mAbs were isolated to a satisfactory purity from bulk material and revealed 2 predominant overall structures, namely elongated and compact dimer forms. The elongated dimers displayed one dimerization site involving the tip of the Fab domain. Depending on the stress applied, these elongated dimers are connected either covalently or non-covalently. In contrast, the compact dimers exhibited non-covalent association. Several interaction points were detected for the compact dimers involving the hinge region or the base of the Fab domain. These results indicate that mAb dimer fractions are rather complex and may contain more than one kind of dimer. Nevertheless, the overall appearance of mAb dimers suggests the existence of 2 predominant dimeric structures, elongated and compact, which are commonly present in preparations of therapeutic mAbs. PMID:27031922

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

    PubMed Central

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

    2012-01-01

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

  20. Biomechanical and biochemical remodeling of stromal extracellular matrix in cancer.

    PubMed

    Malik, Ruchi; Lelkes, Peter I; Cukierman, Edna

    2015-04-01

    The extracellular matrix (ECM) provides structural and biochemical signals that regulate cell function. A well-controlled balance between cells and surroundings (i.e., dynamic reciprocity) is crucial for regulating ECM architecture. During cancer progression, epithelial cells undergo genetic alterations which, together with stromal changes including ECM remodeling, disturb the homeostatic dynamics of the epithelium. A parallel organization of stromal ECM fibrils is associated with tumorigenic responses. In an emerging paradigm, continuous and progressive regulation via mechanical forces and aberrant signaling are believed to be responsible for tumor-associated ECM remodeling. In this review we discuss the discrete biomechanical and biochemical mechanisms that underlie these architectural changes and highlight their particular relevance to the regulation of the alignment of ECM in the mesenchymal stroma. PMID:25708906

  1. 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

  2. Dynamics of lung defense in pneumonia: resistance, resilience, and remodeling.

    PubMed

    Quinton, Lee J; Mizgerd, Joseph P

    2015-01-01

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

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

    PubMed Central

    Quinton, Lee J.; Mizgerd, Joseph P.

    2015-01-01

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

  4. Frequent mutations in chromatin-remodeling genes in pulmonary carcinoids

    PubMed Central

    Lu, Xin; Sun, Ruping; Ozretić, Luka; Seidal, Danila; Zander, Thomas; Leenders, Frauke; George, Julie; Müller, Christian; Dahmen, Ilona; Pinther, Berit; Bosco, Graziella; Konrad, Kathryn; Altmüller, Janine; Nürnberg, Peter; Achter, Viktor; Lang, Ulrich; Schneider, Peter M; Bogus, Magdalena; Soltermann, Alex; Brustugun, Odd Terje; Helland, Åslaug; Solberg, Steinar; Lund-Iversen, Marius; Ansén, Sascha; Stoelben, Erich; Wright, Gavin M.; Russell, Prudence; Wainer, Zoe; Solomon, Benjamin; Field, John K; Hyde, Russell; Davies, Michael PA.; Heukamp, Lukas C; Petersen, Iver; Perner, Sven; Lovly, Christine; Cappuzzo, Federico; Travis, William D; Wolf, Jürgen; Vingron, Martin; Brambilla, Elisabeth; Haas, Stefan A.; Buettner, Reinhard; Thomas, Roman K

    2014-01-01

    Pulmonary carcinoids are rare neuroendocrine tumors of the lung. The molecular alterations underlying the pathogenesis of these tumors have not been systematically studied so far. Here we perform gene copy number analysis (n=54), genome/exome (n=44) and transcriptome (n=69) sequencing of pulmonary carcinoids and observe frequent mutations in chromatin-remodeling genes. Covalent histone modifiers and subunits of the SWI/SNF complex are mutated in 40% and 22.2% of the cases respectively, with MEN1, PSIP1 and ARID1A being recurrently affected. In contrast to small-cell lung cancer and large-cell neuroendocrine tumors, TP53 and RB1 mutations are rare events, suggesting that pulmonary carcinoids are not early progenitor lesions of the highly aggressive lung neuroendocrine tumors but arise through independent cellular mechanisms. These data also suggest that inactivation of chromatin remodeling genes is sufficient to drive transformation in pulmonary carcinoids. PMID:24670920

  5. BIOMECHANICAL and BIOCHEMICAL REMODELING of STROMAL EXTRACELLULAR MATRIX IN CANCER

    PubMed Central

    Malik, Ruchi; Lelkes, Peter I; Cukierman, Edna

    2015-01-01

    The extracellular matrix (ECM) provides structural and biochemical signals that regulate cell function. A well-controlled balance between cells and surroundings (i.e., Dynamic Reciprocity) is crucial for regulating ECM architecture. During cancer progression, epithelial cells undergo genetic alterations, which together with stromal changes, including ECM remodeling, disturb the homeostatic dynamics of the epithelium. A parallel organization of stromal ECM fibrils is associated with tumorigenic responses. In an emerging paradigm, continuous and progressive regulation via mechanical forces and aberrant signaling are believed to be responsible for tumor-associated ECM remodeling. In this review, we discuss the discrete biomechanical and biochemical mechanisms that underlie these architectural changes and highlight their particular relevance to the regulation of the alignment of ECM in the mesenchymal stroma. PMID:25708906

  6. Physical principles of membrane remodelling during cell mechanoadaptation

    NASA Astrophysics Data System (ADS)

    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

    2015-06-01

    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.

  7. Osteocyte Remodeling of the Perilacunar and Pericanalicular Matrix

    PubMed Central

    Qing, Hai; Bonewald, Lynda F

    2009-01-01

    With additional functions of osteocytes being identified, the concept that osteocytes are just “static lacunar-dwelling cells” is no longer accepted. We reviewed most of the relevant literature on osteocyte's function in the direct remodeling of the perilucunar matrix, discussing the advantages and disadvantages. Special attention was paid to how the negative researchers argue about the “osteocytic osteolysis” principle, and how the positive side addressed the arguments. We also discussed the newly found data of osteocytic remodeling function from our group. With more biotechnology in hand, there is increased excitement in the prospect of now being able to answer the two important questions: do osteocytes have the capability to remove mineral from the perilacunar matrix and if so what are the molecular and cellular mechanisms? do osteocytes have the capability to deposit new mineral on the perilacunar matrix and if so what are the cellular and molecular mechanisms? PMID:20687297

  8. 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

  9. ISWI chromatin remodeling complexes in the DNA damage response

    PubMed Central

    Aydin, Özge Z; Vermeulen, Wim; Lans, Hannes

    2014-01-01

    Regulation of chromatin structure is an essential component of the DNA damage response (DDR), which effectively preserves the integrity of DNA by a network of multiple DNA repair and associated signaling pathways. Within the DDR, chromatin is modified and remodeled to facilitate efficient DNA access, to control the activity of repair proteins and to mediate signaling. The mammalian ISWI family has recently emerged as one of the major ATP-dependent chromatin remodeling complex families that function in the DDR, as it is implicated in at least 3 major DNA repair pathways: homologous recombination, non-homologous end-joining and nucleotide excision repair. In this review, we discuss the various manners through which different ISWI complexes regulate DNA repair and how they are targeted to chromatin containing damaged DNA. PMID:25486562

  10. Physical principles of membrane remodelling during cell mechanoadaptation.

    PubMed

    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

  11. Microvascular remodelling in chronic airway inflammation in mice.

    PubMed

    Thurston, G; Maas, K; Labarbara, A; Mclean, J W; McDonald, D M

    2000-10-01

    1. Chronic inflammation is associated with blood vessel remodelling, including vessel proliferation and enlargement, and changes in vessel phenotype. We sought to characterize these changes in chronic airway inflammation and to determine whether corticosteroids that inhibit inflammation, such as dexamethasone, can also reduce microvascular remodelling. 2. Chronic airway inflammation was induced in C3H mice by infection with Mycoplasmapulmonis and the tracheal vessels treatment also decreased the immunoreactivity for P-selectin and the number of adherent leucocytes (595 +/- 203 vs 2,024 +/- 393 cells/ mm2 in treated and non-treated infected mice, respectively). 6. We conclude that microvascular enlargement and changes in vessel phenotype are features of some types of chronic inflammation and, furthermore, that dexamethasone reverses the microvascular enlargement, changes in vessel phenotype and leucocyte influx associated with chronic inflammatory airway disease. PMID:11022979

  12. Remodeling myelination: implications for mechanisms of neural plasticity

    PubMed Central

    Chang, Kae-Jiun; Redmond, Stephanie A; Chan, Jonah R

    2016-01-01

    One of the most significant paradigm shifts in membrane remodeling is the emerging view that membrane transformation is not exclusively controlled by cytoskeletal rearrangement, but also by biophysical constraints, adhesive forces, membrane curvature and compaction. One of the most exquisite examples of membrane remodeling is myelination. The advent of myelin was instrumental in advancing the nervous system during vertebrate evolution. With more rapid and efficient communication between neurons, faster and more complex computations could be performed in a given time and space. Our knowledge of how myelin-forming oligodendrocytes select and wrap axons has been limited by insufficient spatial and temporal resolution. By virtue of recent technological advances, progress has clarified longstanding controversies in the field. Here we review insights into myelination, from target selection to axon wrapping and membrane compaction, and discuss how understanding these processes has unexpectedly opened new avenues of insight into myelination-centered mechanisms of neural plasticity. PMID:26814588

  13. 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

  14. Synaptic remodeling of neuronal circuits in early retinal degeneration

    PubMed Central

    Soto, Florentina; Kerschensteiner, Daniel

    2015-01-01

    Photoreceptor degenerations are a major cause of blindness and among the most common forms of neurodegeneration in humans. Studies of mouse models revealed that synaptic dysfunction often precedes photoreceptor degeneration, and that abnormal synaptic input from photoreceptors to bipolar cells causes circuits in the inner retina to become hyperactive. Here, we provide a brief overview of frequently used mouse models of photoreceptor degenerations. We then discuss insights into circuit remodeling triggered by early synaptic dysfunction in the outer and hyperactivity in the inner retina. We discuss these insights in the context of other experimental manipulations of synaptic function and activity. Knowledge of the plasticity and early remodeling of retinal circuits will be critical for the design of successful vision rescue strategies. PMID:26500497

  15. 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.

  16. Intradialytic Hypotension and Cardiac Remodeling: A Vicious Cycle

    PubMed Central

    Huang, Jenq-Wen; Yen, Chung-Jen

    2015-01-01

    Hemodynamic instability during hemodialysis is a common but often underestimated issue in the nephrologist practice. Intradialytic hypotension, namely, a decrease of systolic or mean blood pressure to a certain level, prohibits the safe and smooth achievement of ultrafiltration and solute removal goal in chronic dialysis patients. Studies have elucidated the potential mechanisms involved in the development of Intradialytic hypotension, including excessive ultrafiltration and loss of compensatory mechanisms for blood pressure maintenance. Cardiac remodeling could also be one important piece of the puzzle. In this review, we intend to discuss the role of cardiac remodeling, including left ventricular hypertrophy, in the development of Intradialytic hypotension. In addition, we will also provide evidence that a bidirectional relationship might exist between Intradialytic hypotension and left ventricular hypertrophy in chronic dialysis patients. A more complete understanding of the complex interactions in between could assist the readers in formulating potential solutions for the reduction of both phenomena. PMID:25654122

  17. Biomarker discovery in asthma-related inflammation and remodeling.

    PubMed

    Calvo, Florence Quesada; Fillet, Marianne; de Seny, Dominique; Meuwis, Marie-Alice; Maree, Raphael; Crahay, Céline; Paulissen, Geneviève; Rocks, Natacha; Gueders, Maud; Wehenkel, Louis; Merville, Marie-Paule; Louis, Renaud; Foidart, Jean-Michel; Noël, Agnes; Cataldo, Didier

    2009-04-01

    Asthma is a complex inflammatory disease of airways. A network of reciprocal interactions between inflammatory cells, peptidic mediators, extracellular matrix components, and proteases is thought to be involved in the installation and maintenance of asthma-related airway inflammation and remodeling. To date, new proteic mediators displaying significant activity in the pathophysiology of asthma are still to be unveiled. The main objective of this study was to uncover potential target proteins by using surface-enhanced laser desorption/ionization-time of flight-mass spectrometry (SELDI-TOF-MS) on lung samples from mouse models of allergen-induced airway inflammation and remodeling. In this model, we pointed out several protein or peptide peaks that were preferentially expressed in diseased mice as compared to controls. We report the identification of different five proteins: found inflammatory zone 1 or RELM alpha (FIZZ-1), calcyclin (S100A6), clara cell secretory protein 10 (CC10), Ubiquitin, and Histone H4. PMID:19322781

  18. 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. PMID:26417726

  19. Making Microvascular Networks Work: Angiogenesis, Remodeling, and Pruning

    PubMed Central

    Secomb, Timothy W.

    2014-01-01

    The adequate and efficient functioning of the microcirculation requires not only numerous vessels providing a large surface area for transport but also a structure that provides short diffusion distances from capillaries to tissue and efficient distribution of convective blood flow. Theoretical models show how a combination of angiogenesis, remodeling, and pruning in response to hemodynamic and metabolic stimuli, termed “angioadaptation,” generates well organized, functional networks. PMID:25362638

  20. Structural analysis of the RSC chromatin-remodeling complex.

    PubMed

    Asturias, Francisco J; Chung, Wen-Hsiang; Kornberg, Roger D; Lorch, Yahli

    2002-10-15

    Electron microscopy of the RSC chromatin-remodeling complex reveals a ring of protein densities around a central cavity. The size and shape of the cavity correspond closely to those of a nucleosome. Results of nuclease protection analysis are consistent with nucleosome binding in the cavity. Such binding could explain the ability of RSC to expose nucleosomal DNA in the presence of ATP without loss of associated histones. PMID:12368485

  1. Bone tissue remodeling and development: focus on matrix metalloproteinase functions.

    PubMed

    Paiva, Katiucia Batista Silva; Granjeiro, José Mauro

    2014-11-01

    Bone-forming cells originate from distinct embryological layers, mesoderm (axial and appendicular bones) and ectoderm (precursor of neural crest cells, which mainly form facial bones). These cells will develop bones by two principal mechanisms: intramembranous and endochondral ossification. In both cases, condensation of multipotent mesenchymal cells occurs, at the site of the future bone, which differentiate into bone and cartilage-forming cells. During long bone development, an initial cartilaginous template is formed and replaced by bone in a coordinated and refined program involving chondrocyte proliferation and maturation, vascular invasion, recruitment of adult stem cells and intense remodeling of cartilage and bone matrix. Matrix metalloproteinases (MMPs) are the most important enzymes for cleaving structural components of the extracellular matrix (ECM), as well as other non-ECM molecules in the ECM space, pericellular perimeter and intracellularly. Thus, the bioactive molecules generated act on several biological events, such as development, tissue remodeling and homeostasis. Since the discovery of collagenase in bone cells, more than half of the MMP members have been detected in bone tissues under both physiological and pathological conditions. Pivotal functions of MMPs during development and bone regeneration have been revealed by knockout mouse models, such as chondrocyte proliferation and differentiation, osteoclast recruitment and function, bone modeling, coupling of bone resorption and formation (bone remodeling), osteoblast recruitment and survival, angiogenesis, osteocyte viability and function (biomechanical properties); as such alterations in MMP function may alter bone quality. In this review, we look at the principal properties of MMPs and their inhibitors (TIMPs and RECK), provide an up-date on their known functions in bone development and remodeling and discuss their potential application to Bone Bioengineering. PMID:25157440

  2. Emphysema and Mechanical Stress-Induced Lung Remodeling

    PubMed Central

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

    2013-01-01

    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. PMID:24186935

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

    PubMed Central

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

    2014-01-01

    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 [R2 = 0.68, p < 0.004], total osteon area [R2=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 inter-individual variation in remodeling differentially impacts skeletal aging and an individuals’ potential response to prophylactic treatments. PMID:24962664

  4. Pulmonary arterial remodeling revealed by microfocal x-ray tomography

    NASA Astrophysics Data System (ADS)

    Karau, Kelly L.; Molthen, Robert C.; Johnson, Roger H.; Dhyani, Anita H.; Haworth, Steven T.; Dawson, Christopher A.

    2001-05-01

    Animal models and micro-CT imaging are useful for understanding the functional consequences of, and identifying the genes involved in, the remodeling of vascular structures that accompanies pulmonary vascular disease. Using a micro-CT scanner to image contrast-enhanced arteries in excised lungs from fawn hooded rats (a strain genetically susceptible to hypoxia induced pulmonary hypertension), we found that portions of the pulmonary arterial tree downstream from a given diameter were morphometrically indistinguishable. This 'self-consistency' property provided a means for summarizing the pulmonary arterial tree architecture and mechanical properties using a parameter vector obtained from measurements of the contiguous set of vessel segments comprising the longest (principal) pathway and its branches over a range of vascular pressures. This parameter vector was used to characterize the pulmonary vascular remodeling that occurred in rats exposed to a hypoxic (11.5% oxygen) environment and provided the input to a hemodynamic model relating structure to function. The major effect of the remodeling was a longitudinally (pulmonary artery to arterioles) uniform decrease in vessel distensibility that resulted in a 90% increase in arterial resistance. Despite the almost uniform change in vessel distensibility, over 50% of the resistance increase was attributable to vessels with unstressed diameters less than 125 microns.

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

    PubMed

    Menzel, Andreas; Waffenschmidt, Tobias

    2009-09-13

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

  6. Galectin-3 inhibition prevents adipose tissue remodelling in obesity.

    PubMed

    Martínez-Martínez, E; Calvier, L; Rossignol, P; Rousseau, E; Fernández-Celis, A; Jurado-López, R; Laville, M; Cachofeiro, V; López-Andrés, N

    2016-06-01

    Extracellular matrix remodelling of the adipose tissue has a pivotal role in the pathophysiology of obesity. Galectin-3 (Gal-3) is increased in obesity and mediates inflammation and fibrosis in the cardiovascular system. However, the effects of Gal-3 on adipose tissue remodelling associated with obesity remain unclear. Male Wistar rats were fed either a high-fat diet (33.5% fat) or a standard diet (3.5% fat) for 6 weeks. Half of the animals of each group were treated with the pharmacological inhibitor of Gal-3, modified citrus pectin (MCP; 100 mg kg(-1) per day) in the drinking water. In adipose tissue, obese animals presented an increase in Gal-3 levels that were accompanied by an increase in pericellular collagen. Obese rats exhibited higher adipose tissue inflammation, as well as enhanced differentiation degree of the adipocytes. Treatment with MCP prevented all the above effects. In mature 3T3-L1 adipocytes, Gal-3 (10(-8 )m) treatment increased fibrosis, inflammatory and differentiation markers. In conclusion, Gal-3 emerges as a potential therapeutic target in adipose tissue remodelling associated with obesity and could have an important role in the development of metabolic alterations associated with obesity. PMID:26853916

  7. Age-dependent motor unit remodelling in human limb muscles.

    PubMed

    Piasecki, Mathew; Ireland, Alex; Jones, David A; McPhee, Jamie S

    2016-06-01

    Voluntary control of skeletal muscle enables humans to interact with and manipulate the environment. Lower muscle mass, weakness and poor coordination are common complaints in older age and reduce physical capabilities. Attention has focused on ways of maintaining muscle size and strength by exercise, diet or hormone replacement. Without appropriate neural innervation, however, muscle cannot function. Emerging evidence points to a neural basis of muscle loss. Motor unit number estimates indicate that by age around 71 years, healthy older people have around 40 % fewer motor units. The surviving low- and moderate-threshold motor units recruited for moderate intensity contractions are enlarged by around 50 % and show increased fibre density, presumably due to collateral reinnervation of denervated fibres. Motor unit potentials show increased complexity and the stability of neuromuscular junction transmissions is decreased. The available evidence is limited by a lack of longitudinal studies, relatively small sample sizes, a tendency to examine the small peripheral muscles and relatively few investigations into the consequences of motor unit remodelling for muscle size and control of movements in older age. Loss of motor neurons and remodelling of surviving motor units constitutes the major change in ageing muscles and probably contributes to muscle loss and functional impairments. The deterioration and remodelling of motor units likely imposes constraints on the way in which the central nervous system controls movements. PMID:26667009

  8. 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.

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

    PubMed

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

    2016-01-01

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

  10. 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

  11. Remodeling of the Methylation Landscape in Breast Cancer Metastasis

    PubMed Central

    Reyngold, Marsha; Turcan, Sevin; Giri, Dilip; Kannan, Kasthuri; Walsh, Logan A.; Viale, Agnes; Drobnjak, Marija; Vahdat, Linda T.; Lee, William; Chan, Timothy A.

    2014-01-01

    The development of breast cancer metastasis is accompanied by dynamic transcriptome changes and dramatic alterations in nuclear and chromatin structure. The basis of these changes is incompletely understood. The DNA methylome of primary breast cancers contribute to transcriptomic heterogeneity and different metastatic behavior. Therefore we sought to characterize methylome remodeling during regional metastasis. We profiled the DNA methylome and transcriptome of 44 matched primary breast tumors and regional metastases. Striking subtype-specific patterns of metastasis-associated methylome remodeling were observed, which reflected the molecular heterogeneity of breast cancers. These divergent changes occurred primarily in CpG island (CGI)-poor areas. Regions of methylome reorganization shared by the subtypes were also observed, and we were able to identify a metastasis-specific methylation signature that was present across the breast cancer subclasses. These alterations also occurred outside of CGIs and promoters, including sequences flanking CGIs and intergenic sequences. Integrated analysis of methylation and gene expression identified genes whose expression correlated with metastasis-specific methylation. Together, these findings significantly enhance our understanding of the epigenetic reorganization that occurs during regional breast cancer metastasis across the major breast cancer subtypes and reveal the nature of methylome remodeling during this process. PMID:25083786

  12. LIGHT is a crucial mediator of airway remodeling.

    PubMed

    Hung, Jen-Yu; Chiang, Shyh-Ren; Tsai, Ming-Ju; Tsai, Ying-Ming; Chong, Inn-Wen; Shieh, Jiunn-Min; Hsu, Ya-Ling

    2015-05-01

    Chronic inflammatory airway diseases like asthma and chronic obstructive pulmonary disease are major health problems globally. Airway epithelial cells play important role in airway remodeling, which is a critical process in the pathogenesis of diseases. This study aimed to demonstrate that LIGHT, an inflammatory factor secreted by T cells after allergen exposure, is responsible for promoting airway remodeling. LIGHT increased primary human bronchial epithelial cells (HBECs) undergoing epithelial-mesenchymal transition (EMT) and expressing MMP-9. The induction of EMT was associated with increased NF-κB activation and p300/NF-κB association. The interaction of NF-κB with p300 facilitated NF-κB acetylation, which in turn, was bound to the promoter of ZEB1, resulting in E-cadherin downregulation. LIGHT also stimulated HBECs to produce numerous cytokines/chemokines that could worsen airway inflammation. Furthermore, LIGHT enhanced HBECs to secrete activin A, which increased bronchial smooth muscle cell (BSMC) migration. In contrast, depletion of activin A decreased such migration. The findings suggest a new molecular determinant of LIGHT-mediated pathogenic changes in HBECs and that the LIGHT-related vicious cycle involving HBECs and BSMCs may be a potential target for the treatment of chronic inflammation airway diseases with airway remodeling. PMID:25251281

  13. Hyperhomocysteinemia promotes vascular remodeling in vein graph in mice.

    PubMed

    Tan, Hongmei; Shi, Chengwei; Jiang, Xiaohua; Lavelle, Muriel; Yu, Caijia; Yang, Xiaofeng; Wang, Hong

    2014-01-01

    This study investigated the role and mechanism of Hyperhomocysteinemia (HHcy) on vascular remodeling in mice. We assessed the effect of HHcy on vascular remodeling using a carotid arterial vein patch model in mice with the gene deletion of cystathionine-beta-synthase (Cbs). Vein grafts were harvested 4 weeks after surgery. Cross sections were analyzed using Verhoeff-van Gieson staining, Masson`s Trichrome staining, and immunostaining for morphological analysis and protein level assessment. The effect of Hcy on collagen secretion was examined in cultured rat aortic smooth muscle cells (RASMC). We found that Cbs-/- mice with severe HHcy exhibited thicker neointima and a higher percentage of luminal narrowing in vein grafts. In addition, severe HHcy increased elastin and collagen deposition in the neointima. Further, severe HHcy increases CD45 positive cells and proliferative cells in vein grafts. Finally, Hcy increases collagen secretion in RASMC. These results demonstrate that HHcy increases neointima formation, elastin and collagen deposition following a carotid arterial vein patch. The capacity of Hcy to promote vascular fibrosis and inflammation may contribute to the development of vascular remodeling. PMID:24896329

  14. Myofibroblast-mediated mechanisms of pathological remodelling of the heart.

    PubMed

    Weber, Karl T; Sun, Yao; Bhattacharya, Syamal K; Ahokas, Robert A; Gerling, Ivan C

    2013-01-01

    The syncytium of cardiomyocytes in the heart is tethered within a matrix composed principally of type I fibrillar collagen. The matrix has diverse mechanical functions that ensure the optimal contractile efficiency of this muscular pump. In the diseased heart, cardiomyocytes are lost to necrotic cell death, and phenotypically transformed fibroblast-like cells-termed 'myofibroblasts'-are activated to initiate a 'reparative' fibrosis. The structural integrity of the myocardium is preserved by this scar tissue, although at the expense of its remodelled architecture, which has increased tissue stiffness and propensity to arrhythmias. A persisting population of activated myofibroblasts turns this fibrous tissue into a living 'secretome' that generates angiotensin II and its type 1 receptor, and fibrogenic growth factors (such as transforming growth factor-β), all of which collectively act as a signal-transducer-effector signalling pathway to type I collagen synthesis and, therefore, fibrosis. Persistent myofibroblasts, and the resultant fibrous tissue they produce, cause progressive adverse myocardial remodelling, a pathological hallmark of the failing heart irrespective of its etiologic origin. Herein, we review relevant cellular, subcellular, and molecular mechanisms integral to cardiac fibrosis and consequent remodelling of atria and ventricles with a heterogeneity in cardiomyocyte size. Signalling pathways that antagonize collagen fibrillogenesis provide novel strategies for cardioprotection. PMID:23207731

  15. Remodeling sensory cortical maps implants specific behavioral memory.

    PubMed

    Bieszczad, K M; Miasnikov, A A; Weinberger, N M

    2013-08-29

    Neural mechanisms underlying the capacity of memory to be rich in sensory detail are largely unknown. A candidate mechanism is learning-induced plasticity that remodels the adult sensory cortex. Here, expansion in the primary auditory cortical (A1) tonotopic map of rats was induced by pairing a 3.66-kHz tone with activation of the nucleus basalis, mimicking the effects of natural associative learning. Remodeling of A1 produced de novo specific behavioral memory, but neither memory nor plasticity was consistently at the frequency of the paired tone, which typically decreased in A1 representation. Rather, there was a specific match between individual subjects' area of expansion and the tone that was strongest in each animal's memory, as determined by post-training frequency generalization gradients. These findings provide the first demonstration of a match between the artificial induction of specific neural representational plasticity and artificial induction of behavioral memory. As such, together with prior and present findings for detection, correlation and mimicry of plasticity with the acquisition of memory, they satisfy a key criterion for neural substrates of memory. This demonstrates that directly remodeling sensory cortical maps is sufficient for the specificity of memory formation. PMID:23639876

  16. 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. PMID:26981458

  17. Reconstructing protein remodeled membranes in molecular detail from mesoscopic models

    PubMed Central

    Lyman, Edward; Cui, Haosheng; Voth, Gregory A.

    2014-01-01

    We present a method for “inverse coarse graining,” rebuilding a higher resolution model from a lower resolution one, in order to rebuild protein coats for remodeled membranes of complex topology. The specific case of membrane remodeling by N-BAR domain containing proteins is considered here, although the overall method is general and thus applicable to other membrane remodeling phenomena. Our approach begins with a previously developed, discretized mesoscopic continuum membrane model (EM2) which has been shown to capture the reticulated membrane topologies often observed for N-BAR/liposome systems by electron microscopy (EM). The information in the EM2 model — directions of the local curvatures and a low resolution sample of the membrane surface — is then used to construct a coarse-grained (CG) system with one site per lipid and 26 sites per protein. We demonstrate the approach on pieces of EM2 structures with three different topologies that have been observed by EM: A tubule, a “Y” junction, and a torus. We show that the approach leads to structures that are stable under subsequent constant temperature CG simulation, and end by considering the future application of the methodology as a hybrid approach that combines experimental information with computer modeling. PMID:21503332

  18. Tribbles 3: A potential player in diabetic aortic remodelling.

    PubMed

    Ti, Yun; Xie, Guo-lu; Wang, Zhi-hao; Ding, Wen-yuan; Zhang, Yun; Zhong, Ming; Zhang, Wei

    2016-01-01

    Tribbles 3, whose expression is up-regulated by insulin resistance, was confirmed to be involved in diabetic cardiomyopathy in our previous study. However, it is not known whether Tribbles 3 has a role on conduit arteries such as the aorta in diabetes. Type 2 diabetic rat model was induced by high-fat diet and low-dose streptozotocin. We evaluated the characteristics of diabetic rats by serial ultrasonography and histopathologic analyses of aortic wall architecture. Diabetic rats displayed increased aortic medial thickness, excessive collagen deposition, diminished elastic fibres and reduced vascular compliance together with Tribbles 3 overexpression. To further investigate the role of Tribbles 3 in aortic remodelling, we used Tribbles 3 gene silencing in vivo 12 weeks after onset of diabetes. Silence of Tribbles 3 significantly reversed pathological aortic remodelling without blood pressure modification. In Tribbles 3-small interfering RNA group, medial thickness and perivascular fibrosis were markedly decreased; moreover, there were prominent reductions in collagen content and collagen/elastin ratio, resulting in an improved arterial compliance. Additionally, with Tribbles 3 silencing, the diminished phosphorylation of PI3K/Akt was restored, and increased activation of MKK4/JNK was decreased. Silence of Tribbles 3 is potent in mediating reversal of aortic remodelling, implicating that Tribbles 3 is proposed to be a potential therapeutic target for vascular complication in diabetes. PMID:26410836

  19. The human tri-peptide GHK and tissue remodeling.

    PubMed

    Pickart, Loren

    2008-01-01

    Tissue remodeling follows the initial phase of wound healing and stops inflammatory and scar-forming processes, then restores the normal tissue morphology. The human peptide Gly-(L-His)-(L-Lys) or GHK, has a copper 2+ (Cu(2+)) affinity similar to the copper transport site on albumin and forms GHK-Cu, a complex with Cu(2+). These two molecules activate a plethora of remodeling related processes: (1) chemoattraction of repair cells such as macrophages, mast cells, capillary cells; (2) anti-inflammatory actions (suppression of free radicals, thromboxane formation, release of oxidizing iron, transforming growth factor beta-1, tumor necrosis factor alpha and protein glycation while increasing superoxide dismutase, vessel vasodilation, blocking ultraviolet damage to skin keratinocytes and improving fibroblast recovery after X-ray treatments); (3) increases protein synthesis of collagen, elastin, metalloproteinases, anti-proteases, vascular endothelial growth factor, fibroblast growth factor 2, nerve growth factor, neutrotropins 3 and 4, and erythropoietin; (4) increases the proliferation of fibroblasts and keratinocytes; nerve outgrowth, angiogenesis, and hair follicle size. GHK-Cu stimulates wound healing in numerous models and in humans. Controlled studies on aged skin demonstrated that it tightens skin, improves elasticity and firmness, reduces fine lines, wrinkles, photodamage and hyperpigmentation. GHK-Cu also improves hair transplant success, protects hepatic tissue from tetrachloromethane poisoning, blocks stomach ulcer development, and heals intestinal ulcers and bone tissue. These results are beginning to define the complex biochemical processes that regulate tissue remodeling. PMID:18644225

  20. 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

  1. Arrhythmogenic and metabolic remodelling of failing human heart.

    PubMed

    Gloschat, C R; Koppel, A C; Aras, K K; Brennan, J A; Holzem, K M; Efimov, I R

    2016-07-15

    Heart failure (HF) is a major cause of morbidity and mortality worldwide. The global burden of HF continues to rise, with prevalence rates estimated at 1-2% and incidence approaching 5-10 per 1000 persons annually. The complex pathophysiology of HF impacts virtually all aspects of normal cardiac function - from structure and mechanics to metabolism and electrophysiology - leading to impaired mechanical contraction and sudden cardiac death. Pharmacotherapy and device therapy are the primary methods of treating HF, but neither is able to stop or reverse disease progression. Thus, there is an acute need to translate basic research into improved HF therapy. Animal model investigations are a critical component of HF research. However, the translation from cellular and animal models to the bedside is hampered by significant differences between species and among physiological scales. Our studies over the last 8 years show that hypotheses generated in animal models need to be validated in human in vitro models. Importantly, however, human heart investigations can establish translational platforms for safety and efficacy studies before embarking on costly and risky clinical trials. This review summarizes recent developments in human HF investigations of electrophysiology remodelling, metabolic remodelling, and β-adrenergic remodelling and discusses promising new technologies for HF research. PMID:27019074

  2. On the Strain Rate Sensitivity of Abs and Abs Plus Fused Deposition Modeling Parts

    NASA Astrophysics Data System (ADS)

    Vairis, A.; Petousis, M.; Vidakis, N.; Savvakis, K.

    2016-06-01

    In this work the effect of strain rate on the tensile strength of fused deposition modeling parts built with Acrylonitrile-butadiene-styrene (ABS) and ABS plus material is presented. ASTM D638-02a specimens were built with ABS and ABS plus and they were tested on a Schenck Trebel Co. tensile test machine at three different test speeds, equal, lower, and higher to the test speed required by the ASTM D638-02a standard. The experimental tensile strength results were compared and evaluated. The fracture surfaces of selected specimens were examined with a scanning electron microscope, to determine failure mode of the filament strands. It was found that, as the test speed increases, specimens develop higher tensile strength and have higher elastic modulus. Specimens tested in the highest speed of the experiment had on average about 10% higher elastic modulus and developed on average about 11% higher tensile strength.

  3. Rapid digestion of Cry34Ab1 and Cry35Ab1 in simulated gastric fluid.

    PubMed

    Herman, Rod A; Schafer, Barry W; Korjagin, Valerie A; Ernest, April D

    2003-11-01

    Two genes were identified in Bacillus thuringiensis Berliner (Bt) that code for the proteins that comprise a Cry34Ab1/Cry35Ab1 binary insecticidal crystal protein. Maize, Zea mays L., plants have been transformed to express the Cry34Ab1/Cry35Ab1 proteins, and as a result, these plants are resistant to attack by western corn rootworm, Diabrotica virgifera virgifera LeConte, a major pest in the Midwestern corn-growing area of the U.S.A. As part of the safety assessment for the proteins, digestibility studies were conducted. Digestion experiments with both proteins demonstrated rapid degradation in simulated gastric fluid, comparable to other registered plant-incorporated protectants. Quantitative and qualitative approaches for determining digestibility are illustrated. PMID:14582981

  4. A high-affinity fully human anti-IL-6 mAb (OP-R003-1, 1339) for the treatment of Multiple Myeloma

    PubMed Central

    Fulciniti, Mariateresa; Hideshima, Teru; Vermot-Desroches, Claudine; Pozzi, Samantha; Nanjappa, Puru; Shen, Zhenxin; Patel, Nipun; Smith, Ernest S; Prabhala, Rao; Tai, Yu-tzu; Tassone, Pierfrancesco; Anderson, Kenneth C.; Munshi, Nikhil C.

    2009-01-01

    Purpose We investigated the in vitro and in vivo anti-MM activity of mAb 1339, a high-affinity fully humanized anti-IL-6 mAb (IgG1), alone and in combination with conventional and novel anti-MM agents, as well as its effect on bone turnover. Experimental Design We examined the growth inhibitory effect of 1339 against MM cell lines in the absence and in the presence of bone marrow stromal cells (BMSC) alone or in combination with dexamethasone, bortezomib, perifosine and revlimid. Using the SCID-hu murine model of MM, we also examined the effect of 1339 on MM cell growth and MM bone disease. Results mAb 1339 significantly inhibited growth of MM cell in the presence of BMSC in vitro, associated with inhibition of phosphorylation of STAT3, ERK1/2 and Akt. In addition, mAb 1339 enhanced cytotoxicity induced by dexamethasone as well as bortezomib, lenalidomide, and perifosine in a synergistic fashion. Importantly mAb 1339 significantly enhanced growth inhibitory effects of dexamethasone in vivo in SCID-hu mouse model of MM. mAb 1339 treatment also resulted in inhibition of osteoclastogenesis in vitro and bone remodeling in SCID-hu model. Conclusions Our data confirm both in vitro and in vivo anti-MM activity, as well as inhibition of bone turnover by fully humanized mAb 1339 as a single agent and in combination with conventional and novel agents providing a rationale for its clinical evaluation in MM. PMID:19934301

  5. A gene-centric study of common carotid artery remodelling

    PubMed Central

    Harrison, Seamus C.; Zabaneh, Delilah; Asselbergs, Folkert W.; Drenos, Fotios; Jones, Gregory T.; Shah, Sonia; Gertow, Karl; Sennblad, Bengt; Strawbridge, Rona J.; Gigante, Bruna; Holewijn, Suzanne; De Graaf, Jacqueline; Vermeulen, Sita; Folkersen, Lasse; van Rij, Andre M.; Baldassarre, Damiano; Veglia, Fabrizio; Talmud, Philippa J.; Deanfield, John E.; Agu, Obi; Kivimaki, Mika; Kumari, Meena; Bown, Matthew J.; Nyyssönen, Kristiina; Rauramaa, Rainer; Smit, Andries J.; Franco-Cereceda, Anders; Giral, Philippe; Mannarino, Elmo; Silveira, Angela; Syvänen, Ann-Christine; de Borst, Gert J.; van der Graaf, Yolanda; de Faire, Ulf; Baas, Annette F.; Blankensteijn, Jan D.; Wareham, Nicholas J.; Fowkes, Gerry; Tzoulaki, Ionna; Price, Jacqueline F.; Tremoli, Elena; Hingorani, Aroon D.; Eriksson, Per; Hamsten, Anders; Humphries, Steve E.

    2013-01-01

    Background Expansive remodelling is the process of compensatory arterial enlargement in response to atherosclerotic stimuli. The genetic determinants of this process are poorly characterized. Methods Genetic association analyses of inter-adventitial common carotid artery diameter (ICCAD) in the IMPROVE study (n = 3427) using the Illumina 200k Metabochip was performed. Single nucleotide polymorphisms (SNPs) that met array-wide significance were taken forward for analysis in three further studies (n = 5704), and tested for association with Abdominal Aortic Aneurysm (AAA). Results rs3768445 on Chromosome 1q24.3, in a cluster of protein coding genes (DNM3, PIGC, C1orf105) was associated with larger ICCAD in the IMPROVE study. For each copy of the rare allele carried, ICCAD was on average 0.13 mm greater (95% CI 0.08–0.18 mm, P = 8.2 × 10−8). A proxy SNP (rs4916251, R2 = 0.99) did not, however, show association with ICCAD in three follow-up studies (P for replication = 0.29). There was evidence of interaction between carotid intima-media thickness (CIMT) and rs4916251 on ICCAD in two of the cohorts studies suggesting that it plays a role in the remodelling response to atherosclerosis. In meta-analysis of 5 case–control studies pooling data from 5007 cases and 43,630 controls, rs4916251 was associated with presence of AAA 1.10, 95% CI 1.03–1.17, p = 2.8 × 10−3, I2 = 18.8, Q = 0.30). A proxy SNP, rs4916251 was also associated with increased expression of PIGC in aortic tissue, suggesting that this may the mechanism by which this locus affects vascular remodelling. Conclusions Common variation at 1q24.3 is associated with expansive vascular remodelling and risk of AAA. These findings support a hypothesis that pathways involved in systemic vascular remodelling play a role in AAA development. PMID:23246012

  6. Ab initio infrared and Raman spectra

    NASA Astrophysics Data System (ADS)

    Fredkin, Donald R.; Komornicki, Andrew; White, Steven R.; Wilson, Kent R.

    1983-06-01

    We discuss several ways in which molecular absorption and scattering spectra can be computed ab initio, from the fundamental constants of nature. These methods can be divided into two general categories. In the first, or sequential, type of approach, one first solves the electronic part of the Schrödinger equation in the Born-Oppenheimer approximation, mapping out the potential energy, dipole moment vector (for infrared absorption) and polarizability tensor (for Raman scattering) as functions of nuclear coordinates. Having completed the electronic part of the calculation, one then solves the nuclear part of the problem either classically or quantum mechanically. As an example of the sequential ab initio approach, the infrared and Raman rotational and vibrational-rotational spectral band contours for the water molecule are computed in the simplest rigid rotor, normal mode approximation. Quantum techniques are used to calculate the necessary potential energy, dipole moment, and polarizability information at the equilibrium geometry. A new quick, accurate, and easy to program classical technique involving no reference to Euler angles or special functions is developed to compute the infrared and Raman band contours for any rigid rotor, including asymmetric tops. A second, or simultaneous, type of ab initio approach is suggested for large systems, particularly those for which normal mode analysis is inappropriate, such as liquids, clusters, or floppy molecules. Then the curse of dimensionality prevents mapping out in advance the complete potential, dipole moment, and polarizability functions over the whole space of nuclear positions of all atoms, and a solution in which the electronic and nuclear parts of the Born-Oppenheimer approximation are simultaneously solved is needed. A quantum force classical trajectory (QFCT) molecular dynamic method, based on linear response theory, is described, in which the forces, dipole moment, and polarizability are computed quantum

  7. Epigenetic Regulation by ATP-Dependent Chromatin-Remodeling Enzymes: SNF-ing Out Crosstalk.

    PubMed

    Runge, John S; Raab, Jesse R; Magnuson, Terry

    2016-01-01

    Cells utilize precise mechanisms to access genomic DNA with spatiotemporal accuracy. ATP-dependent chromatin-remodeling enzymes (also known simply as "remodelers") comprise a specialized class of enzymes that is intimately involved in genomic organization and accessibility. Remodelers selectively position nucleosomes to either alleviate chromatin compaction or achieve genomic condensation locally, based on a multitude of cellular signals. By dictating nucleosome position, remodelers control local euchromatic and heterochromatic states. These activities govern the accessibility of regulatory regions like promoters and enhancers to transcription factors, RNA polymerases, and coactivators or -repressors. As studies unravel the complexities of epigenetic topography, evidence points to a chromatin-based interactome where regulators interact competitively, cooperatively, and/or codependently through physical and functional means. These types of interactions, or crosstalk, between remodelers raise important questions for tissue development. Here, we briefly review the evidence for remodeler interactions and argue for additional studies examining crosstalk. PMID:26969969

  8. Collective rotation from ab initio theory

    NASA Astrophysics Data System (ADS)

    Caprio, Mark A.; Maris, Pieter; Vary, James P.

    2015-10-01

    The challenge of ab initio nuclear theory is to quantitatively predict the complex and highly-correlated behavior of the nuclear many-body system, starting from the underlying internucleon interactions. We may now seek to understand the wealth of nuclear collective phenomena through ab initio approaches. No-core configuration interaction (NCCI) calculations for p-shell nuclei give rise to rotational bands, as evidenced by rotational patterns for excitation energies, electromagnetic moments, and electromagnetic transitions. In this talk, the intrinsic structure of these bands is discussed, and the predicted rotational bands are compared to experiment. Supported by the US DOE under Award Nos. DE-FG02-95ER-40934, DESC0008485 (SciDAC/NUCLEI), and DE-FG02-87ER40371 and the US NSF under Award No. 0904782. Computational resources provided by NERSC (US DOE Contract No. DE-AC02-05CH11231).

  9. Ab initio infrared and Raman spectra

    NASA Technical Reports Server (NTRS)

    Fredkin, D. R.; White, S. R.; Wilson, K. R.; Komornicki, A.

    1983-01-01

    It is pointed out that with increased computer power and improved computational techniques, such as the gradients developed in recent years, it is becoming practical to compute spectra ab initio, from the fundamental constants of nature, for systems of increasing complexity. The present investigation has the objective to explore several possible ab initio approaches to spectra, giving particular attention to infrared and nonresonance Raman. Two approaches are discussed. The sequential approach, in which first the electronic part and then later the nuclear part of the Born-Oppenheimer approximation is solved, is appropriate for small systems. The simultaneous approach, in which the electronic and nuclear parts are solved at the same time, is more appropriate for many-atom systems. A review of the newer quantum gradient techniques is provided, and the infrared and Raman spectral band contours for the water molecule are computed.

  10. Interaction of vermiculite with Katamin AB

    SciTech Connect

    Veksler, V.I.; Makashev, Yu.A.; Mikhailova, V.N.; Aleksandrova, E.M.; Vinogradova, I.A.

    1986-12-10

    Vermiculite can interact with quaternary ammonium salts to form organmineral compounds in the ion-exchange adsorption of these salts from waste water. This paper investigates this interaction between vermiculite and Katamin AB, a commercial cationic surfactant consisting of an aqueous solution of alkylbenyldimethylammonium chloride homologs. It is shown that ion exchange and molecular sorption occur simultaneously during the interaction and that vermiculite is a highly effective adsorbent in process water purification.

  11. Ab initio vel ex eventu. II

    NASA Astrophysics Data System (ADS)

    Thiessen, P. A.; Treder, H.-J.

    Jedes initium wird durch experimenta crucis zum eventus. Jedes theoretisch interpretierbare ex-eventu-Resultat führt auf ein neues Initium. Gerade dies ist die gemeinsame Aussage von Atomistik, Quantenmechanik und Relativitätstheorie.Translated AbstractAb initio vel ex eventu. IIEvery initium becomes an eventus by experimenta crucis. Every theoretically interpretable ex-eventu result leads to a new initium. Right this is the joint assertion of atomism, quantum mechanics, and relativity.

  12. Protective effects of activated protein C on neurovascular unit in a rat model of intrauterine infection-induced neonatal white matter injury.

    PubMed

    Jin, Sheng-juan; Liu, Yan; Deng, Shi-hua; Lin, Tu-lian; Rashid, Abid; Liao, Li-hong; Ning, Qin; Luo, Xiao-ping

    2015-12-01

    Activated protein C (APC), a natural anticoagulant, has been reported to exert direct vasculoprotective, neural protective, anti-inflammatory, and proneurogenic activities in the central nervous system. This study was aimed to explore the neuroprotective effects and potential mechanisms of APC on the neurovascular unit of neonatal rats with intrauterine infection-induced white matter injury. Intraperitoneal injection of 300 μg/kg lipopolysaccharide (LPS) was administered consecutively to pregnant Sprague-Dawley rats at embryonic days 19 and 20 to establish the rat model of intrauterine infection- induced white matter injury. Control rats were injected with an equivalent amount of sterile saline on the same time. APC at the dosage of 0.2 mg/kg was intraperitoneally injected to neonatal rats immediately after birth. Brain tissues were collected at postnatal day 7 and stained with hematoxylin and eosin (H&E). Immunohistochemistry was used to evaluate myelin basic protein (MBP) expression in the periventricular white matter region. Blood-brain barrier (BBB) permeability and brain water content were measured using Evens Blue dye and wet/dry weight method. Double immunofluorescence staining and real-time quantitative PCR were performed to detect microglial activation and the expression of protease activated receptor 1 (PAR1). Typical pathological changes of white matter injury were observed in rat brains exposed to LPS, and MBP expression in the periventricular region was significantly decreased. BBB was disrupted and the brain water content was increased. Microglia were largely activated and the mRNA and protein levels of PAR1 were elevated. APC administration ameliorated the pathological lesions of the white matter and increased MBP expression. BBB permeability and brain water content were reduced. Microglia activation was inhibited and the PAR1 mRNA and protein expression levels were both down-regulated. Our results suggested that APC exerted neuroprotective effects

  13. Ab initio Bogoliubov coupled cluster theory

    NASA Astrophysics Data System (ADS)

    Signoracci, Angelo; Hagen, Gaute; Duguet, Thomas

    2014-09-01

    Coupled cluster (CC) theory has become a standard method in nuclear theory for realistic ab initio calculations of medium mass nuclei, but remains limited by its requirement of a Slater determinant reference state which reasonably approximates the nuclear system of interest. Extensions of the method, such as equation-of-motion CC, permit the calculation of nuclei with one or two nucleons added or removed from a doubly magic core, yet still only a few dozen nuclei are accessible with modern computational restrictions. In order to extend the applicability of ab initio methods to open-shell systems, the superfluid nature of nuclei must be taken into account. By utilizing Bogoliubov algebra and employing spontaneous symmetry breaking with respect to particle number conservation, superfluid systems can be treated by a single reference state. An ab initio theory to include correlations on top of a Bogoliubov reference state has been developed in the guise of standard CC theory. The formalism and first results of this Bogoliubov coupled cluster theory will be presented to demonstrate the applicability of the method.

  14. Ab interno trabeculectomy: patient selection and perspectives

    PubMed Central

    Vinod, Kateki; Gedde, Steven J

    2016-01-01

    Ab interno trabeculectomy is one among several recently introduced minimally invasive glaucoma surgeries that avoid a conjunctival incision and full-thickness sclerostomy involved in traditional glaucoma surgery. Ablation of the trabecular meshwork and inner wall of Schlemm’s canal is performed in an arcuate fashion via a clear corneal incision, alone or in combination with phacoemulsification cataract surgery. Intraocular pressure reduction following ab interno trabeculectomy is limited by resistance in distal outflow pathways and generally stabilizes in the mid-to-high teens. Relief of medication burden has been demonstrated by some studies. A very low rate of complications, most commonly transient hyphema and intraocular pressure elevations in the immediate postoperative period, have been reported. However, available data are derived from small retrospective and prospective case series. Randomized, controlled trials are needed to better elucidate the potential merits of ab interno trabeculectomy in the combined setting versus phacoemulsification cataract surgery alone and to compare it with other minimally invasive glaucoma surgeries. PMID:27574396

  15. Ab-inition melting curve of titanium

    NASA Astrophysics Data System (ADS)

    Stutzmann, Vincent; Bouchet, Johann; Bottin, Francois

    2014-03-01

    Thermodynamical properties of titanium are of great interest for aerospace and aviation industries and many studies are done in order to understand its behaviour under pressure (P) and temperature (T) : phase transitions at low T, melting curve at high T and P. In this work we compute the first ab-initio melting curve of titanium. This one is obtained with the Abinit package using DFT, in the GGA approximation, and in the framework of the projector augmented wave method (PAW). At first, we perform ground state calculations and study the five allotropic phases of titanium. Two PAW atomic data are generated with two different cutoff radius. The larger one gives results near previews ab-initio calculations, whereas the smaller one gives results near all electron calculation. Using the second PAW atomic data and performing ab-initio molecular dynamic simulations, we then compute the melting curve of titanium with three different methods. Results show relevance of our calculations, but also discrepencies with experimental data.

  16. Alteration of Pulse Pressure Stimulates Arterial Wall Matrix Remodeling

    PubMed Central

    Yao, Qingping; Hayman, Danika M.; Dai, Qiuxia; Lindsey, Merry L.; Han, Hai-Chao

    2010-01-01

    The effect of pulse pressure on arterial wall remodeling remains unclear, although remodeling of the arterial wall under hypertensive pressure and elevated flow has been well documented. The objective of this study was to evaluate matrix remodeling in arteries under nonpulsatile and hyperpulsatile pressure as compared to arteries under normal pulsatile pressure. Using a novel ex vivo organ culture model that allowed us to change pressure pulsatility without changing mean pressure or flow, arteries were cultured for 7 days under normal, nonpulsatile, and hyperpulsatile pressures with the same mean pressure and flow rate. Fenestrae in internal elastic lamina (IEL), collagen content, connexin 43, and fibronectin proteins were examined in these arteries using confocal microscopy, immunoblotting, and immunohistochemistry. Our results showed that the mean fenestrae size and area fraction of fenestrae to total area of IEL decreased 51 % and 45 % in arteries cultured under nonpulsatile pressure and decreased 45 % and 54 % under hyperpulsatile pressure, respectively, compared to arteries under normal pulsatile pressure. There was no difference in fibronectin (FN) and collagen III levels among the three pulse groups, while collagen I and connexin 43 expression increased 80.8% and 35.3% in the hyperpulsatile arteries, respectively, but not in nonpulsatile arteries. In conclusion, our results demonstrated, for the first time, that an increase or elimination in pulse pressure from its normal physiologic level stimulates arterial wall matrix structural changes. Hyperpulsatile pressure has a more pronounced effect than the diminished pulse pressure, which may provide a mechanism for increased wall stiffness in arteries under hyperpulsatile pressure. PMID:19831481

  17. Extracellular Ubiquitin: Role in Myocyte Apoptosis and Myocardial Remodeling.

    PubMed

    Scofield, Stephanie L C; Amin, Parthiv; Singh, Mahipal; Singh, Krishna

    2015-01-01

    Ubiquitin (UB) is a highly conserved low molecular weight (8.5 kDa) protein. It consists of 76 amino acid residues and is found in all eukaryotic cells. The covalent linkage of UB to a variety of cellular proteins (ubiquitination) is one of the most common posttranslational modifications in eukaryotic cells. This modification generally regulates protein turnover and protects the cells from damaged or misfolded proteins. The polyubiquitination of proteins serves as a signal for degradation via the 26S proteasome pathway. UB is present in trace amounts in body fluids. Elevated levels of UB are described in the serum or plasma of patients under a variety of conditions. Extracellular UB is proposed to have pleiotropic roles including regulation of immune response, anti-inflammatory, and neuroprotective activities. CXCR4 is identified as receptor for extracellular UB in hematopoietic cells. Heart failure represents a major cause of morbidity and mortality in western society. Cardiac remodeling is a determinant of the clinical course of heart failure. The components involved in myocardial remodeling include-myocytes, fibroblasts, interstitium, and coronary vasculature. Increased sympathetic nerve activity in the form of norepinephrine is a common feature during heart failure. Acting via β-adrenergic receptor (β-AR), norepinephrine is shown to induce myocyte apoptosis and myocardial fibrosis. β-AR stimulation increases extracellular levels of UB in myocytes, and UB inhibits β-AR-stimulated increases in myocyte apoptosis and myocardial fibrosis. This review summarizes intracellular and extracellular functions of UB with particular emphasis on the role of extracellular UB in cardiac myocyte apoptosis and myocardial remodeling. PMID:26756642

  18. Galectin-3 Participates in Cardiovascular Remodeling Associated With Obesity.

    PubMed

    Martínez-Martínez, Ernesto; López-Ándres, Natalia; Jurado-López, Raquel; Rousseau, Elodie; Bartolomé, Mará Visitación; Fernández-Celis, Amaya; Rossignol, Patrick; Islas, Fabian; Antequera, Alfonso; Prieto, Santiago; Luaces, María; Cachofeiro, Victoria

    2015-11-01

    Remodeling, diastolic dysfunction, and arterial stiffness are some of the alterations through which obesity affects the cardiovascular system. Fibrosis and inflammation are important mechanisms underlying cardiovascular remodeling, although the precise promoters involved in these processes are still unclear. Galectin-3 (Gal-3) induces inflammation and fibrosis in the cardiovascular system. We have investigated the potential role of Gal-3 in cardiac damage in morbidly obese patients, and we have evaluated the protective effect of the Gal-3 inhibition in the occurrence of cardiovascular fibrosis and inflammation in an experimental model of obesity. Morbid obesity is associated with alterations in cardiac remodeling, mainly left ventricular hypertrophy and diastolic dysfunction. Obesity and hypertension are the main determinants of left ventricular hypertrophy. Insulin resistance, left ventricular hypertrophy, and circulating levels of C-reactive protein and Gal-3 are associated with a worsening of diastolic function in morbidly obese patients. Obesity upregulates Gal-3 production in the cardiovascular system in a normotensive animal model of diet-induced obesity by feeding for 6 weeks a high-fat diet (33.5% fat). Gal-3 inhibition with modified citrus pectin (100 mg/kg per day) reduced cardiovascular levels of Gal-3, total collagen, collagen I, transforming and connective growth factors, osteopontin, and monocyte chemoattractant protein-1 in the heart and aorta of obese animals without changes in body weight or blood pressure. In morbidly obese patients, Gal-3 levels are associated with diastolic dysfunction. In obese animals, Gal-3 blockade decreases cardiovascular fibrosis and inflammation. These data suggest that Gal-3 could be a novel therapeutic target in cardiac fibrosis and inflammation associated with obesity. PMID:26351031

  19. Hypothyroidism and Its Rapid Correction Alter Cardiac Remodeling

    PubMed Central

    Itani, Tarek; Moubarak, Majed; Aftimos, Georges; Farès, Nassim

    2014-01-01

    The cardiovascular effects of mild and overt thyroid disease include a vast array of pathological changes. As well, thyroid replacement therapy has been suggested for preserving cardiac function. However, the influence of thyroid hormones on cardiac remodeling has not been thoroughly investigated at the molecular and cellular levels. The purpose of this paper is to study the effect of hypothyroidism and thyroid replacement therapy on cardiac alterations. Thirty Wistar rats were divided into 2 groups: a control (n = 10) group and a group treated with 6-propyl-2-thiouracil (PTU) (n = 20) to induce hypothyroidism. Ten of the 20 rats in the PTU group were then treated with L-thyroxine to quickly re-establish euthyroidism. The serum levels of inflammatory markers, such as C-reactive protein (CRP), tumor necrosis factor alpha (TNF-α), interleukin 6 (IL6) and pro-fibrotic transforming growth factor beta 1 (TGF-β1), were significantly increased in hypothyroid rats; elevations in cardiac stress markers, brain natriuretic peptide (BNP) and cardiac troponin T (cTnT) were also noted. The expressions of cardiac remodeling genes were induced in hypothyroid rats in parallel with the development of fibrosis, and a decline in cardiac function with chamber dilation was measured by echocardiography. Rapidly reversing the hypothyroidism and restoring the euthyroid state improved cardiac function with a decrease in the levels of cardiac remodeling markers. However, this change further increased the levels of inflammatory and fibrotic markers in the plasma and heart and led to myocardial cellular infiltration. In conclusion, we showed that hypothyroidism is related to cardiac function decline, fibrosis and inflammation; most importantly, the rapid correction of hypothyroidism led to cardiac injuries. Our results might offer new insights for the management of hypothyroidism-induced heart disease. PMID:25333636

  20. VEGF receptors mediate hypoxic remodeling of adult ovine carotid arteries.

    PubMed

    Adeoye, Olayemi O; Bouthors, Vincent; Hubbell, Margaret C; Williams, James M; Pearce, William J

    2014-10-01

    Recent studies suggest that VEGF contributes to hypoxic remodeling of arterial smooth muscle, although hypoxia produces only transient increases in VEGF that return to normoxic levels despite sustained changes in arterial structure and function. To explore how VEGF might contribute to long-term hypoxic vascular remodeling, this study explores the hypothesis that chronic hypoxia produces sustained increases in smooth muscle VEGF receptor density that mediate long-term vascular effects of hypoxia. Carotid arteries from adult sheep maintained at sea level or altitude (3,820 m) for 110 days were harvested and denuded of endothelium. VEGF levels were similar in chronically hypoxic and normoxic arteries, as determined by immunoblotting. In contrast, VEGF receptor levels were significantly increased by 107% (VEGF-R1) and 156% (VEGF-R2) in hypoxic compared with normoxic arteries. In arteries that were organ cultured 24 h with 3 nM VEGF, VEGF replicated effects of hypoxia on abundances of smooth muscle α actin (SMαA), myosin light chain kinase (MLCK), and MLC20 and the effects of hypoxia on colocalization of MLC20 with SMαA, as measured via confocal microscopy. VEGF did not replicate the effects of chronic hypoxia on colocalization of MLCK with SMαA or MLCK with MLC20, suggesting that VEGF's role in hypoxic remodeling is highly protein specific, particularly for contractile protein organization. VEGF effects in organ culture were inhibited by VEGF receptor blockers vatalinib (240 nM) and dasatinib (6.3 nM). These findings support the hypothesis that long-term upregulation of VEGF receptors help mediate sustained effects of hypoxia on the abundance and colocalization of contractile proteins in arterial smooth muscle. PMID:25038104

  1. Ghrelin signaling in heart remodeling of adult obese mice.

    PubMed

    Lacerda-Miranda, Glauciane; Soares, Vivian M; Vieira, Anatalia K G; Lessa, Juliana G; Rodrigues-Cunha, Alessandra C S; Cortez, Erika; Garcia-Souza, Erica P; Moura, Anibal S

    2012-05-01

    Ghrelin, an endogenous ligand of the growth hormone secretagogue receptor (GHS-R), has been suggested to be associated to obesity, insulin secretion, cardiovascular growth and homeostasis. GHS-R has been found in most of the tissues, and among the hormone action it is included the regulation of heart energy metabolism. Therefore, hypernutrition during early life leads to obesity, induces cardiac hypertrophy, compromises myocardial function, inducing heart failure in adulthood. We examined ghrelin signaling process in cardiac remodeling in these obese adult mice. The cardiomyocytes (cmy) of left ventricle were analyzed by light microscopy and stereology, content and phosphorilation of cardiac proteins: ghrelin receptor (growth hormone secretagogue receptor 1a, GHSR-1a), protein kinase B (AKT and pAKT), phosphatidil inositol 3 kinase (PI3K), AMP-activated protein kinase (AMPK and pAMPK) and actin were achieved by Western blotting. GHSR-1a gene expression was analyzed by Real Time-PCR. We observed hyperglycemia and higher liver and visceral fat weight in obese when compared to control group. Obese mice presented a marked increase in heart weight/tibia length, indicating an enlarged heart size or a remodeling process. Obese mice had increased GHSR-1a content and expression in the heart associated to PI3K content and increased AKT content and phosphorylation. In contrast, AMPK content and phosphorylation in heart was not different between experimental groups. Ghrelin plasma levels in obese group were decreased when compared to control group. Our data suggest that remodeled myocardial in adult obese mice overnourished in early life are associated with higher phosphorylation of GHSR-1a, PI3K and AKT but not with AMPK. PMID:22407166

  2. Global remodeling of nucleosome positions in C. elegans

    PubMed Central

    2013-01-01

    Background Eukaryotic chromatin architecture is affected by intrinsic histone-DNA sequence preferences, steric exclusion between nucleosome particles, formation of higher-order structures, and in vivo activity of chromatin remodeling enzymes. Results To disentangle sequence-dependent nucleosome positioning from the other factors, we have created two high-throughput maps of nucleosomes assembled in vitro on genomic DNA from the nematode worm Caenorhabditis elegans. A comparison of in vitro nucleosome positions with those observed in a mixed-stage, mixed-tissue population of C. elegans cells reveals that in vivo sequence preferences are modified on the genomic scale. Indeed, G/C dinucleotides are predicted to be most favorable for nucleosome formation in vitro but not in vivo. Nucleosome sequence read coverage in vivo is distinctly lower in chromosome arms than in central regions; the observed changes in apparent nucleosome sequence specificity, likely due to genome-wide chromatin remodeler activity, contribute to the formation of these megabase-scale chromatin domains. We also observe that the majority of well-positioned in vivo nucleosomes do not occupy thermodynamically favorable sequences observed in vitro. Finally, we find that exons are intrinsically more amenable to nucleosome formation compared to introns. Nucleosome occupancy of introns and exons consistently increases with G/C content in vitro but not in vivo, in agreement with our observation that G/C dinucleotide enrichment does not strongly promote in vivo nucleosome formation. Conclusions Our findings highlight the importance of both sequence specificity and active nucleosome repositioning in creating large-scale chromatin domains, and the antagonistic roles of intrinsic sequence preferences and chromatin remodelers in C. elegans. Sequence read data has been deposited into Sequence Read Archive (http://www.ncbi.nlm.nih.gov/sra; accession number SRA050182). Additional data, software and computational

  3. Phosphodiesterase 10A Upregulation Contributes to Pulmonary Vascular Remodeling

    PubMed Central

    Tian, Xia; Vroom, Christina; Ghofrani, Hossein Ardeschir; Weissmann, Norbert; Bieniek, Ewa; Grimminger, Friedrich; Seeger, Werner; Schermuly, Ralph Theo; Pullamsetti, Soni Savai

    2011-01-01

    Phosphodiesterases (PDEs) modulate the cellular proliferation involved in the pathophysiology of pulmonary hypertension (PH) by hydrolyzing cAMP and cGMP. The present study was designed to determine whether any of the recently identified PDEs (PDE7-PDE11) contribute to progressive pulmonary vascular remodeling in PH. All in vitro experiments were performed with lung tissue or pulmonary arterial smooth muscle cells (PASMCs) obtained from control rats or monocrotaline (MCT)-induced pulmonary hypertensive (MCT-PH) rats, and we examined the effects of the PDE10 inhibitor papaverine (Pap) and specific small interfering RNA (siRNA). In addition, papaverine was administrated to MCT-induced PH rats from day 21 to day 35 by continuous intravenous infusion to examine the in vivo effects of PDE10A inhibition. We found that PDE10A was predominantly present in the lung vasculature, and the mRNA, protein, and activity levels of PDE10A were all significantly increased in MCT PASMCs compared with control PASMCs. Papaverine and PDE10A siRNA induced an accumulation of intracellular cAMP, activated cAMP response element binding protein and attenuated PASMC proliferation. Intravenous infusion of papaverine in MCT-PH rats resulted in a 40%–50% attenuation of the effects on pulmonary hypertensive hemodynamic parameters and pulmonary vascular remodeling. The present study is the first to demonstrate a central role of PDE10A in progressive pulmonary vascular remodeling, and the results suggest a novel therapeutic approach for the treatment of PH. PMID:21494592

  4. Phosphodiesterase 10A upregulation contributes to pulmonary vascular remodeling.

    PubMed

    Tian, Xia; Vroom, Christina; Ghofrani, Hossein Ardeschir; Weissmann, Norbert; Bieniek, Ewa; Grimminger, Friedrich; Seeger, Werner; Schermuly, Ralph Theo; Pullamsetti, Soni Savai

    2011-01-01

    Phosphodiesterases (PDEs) modulate the cellular proliferation involved in the pathophysiology of pulmonary hypertension (PH) by hydrolyzing cAMP and cGMP. The present study was designed to determine whether any of the recently identified PDEs (PDE7-PDE11) contribute to progressive pulmonary vascular remodeling in PH. All in vitro experiments were performed with lung tissue or pulmonary arterial smooth muscle cells (PASMCs) obtained from control rats or monocrotaline (MCT)-induced pulmonary hypertensive (MCT-PH) rats, and we examined the effects of the PDE10 inhibitor papaverine (Pap) and specific small interfering RNA (siRNA). In addition, papaverine was administrated to MCT-induced PH rats from day 21 to day 35 by continuous intravenous infusion to examine the in vivo effects of PDE10A inhibition. We found that PDE10A was predominantly present in the lung vasculature, and the mRNA, protein, and activity levels of PDE10A were all significantly increased in MCT PASMCs compared with control PASMCs. Papaverine and PDE10A siRNA induced an accumulation of intracellular cAMP, activated cAMP response element binding protein and attenuated PASMC proliferation. Intravenous infusion of papaverine in MCT-PH rats resulted in a 40%-50% attenuation of the effects on pulmonary hypertensive hemodynamic parameters and pulmonary vascular remodeling. The present study is the first to demonstrate a central role of PDE10A in progressive pulmonary vascular remodeling, and the results suggest a novel therapeutic approach for the treatment of PH. PMID:21494592

  5. Systemic and Pulmonary Vascular Remodelling in Chronic Obstructive Pulmonary Disease

    PubMed Central

    Muñoz-Esquerre, Mariana; López-Sánchez, Marta; Escobar, Ignacio; Huertas, Daniel; Penín, Rosa; Molina-Molina, María; Manresa, Frederic; Dorca, Jordi; Santos, Salud

    2016-01-01

    Background Chronic Obstructive Pulmonary Disease (COPD) is associated with subclinical systemic atherosclerosis and pulmonary vascular remodelling characterized by intimal hyperplasia and luminal narrowing. We aimed to determine differences in the intimal thickening of systemic and pulmonary arteries in COPD subjects and smokers. Secondary aims include comparisons with a non-smokers group; determining the clinical variables associated with systemic and pulmonary intimal thickening, and the correlations between systemic and pulmonary remodelling changes. Methods All consecutive subjects undergoing lung resection were included and divided into 3 groups: 1) COPD, 2) smokers, and 3) non-smokers. Sections of the 5th intercostal artery and muscular pulmonary arteries were measured by histo-morphometry. Four parameters of intimal thickening were evaluated: 1) percentage of intimal area (%IA), 2) percentage of luminal narrowing, 3) intimal thickness index, and 4) intima-to-media ratio. Results In the adjusted analysis, the systemic arteries of COPD subjects showed greater intimal thickening (%IA) than those of smokers (15.6±1.5% vs. 14.2±1.6%, p = 0.038). In the pulmonary arteries, significant differences were observed for %IA between the 2 groups (37.3±2.2% vs. 29.3±2.3%, p = 0.016). Among clinical factors, metabolic syndrome, gender and COPD status were associated with the systemic intimal thickening, while only COPD status was associated with pulmonary intimal thickening. A correlation between the %IA of the systemic and pulmonary arteries was observed (Spearman’s rho = 0.46, p = 0.008). Conclusions Greater intimal thickening in systemic and pulmonary arteries is observed in COPD patients than in smokers. There is a correlation between systemic and pulmonary vascular remodelling in the overall population. PMID:27046203

  6. Hypothyroidism and its rapid correction alter cardiac remodeling.

    PubMed

    Hajje, Georges; Saliba, Youakim; Itani, Tarek; Moubarak, Majed; Aftimos, Georges; Farès, Nassim

    2014-01-01

    The cardiovascular effects of mild and overt thyroid disease include a vast array of pathological changes. As well, thyroid replacement therapy has been suggested for preserving cardiac function. However, the influence of thyroid hormones on cardiac remodeling has not been thoroughly investigated at the molecular and cellular levels. The purpose of this paper is to study the effect of hypothyroidism and thyroid replacement therapy on cardiac alterations. Thirty Wistar rats were divided into 2 groups: a control (n = 10) group and a group treated with 6-propyl-2-thiouracil (PTU) (n = 20) to induce hypothyroidism. Ten of the 20 rats in the PTU group were then treated with L-thyroxine to quickly re-establish euthyroidism. The serum levels of inflammatory markers, such as C-reactive protein (CRP), tumor necrosis factor alpha (TNF-α), interleukin 6 (IL6) and pro-fibrotic transforming growth factor beta 1 (TGF-β1), were significantly increased in hypothyroid rats; elevations in cardiac stress markers, brain natriuretic peptide (BNP) and cardiac troponin T (cTnT) were also noted. The expressions of cardiac remodeling genes were induced in hypothyroid rats in parallel with the development of fibrosis, and a decline in cardiac function with chamber dilation was measured by echocardiography. Rapidly reversing the hypothyroidism and restoring the euthyroid state improved cardiac function with a decrease in the levels of cardiac remodeling markers. However, this change further increased the levels of inflammatory and fibrotic markers in the plasma and heart and led to myocardial cellular infiltration. In conclusion, we showed that hypothyroidism is related to cardiac function decline, fibrosis and inflammation; most importantly, the rapid correction of hypothyroidism led to cardiac injuries. Our results might offer new insights for the management of hypothyroidism-induced heart disease. PMID:25333636

  7. Atrial Remodeling and Atrial Tachyarrhythmias in Arrhythmogenic Right Ventricular Cardiomyopathy.

    PubMed

    Wu, Lingmin; Guo, Jinrui; Zheng, Lihui; Chen, Gang; Ding, Ligang; Qiao, Yu; Sun, Wei; Yao, Yan; Zhang, Shu

    2016-09-01

    Less is known about atrial remodeling and atrial tachyarrhythmias (ATa) in arrhythmogenic right ventricular cardiomyopathy (ARVC); this cross-sectional study aimed to determine the prevalence, characterization, and predictors of atrial remodeling and ATa in a large series of patients with ARVC. From February 2004 to September 2014, 294 consecutive patients who met the task force criteria for ARVC were enrolled. The prevalence, characterization, and predictors of atrial dilation and ATa were investigated. Right atrium (RA) dilation was identified in 160 patients (54.4%) and left atrium dilation in 66 patients (22.4%). Both RA and left atrium dilation were found in 44 patients (15.0%). Twenty-five patients (8.5%) had atrial fibrillation (AF), whereas 19 patients (6.5%) had atrial flutter (AFL). Of which, 7 patients (2.4%) had both AF and AFL. Multivariate analysis showed that AFL (odds ratio [OR] 10.309; 95% confidence interval [CI] 2.770 to 38.462; p <0.001), hypertension (OR 9.174; 95% CI 2.364 to 35.714; p = 0.001), and RA dilation (OR 6.993; 95% CI 1.623 to 30.303; p = 0.009) were associated with increased risk for AF. AF (OR 10.526; 95% CI 2.786 to 40.000; p = 0.001) increased the risk of AFL. In conclusion, atrial remodeling and ATa were common in patients with ARVC. PMID:27378141

  8. High molecular weight fibroblast growth factor-2 in the human heart is a potential target for prevention of cardiac remodeling.

    PubMed

    Santiago, Jon-Jon; McNaughton, Leslie J; Koleini, Navid; Ma, Xin; Bestvater, Brian; Nickel, Barbara E; Fandrich, Robert R; Wigle, Jeffrey T; Freed, Darren H; Arora, Rakesh C; Kardami, Elissavet

    2014-01-01

    Fibroblast growth factor 2 (FGF-2) is a multifunctional protein synthesized as high (Hi-) and low (Lo-) molecular weight isoforms. Studies using rodent models showed that Hi- and Lo-FGF-2 exert distinct biological activities: after myocardial infarction, rat Lo-FGF-2, but not Hi-FGF-2, promoted sustained cardioprotection and angiogenesis, while Hi-FGF-2, but not Lo-FGF-2, promoted myocardial hypertrophy and reduced contractile function. Because there is no information regarding Hi-FGF-2 in human myocardium, we undertook to investigate expression, regulation, secretion and potential tissue remodeling-associated activities of human cardiac (atrial) Hi-FGF-2. Human patient-derived atrial tissue extracts, as well as pericardial fluid, contained Hi-FGF-2 isoforms, comprising, respectively, 53%(±20 SD) and 68% (±25 SD) of total FGF-2, assessed by western blotting. Human atrial tissue-derived primary myofibroblasts (hMFs) expressed and secreted predominantly Hi-FGF-2, at about 80% of total. Angiotensin II (Ang II) up-regulated Hi-FGF-2 in hMFs, via activation of both type 1 and type 2 Ang II receptors; the ERK pathway; and matrix metalloprotease-2. Treatment of hMFs with neutralizing antibodies selective for human Hi-FGF-2 (neu-AbHi-FGF-2) reduced accumulation of proteins associated with fibroblast-to-myofibroblast conversion and fibrosis, including α-smooth muscle actin, extra-domain A fibronectin, and procollagen. Stimulation of hMFs with recombinant human Hi-FGF-2 was significantly more potent than Lo-FGF-2 in upregulating inflammation-associated proteins such as pro-interleukin-1β and plasminogen-activator-inhibitor-1. Culture media conditioned by hMFs promoted cardiomyocyte hypertrophy, an effect that was prevented by neu-AbHi-FGF-2 in vitro. In conclusion, we have documented that Hi-FGF-2 represents a substantial fraction of FGF-2 in human cardiac (atrial) tissue and in pericardial fluid, and have shown that human Hi-FGF-2, unlike Lo-FGF-2, promotes deleterious

  9. Left atrium remodeling after acute myocardial infarction (results of the GISSI-3 Echo Substudy).

    PubMed

    Popescu, Bogdan A; Macor, Franco; Antonini-Canterin, Francesco; Giannuzzi, Pantaleo; Temporelli, Pier L; Bosimini, Enzo; Gentile, Francesco; Maggioni, Aldo P; Tavazzi, Luigi; Piazza, Rita; Ascione, Luigi; Stoian, Ioana; Cervesato, Eugenio; Nicolosi, Gian L

    2004-05-01

    To evaluate the existence, timing, and determinants of post-infarction left atrial remodeling, we studied a subgroup of 514 patients from the Third Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico Echo Substudy who underwent 4 serial 2-dimensional echocardiograms up to 6 months after acute myocardial infarction. This study is the first to demonstrate, in a large series of patients, the existence of early and late left atrial remodeling after low-risk acute myocardial infarction and the relation of left atrial remodeling to left ventricular remodeling. PMID:15110211

  10. Biochemical Assays for Analyzing Activities of ATP-dependent Chromatin Remodeling Enzymes

    PubMed Central

    Chen, Lu; Ooi, Soon-Keat; Conaway, Joan W.; Conaway, Ronald C.

    2014-01-01

    Members of the SNF2 family of ATPases often function as components of multi-subunit chromatin remodeling complexes that regulate nucleosome dynamics and DNA accessibility by catalyzing ATP-dependent nucleosome remodeling. Biochemically dissecting the contributions of individual subunits of such complexes to the multi-step ATP-dependent chromatin remodeling reaction requires the use of assays that monitor the production of reaction products and measure the formation of reaction intermediates. This JOVE protocol describes assays that allow one to measure the biochemical activities of chromatin remodeling complexes or subcomplexes containing various combinations of subunits. Chromatin remodeling is measured using an ATP-dependent nucleosome sliding assay, which monitors the movement of a nucleosome on a DNA molecule using an electrophoretic mobility shift assay (EMSA)-based method. Nucleosome binding activity is measured by monitoring the formation of remodeling complex-bound mononucleosomes using a similar EMSA-based method, and DNA- or nucleosome-dependent ATPase activity is assayed using thin layer chromatography (TLC) to measure the rate of conversion of ATP to ADP and phosphate in the presence of either DNA or nucleosomes. Using these assays, one can examine the functions of subunits of a chromatin remodeling complex by comparing the activities of the complete complex to those lacking one or more subunits. The human INO80 chromatin remodeling complex is used as an example; however, the methods described here can be adapted to the study of other chromatin remodeling complexes. PMID:25407555

  11. Bone ingrowth: an application of the boundary element method to bone remodeling at the implant interface.

    PubMed

    Sadegh, A M; Luo, G M; Cowin, S C

    1993-02-01

    Surface bone remodeling theory and the boundary element method are employed to investigate the microstructural remodeling of bone at the bone-implant interface. Three situations are considered: remodeling-induced penetration between the screw threads of an implanted screw, penetration of bone tissue into a slot or cavity in an implant, and the interaction of individual trabeculae in the remodeling processes near an implant. For each case the bone ingrowth is determined as a function of the geometry and the applied load. PMID:8429059

  12. Genome-wide nucleosome specificity and function of chromatin remodellers in ES cells

    PubMed Central

    de Dieuleveult, Maud; Yen, Kuangyu; Hmitou, Isabelle; Depaux, Arnaud; Boussouar, Fayçal; Dargham, Daria Bou; Jounier, Sylvie; Humbertclaude, Hélène; Ribierre, Florence; Baulard, Céline; Farrell, Nina P.; Park, Bongsoo; Keime, Céline; Carrière, Lucie; Berlivet, Soizick; Gut, Marta; Gut, Ivo; Werner, Michel; Deleuze, Jean-François; Olaso, Robert; Aude, Jean-Christophe; Chantalat, Sophie; Pugh, B. Franklin; Gérard, Matthieu

    2015-01-01

    Summary ATP-dependent chromatin remodellers allow access to DNA for transcription factors and the general transcription machinery, but whether mammalian chromatin remodellers1–3 target specific nucleosomes to regulate transcription is unclear. Here, we present genome-wide remodeller-nucleosome interaction profiles for Chd1, Chd2, Chd4, Chd6, Chd8, Chd9, Brg1 and Ep400 in mouse embryonic stem (ES) cells. These remodellers bind one or both full nucleosomes that flank MNase-defined nucleosome-free promoter regions (NFRs), where they separate divergent transcription. Surprisingly, large CpG-rich NFRs that extend downstream of annotated transcriptional start sites (TSSs) are nevertheless chromatinized with non-nucleosomal or subnucleosomal histone variants (H3.3 and H2A.Z) and modifications (H3K4me3 and H3K27ac). RNA polymerase (pol) II therefore navigates hundreds of bp of altered chromatin in the sense direction before encountering an MNase-resistant nucleosome at the 3′ end of the NFR. Transcriptome analysis upon remodeller depletion reveals reciprocal mechanisms of transcriptional regulation by remodellers. Whereas at active genes individual remodellers play either positive or negative roles via altering nucleosome stability, at polycomb-enriched bivalent genes the same remodellers act in an opposite manner. These findings indicate that remodellers target specific nucleosomes at the edge of NFRs, where they regulate ES cell transcriptional programs. PMID:26814966

  13. Histone octamer transfer by a chromatin-remodeling complex.

    PubMed

    Lorch, Y; Zhang, M; Kornberg, R D

    1999-02-01

    RSC, an abundant, essential chromatin-remodeling complex related to SWI/SNF complex, catalyzes the transfer of a histone octamer from a nucleosome core particle to naked DNA. The newly formed octamer-DNA complex is identical with a nucleosome in all respects. The reaction requires ATP and involves an activated RSC-nucleosome intermediate. The mechanism may entail formation of a duplex displacement loop on the nucleosome, facilitating the entry of exogeneous DNA and the release of the endogenous molecule. PMID:10025404

  14. Expression of RANKL/OPG during bone remodeling in vivo

    SciTech Connect

    Tanaka, H.; Mine, T.; Ogasa, H.; Taguchi, T.; Liang, C.T.

    2011-08-12

    Highlights: {yields} This is the first study to determine the relationship between osteogenic differentiation and RANKL/OPG expression during bone remodeling in vivo. {yields} The OPG expression peak occurred during the bone formation phase, whereas the marked elevation of RANKL expression was observed during the bone resorption phase. {yields} Histological analysis showed that RANKL/OPG immunoreactivity was predominantly associated with bone marrow cells in the marrow cavity. {yields} The present study confirmed that RANKL/OPG are key factors linking bone formation to resorption during the bone remodeling process. -- Abstract: The interaction between receptor activator of nuclear factor {kappa}B ligand (RANKL) and osteoprotegerin (OPG) plays a dominant role in osteoclastogenesis. As both proteins are produced by osteoblast lineage cells, they are considered to represent a key link between bone formation and resorption. In this study, we investigated the expression of RANKL and OPG during bone remodeling in vivo to determine the relationship between osteoclastogenic stimulation and osteoblastic differentiation. Total RNA was prepared from rat femurs after marrow ablation on days 0, 3, 6, and 9. The temporal activation patterns of osteoblast-related genes (procollagen {alpha}1 (I), alkaline phosphatase, osteopontin, and osteocalcin) were examined by Northern blot analysis. An appreciable increase in the expression of these osteoblast markers was observed on day 3. The peak increase in gene expression was observed on day 6 followed by a slight reduction by day 9. Real-time PCR analysis showed that the OPG mRNA expression was markedly upregulated on day 6 and slightly decreased on day 9. In contrast, RANKL mRNA expression was increased by more than 20-fold on day 9. The RANKL/OPG ratio, an index of osteoclastogenic stimulation, peaked on day 9. Histological analysis showed that RANKL and OPG immunoreactivity were predominantly associated with bone marrow cells. The

  15. Altered thermogenesis and impaired bone remodeling in Misty mice.

    PubMed

    Motyl, Katherine J; Bishop, Kathleen A; DeMambro, Victoria E; Bornstein, Sheila A; Le, Phuong; Kawai, Masanobu; Lotinun, Sutada; Horowitz, Mark C; Baron, Roland; Bouxsein, Mary L; Rosen, Clifford J

    2013-09-01

    Fat mass may be modulated by the number of brown-like adipocytes in white adipose tissue (WAT) in humans and rodents. Bone remodeling is dependent on systemic energy metabolism and, with age, bone remodeling becomes uncoupled and brown adipose tissue (BAT) function declines. To test the interaction between BAT and bone, we employed Misty (m/m) mice, which were reported be deficient in BAT. We found that Misty mice have accelerated age-related trabecular bone loss and impaired brown fat function (including reduced temperature, lower expression of Pgc1a, and less sympathetic innervation compared to wild-type (+/ +)). Despite reduced BAT function, Misty mice had normal core body temperature, suggesting heat is produced from other sources. Indeed, upon acute cold exposure (4°C for 6 hours), inguinal WAT from Misty mice compensated for BAT dysfunction by increasing expression of Acadl, Pgc1a, Dio2, and other thermogenic genes. Interestingly, acute cold exposure also decreased Runx2 and increased Rankl expression in Misty bone, but only Runx2 was decreased in wild-type. Browning of WAT is under the control of the sympathetic nervous system (SNS) and, if present at room temperature, could impact bone metabolism. To test whether SNS activity could be responsible for accelerated trabecular bone loss, we treated wild-type and Misty mice with the β-blocker, propranolol. As predicted, propranolol slowed trabecular bone volume/total volume (BV/TV) loss in the distal femur of Misty mice without affecting wild-type. Finally, the Misty mutation (a truncation of DOCK7) also has a significant cell-autonomous role. We found DOCK7 expression in whole bone and osteoblasts. Primary osteoblast differentiation from Misty calvaria was impaired, demonstrating a novel role for DOCK7 in bone remodeling. Despite the multifaceted effects of the Misty mutation, we have shown that impaired brown fat function leads to altered SNS activity and bone loss, and for the first time that cold

  16. Thermally Induced Osteocyte Damage Initiates a Remodelling Signaling Cascade

    PubMed Central

    Dolan, Eimear B.; McNamara, Laoise M.

    2015-01-01

    Thermal elevations experienced by bone during orthopaedic procedures, such as cutting and drilling, exothermal reactions from bone cement, and thermal therapies such as tumor ablation, can result in thermal damage leading to death of native bone cells (osteocytes, osteoblasts, osteoclasts and mesenchymal stem cells). Osteocytes are believed to be the orchestrators of bone remodeling, which recruit nearby osteoclast and osteoblasts to control resorption and bone growth in response to mechanical stimuli and physical damage. However, whether heat-induced osteocyte damage can directly elicit bone remodelling has yet to be determined. This study establishes the link between osteocyte thermal damage and the remodeling cascade. We show that osteocytes directly exposed to thermal elevations (47°C for 1 minute) become significantly apoptotic and alter the expression of osteogenic genes (Opg and Cox2). The Rankl/Opg ratio is consistently down-regulated, at days 1, 3 and 7 in MLO-Y4s heat-treated to 47°C for 1 minute. Additionally, the pro-osteoblastogenic signaling marker Cox2 is significantly up-regulated in heat-treated MLO-Y4s by day 7. Furthermore, secreted factors from heat-treated MLO-Y4s administered to MSCs using a novel co-culture system are shown to activate pre-osteoblastic MSCs to increase production of the pro-osteoblastic differentiation marker, alkaline phosphatase (day 7, 14), and calcium deposition (day 21). Most interestingly, an initial pro-osteoclastogenic signaling response (increase Rankl and Rankl/Opg ratio at day 1) followed by later stage pro-osteoblastogenic signaling (down-regulation in Rankl and the Rankl/Opg ratio and an up-regulation in Opg and Cox2 by day 7) was observed in non-heat-treated MLO-Y4s in co-culture when these were exposed to the biochemicals produced by heat-treated MLO-Y4s. Taken together, these results elucidate the vital role of osteocytes in detecting and responding to thermal damage by means of thermally induced apoptosis

  17. Thermally induced osteocyte damage initiates a remodelling signaling cascade.

    PubMed

    Dolan, Eimear B; Haugh, Matthew G; Voisin, Muriel C; Tallon, David; McNamara, Laoise M

    2015-01-01

    Thermal elevations experienced by bone during orthopaedic procedures, such as cutting and drilling, exothermal reactions from bone cement, and thermal therapies such as tumor ablation, can result in thermal damage leading to death of native bone cells (osteocytes, osteoblasts, osteoclasts and mesenchymal stem cells). Osteocytes are believed to be the orchestrators of bone remodeling, which recruit nearby osteoclast and osteoblasts to control resorption and bone growth in response to mechanical stimuli and physical damage. However, whether heat-induced osteocyte damage can directly elicit bone remodelling has yet to be determined. This study establishes the link between osteocyte thermal damage and the remodeling cascade. We show that osteocytes directly exposed to thermal elevations (47°C for 1 minute) become significantly apoptotic and alter the expression of osteogenic genes (Opg and Cox2). The Rankl/Opg ratio is consistently down-regulated, at days 1, 3 and 7 in MLO-Y4s heat-treated to 47°C for 1 minute. Additionally, the pro-osteoblastogenic signaling marker Cox2 is significantly up-regulated in heat-treated MLO-Y4s by day 7. Furthermore, secreted factors from heat-treated MLO-Y4s administered to MSCs using a novel co-culture system are shown to activate pre-osteoblastic MSCs to increase production of the pro-osteoblastic differentiation marker, alkaline phosphatase (day 7, 14), and calcium deposition (day 21). Most interestingly, an initial pro-osteoclastogenic signaling response (increase Rankl and Rankl/Opg ratio at day 1) followed by later stage pro-osteoblastogenic signaling (down-regulation in Rankl and the Rankl/Opg ratio and an up-regulation in Opg and Cox2 by day 7) was observed in non-heat-treated MLO-Y4s in co-culture when these were exposed to the biochemicals produced by heat-treated MLO-Y4s. Taken together, these results elucidate the vital role of osteocytes in detecting and responding to thermal damage by means of thermally induced apoptosis

  18. Imaging membrane remodeling during regulated exocytosis in live mice.

    PubMed

    Shitara, Akiko; Weigert, Roberto

    2015-10-01

    In this mini-review we focus on the use of time-lapse light microscopy to study membrane remodeling during protein secretion in live animals. In particular, we highlight how subcellular intravital microscopy has enabled imaging the dynamics of both individual secretory vesicles and the plasma membrane, during different steps in the exocytic process. This powerful approach has provided us with the unique opportunity to unravel the role of the actin cytoskeleton in regulating this process under physiological conditions, and to overcome the shortcomings of more reductionist model systems. PMID:26160452

  19. Development of Bone Remodeling Model for Spaceflight Bone Physiology Analysis

    NASA Technical Reports Server (NTRS)

    Pennline, James A.; Werner, Christopher R.; Lewandowski, Beth; Thompson, Bill; Sibonga, Jean; Mulugeta, Lealem

    2015-01-01

    Current spaceflight exercise countermeasures do not eliminate bone loss. Astronauts lose bone mass at a rate of 1-2% a month (Lang et al. 2004, Buckey 2006, LeBlanc et al. 2007). This may lead to early onset osteoporosis and place the astronauts at greater risk of fracture later in their lives. NASA seeks to improve understanding of the mechanisms of bone remodeling and demineralization in 1g in order to appropriately quantify long term risks to astronauts and improve countermeasures. NASA's Digital Astronaut Project (DAP) is working with NASA's bone discipline to develop a validated computational model to augment research efforts aimed at achieving this goal.

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

    NASA Astrophysics Data System (ADS)

    Fratzl, Peter; Weinkamer, Richard

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

  1. Artery Remodeling Under Axial Twist in Three Days Organ Culture.

    PubMed

    Wang, Guo-Liang; Xiao, Yangming; Voorhees, Andrew; Qi, Ying-Xin; Jiang, Zong-Lai; Han, Hai-Chao

    2015-08-01

    Arteries often endure axial twist due to body movement and surgical procedures, but how arteries remodel under axial twist remains unclear. The objective of this study was to investigate early stage arterial wall remodeling under axial twist. Porcine carotid arteries were twisted axially and maintained for three days in ex vivo organ culture systems while the pressure and flow remained the same as untwisted controls. Cell proliferation, internal elastic lamina (IEL) fenestrae shape and size, endothelial cell (EC) morphology and orientation, as well as the expression of matrix metalloproteinases (MMPs), MMP-2 and MMP-9, and tissue inhibitor of metalloproteinase-2 (TIMP-2) were quantified using immunohistochemistry staining and immunoblotting. Our results demonstrated that cell proliferation in both the intima and media were significantly higher in the twisted arteries compared to the controls. The cell proliferation in the intima increased from 1.33 ± 0.21% to 7.63 ± 1.89%, and in the media from 1.93 ± 0.84% to 8.27 ± 2.92% (p < 0.05). IEL fenestrae total area decreased from 26.07 ± 2.13% to 14.74 ± 0.61% and average size decreased from 169.03 ± 18.85 μm(2) to 80.14 ± 1.96 μm(2) (p < 0.01), but aspect ratio increased in the twist group from 2.39 ± 0.15 to 2.83 ± 0.29 (p < 0.05). MMP-2 expression significantly increased (p < 0.05) while MMP-9 and TIMP-2 showed no significant difference in the twist group. The ECs in the twisted arteries were significantly elongated compared to the controls after three days. The angle between the major axis of the ECs and blood flow direction under twist was 7.46 ± 2.44 degrees after 3 days organ culture, a decrease from the initial 15.58 ± 1.29 degrees. These results demonstrate that axial twist can stimulate artery remodeling. These findings complement our understanding of arterial wall remodeling under mechanical stress resulting from pressure and flow variations. PMID:25503524

  2. The Detection and Exclusion of the Prostate Neuro-Vascular Bundle (NVB) in Automated HIFU Treatment Planning Using a Pulsed-Wave Doppler Ultrasound System

    NASA Astrophysics Data System (ADS)

    Chen, Wohsing; Carlson, Roy F.; Fedewa, Russell; Seip, Ralf; Sanghvi, Narendra T.; Dines, Kris A.; Pfile, Richard; Penna, Michael A.; Gardner, Thomas A.

    2005-03-01

    Men with prostate cancer are likely to develop impotence after prostate cancer therapy if the treatment damages the neuro-vascular bundles (NVB). The NVB are generally located at the periphery of the prostate gland. To preserve the NVB, a Doppler system is used to detect and localize the associated blood vessels. This information is used during the therapy planning procedure to avoid treatment surrounding the blood vessel areas. The Sonablate®500 (Focus Surgery, Inc.) image-guided HIFU device is enhanced with a pulse-wave multi-gate Doppler system that uses the current imaging transducer and mechanical scanner to acquire Doppler data. Doppler detection is executed after the regular B-mode images are acquired from the base to the apex of the prostate using parallel sector scans. The results are stored and rendered in 3-D display, registered with additional models generated for the capsule, urethra, and rectal wall, and the B-mode data and treatment plan itself. The display of the blood flow can be in 2-D color overlaid on the B-mode image or in 3-D color structure. Based on this 3-D model, the HIFU treatment planning can be executed in automated or manual mode by the physician to remove originally defined treatment zones that overlap with the NVB (for preservation of NVB). The results of the NVB detection in animal experiments, and the 3-D modeling and data registration of the prostate will be presented.

  3. Wnt/β-catenin coupled with HIF-1α/VEGF signaling pathways involved in galangin neurovascular unit protection from focal cerebral ischemia

    PubMed Central

    Wu, Chuanhong; Chen, Jianxin; Chen, Chang; Wang, Wei; Wen, Limei; Gao, Kuo; Chen, Xiuping; Xiong, Sihuai; Zhao, Huihui; Li, Shaojing

    2015-01-01

    Microenvironmental regulation has become a promising strategy for complex disease treatment. The neurovascular unit (NVU), as the key structural basis to maintain an optimal brain microenvironment, has emerged as a new paradigm to understand the pathology of stroke. In this study, we investigated the effects of galangin, a natural flavonoid isolated from the rhizome of Alpina officinarum Hance, on NVU microenvironment improvement and associated signal pathways in rats impaired by middle cerebral artery occlusion (MCAO). Galangin ameliorated neurological scores, cerebral infarct volume and cerebral edema and reduced the concentration of Evans blue (EB) in brain tissue. NVU ultrastructural changes were also improved by galangin. RT-PCR and western blot revealed that galangin protected NVUs through the Wnt/β-catenin pathway coupled with HIF-1α and vascular endothelial growth factor (VEGF). VEGF and β-catenin could be the key nodes of these two coupled pathways. In conclusion, Galangin might function as an anti-ischemic stroke drug by improving the microenvironment of NVUs. PMID:26537366

  4. Synergy of endothelial and neural progenitor cells from adipose-derived stem cells to preserve neurovascular structures in rat hypoxic-ischemic brain injury

    PubMed Central

    Hsueh, Yuan-Yu; Chang, Ya-Ju; Huang, Chia-Wei; Handayani, Fitri; Chiang, Yi-Lun; Fan, Shih-Chen; Ho, Chien-Jung; Kuo, Yu-Min; Yang, Shang-Hsun; Chen, Yuh-Ling; Lin, Sheng-Che; Huang, Chao-Ching; Wu, Chia-Ching

    2015-01-01

    Perinatal cerebral hypoxic-ischemic (HI) injury damages the architecture of neurovascular units (NVUs) and results in neurological disorders. Here, we differentiated adipose-derived stem cells (ASCs) toward the progenitor of endothelial progenitor cells (EPCs) and neural precursor cells (NPCs) via microenvironmental induction and investigated the protective effect by transplanting ASCs, EPCs, NPCs, or a combination of EPCs and NPCs (E+N) into neonatal HI injured rat pups. The E+N combination produced significant reduction in brain damage and cell apoptosis and the most comprehensive restoration in NVUs regarding neuron number, normal astrocytes, and vessel density. Improvements in cognitive and motor functions were also achieved in injured rats with E+N therapy. Synergistic interactions to facilitate transmigration under in vitro hypoxic microenvironment were discovered with involvement of the neuropilin-1 (NRP1) signal in EPCs and the C-X-C chemokine receptor 4 (CXCR4) and fibroblast growth factor receptor 1 (FGFR1) signals in NPCs. Therefore, ASCs exhibit great potential for cell sources in endothelial and neural lineages to prevent brain from HI damage. PMID:26447335

  5. Synergy of endothelial and neural progenitor cells from adipose-derived stem cells to preserve neurovascular structures in rat hypoxic-ischemic brain injury.

    PubMed

    Hsueh, Yuan-Yu; Chang, Ya-Ju; Huang, Chia-Wei; Handayani, Fitri; Chiang, Yi-Lun; Fan, Shih-Chen; Ho, Chien-Jung; Kuo, Yu-Min; Yang, Shang-Hsun; Chen, Yuh-Ling; Lin, Sheng-Che; Huang, Chao-Ching; Wu, Chia-Ching

    2015-01-01

    Perinatal cerebral hypoxic-ischemic (HI) injury damages the architecture of neurovascular units (NVUs) and results in neurological disorders. Here, we differentiated adipose-derived stem cells (ASCs) toward the progenitor of endothelial progenitor cells (EPCs) and neural precursor cells (NPCs) via microenvironmental induction and investigated the protective effect by transplanting ASCs, EPCs, NPCs, or a combination of EPCs and NPCs (E+N) into neonatal HI injured rat pups. The E+N combination produced significant reduction in brain damage and cell apoptosis and the most comprehensive restoration in NVUs regarding neuron number, normal astrocytes, and vessel density. Improvements in cognitive and motor functions were also achieved in injured rats with E+N therapy. Synergistic interactions to facilitate transmigration under in vitro hypoxic microenvironment were discovered with involvement of the neuropilin-1 (NRP1) signal in EPCs and the C-X-C chemokine receptor 4 (CXCR4) and fibroblast growth factor receptor 1 (FGFR1) signals in NPCs. Therefore, ASCs exhibit great potential for cell sources in endothelial and neural lineages to prevent brain from HI damage. PMID:26447335

  6. Pay attention to cardiac remodeling in cancer cachexia.

    PubMed

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

    2016-07-01

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

  7. Defective Membrane Remodeling in Neuromuscular Diseases: Insights from Animal Models

    PubMed Central

    Muller, Jean; Laporte, Jocelyn

    2012-01-01

    Proteins involved in membrane remodeling play an essential role in a plethora of cell functions including endocytosis and intracellular transport. Defects in several of them lead to human diseases. Myotubularins, amphiphysins, and dynamins are all proteins implicated in membrane trafficking and/or remodeling. Mutations in myotubularin, amphiphysin 2 (BIN1), and dynamin 2 lead to different forms of centronuclear myopathy, while mutations in myotubularin-related proteins cause Charcot-Marie-Tooth neuropathies. In addition to centronuclear myopathy, dynamin 2 is also mutated in a dominant form of Charcot-Marie-Tooth neuropathy. While several proteins from these different families are implicated in similar diseases, mutations in close homologues or in the same protein in the case of dynamin 2 lead to diseases affecting different tissues. This suggests (1) a common molecular pathway underlying these different neuromuscular diseases, and (2) tissue-specific regulation of these proteins. This review discusses the pathophysiology of the related neuromuscular diseases on the basis of animal models developed for proteins of the myotubularin, amphiphysin, and dynamin families. A better understanding of the common mechanisms between these neuromuscular disorders will lead to more specific health care and therapeutic approaches. PMID:22496665

  8. SHREC Silences Heterochromatin via Distinct Remodeling and Deacetylation Modules.

    PubMed

    Job, Godwin; Brugger, Christiane; Xu, Tao; Lowe, Brandon R; Pfister, Yvan; Qu, Chunxu; Shanker, Sreenath; Baños Sanz, José I; Partridge, Janet F; Schalch, Thomas

    2016-04-21

    Nucleosome remodeling and deacetylation (NuRD) complexes are co-transcriptional regulators implicated in differentiation, development, and diseases. Methyl-CpG binding domain (MBD) proteins play an essential role in recruitment of NuRD complexes to their target sites in chromatin. The related SHREC complex in fission yeast drives transcriptional gene silencing in heterochromatin through cooperation with HP1 proteins. How remodeler and histone deacetylase (HDAC) cooperate within NuRD complexes remains unresolved. We determined that in SHREC the two modules occupy distant sites on the scaffold protein Clr1 and that repressive activity of SHREC can be modulated by the expression level of the HDAC-associated Clr1 domain alone. Moreover, the crystal structure of Clr2 reveals an MBD-like domain mediating recruitment of the HDAC module to heterochromatin. Thus, SHREC bi-functionality is organized in two separate modules with separate recruitment mechanisms, which work together to elicit transcriptional silencing at heterochromatic loci. PMID:27105116

  9. Embryonic multipotent progenitors remodel the Drosophila airways during metamorphosis

    PubMed Central

    Pitsouli, Chrysoula; Perrimon, Norbert

    2010-01-01

    Adult structures in holometabolous insects such as Drosophila are generated by groups of imaginal cells dedicated to the formation of different organs. Imaginal cells are specified in the embryo and remain quiescent until the larval stages, when they proliferate and differentiate to form organs. The Drosophila tracheal system is extensively remodeled during metamorphosis by a small number of airway progenitors. Among these, the spiracular branch tracheoblasts are responsible for the generation of the pupal and adult abdominal airways. To understand the coordination of proliferation and differentiation during organogenesis of tubular organs, we analyzed the remodeling of Drosophila airways during metamorphosis. We show that the embryonic spiracular branch tracheoblasts are multipotent cells that express the homeobox transcription factor Cut, which is necessary for their survival and normal development. They give rise to three distinct cell populations at the end of larval development, which generate the adult tracheal tubes, the spiracle and the epidermis surrounding the spiracle. Our study establishes the series of events that lead to the formation of an adult tubular structure in Drosophila. PMID:20940225

  10. A CARTILAGE GROWTH MIXTURE MODEL WITH COLLAGEN REMODELING: VALIDATION PROTOCOLS

    PubMed Central

    Klisch, Stephen M.; Asanbaeva, Anna; Oungoulian, Sevan R.; Masuda, Koichi; Thonar, Eugene J-MA; Davol, Andrew; Sah, Robert L.

    2009-01-01

    A cartilage growth mixture (CGM) model is proposed to address limitations of a model used in a previous study. New stress constitutive equations for the solid matrix are derived and collagen (COL) remodeling is incorporated into the CGM model by allowing the intrinsic COL material constants to evolve during growth. An analytical validation protocol based on experimental data from a recent in vitro growth study is developed. Available data included measurements of tissue volume, biochemical composition, and tensile modulus for bovine calf articular cartilage (AC) explants harvested at three depths and incubated for 13 days in 20% FBS and 20% FBS+β-aminopropionitrile. The proposed CGM model can match tissue biochemical content and volume exactly while predicting theoretical values of tensile moduli that do not significantly differ from experimental values. Also, theoretical values of a scalar COL remodeling factor are positively correlated with COL crosslink content, and mass growth functions are positively correlated with cell density. The results suggest that the CGM model may help to guide in vitro growth protocols for AC tissue via the a priori prediction of geometric and biomechanical properties. PMID:18532855

  11. Actin remodeling by Nck regulates endothelial lumen formation.

    PubMed

    Chaki, Sankar P; Barhoumi, Rola; Rivera, Gonzalo M

    2015-09-01

    Multiple angiogenic cues modulate phosphotyrosine signaling to promote vasculogenesis and angiogenesis. Despite its functional and clinical importance, how vascular cells integrate phosphotyrosine-dependent signaling to elicit cytoskeletal changes required for endothelial morphogenesis remains poorly understood. The family of Nck adaptors couples phosphotyrosine signals with actin dynamics and therefore is well positioned to orchestrate cellular processes required in vascular formation and remodeling. Culture of endothelial cells in three-dimensional collagen matrices in the presence of VEGF stimulation was combined with molecular genetics, optical imaging, and biochemistry to show that Nck-dependent actin remodeling promotes endothelial cell elongation and proper organization of VE-cadherin intercellular junctions. Major morphogenetic defects caused by abrogation of Nck signaling included loss of endothelial apical-basal polarity and impaired lumenization. Time-lapse imaging using a Förster resonance energy transfer biosensor, immunostaining with phospho-specific antibodies, and GST pull-down assays showed that Nck determines spatiotemporal patterns of Cdc42/aPKC activation during endothelial morphogenesis. Our results demonstrate that Nck acts as an important hub integrating angiogenic cues with cytoskeletal changes that enable endothelial apical-basal polarization and lumen formation. These findings point to Nck as an emergent target for effective antiangiogenic therapy. PMID:26157164

  12. Danger Control Programs Cause Tissue Injury and Remodeling

    PubMed Central

    Hagemann, Jan H.; Haegele, Holger; Müller, Susanna; Anders, Hans-Joachim

    2013-01-01

    Are there common pathways underlying the broad spectrum of tissue pathologies that develop upon injuries and from subsequent tissue remodeling? Here, we explain the pathophysiological impact of a set of evolutionary conserved danger control programs for tissue pathology. These programs date back to the survival benefits of the first multicellular organisms upon traumatic injuries by launching a series of danger control responses, i.e., 1. Haemostasis, or clotting to control bleeding; 2. Host defense, to control pathogen entry and spreading; 3. Re-epithelialisation, to recover barrier functions; and 4. Mesenchymal, to repair to regain tissue stability. Taking kidney pathology as an example, we discuss how clotting, inflammation, epithelial healing, and fibrosis/sclerosis determine the spectrum of kidney pathology, especially when they are insufficiently activated or present in an overshooting and deregulated manner. Understanding the evolutionary benefits of these response programs may refine the search for novel therapeutic targets to limit organ dysfunction in acute injuries and in progressive chronic tissue remodeling. PMID:23759985

  13. Vascular Remodelling and Mesenchymal Transition in Systemic Sclerosis

    PubMed Central

    Nicolosi, Pier Andrea; Tombetti, Enrico; Maugeri, Norma; Rovere-Querini, Patrizia; Brunelli, Silvia; Manfredi, Angelo A.

    2016-01-01

    Fibrosis of the skin and of internal organs, autoimmunity, and vascular inflammation are hallmarks of Systemic Sclerosis (SSc). The injury and activation of endothelial cells, with hyperplasia of the intima and eventual obliteration of the vascular lumen, are early features of SSc. Reduced capillary blood flow coupled with deficient angiogenesis leads to chronic hypoxia and tissue ischemia, enforcing a positive feed-forward loop sustaining vascular remodelling, further exacerbated by extracellular matrix accumulation due to fibrosis. Despite numerous developments and a growing number of controlled clinical trials no treatment has been shown so far to alter SSc natural history, outlining the need of further investigation in the molecular pathways involved in the pathogenesis of the disease. We review some processes potentially involved in SSc vasculopathy, with attention to the possible effect of sustained vascular inflammation on the plasticity of vascular cells. Specifically we focus on mesenchymal transition, a key phenomenon in the cardiac and vascular development as well as in the remodelling of injured vessels. Recent work supports the role of transforming growth factor-beta, Wnt, and Notch signaling in these processes. Importantly, endothelial-mesenchymal transition may be reversible, possibly offering novel cues for treatment. PMID:27069480

  14. Remodeling of tissue-engineered bone structures in vivo.

    PubMed

    Hofmann, Sandra; Hilbe, Monika; Fajardo, Robert J; Hagenmüller, Henri; Nuss, Katja; Arras, Margarete; Müller, Ralph; von Rechenberg, Brigitte; Kaplan, David L; Merkle, Hans P; Meinel, Lorenz

    2013-09-01

    Implant design for bone regeneration is expected to be optimized when implant structures resemble the anatomical situation of the defect site. We tested the validity of this hypothesis by exploring the feasibility of generating different in vitro engineered bone-like structures originating from porous silk fibroin scaffolds decorated with RGD sequences (SF-RGD), seeded with human mesenchymal stem cells (hMSC). Scaffolds with small (106-212 μm), medium (212-300 μm), and large pore diameter ranges (300-425 μm) were seeded with hMSC and subsequently differentiated in vitro into bone-like tissue resembling initial scaffold geometries and featuring bone-like structures. Eight weeks after implantation into calvarial defects in mice, the in vitro engineered bone-like tissues had remodeled into bone featuring different proportions of woven/lamellar bone bridging the defects. Regardless of pore diameter, all implants integrated well, vascularization was advanced, and bone marrow ingrowth had started. Ultimately, in this defect model, the geometry of the in vitro generated tissue-engineered bone structure, trabecular- or plate-like, had no significant impact on the healing of the defect, owing to an efficient remodeling of its structure after implantation. PMID:23958323

  15. FIBROBLAST CYTOSKELETAL REMODELING CONTRIBUTES TO CONNECTIVE TISSUE TENSION

    PubMed Central

    Langevin, Helene M.; Bouffard, Nicole A.; Fox, James R.; Palmer, Bradley M.; Wu, Junru; Iatridis, James C.; Barnes, William D.; Badger, Gary J.; Howe, Alan K.

    2011-01-01

    The viscoelastic behavior of connective tissue is generally attributed to the material properties of the extracellular matrix rather than cellular activity. We have previously shown that fibroblasts within areolar connective tissue exhibit dynamic cytoskeletal remodeling within minutes in response to tissue stretch ex vivo and in vivo. Here, we tested the hypothesis that fibroblasts, through this cytoskeletal remodeling, actively contribute to the viscoelastic behavior of the whole tissue. We measured significantly increased tissue tension when cellular function was broadly inhibited by sodium azide and when cytoskeletal dynamics were compromised by disrupting microtubules (with colchicine) or actomyosin contractility (via Rho kinase inhibition). These treatments led to a decrease in cell body cross-sectional area and cell field perimeter (obtained by joining the end of all of a fibroblast’s processes). Suppressing lamellipodia formation by inhibiting Rac-1 decreased cell body cross-sectional area but did not affect cell field perimeter or tissue tension. Thus, by changing shape, fibroblasts can dynamically modulate the viscoelastic behavior of areolar connective tissue through Rho-dependent cytoskeletal mechanisms. These results have broad implications for our understanding of the dynamic interplay of forces between fibroblasts and their surrounding matrix, as well as for the neural, vascular and immune cell populations residing within connective tissue. PMID:20945345

  16. Cell Wall Composition, Biosynthesis and Remodeling during Pollen Tube Growth

    PubMed Central

    Mollet, Jean-Claude; Leroux, Christelle; Dardelle, Flavien; Lehner, Arnaud

    2013-01-01

    The pollen tube is a fast tip-growing cell carrying the two sperm cells to the ovule allowing the double fertilization process and seed setting. To succeed in this process, the spatial and temporal controls of pollen tube growth within the female organ are critical. It requires a massive cell wall deposition to promote fast pollen tube elongation and a tight control of the cell wall remodeling to modify the mechanical properties. In addition, during its journey, the pollen tube interacts with the pistil, which plays key roles in pollen tube nutrition, guidance and in the rejection of the self-incompatible pollen. This review focuses on our current knowledge in the biochemistry and localization of the main cell wall polymers including pectin, hemicellulose, cellulose and callose from several pollen tube species. Moreover, based on transcriptomic data and functional genomic studies, the possible enzymes involved in the cell wall remodeling during pollen tube growth and their impact on the cell wall mechanics are also described. Finally, mutant analyses have permitted to gain insight in the function of several genes involved in the pollen tube cell wall biosynthesis and their roles in pollen tube growth are further discussed. PMID:27137369

  17. Actin remodeling by Nck regulates endothelial lumen formation

    PubMed Central

    Chaki, Sankar P.; Barhoumi, Rola; Rivera, Gonzalo M.

    2015-01-01

    Multiple angiogenic cues modulate phosphotyrosine signaling to promote vasculogenesis and angiogenesis. Despite its functional and clinical importance, how vascular cells integrate phosphotyrosine-dependent signaling to elicit cytoskeletal changes required for endothelial morphogenesis remains poorly understood. The family of Nck adaptors couples phosphotyrosine signals with actin dynamics and therefore is well positioned to orchestrate cellular processes required in vascular formation and remodeling. Culture of endothelial cells in three-dimensional collagen matrices in the presence of VEGF stimulation was combined with molecular genetics, optical imaging, and biochemistry to show that Nck-dependent actin remodeling promotes endothelial cell elongation and proper organization of VE-cadherin intercellular junctions. Major morphogenetic defects caused by abrogation of Nck signaling included loss of endothelial apical-basal polarity and impaired lumenization. Time-lapse imaging using a Förster resonance energy transfer biosensor, immunostaining with phospho-specific antibodies, and GST pull-down assays showed that Nck determines spatiotemporal patterns of Cdc42/aPKC activation during endothelial morphogenesis. Our results demonstrate that Nck acts as an important hub integrating angiogenic cues with cytoskeletal changes that enable endothelial apical-basal polarization and lumen formation. These findings point to Nck as an emergent target for effective antiangiogenic therapy. PMID:26157164

  18. Structural stability and functional remodeling of high-density lipoproteins.

    PubMed

    Gursky, Olga

    2015-09-14

    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 the biophysical studies that revealed the 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 the functional role of structural disorder. A mechanism for the 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 forms 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

  19. Circadian Epigenomic Remodeling and Hepatic Lipogenesis: Lessons from HDAC3

    PubMed Central

    Sun, Zheng; Feng, Dan; Everett, Logan J.; Bugge, Anne; Lazar, Mitchell A.

    2013-01-01

    Circadian rhythms have evolved to anticipate metabolic needs across the 24-hour light/dark cycle. This is accomplished by circadian expression of metabolic genes orchestrated by transcription factors through chromatin remodeling and histone modifications. Our recent genome-wide study on histone deacetylase 3 (HDAC3) in mouse liver provides novel insights into the molecular link between circadian rhythm and hepatic de novo lipogenesis. We found that liver-specific knockout of HDAC3 in adult mouse display severe hepatic steatosis associated with enhanced de novo lipogenesis and increased expression of lipogenic genes. Genome-wide analysis (ChIP-seq) revealed a pronounced circadian pattern of HDAC3 occupancy on genes involved in lipid metabolism, which is inversely related to histone acetylation and RNA polymerase II recruitment at these sites. The cistromes of HDAC3 and its binding partner, nuclear receptor co-repressor (NCoR), significantly overlap with that of Rev-erbα, a nuclear receptor directly involved in the core circadian machinery. Knockout of Rev-erbα in mouse also leads to hepatic steatosis and enhanced de novo lipogenesis. Collectively, these data suggest that the circadian epigenomic remodeling controlled by HDAC3, and largely directed by Rev-erbα, is essential for homeostasis of the lipogenic process in liver. PMID:21900149

  20. Extracellular Matrix Molecular Remodeling in Human Liver Fibrosis Evolution

    PubMed Central

    Baiocchini, Andrea; Montaldo, Claudia; Conigliaro, Alice; Grimaldi, Alessio; Correani, Virginia; Mura, Francesco; Ciccosanti, Fabiola; Rotiroti, Nicolina; Brenna, Alessia; Montalbano, Marzia; D’Offizi, Gianpiero; Capobianchi, Maria Rosaria; Alessandro, Riccardo; Piacentini, Mauro; Schininà, Maria Eugenia; Maras, Bruno; Del Nonno, Franca; Tripodi, Marco; Mancone, Carmine

    2016-01-01

    Chronic liver damage leads to pathological accumulation of ECM proteins (liver fibrosis). Comprehensive characterization of the human ECM molecular composition is essential for gaining insights into the mechanisms of liver disease. To date, studies of ECM remodeling in human liver diseases have been hampered by the unavailability of purified ECM. Here, we developed a decellularization method to purify ECM scaffolds from human liver tissues. Histological and electron microscopy analyses demonstrated that the ECM scaffolds, devoid of plasma and cellular components, preserved the three-dimensional ECM structure and zonal distribution of ECM components. This method has been then applied on 57 liver biopsies of HCV-infected patients at different stages of liver fibrosis according to METAVIR classification. Label-free nLC-MS/MS proteomics and computation biology were performed to analyze the ECM molecular composition in liver fibrosis progression, thus unveiling protein expression signatures specific for the HCV-related liver fibrotic stages. In particular, the ECM molecular composition of liver fibrosis was found to involve dynamic changes in matrix stiffness, flexibility and density related to the dysregulation of predominant collagen, elastic fibers and minor components with both structural and signaling properties. This study contributes to the understanding of the molecular bases underlying ECM remodeling in liver fibrosis and suggests new molecular targets for fibrolytic strategies. PMID:26998606

  1. Remodeling of tissue-engineered bone structures in vivo

    PubMed Central

    Hofmann, Sandra; Hilbe, Monika; Fajardo, Robert J.; Hagenmüller, Henri; Nuss, Katja; Arras, Margarete; Müller, Ralph; von Rechenberg, Brigitte; Kaplan, David L.; Merkle, Hans P.; Meinel, Lorenz

    2013-01-01

    Implant design for bone regeneration is expected to be optimized when implant structures resemble the anatomical situation of the defect site. We tested the validity of this hypothesis by exploring the feasibility of generating different in vitro engineered bone-like structures originating from porous silk fibroin scaffolds decorated with RGD sequences (SF-RGD), seeded with human mesenchymal stem cells (hMSC). Scaffolds with small (106 – 212 μm), medium (212 – 300 μm) and large pore diameter ranges (300 – 425 μm) were seeded with hMSC and subsequently differentiated in vitro into bone-like tissue resembling initial scaffold geometries and featuring bone-like structures. Eight weeks after implantation into calvarial defects in mice, the in vitro engineered bone-like tissues had remodeled into bone featuring different proportions of woven/lamellar bone bridging the defects. Regardless of pore diameter all implants integrated well, vascularization was advanced and, bone marrow ingrowth had started. Ultimately, in this defect model, the geometry of the in vitro generated tissue-engineered bone structure, trabecular- or plate-like, had no significant impact on the healing of the defect, owing to an efficient remodeling of its structure after implantation. PMID:23958323

  2. Facilitation of base excision repair by chromatin remodeling.

    PubMed

    Hinz, John M; Czaja, Wioletta

    2015-12-01

    Base Excision Repair (BER) is a conserved, intracellular DNA repair system that recognizes and removes chemically modified bases to insure genomic integrity and prevent mutagenesis. Aberrant BER has been tightly linked with a broad spectrum of human pathologies, such as several types of cancer, neurological degeneration, developmental abnormalities, immune dysfunction and aging. In the cell, BER must recognize and remove DNA lesions from the tightly condensed, protein-coated chromatin. Because chromatin is necessarily refractory to DNA metabolic processes, like transcription and replication, the compaction of the genomic material is also inhibitory to the repair systems necessary for its upkeep. Multiple ATP-dependent chromatin remodelling (ACR) complexes play essential roles in modulating the protein-DNA interactions within chromatin, regulating transcription and promoting activities of some DNA repair systems, including double-strand break repair and nucleotide excision repair. However, it remains unclear how BER operates in the context of chromatin, and if the chromatin remodelling processes that govern transcription and replication also actively regulate the efficiency of BER. In this review we highlight the emerging role of ACR in regulation of BER. PMID:26422134

  3. Nucleosome breathing and remodeling constrain CRISPR-Cas9 function

    PubMed Central

    Isaac, R Stefan; Jiang, Fuguo; Doudna, Jennifer A; Lim, Wendell A; Narlikar, Geeta J; Almeida, Ricardo

    2016-01-01

    The CRISPR-Cas9 bacterial surveillance system has become a versatile tool for genome editing and gene regulation in eukaryotic cells, yet how CRISPR-Cas9 contends with the barriers presented by eukaryotic chromatin is poorly understood. Here we investigate how the smallest unit of chromatin, a nucleosome, constrains the activity of the CRISPR-Cas9 system. We find that nucleosomes assembled on native DNA sequences are permissive to Cas9 action. However, the accessibility of nucleosomal DNA to Cas9 is variable over several orders of magnitude depending on dynamic properties of the DNA sequence and the distance of the PAM site from the nucleosome dyad. We further find that chromatin remodeling enzymes stimulate Cas9 activity on nucleosomal templates. Our findings imply that the spontaneous breathing of nucleosomal DNA together with the action of chromatin remodelers allow Cas9 to effectively act on chromatin in vivo. DOI: http://dx.doi.org/10.7554/eLife.13450.001 PMID:27130520

  4. Steroid control of muscle remodeling during metamorphosis in Manduca sexta.

    PubMed

    Hegstrom, C D; Truman, J W

    1996-04-01

    During metamorphosis in the tobacco hornworm, Manduca sexta, the abdominal body-wall muscle DEO1 is remodeled to form the adult muscle DE5. The degeneration of muscle DEO1 involves the dismantling of its contractile apparatus followed by the degeneration of muscle nuclei. As some nuclei are degenerating, others begin to incorporate 5-bromodeoxyuridine (BrdU), indicating the onset of nuclear proliferation. This proliferation is initially most evident at the site where the motoneuron contacts the muscle remnant. The developmental events involved in muscle remodeling are under the control of the steroid hormones, the ecdysteroids. The loss of the contractile elements of the larval muscle requires the rise and fall of the prepupal peak of ecdysteroids, whereas the subsequent loss of muscle nuclei is influenced by the slight rise in ecdysteroids seen after pupal ecdysis. Incorporation of BrdU by muscle nuclei depends on both the adult peak of the ecdysteroids and contact with the motoneuron. Unilateral axotomy blocks proliferation within the rudiment, but it does not block its subsequent differentiation into a very thin muscle in the adult. PMID:8656216

  5. Protective Effects of Paricalcitol on Peritoneal Remodeling during Peritoneal Dialysis

    PubMed Central

    Stavenuiter, Andrea W. D.; Farhat, Karima; Vila Cuenca, Marc; Schilte, Margot N.; Keuning, Eelco D.; Paauw, Nanne J.; ter Wee, Pieter M.; Beelen, Robert H. J.; Vervloet, Marc G.

    2015-01-01

    Peritoneal dialysis (PD) is associated with structural and functional alterations of the peritoneal membrane, consisting of fibrosis, angiogenesis, and loss of ultrafiltration capacity. Vitamin D receptor activation (VDRA) plays an important role in mineral metabolism and inflammation, but also antiangiogenic and antifibrotic properties have been reported. Therefore, the effects of active vitamin D treatment on peritoneal function and remodeling were investigated. Rats were either kept naïve to PDF exposure or daily exposed to 10 mL PDF and were treated for five or seven weeks with oral paricalcitol or vehicle control. Non-PDF-exposed rats showed no peritoneal changes upon paricalcitol treatment. Paricalcitol reduced endogenous calcitriol but did not affect mineral homeostasis. However, upon PDF exposure, loss of ultrafiltration capacity ensued which was fully rescued by paricalcitol treatment. Furthermore, PD-induced ECM thickening was significantly reduced and omental PD-induced angiogenesis was less pronounced upon paricalcitol treatment. No effect of paricalcitol treatment on total amount of peritoneal cells, peritoneal leukocyte composition, and epithelial to mesenchymal transition (EMT) was observed. Our data indicates that oral VDRA reduces tissue remodeling during chronic experimental PD and prevents loss of ultrafiltration capacity. Therefore, VDRA is potentially relevant in the prevention of treatment technique failure in PD patients. PMID:26605330

  6. Antenatal Hypoxia and Pulmonary Vascular Function and Remodeling

    PubMed Central

    Papamatheakis, Demosthenes G.; Blood, Arlin B.; Kim, Joon H.; Wilson, Sean M.

    2015-01-01

    This review provides evidence that antenatal hypoxia, which represents a significant and worldwide problem, causes prenatal programming of the lung. A general overview of lung development is provided along with some background regarding transcriptional and signaling systems of the lung. The review illustrates that antenatal hypoxic stress can induce a continuum of responses depending on the species examined. Fetuses and newborns of certain species and specific human populations are well acclimated to antenatal hypoxia. However, antenatal hypoxia causes pulmonary vascular disease in fetuses and newborns of most mammalian species and humans. Disease can range from mild pulmonary hypertension, to severe vascular remodeling and dangerous elevations in pressure. The timing, length, and magnitude of the intrauterine hypoxic stress are important to disease development, however there is also a genetic-environmental relationship that is not yet completely understood. Determining the origins of pulmonary vascular remodeling and pulmonary hypertension and their associated effects is a challenging task, but is necessary in order to develop targeted therapies for pulmonary hypertension in the newborn due to antenatal hypoxia that can both treat the symptoms and curtail or reverse disease progression. PMID:24063380

  7. Integrative models of vascular remodeling during tumor growth

    PubMed Central

    Rieger, Heiko; Welter, Michael

    2015-01-01

    Malignant solid tumors recruit the blood vessel network of the host tissue for nutrient supply, continuous growth, and gain of metastatic potential. Angiogenesis (the formation of new blood vessels), vessel cooption (the integration of existing blood vessels into the tumor vasculature), and vessel regression remodel the healthy vascular network into a tumor-specific vasculature that is in many respects different from the hierarchically organized arterio-venous blood vessel network of the host tissues. Integrative models based on detailed experimental data and physical laws implement in silico the complex interplay of molecular pathways, cell proliferation, migration, and death, tissue microenvironment, mechanical and hydrodynamic forces, and the fine structure of the host tissue vasculature. With the help of computer simulations high-precision information about blood flow patterns, interstitial fluid flow, drug distribution, oxygen and nutrient distribution can be obtained and a plethora of therapeutic protocols can be tested before clinical trials. In this review, we give an overview over the current status of integrative models describing tumor growth, vascular remodeling, blood and interstitial fluid flow, drug delivery, and concomitant transformations of the microenvironment. © 2015 The Authors. WIREs Systems Biology and Medicine published by Wiley Periodicals, Inc. PMID:25808551

  8. LPS Remodeling Triggers Formation of Outer Membrane Vesicles in Salmonella

    PubMed Central

    Elhenawy, Wael; Bording-Jorgensen, Michael; Valguarnera, Ezequiel; Haurat, M. Florencia; Wine, Eytan

    2016-01-01

    ABSTRACT Outer membrane vesicles (OMV) are proposed to mediate multiple functions during pathogenesis and symbiosis. However, the mechanisms responsible for OMV formation remain poorly understood. It has been shown in eukaryotic membranes that lipids with an inverted-cone shape favor the formation of positive membrane curvatures. Based on these studies, we formulated the hypothesis that lipid A deacylation might impose shape modifications that result in the curvature of the outer membrane (OM) and subsequent OMV formation. We tested the effect of lipid A remodeling on OMV biogenesis employing Salmonella enterica serovar Typhimurium as a model organism. Expression of the lipid A deacylase PagL resulted in increased vesiculation, without inducing an envelope stress response. Mass spectrometry analysis revealed profound differences in the patterns of lipid A in OM and OMV, with accumulation of deacylated lipid A forms exclusively in OMV. OMV biogenesis by intracellular bacteria upon macrophage infection was drastically reduced in a pagL mutant strain. We propose a novel mechanism for OMV biogenesis requiring lipid A deacylation in the context of a multifactorial process that involves the orchestrated remodeling of the outer membrane. PMID:27406567

  9. Multifractal and Lacunarity Analysis of Microvascular Morphology and Remodeling

    PubMed Central

    Gould, Daniel J.; Vadakkan, Tegy J.; Poché, Ross A.; Dickinson, Mary E.

    2011-01-01

    Purpose Classical measures of vessel morphology including diameter and density are employed to study microvasculature in endothelial membrane labeled mice. These measurements prove sufficient for some studies; however they are less well suited for quantifying changes in microcirculatory networks lacking hierarchical structure. We demonstrate automated multifractal analysis and lacunarity may be used with classical methods to quantify microvascular morphology. Methods We present an automated extraction tool with a processing pipeline to characterize 2D representations of 3D microvasculature, using multifractal analysis and lacunarity. We apply our analysis on four tissues and the hyaloid vasculature during remodeling. Results We found that the vessel networks analyzed have multifractal geometries and that kidney microvasculature has the largest fractal dimension and the lowest lacunarity compared to microvasculature networks in the cortex, skin, and thigh muscle. Also, we found that during hyaloid remodeling, there were differences in multifractal spectra reflecting the functional transition from a space filling vasculature which nurtures the lens to a less dense vasculature as it regresses, permitting unobstructed vision. Conclusion Multifractal analysis and lacunarity are valuable additions to classical measures of vascular morphology and will have utility in future studies of normal, developing and pathological tissues. PMID:21166933

  10. Pulmonary arterial remodeling in chronic obstructive pulmonary disease is lobe dependent.

    PubMed

    Wrobel, Jeremy P; McLean, Catriona A; Thompson, Bruce R; Stuart-Andrews, Christopher R; Paul, Eldho; Snell, Gregory I; Williams, Trevor J

    2013-09-01

    Abstract Pulmonary arterial remodeling has been demonstrated in patients with severe chronic obstructive pulmonary disease (COPD), but it is not known whether lobar heterogeneity of remodeling occurs. Furthermore, the relationship between pulmonary hypertension (PH) and pulmonary arterial remodeling in COPD has not been established. Muscular pulmonary arterial remodeling in arteries 0.10-0.25 mm in diameter was assessed in COPD-explanted lungs and autopsy controls. Remodeling was quantified as the percentage wall thickness to vessel diameter (%WT) using digital image analysis. Repeat measures mixed-effects remodeling for %WT was performed according to lobar origin (upper and lower), muscular pulmonary arterial size (small, medium, and large), and echocardiography-based pulmonary arterial pressure (no PH, mild PH, and moderate-to-severe PH). Lobar perfusion and emphysema indices were determined from ventilation-perfusion and computed tomography scans, respectively. Overall, %WT was greater in 42 subjects with COPD than in 5 control subjects ([Formula: see text]). Within the COPD group, %WT was greater in the upper lobes ([Formula: see text]) and in the small muscular pulmonary arteries ([Formula: see text]). Lobar differences were most pronounced in medium and large arteries. Lobar emphysema index was not associated with arterial remodeling. However, there was a significant positive relationship between the lobar perfusion index and pulmonary arterial remodeling ([Formula: see text]). The presence of PH on echocardiography showed only a trend to a small effect on lower lobe remodeling. The pattern of pulmonary arterial remodeling in COPD is complicated and lobe dependent. Differences in regional blood flow partially account for the lobar heterogeneity of pulmonary arterial remodeling in COPD. PMID:24618551

  11. Undoing Gender Through Legislation and Schooling: the Case of AB 537 and AB 394 IN California, USA

    NASA Astrophysics Data System (ADS)

    Knotts, Greg

    2009-11-01

    This article investigates California laws AB 537: The Student Safety and Violence Prevention Act of 2000, and the recently enacted AB 394: Safe Place to Learn Act. Both demand that gender identity and sexual orientation be added to the lexicon of anti-harassment protection in public education. However, despite these progressive measures, schools have an unconscious acceptance of heteronormativity and gendered norms, which undermines both the spirit and language of these laws. This paper examines how California schools can both change standard practices and realise the transformative social change that laws like AB 537 and AB 394 can instigate. I assert that the systemic implementation of these laws, through the adoption, enforcement and evaluation of existing AB 537 Task Force Recommendations, is necessary for their success. My second assertion is that AB 537 and AB 394 have the potential to change and reconstitute gender-based and heteronormative standards at school sites.

  12. 40 CFR 174.506 - Bacillus thuringiensis Cry34Ab1 and Cry35Ab1 proteins in corn; exemption from the requirement of...

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... Cry35Ab1 proteins in corn; exemption from the requirement of a tolerance. 174.506 Section 174.506... thuringiensis Cry34Ab1 and Cry35Ab1 proteins in corn; exemption from the requirement of a tolerance. Residues of Bacillus thuringiensis Cry34Ab1 and Cry35Ab1 proteins in corn are exempted from the requirement of...

  13. 40 CFR 174.506 - Bacillus thuringiensis Cry34Ab1 and Cry35Ab1 proteins in corn; exemption from the requirement of...

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... Cry35Ab1 proteins in corn; exemption from the requirement of a tolerance. 174.506 Section 174.506... thuringiensis Cry34Ab1 and Cry35Ab1 proteins in corn; exemption from the requirement of a tolerance. Residues of Bacillus thuringiensis Cry34Ab1 and Cry35Ab1 proteins in corn are exempted from the requirement of...

  14. 40 CFR 174.506 - Bacillus thuringiensis Cry34Ab1 and Cry35Ab1 proteins in corn; exemption from the requirement of...

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... Cry35Ab1 proteins in corn; exemption from the requirement of a tolerance. 174.506 Section 174.506... thuringiensis Cry34Ab1 and Cry35Ab1 proteins in corn; exemption from the requirement of a tolerance. Residues of Bacillus thuringiensis Cry34Ab1 and Cry35Ab1 proteins in corn are exempted from the requirement of...

  15. 40 CFR 174.506 - Bacillus thuringiensis Cry34Ab1 and Cry35Ab1 proteins in corn; exemption from the requirement of...

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... Cry35Ab1 proteins in corn; exemption from the requirement of a tolerance. 174.506 Section 174.506... thuringiensis Cry34Ab1 and Cry35Ab1 proteins in corn; exemption from the requirement of a tolerance. Residues of Bacillus thuringiensis Cry34Ab1 and Cry35Ab1 proteins in corn are exempted from the requirement of...

  16. Proteomics of bronchial biopsies: galectin-3 as a predictive biomarker of airway remodelling modulation in omalizumab-treated severe asthma patients.

    PubMed

    Mauri, Pierluigi; Riccio, Anna Maria; Rossi, Rossana; Di Silvestre, Dario; Benazzi, Louise; De Ferrari, Laura; Dal Negro, Roberto Walter; Holgate, Stephen T; Canonica, Giorgio Walter

    2014-11-01

    Asthma is a chronic inflammatory disease. Reticular basement membrane (RBM) thickening is considered feature of airway remodelling (AR) particularly in severe asthma (SA). Omalizumab, mAb to IgE is effective in SA and can modulate AR. Herein we describe protein profiles of bronchial biopsies to detect biomarkers of anti-IgE effects on AR and to explain potential mechanisms/pathways. We defined the bronchial biopsy protein profiles, before and after treatment. Unsupervised clustering of baseline proteomes resulted in very good agreement with the morphometric analysis of AR. Protein profiles of omalizumab responders (ORs) were significantly different from those of non-omalizumab responders (NORs). The major differences between ORs and NORs lied to smooth muscle and extra cellular matrix proteins. Notably, an IgE-binding protein (galectin-3) was reliable, stable and predictive biomarker of AR modulation. Omalizumab down-regulated bronchial smooth muscle proteins in SA. These findings suggest that omalizumab may exert disease-modifying effects on remodelling components. PMID:25194755

  17. Ab initio melting curve of osmium

    NASA Astrophysics Data System (ADS)

    Burakovsky, L.; Burakovsky, N.; Preston, D. L.

    2015-11-01

    The melting curve of osmium up to a pressure P of 500 GPa is obtained from an extensive suite of ab initio quantum molecular dynamics (QMD) simulations using the Z method. The ab initio P =0 melting point of Os is 3370 ±75 K; this range encompasses all of the available data in the literature and corroborates the conclusion of J. W. Arblaster [Platinum Metals Rev. 49, 166 (2005)], 10.1595/147106705X70264 that the melting temperature of pure Os is 3400 ±50 K and that the 3300 K typically quoted in the literature is the melting point of impure Os. The T =0 equation of state (EOS) of Os and the P dependence of the optimized c /a ratio for the hexagonal unit cell, both to pressures ˜900 GPa, are obtained in the ab initio approach as validation of its use. Although excellent agreement with the available experimental data (P ≲80 GPa) is found, it is the third-order Birch-Murnaghan EOS with B0'=5 rather than the more widely accepted B0'=4 that describes the QMD data to higher pressures, in agreement with the more recent experimental EOS by Godwal et al. The theoretical melting curve of Os obtained earlier by Joshi et al. is shown to be inconsistent with our QMD results, and the possible reason for this discrepancy is suggested. Regularities in the melting curves of Os and five other third-row transition metals (Ta, W, Re, Pt, Au) could be used to estimate the currently unknown melting curves of Hf and Ir.

  18. New challenges to medicare beneficiary access to mAbs

    PubMed Central

    Wilson, Andrew

    2009-01-01

    Precision binding of monoclonal antibodies (mAbs) to biological targets, their relative clinical success, and expansion of indications following initial approval, are distinctive clinical features. The relatively high cost of mAbs, together with the absence of a regulatory pathway to generics, stand out as distinctive economic features. Based on both literature review and primary data collection we enumerated mAb original approvals, supplemental indications and off-label uses, assessed payer formulary management of mAbs, and determined new challenges to Medicare beneficiary access to mAbs. We found that the FDA has approved 22 mAbs and 30 supplemental indications pertaining to the originally approved mAbs. In addition, there are 46 off-label use citations in officially recognized pharmaceutical compendia. Across Part B carriers and Part D plans, we found considerable variation in terms of coverage and conditions of reimbursement related to on- and off-label uses of mAbs. Our results point to four major challenges facing mAb developers, health care providers, Medicare beneficiaries, payers and policymakers. These include administrative price controls, coverage variation, projected shift from physician- to self-administered mAbs, and comparative effectiveness. We suggest more systematic use of “coverage with evidence development” as a means of optimally addressing these challenges. PMID:20046575

  19. Ab initio quantum chemistry: Methodology and applications

    PubMed Central

    Friesner, Richard A.

    2005-01-01

    This Perspective provides an overview of state-of-the-art ab initio quantum chemical methodology and applications. The methods that are discussed include coupled cluster theory, localized second-order Moller–Plesset perturbation theory, multireference perturbation approaches, and density functional theory. The accuracy of each approach for key chemical properties is summarized, and the computational performance is analyzed, emphasizing significant advances in algorithms and implementation over the past decade. Incorporation of a condensed-phase environment by means of mixed quantum mechanical/molecular mechanics or self-consistent reaction field techniques, is presented. A wide range of illustrative applications, focusing on materials science and biology, are discussed briefly. PMID:15870212

  20. Testing Distributed ABS System with Fault Injection

    NASA Astrophysics Data System (ADS)

    Trawczyński, Dawid; Sosnowski, Janusz; Gawkowski, Piotr

    The paper deals with the problem of adapting software implemented fault injection technique (SWIFI) to evaluate dependability of reactive microcontroller systems. We present an original methodology of disturbing controller operation and analyzing fault effects taking into account reactions of the controlled object and the impact of the system environment. Faults can be injected randomly (in space and time) or targeted at the most sensitive elements of the controller to check it at high stresses. This approach allows identifying rarely encountered problems, usually missed in classical approaches. The developed methodology has been used successfully to verify dependability of ABS system. Experimental results are commented in the paper.