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Sample records for block factorization preconditioning

  1. Incomplete block factorization preconditioning for indefinite elliptic problems

    SciTech Connect

    Guo, Chun-Hua

    1996-12-31

    The application of the finite difference method to approximate the solution of an indefinite elliptic problem produces a linear system whose coefficient matrix is block tridiagonal and symmetric indefinite. Such a linear system can be solved efficiently by a conjugate residual method, particularly when combined with a good preconditioner. We show that specific incomplete block factorization exists for the indefinite matrix if the mesh size is reasonably small. And this factorization can serve as an efficient preconditioner. Some efforts are made to estimate the eigenvalues of the preconditioned matrix. Numerical results are also given.

  2. Incomplete block SSOR preconditionings for high order discretizations

    SciTech Connect

    Kolotilina, L.

    1994-12-31

    This paper considers the solution of linear algebraic systems Ax = b resulting from the p-version of the Finite Element Method (FEM) using PCG iterations. Contrary to the h-version, the p-version ensures the desired accuracy of a discretization not by refining an original finite element mesh but by introducing higher degree polynomials as additional basis functions which permits to reduce the size of the resulting linear system as compared with the h-version. The suggested preconditionings are the so-called Incomplete Block SSOR (IBSSOR) preconditionings.

  3. Enhanced multi-level block ILU preconditioning strategies for general sparse linear systems

    NASA Astrophysics Data System (ADS)

    Saad, Yousef; Zhang, Jun

    2001-05-01

    This paper introduces several strategies to deal with pivot blocks in multi-level block incomplete LU factorization (BILUM) preconditioning techniques. These techniques are aimed at increasing the robustness and controlling the amount of fill-ins of BILUM for solving large sparse linear systems when large-size blocks are used to form block-independent set. Techniques proposed in this paper include double-dropping strategies, approximate singular-value decomposition, variable size blocks and use of an arrowhead block submatrix. We point out the advantages and disadvantages of these strategies and discuss their efficient implementations. Numerical experiments are conducted to show the usefulness of the new techniques in dealing with hard-to-solve problems arising from computational fluid dynamics. In addition, we discuss the relation between multi-level ILU preconditioning methods and algebraic multi-level methods.

  4. Block LU factorization

    NASA Technical Reports Server (NTRS)

    Demmel, James W.; Higham, Nicholas J.; Schreiber, Robert S.

    1992-01-01

    Many of the currently popular 'block algorithms' are scalar algorithms in which the operations have been grouped and reordered into matrix operations. One genuine block algorithm in practical use is block LU factorization, and this has recently been shown by Demmel and Higham to be unstable in general. It is shown here that block LU factorization is stable if A is block diagonally dominant by columns. Moreover, for a general matrix the level of instability in block LU factorization can be founded in terms of the condition number kappa(A) and the growth factor for Gaussian elimination without pivoting. A consequence is that block LU factorization is stable for a matrix A that is symmetric positive definite or point diagonally dominant by rows or columns as long as A is well-conditioned.

  5. Accelerated Block Preconditioned Gradient method for large scale wave functions calculations in Density Functional Theory

    SciTech Connect

    Fattebert, J.-L.

    2010-01-20

    An Accelerated Block Preconditioned Gradient (ABPG) method is proposed to solve electronic structure problems in Density Functional Theory. This iterative algorithm is designed to solve directly the non-linear Kohn-Sham equations for accurate discretization schemes involving a large number of degrees of freedom. It makes use of an acceleration scheme similar to what is known as RMM-DIIS in the electronic structure community. The method is illustrated with examples of convergence for large scale applications using a finite difference discretization and multigrid preconditioning.

  6. Comparison of nested factorization, constrained pressure residual, and incomplete factorization preconditionings

    SciTech Connect

    Behie, A.

    1985-02-01

    Two recently developed methods for the solution of the sparse block-banded linear equation sets generated by fully implicit reservoir simulators are investigated. Nested factorization is a new approach to forming an incomplete factorization of the linear system. Comparisons are made of the nested factorization approach and the incomplete LU factorization (ILU) approach. Tests are done on both model problems and on problems generated by reservoir simulators. The nested factorization was no better than the best ILU method on both types of problems in most cases. In some cases it was considerably worse. Constrained pressure residual preconditioning (CPR) is a variant of the COMBINATIVE method. These two methods are compared on problems generated by black oil and steam simulators. CPR gives small improvements in convergence rates in some cases.

  7. Real Space DFT by Locally Optimal Block Preconditioned Conjugate Gradient Method

    NASA Astrophysics Data System (ADS)

    Michaud, Vincent; Guo, Hong

    2012-02-01

    Real space approaches solve the Kohn-Sham (KS) DFT problem as a system of partial differential equations (PDE) in real space numerical grids. In such techniques, the Hamiltonian matrix is typically much larger but sparser than the matrix arising in state-of-the-art DFT codes which are often based on directly minimizing the total energy functional. Evidence of good performance of real space methods - by Chebyshev filtered subspace iteration (CFSI) - was reported by Zhou, Saad, Tiago and Chelikowsky [1]. We found that the performance of the locally optimal block preconditioned conjugate gradient method (LOGPCG) introduced by Knyazev [2], when used in conjunction with CFSI, generally exceeds that of CFSI for solving the KS equations. We will present our implementation of the LOGPCG based real space electronic structure calculator. [4pt] [1] Y. Zhou, Y. Saad, M. L. Tiago, and J. R. Chelikowsky, ``Self-consistent-field calculations using Chebyshev-filtered subspace iteration,'' J. Comput. Phys., vol. 219,pp. 172-184, November 2006. [0pt] [2] A. V. Knyazev, ``Toward the optimal preconditioned eigensolver: Locally optimal block preconditioned conjugate gradient method,'' SIAM J. Sci. Comput, vol. 23, pp. 517-541, 2001.

  8. Hypoxia-Inducible Factor 1: Regulator of Mitochondrial Metabolism and Mediator of Ischemic Preconditioning

    PubMed Central

    Semenza, Gregg L.

    2010-01-01

    Hypoxia-inducible factor 1 (HIF-1) mediates adaptive responses to reduced oxygen availability by regulating gene expression. A critical cell-autonomous adaptive response to chronic hypoxia controlled by HIF-1 is reduced mitochondrial mass and/or metabolism. Exposure of HIF-1-deficient fibroblasts to chronic hypoxia results in cell death due to excessive levels of reactive oxygen species (ROS). HIF-1 reduces ROS production under hypoxic conditions by multiple mechanisms including: a subunit switch in cytochrome c oxidase from the COX4-1 to COX4-2 regulatory subunit that increases the efficiency of complex IV; induction of pyruvate dehydrogenase kinase 1, which shunts pyruvate away from the mitochondria; induction of BNIP3, which triggers mitochondrial selective autophagy; and induction of microRNA-210, which blocks assembly of Fe/S clusters that are required for oxidative phosphorylation. HIF-1 is also required for ischemic preconditioning and this effect may be due in part to its induction of CD73, the enzyme that produces adenosine. HIF-1-dependent regulation of mitochondrial metabolism may also contribute to the protective effects of ischemic preconditioning. PMID:20732359

  9. Stabilization and scalable block preconditioning for the Navier-Stokes equations

    NASA Astrophysics Data System (ADS)

    Cyr, Eric C.; Shadid, John N.; Tuminaro, Raymond S.

    2012-01-01

    This study compares several block-oriented preconditioners for the stabilized finite element discretization of the incompressible Navier-Stokes equations. This includes standard additive Schwarz domain decomposition methods, aggressive coarsening multigrid, and three preconditioners based on an approximate block LU factorization, specifically SIMPLEC, LSC, and PCD. Robustness is considered with a particular focus on the impact that different stabilization methods have on preconditioner performance. Additionally, parallel scaling studies are undertaken. The numerical results indicate that aggressive coarsening multigrid, LSC and PCD all have good algorithmic scalability. Coupling this with the fact that block methods can be applied to systems arising from stable mixed discretizations implies that these techniques are a promising direction for developing scalable methods for Navier-Stokes.

  10. Multiple solutions to dense systems in radar scattering using a preconditioned block GMRES solver

    SciTech Connect

    Boyse, W.E.

    1996-12-31

    Multiple right-hand sides occur in radar scattering calculations in the computation of the simulated radar return from a body at a large number of angles. Each desired angle requires a right-hand side vector to be computed and the solution generated. These right-hand sides are naturally smooth functions of the angle parameters and this property is utilized in a novel way to compute solutions an order of magnitude faster than LINPACK The modeling technique addressed is the Method of Moments (MOM), i.e. a boundary element method for time harmonic Maxwell`s equations. Discretization by this method produces general complex dense systems of rank 100`s to 100,000`s. The usual way to produce the required multiple solutions is via LU factorization and solution routines such as found in LINPACK. Our method uses the block GMRES iterative method to directly iterate a subset of the desired solutions to convergence.

  11. Bundle block adjustment of large-scale remote sensing data with Block-based Sparse Matrix Compression combined with Preconditioned Conjugate Gradient

    NASA Astrophysics Data System (ADS)

    Zheng, Maoteng; Zhang, Yongjun; Zhou, Shunping; Zhu, Junfeng; Xiong, Xiaodong

    2016-07-01

    In recent years, new platforms and sensors in photogrammetry, remote sensing and computer vision areas have become available, such as Unmanned Aircraft Vehicles (UAV), oblique camera systems, common digital cameras and even mobile phone cameras. Images collected by all these kinds of sensors could be used as remote sensing data sources. These sensors can obtain large-scale remote sensing data which consist of a great number of images. Bundle block adjustment of large-scale data with conventional algorithm is very time and space (memory) consuming due to the super large normal matrix arising from large-scale data. In this paper, an efficient Block-based Sparse Matrix Compression (BSMC) method combined with the Preconditioned Conjugate Gradient (PCG) algorithm is chosen to develop a stable and efficient bundle block adjustment system in order to deal with the large-scale remote sensing data. The main contribution of this work is the BSMC-based PCG algorithm which is more efficient in time and memory than the traditional algorithm without compromising the accuracy. Totally 8 datasets of real data are used to test our proposed method. Preliminary results have shown that the BSMC method can efficiently decrease the time and memory requirement of large-scale data.

  12. Graph Embedding Techniques for Bounding Condition Numbers of Incomplete Factor Preconditioning

    NASA Technical Reports Server (NTRS)

    Guattery, Stephen

    1997-01-01

    We extend graph embedding techniques for bounding the spectral condition number of preconditioned systems involving symmetric, irreducibly diagonally dominant M-matrices to systems where the preconditioner is not diagonally dominant. In particular, this allows us to bound the spectral condition number when the preconditioner is based on an incomplete factorization. We provide a review of previous techniques, describe our extension, and give examples both of a bound for a model problem, and of ways in which our techniques give intuitive way of looking at incomplete factor preconditioners.

  13. Identifying the Source of a Humoral Factor of Remote (Pre)Conditioning Cardioprotection

    PubMed Central

    Mastitskaya, Svetlana; Basalay, Marina; Hosford, Patrick S.; Ramage, Andrew G.; Gourine, Andrey; Gourine, Alexander V.

    2016-01-01

    Signalling pathways underlying the phenomenon of remote ischaemic preconditioning (RPc) cardioprotection are not completely understood. The existing evidence agrees that intact sensory innervation of the remote tissue/organ is required for the release into the systemic circulation of preconditioning factor(s) capable of protecting a transplanted or isolated heart. However, the source and molecular identities of these factors remain unknown. Since the efficacy of RPc cardioprotection is critically dependent upon vagal activity and muscarinic mechanisms, we hypothesized that the humoral RPc factor is produced by the internal organ(s), which receive rich parasympathetic innervation. In a rat model of myocardial ischaemia/reperfusion injury we determined the efficacy of limb RPc in establishing cardioprotection after denervation of various visceral organs by sectioning celiac, hepatic, anterior and posterior gastric branches of the vagus nerve. Electrical stimulation was applied to individually sectioned branches to determine whether enhanced vagal input to a particular target area is sufficient to establish cardioprotection. It was found that RPc cardioprotection is abolished in conditions of either total subdiaphragmatic vagotomy, gastric vagotomy or sectioning of the posterior gastric branch. The efficacy of RPc cardioprotection was preserved when hepatic, celiac or anterior gastric vagal branches were cut. In the absence of remote ischaemia/reperfusion, electrical stimulation of the posterior gastric branch reduced infarct size, mimicking the effect of RPc. These data suggest that the circulating factor (or factors) of RPc are produced and released into the systemic circulation by the visceral organ(s) innervated by the posterior gastric branch of the vagus nerve. PMID:26918777

  14. The neuroprotective effects of preconditioning exercise on brain damage and neurotrophic factors after focal brain ischemia in rats.

    PubMed

    Otsuka, Shotaro; Sakakima, Harutoshi; Sumizono, Megumi; Takada, Seiya; Terashi, Takuto; Yoshida, Yoshihiro

    2016-04-15

    Preconditioning exercise can exert neuroprotective effects after stroke. However, the mechanism underlying these neuroprotective effects by preconditioning exercise remains unclear. We investigated the neuroprotective effects of preconditioning exercise on brain damage and the expression levels of the midkine (MK) and brain-derived neurotrophic factor (BDNF) after brain ischemia. Animals were assigned to one of 4 groups: exercise and ischemia (Ex), no exercise and ischemia (No-Ex), exercise and no ischemia (Ex-only), and no exercise and intact (Control). Rats ran on a treadmill for 30 min once a day at a speed of 25 m/min for 5 days a week for 3 weeks. After the exercise program, stroke was induced by a 60 min left middle cerebral artery occlusion using an intraluminal filament. The infarct volume, motor function, neurological deficits, and the cellular expressions levels of MK, BDNF, GFAP, PECAM-1, caspase 3, and nitrotyrosine (NT) were evaluated 48 h after the induction of ischemia. The infarct volume, neurological deficits and motor function in the Ex group were significantly improved compared to that of the No-Ex group. The expression levels of MK, BDNF, GFAP, and PECAM-1 were enhanced in the Ex group compared to the expression levels in the No-Ex group after brain ischemia, while the expression levels of activated caspase 3 and NT were reduced in the area surrounding the necrotic lesion. Our findings suggest that preconditioning exercise reduced the infract volume and ameliorated motor function, enhanced expression levels of MK and BDNF, increased astrocyte proliferation, increased angiogenesis, and reduced neuronal apoptosis and oxidative stress. PMID:26808606

  15. ERK5/KLF4 signaling as a common mediator of the neuroprotective effects of both nerve growth factor and hydrogen peroxide preconditioning.

    PubMed

    Su, Chang; Sun, Fen; Cunningham, Rebecca L; Rybalchenko, Nataliya; Singh, Meharvan

    2014-01-01

    Oxidative stress has long been implicated in the pathogenesis of various neurodegenerative disorders such as Alzheimer's disease and stroke. While high levels of oxidative stress are generally associated with cell death, a slight rise of reactive oxygen species (ROS) levels can be protective by "preconditioning" cells to develop a resistance against subsequent challenges. However, the mechanisms underlying such preconditioning (PC)-induced protection are still poorly understood. Previous studies have supported a role of ERK5 (mitogen-activated protein [MAP] kinase 5) in neuroprotection and ischemic tolerance in the hippocampus. In agreement with these findings, our data suggest that ERK5 mediates both hydrogen peroxide (H2O2)-induced PC as well as nerve growth factor (NGF)-induced neuroprotection. Activation of ERK5 partially rescued pheochromocytoma PC12 cells as well as primary hippocampal neurons from H2O2-caused death, while inhibition of ERK5 abolished NGF or PC-induced protection. These results implicate ERK5 signaling as a common downstream pathway for NGF and PC. Furthermore, both NGF and PC increased the expression of the transcription factor, KLF4, which can initiate an anti-apoptotic response in various cell types. Induction of KLF4 by NGF or PC was blocked by siERK5, suggesting that ERK5 is required in this process. siKLF4 can also attenuate NGF- or PC-induced neuroprotection. Overexpression of active MEK5 or KLF4 in H2O2-stressed cells increased Bcl-2/Bax ratio and the expression of NAIP (neuronal apoptosis inhibitory protein). Taken together, our data suggest that ERK5/KLF4 cascade is a common signaling pathway shared by at least two important mechanisms by which neurons can be protected from cell death. PMID:25015774

  16. Multigrid block preconditioning for a coupled system of partial differential equations modeling the electrical activity in the heart.

    PubMed

    Sundnes, J; Lines, G T; Mardal, K A; Tveito, A

    2002-12-01

    The electrical activity of the heart may be modeled with a system of partial differential equations (PDEs) known as the bidomain model. Computer simulations based on these equations may become a helpful tool to understand the relationship between changes in the electrical field and various heart diseases. Because of the rapid variations in the electrical field, sufficiently accurate simulations require a fine-scale discretization of the equations. For realistic geometries this leads to a large number of grid points and consequently large linear systems to be solved for each time step. In this paper, we present a fully coupled discretization of the bidomain model, leading to a block structured linear system. We take advantage of the block structure to construct an efficient preconditioner for the linear system, by combining multigrid with an operator splitting technique. PMID:12468421

  17. Hypoxia/Reoxygenation-Preconditioned Human Bone Marrow-Derived Mesenchymal Stromal Cells Rescue Ischemic Rat Cortical Neurons by Enhancing Trophic Factor Release.

    PubMed

    Kim, Young Seo; Noh, Min Young; Cho, Kyung Ah; Kim, Hyemi; Kwon, Min-Soo; Kim, Kyung Suk; Kim, Juhan; Koh, Seong-Ho; Kim, Seung Hyun

    2015-08-01

    Bone marrow-derived mesenchymal stromal cells (BM-MSCs) represent a promising tool for stem cell-based therapies. However, the majority of MSCs fail to reach the injury site and have only minimal therapeutic effect. In this study, we assessed whether hypoxia/reoxygenation (H/R) preconditioning of human BM-MSCs could increase their functional capacity and beneficial effect on ischemic rat cortical neurons. Human BM-MSCs were cultured under hypoxia (1% O2) and with long-term reoxygenation for various times to identify the optimal conditions for increasing their viability and proliferation. The effects of H/R preconditioning on the BM-MSCs were assessed by analyzing the expression of prosurvival genes, trophic factors, and cell migration assays. The functionally improved BM-MSCs were cocultured with ischemic rat cortical neurons to compare with normoxic cultured BM-MSCs. Although the cell viability and proliferation of BM-MSCs were reduced after 1 day of hypoxic culture (1% O2), when this was followed by 5-day reoxygenation, the BM-MSCs recovered and multiplied extensively. The immunophenotype and trilineage differentiation of BM-MSCs were also maintained under this H/R preconditioning. In addition, the preconditioning enhanced the expression of prosurvival genes, the messenger RNA (mRNA) levels of various trophic factors and migration capacity. Finally, coculture with the H/R-preconditioned BM-MSCs promoted the survival of ischemic rat cortical neurons. H/R preconditioning of BM-MSCs increases prosurvival signals, trophic factor release, and cell migration and appears to increase their ability to rescue ischemic cortical neurons. This optimized H/R preconditioning procedure could provide the basis for a new strategy for stem cell therapy in ischemic stroke patients. PMID:25288154

  18. Krylov methods preconditioned with incompletely factored matrices on the CM-2

    NASA Technical Reports Server (NTRS)

    Berryman, Harry; Saltz, Joel; Gropp, William; Mirchandaney, Ravi

    1989-01-01

    The performance is measured of the components of the key interative kernel of a preconditioned Krylov space interative linear system solver. In some sense, these numbers can be regarded as best case timings for these kernels. Sweeps were timed over meshes, sparse triangular solves, and inner products on a large 3-D model problem over a cube shaped domain discretized with a seven point template. The performance of the CM-2 is highly dependent on the use of very specialized programs. These programs mapped a regular problem domain onto the processor topology in a careful manner and used the optimized local NEWS communications network. The rather dramatic deterioration in performance was documented when these ideal conditions no longer apply. A synthetic workload generator was developed to produce and solve a parameterized family of increasingly irregular problems.

  19. Biomarkers for ischemic preconditioning: finding the responders

    PubMed Central

    Koch, Sebastian; Della-Morte, David; Dave, Kunjan R; Sacco, Ralph L; Perez-Pinzon, Miguel A

    2014-01-01

    Ischemic preconditioning is emerging as an innovative and novel cytoprotective strategy to counter ischemic vascular disease. At the root of the preconditioning response is the upregulation of endogenous defense systems to achieve ischemic tolerance. Identifying suitable biomarkers to show that a preconditioning response has been induced remains a translational research priority. Preconditioning leads to a widespread genomic and proteonomic response with important effects on hemostatic, endothelial, and inflammatory systems. The present article summarizes the relevant preclinical studies defining the mechanisms of preconditioning, reviews how the human preconditioning response has been investigated, and which of these bioresponses could serve as a suitable biomarker. Human preconditioning studies have investigated the effects of preconditioning on coagulation, endothelial factors, and inflammatory mediators as well as on genetic expression and tissue blood flow imaging. A biomarker for preconditioning would significantly contribute to define the optimal preconditioning stimulus and the extent to which such a response can be elicited in humans and greatly aid in dose selection in the design of phase II trials. Given the manifold biologic effects of preconditioning a panel of multiple serum biomarkers or genomic assessments of upstream regulators may most accurately reflect the full spectrum of a preconditioning response. PMID:24643082

  20. Automatic Blocking Of QR and LU Factorizations for Locality

    SciTech Connect

    Yi, Q; Kennedy, K; You, H; Seymour, K; Dongarra, J

    2004-03-26

    QR and LU factorizations for dense matrices are important linear algebra computations that are widely used in scientific applications. To efficiently perform these computations on modern computers, the factorization algorithms need to be blocked when operating on large matrices to effectively exploit the deep cache hierarchy prevalent in today's computer memory systems. Because both QR (based on Householder transformations) and LU factorization algorithms contain complex loop structures, few compilers can fully automate the blocking of these algorithms. Though linear algebra libraries such as LAPACK provides manually blocked implementations of these algorithms, by automatically generating blocked versions of the computations, more benefit can be gained such as automatic adaptation of different blocking strategies. This paper demonstrates how to apply an aggressive loop transformation technique, dependence hoisting, to produce efficient blockings for both QR and LU with partial pivoting. We present different blocking strategies that can be generated by our optimizer and compare the performance of auto-blocked versions with manually tuned versions in LAPACK, both using reference BLAS, ATLAS BLAS and native BLAS specially tuned for the underlying machine architectures.

  1. Desflurane preconditioning protects human umbilical vein endothelial cells against anoxia/reoxygenation by upregulating NLRP12 and inhibiting non-canonical nuclear factor-κB signaling.

    PubMed

    Sun, Zhirong; Lv, Jianing; Zhu, Yun; Song, Dongli; Zhu, Biao; Miao, Changhong

    2015-11-01

    Volatile anesthetics modulate endothelial cell apoptosis and inhibit nuclear factor-κB (NF-κB) signaling. In this study, we aimed to assess whether desflurane preconditioning protects human umbilical vein endothelial cells (HUVECs) agaist anoxia/reoxygenation (A/R) injury. HUVECs were pre-conditioned with desflurane (1.0 MAC) for 30 min, followed by a 15-min washout, then exposed to 60 min anoxia and 60 min reoxygenation (A/R), and incubated with 10 ng/ml tumor necrosis factor (TNF)-α for 60 min. HUVEC viability and apoptosis were measured by MTT assay and annexin V staining, and immunoblot analysis was used to measure the levels of Smac and cellular inhibitor of apoptosis 1 (cIAP1). NF-κB activation was assessed using the NF-κB signaling pathway real‑time PCR array, and the levels of NF-κB inducing kinase (NIK), p52, IκB kinase (IKK)α, p100, RelB and NLR family, pyrin domain containing 12 (NLRP12) were assessed by immunoblot analysis. Desflurane preconditioning attenuated the effects of A/R and/or A/R plus TNF-α on cell viability, decreasing the levels of Smac and enhancing the levels of of cIAP1 (P<0.05). Preconditioning with desflurane also enhanced the mRNA levels of interleukin (IL)-10 and NLRP12 in the cells exposed to A/R by 2.40- and 2.16‑fold, respectively. The HUVECs exposed to A/R had greater levels of NIK and p100 and reduced levels of p52 and IKKα. Desflurance preconditioning further increased p100 levels, decreased the level of NIK, further decreased p52 levels and further reduced IKKα levels. A/R in combination with TNF-α increased the NIK, IKKα, p100 and RelB levels, and this increase was significantly attenuated by desflurance preconditioning (all P<0.05). Desflurane preconditioning enhanced HUVEC survival and protected the cells against A/R injury, and our results suggested that this process involved the upregulation of NLRP12 and the inhibition of non-canonical NF-κB signaling. PMID:26329693

  2. Cerebral Ischemic Preconditioning: the Road So Far….

    PubMed

    Thushara Vijayakumar, N; Sangwan, Amit; Sharma, Bhargy; Majid, Arshad; Rajanikant, G K

    2016-05-01

    Cerebral preconditioning constitutes the brain's adaptation to lethal ischemia when first exposed to mild doses of a subtoxic stressor. The phenomenon of preconditioning has been largely studied in the heart, and data from in vivo and in vitro models from past 2-3 decades have provided sufficient evidence that similar machinery exists in the brain as well. Since preconditioning results in a transient protective phenotype labeled as ischemic tolerance, it can open many doors in the medical warfare against stroke, a debilitating cerebrovascular disorder that kills or cripples thousands of people worldwide every year. Preconditioning can be induced by a variety of stimuli from hypoxia to pharmacological anesthetics, and each, in turn, induces tolerance by activating a multitude of proteins, enzymes, receptors, transcription factors, and other biomolecules eventually leading to genomic reprogramming. The intracellular signaling pathways and molecular cascades behind preconditioning are extensively being investigated, and several first-rate papers have come out in the last few years centered on the topic of cerebral ischemic tolerance. However, translating the experimental knowledge into the clinical scaffold still evades practicality and faces several challenges. Of the various preconditioning strategies, remote ischemic preconditioning and pharmacological preconditioning appears to be more clinically relevant for the management of ischemic stroke. In this review, we discuss current developments in the field of cerebral preconditioning and then examine the potential of various preconditioning agents to confer neuroprotection in the brain. PMID:26081149

  3. Choriocarcinoma: blocking factor and monoclonal antibody iodine 131 imaging

    SciTech Connect

    Pattillo, R.A.; Khazaeli, M.B.; Ruckert, A.C.; Hussa, R.O.; Collier, B.D.; Beierwaltes, W.; Mattingly, R.F.

    1984-04-01

    Postoperative iodine 131 monoclonal antibody localization in metastatic choriocarcinoma was accomplished in this study. The monoclonal antibody was prepared to male choriocarcinoma which cross reacted with gestational choriocarcinoma. The antibody was raised against whole choriocarcinoma cells and human chorionic gonadotropin (hCG) cross reactivity was excluded. The purified antibody was iodinated with /sup 131/I and successfully imaged BeWo choriocarcinoma transplanted in nude mice; however, imaging of choriocarcinoma in a patient was verified only after resection. It is our belief that failure to sufficiently concentrate the antibody in the tumor before operation was due to blocking factor in the serum of the patient. Blocking factor and hCG dropped postoperatively. Blocking factor activity in 15 patients with metastatic trophoblastic disease was monitored and, like hCG, was found to be a sensitive indicator of the presence of disease. Its efficacy may be in the small number of patients without hCG but with persistent disease.

  4. Ischemic preconditioning protects against ischemic brain injury.

    PubMed

    Ma, Xiao-Meng; Liu, Mei; Liu, Ying-Ying; Ma, Li-Li; Jiang, Ying; Chen, Xiao-Hong

    2016-05-01

    In this study, we hypothesized that an increase in integrin αvβ3 and its co-activator vascular endothelial growth factor play important neuroprotective roles in ischemic injury. We performed ischemic preconditioning with bilateral common carotid artery occlusion for 5 minutes in C57BL/6J mice. This was followed by ischemic injury with bilateral common carotid artery occlusion for 30 minutes. The time interval between ischemic preconditioning and lethal ischemia was 48 hours. Histopathological analysis showed that ischemic preconditioning substantially diminished damage to neurons in the hippocampus 7 days after ischemia. Evans Blue dye assay showed that ischemic preconditioning reduced damage to the blood-brain barrier 24 hours after ischemia. This demonstrates the neuroprotective effect of ischemic preconditioning. Western blot assay revealed a significant reduction in protein levels of integrin αvβ3, vascular endothelial growth factor and its receptor in mice given ischemic preconditioning compared with mice not given ischemic preconditioning 24 hours after ischemia. These findings suggest that the neuroprotective effect of ischemic preconditioning is associated with lower integrin αvβ3 and vascular endothelial growth factor levels in the brain following ischemia. PMID:27335560

  5. Ischemic preconditioning protects against ischemic brain injury

    PubMed Central

    Ma, Xiao-meng; Liu, Mei; Liu, Ying-ying; Ma, Li-li; Jiang, Ying; Chen, Xiao-hong

    2016-01-01

    In this study, we hypothesized that an increase in integrin αvβ3 and its co-activator vascular endothelial growth factor play important neuroprotective roles in ischemic injury. We performed ischemic preconditioning with bilateral common carotid artery occlusion for 5 minutes in C57BL/6J mice. This was followed by ischemic injury with bilateral common carotid artery occlusion for 30 minutes. The time interval between ischemic preconditioning and lethal ischemia was 48 hours. Histopathological analysis showed that ischemic preconditioning substantially diminished damage to neurons in the hippocampus 7 days after ischemia. Evans Blue dye assay showed that ischemic preconditioning reduced damage to the blood-brain barrier 24 hours after ischemia. This demonstrates the neuroprotective effect of ischemic preconditioning. Western blot assay revealed a significant reduction in protein levels of integrin αvβ3, vascular endothelial growth factor and its receptor in mice given ischemic preconditioning compared with mice not given ischemic preconditioning 24 hours after ischemia. These findings suggest that the neuroprotective effect of ischemic preconditioning is associated with lower integrin αvβ3 and vascular endothelial growth factor levels in the brain following ischemia. PMID:27335560

  6. Estimate Soil Erodibility Factors Distribution for Maioli Block

    NASA Astrophysics Data System (ADS)

    Lee, Wen-Ying

    2014-05-01

    The natural conditions in Taiwan are poor. Because of the steep slopes, rushing river and fragile geology, soil erosion turn into a serious problem. Not only undermine the sloping landscape, but also created sediment disaster like that reservoir sedimentation, river obstruction…etc. Therefore, predict and control the amount of soil erosion has become an important research topic. Soil erodibility factor (K) is a quantitative index of distinguish the ability of soil to resist the erosion separation and handling. Taiwan soil erodibility factors have been calculated 280 soil samples' erodibility factors by Wann and Huang (1989) use the Wischmeier and Smith nomorgraph. 221 samples were collected at the Maioli block in Miaoli. The coordinates of every sample point and the land use situations were recorded. The physical properties were analyzed for each sample. Three estimation methods, consist of Kriging, Inverse Distance Weighted (IDW) and Spline, were applied to estimate soil erodibility factors distribution for Maioli block by using 181 points data, and the remaining 40 points for the validation. Then, the SPSS regression analysis was used to comparison of the accuracy of the training data and validation data by three different methods. Then, the best method can be determined. In the future, we can used this method to predict the soil erodibility factors in other areas.

  7. Combination of numerical and structured approaches to the construction of a second-order incomplete triangular factorization in parallel preconditioning methods

    NASA Astrophysics Data System (ADS)

    Milyukova, O. Yu.

    2016-05-01

    Parallel versions of the stabilized second-order incomplete triangular factorization conjugate gradient method in which the reordering of the coefficient matrix corresponding to the ordering based on splitting into subdomains with separators are considered. The incomplete triangular factorization is organized using the truncation of fill-in "by value" at internal nodes of subdomains, and "by value" and `by positions" on the separators. This approach is generalized for the case of constructing a parallel version of preconditioning the second-order incomplete LU factorization for nonsymmetric diagonally dominant matrices with. The reliability and convergence rate of the proposed parallel methods is analyzed. The proposed algorithms are implemented using MPI, results of solving benchmark problems with matrices from the collection of the University of Florida are presented.

  8. Preconditioning Techniques for a Newton-Krylov Algorithm for the Compressible Navier-Stokes Equations

    NASA Astrophysics Data System (ADS)

    Gatsis, John

    An investigation of preconditioning techniques is presented for a Newton-Krylov algorithm that is used for the computation of steady, compressible, high Reynolds number flows about airfoils. A second-order centred-difference method is used to discretize the compressible Navier-Stokes (NS) equations that govern the fluid flow. The one-equation Spalart-Allmaras turbulence model is used. The discretized equations are solved using Newton's method and the generalized minimal residual (GMRES) Krylov subspace method is used to approximately solve the linear system. These preconditioning techniques are first applied to the solution of the discretized steady convection-diffusion equation. Various orderings, iterative block incomplete LU (BILU) preconditioning and multigrid preconditioning are explored. The baseline preconditioner is a BILU factorization of a lower-order discretization of the system matrix in the Newton linearization. An ordering based on the minimum discarded fill (MDF) ordering is developed and compared to the widely popular reverse Cuthill-McKee ordering. An evolutionary algorithm is used to investigate and enhance this ordering. For the convection-diffusion equation, the MDF-based ordering performs well and RCM is superior for the NS equations. Experiments for inviscid, laminar and turbulent cases are presented to show the effectiveness of iterative BILU preconditioning in terms of reducing the number of GMRES iterations, and hence the memory requirements of the Newton-Krylov algorithm. Multigrid preconditioning also reduces the number of GMRES iterations. The framework for the iterative BILU and BILU-smoothed multigrid preconditioning algorithms is presented in detail.

  9. Molecular mechanism of preconditioning.

    PubMed

    Das, Manika; Das, Dipak K

    2008-04-01

    During the last 20 years, since the appearance of the first publication on ischemic preconditioning (PC), our knowledge of this phenomenon has increased exponentially. PC is defined as an increased tolerance to ischemia and reperfusion induced by previous sublethal period ischemia. This is the most powerful mechanism known to date for limiting the infract size. This adaptation occurs in a biphasic pattern (i) early preconditioning (lasts for 2-3 h) and (ii) late preconditioning (starting at 24 h lasting until 72-96 h after initial ischemia). Early preconditioning is more potent than delayed preconditioning in reducing infract size. Late preconditioning attenuates myocardial stunning and requires genomic activation with de novo protein synthesis. Early preconditioning depends on adenosine, opioids and to a lesser degree, on bradykinin and prostaglandins, released during ischemia. These molecules activate G-protein-coupled receptor, initiate activation of K(ATP) channel and generate oxygen-free radicals, and stimulate a series of protein kinases, which include protein kinase C, tyrosine kinase, and members of MAP kinase family. Late preconditioning is triggered by a similar sequence of events, but in addition essentially depends on newly synthesized proteins, which comprise iNOS, COX-2, manganese superoxide dismutase, and possibly heat shock proteins. The final mechanism of PC is still not very clear. The present review focuses on the possible role signaling molecules that regulate cardiomyocyte life and death during ischemia and reperfusion. PMID:18344203

  10. Preconditioning Strategy in Stem Cell Transplantation Therapy

    PubMed Central

    Yu, Shan Ping; Wei, Zheng; Wei, Ling

    2013-01-01

    Stem cell transplantation therapy has emerged as a promising regenerative medicine for ischemic stroke and other neurodegenerative disorders. However, many issues and problems remain to be resolved before successful clinical applications of the cell-based therapy. To this end, some recent investigations have sought to benefit from well-known mechanisms of ischemic/hypoxic preconditioning. Ischemic/hypoxic preconditioning activates endogenous defense mechanisms that show marked protective effects against multiple insults found in ischemic stroke and other acute attacks. As in many other cell types, a sub-lethal hypoxic exposure significantly increases the tolerance and regenerative properties of stem cells and progenitor cells. So far, a variety of preconditioning triggers have been tested on different stem cells and progenitor cells. Preconditioned stem cells and progenitors generally show much better cell survival, increased neuronal differentiation, enhanced paracrine effects leading to increased trophic support, and improved homing to the lesion site. Transplantation of preconditioned cells helps to suppress inflammatory factors and immune responses, and promote functional recovery. Although the preconditioning strategy in stem cell therapy is still an emerging research area, accumulating information from reports over the last few years already indicates it as an attractive, if not essential, prerequisite for transplanted cells. It is expected that stem cell preconditioning and its clinical applications will attract more attention in both the basic research field of preconditioning as well as in the field of stem cell translational research. This review summarizes the most important findings in this active research area, covering the preconditioning triggers, potential mechanisms, mediators, and functional benefits for stem cell transplant therapy. PMID:23914259

  11. Factors influencing teaching style in block-scheduled science classrooms

    NASA Astrophysics Data System (ADS)

    Schoen Giddings, Linda

    This survey study sought to determine the extent to which teachers' personal belief systems, the leadership practices of the principal, and the nature of the organization as a professional learning community influence their teaching methodologies. The data were contributed by 172 South Carolina science teachers from 65 4 x 4 block-scheduled high schools. The teachers were pre-identified by teaching style as predominantly constructivist or traditional. The online survey consisted of two parts. Part I was the CTBA (Torff & Warburton 2005), which examined teacher beliefs regarding critical-thinking classroom strategies. Part II was the short form of the LOLSO Project Questionnaires (Shins et al., 2002), which examined teacher perceptions of their principal as a transformational leader and of their school as a learning organization. Logistic regression analysis identified two significant factors differentiating constructivist and traditional teachers. Traditional teachers were more likely to believe that low critical-thinking strategies were appropriate strategies for use in the classroom and constructivist teachers were more likely to perceive their schools as learning organizations. These two factors, when entered into the logistic regression predictive equation, could predict group membership with a 61% accuracy level. While not a differentiating factor, there was also a strong correlation between leadership and organizational learning (r = .86). These findings are consistent with other research that has found that schools which are learning organizations support more constructivist pedagogy and student-centered classrooms and are dependent upon strong support from school leadership.

  12. Preconditioned Krylov subspace methods for eigenvalue problems

    SciTech Connect

    Wu, Kesheng; Saad, Y.; Stathopoulos, A.

    1996-12-31

    Lanczos algorithm is a commonly used method for finding a few extreme eigenvalues of symmetric matrices. It is effective if the wanted eigenvalues have large relative separations. If separations are small, several alternatives are often used, including the shift-invert Lanczos method, the preconditioned Lanczos method, and Davidson method. The shift-invert Lanczos method requires direct factorization of the matrix, which is often impractical if the matrix is large. In these cases preconditioned schemes are preferred. Many applications require solution of hundreds or thousands of eigenvalues of large sparse matrices, which pose serious challenges for both iterative eigenvalue solver and preconditioner. In this paper we will explore several preconditioned eigenvalue solvers and identify the ones suited for finding large number of eigenvalues. Methods discussed in this paper make up the core of a preconditioned eigenvalue toolkit under construction.

  13. Management of Preconditioned Calves and Impacts of Preconditioning.

    PubMed

    Hilton, W Mark

    2015-07-01

    When studying the practice of preconditioning (PC) calves, many factors need to be examined to determine if cow-calf producers should make this investment. Factors such as average daily gain, feed efficiency, available labor, length of the PC period, genetics, and marketing options must be analyzed. The health sales price advantage is an additional benefit in producing and selling PC calves but not the sole determinant of PC's financially feasibility. Studies show that a substantial advantage of PC is the selling of additional pounds at a cost of gain well below the marginal return of producing those additional pounds. PMID:26139187

  14. Small Peptides Blocking Inhibition of Factor Xa and Tissue Factor-Factor VIIa by Tissue Factor Pathway Inhibitor (TFPI)*

    PubMed Central

    Dockal, Michael; Hartmann, Rudolf; Fries, Markus; Thomassen, M. Christella L. G. D.; Heinzmann, Alexandra; Ehrlich, Hartmut; Rosing, Jan; Osterkamp, Frank; Polakowski, Thomas; Reineke, Ulrich; Griessner, Andreas; Brandstetter, Hans; Scheiflinger, Friedrich

    2014-01-01

    Tissue factor pathway inhibitor (TFPI) is a Kunitz-type protease inhibitor that inhibits activated factor X (FXa) via a slow-tight binding mechanism and tissue factor-activated FVII (TF-FVIIa) via formation of a quaternary FXa-TFPI-TF-FVIIa complex. Inhibition of TFPI enhances coagulation in hemophilia models. Using a library approach, we selected and subsequently optimized peptides that bind TFPI and block its anticoagulant activity. One peptide (termed compound 3), bound with high affinity to the Kunitz-1 (K1) domain of TFPI (Kd ∼1 nm). We solved the crystal structure of this peptide in complex with the K1 of TFPI at 2.55-Å resolution. The structure of compound 3 can be segmented into a N-terminal anchor; an Ω-shaped loop; an intermediate segment; a tight glycine-loop; and a C-terminal α-helix that is anchored to K1 at its reactive center loop and two-stranded β-sheet. The contact surface has an overall hydrophobic character with some charged hot spots. In a model system, compound 3 blocked FXa inhibition by TFPI (EC50 = 11 nm) and inhibition of TF-FVIIa-catalyzed FX activation by TFPI (EC50 = 2 nm). The peptide prevented transition from the loose to the tight FXa-TFPI complex, but did not affect formation of the loose FXa-TFPI complex. The K1 domain of TFPI binds and inhibits FVIIa and the K2 domain similarly inhibits FXa. Because compound 3 binds to K1, our data show that K1 is not only important for FVIIa inhibition but also for FXa inhibition, i.e. for the transition of the loose to the tight FXa-TFPI complex. This mode of action translates into normalization of coagulation of hemophilia plasmas. Compound 3 thus bears potential to prevent bleeding in hemophilia patients. PMID:24275667

  15. On the factorization of block-tridiagonals without storage constraints

    NASA Technical Reports Server (NTRS)

    Merriam, M. L.

    1985-01-01

    In many programs solving difference equations, problem size is restricted by the number of available memory cells. A strategy has been developed to permit trade-offs between the number of floating point operations required and storage requirements for the solution of certain problems such as block tridiagonal systems of equations. This is done by recomputing some intermediate results instead of storing them. Reducing the storage to the square root of the current requirement will roughly double the number of computations. In theory, if m is the order of each sub-matrix in the block tridiagonal matrix, one can solve any linear system with only 5 sq m + 1 temporary storage cells. This method lends itself to efficient use on computers with parallel processing or vector processing architectures. On these computers the larger number of floating point operations is more than offset by the decrease in I/O and the increased percentage of vector operations made possible by this algorithm.

  16. Preconditioned Iterative Solver

    Energy Science and Technology Software Center (ESTSC)

    2002-08-01

    AztecOO contains a collection of preconditioned iterative methods for the solution of sparse linear systems of equations. In addition to providing many of the common algebraic preconditioners and basic iterative methods, AztecOO can be easily extended to interact with user-provided preconditioners and matrix operators.

  17. Preconditioning the Helmholtz Equation for Rigid Ducts

    NASA Technical Reports Server (NTRS)

    Baumeister, Kenneth J.; Kreider, Kevin L.

    1998-01-01

    An innovative hyperbolic preconditioning technique is developed for the numerical solution of the Helmholtz equation which governs acoustic propagation in ducts. Two pseudo-time parameters are used to produce an explicit iterative finite difference scheme. This scheme eliminates the large matrix storage requirements normally associated with numerical solutions to the Helmholtz equation. The solution procedure is very fast when compared to other transient and steady methods. Optimization and an error analysis of the preconditioning factors are present. For validation, the method is applied to sound propagation in a 2D semi-infinite hard wall duct.

  18. Parallel Preconditioning for CFD Problems on the CM-5

    NASA Technical Reports Server (NTRS)

    Simon, Horst D.; Kremenetsky, Mark D.; Richardson, John; Lasinski, T. A. (Technical Monitor)

    1994-01-01

    Up to today, preconditioning methods on massively parallel systems have faced a major difficulty. The most successful preconditioning methods in terms of accelerating the convergence of the iterative solver such as incomplete LU factorizations are notoriously difficult to implement on parallel machines for two reasons: (1) the actual computation of the preconditioner is not very floating-point intensive, but requires a large amount of unstructured communication, and (2) the application of the preconditioning matrix in the iteration phase (i.e. triangular solves) are difficult to parallelize because of the recursive nature of the computation. Here we present a new approach to preconditioning for very large, sparse, unsymmetric, linear systems, which avoids both difficulties. We explicitly compute an approximate inverse to our original matrix. This new preconditioning matrix can be applied most efficiently for iterative methods on massively parallel machines, since the preconditioning phase involves only a matrix-vector multiplication, with possibly a dense matrix. Furthermore the actual computation of the preconditioning matrix has natural parallelism. For a problem of size n, the preconditioning matrix can be computed by solving n independent small least squares problems. The algorithm and its implementation on the Connection Machine CM-5 are discussed in detail and supported by extensive timings obtained from real problem data.

  19. Desflurane Preconditioning Induces Oscillation of NF-κB in Human Umbilical Vein Endothelial Cells

    PubMed Central

    Miao, Changhong; Tang, Jianguo; Zhu, Biao

    2013-01-01

    Background Nuclear factor kappa B (NF-κB) has been implicated in anesthetic preconditioning (APC) induced protection against anoxia and reoxygenation (A/R) injury. The authors hypothesized that desflurane preconditioning would induce NF-κB oscillation and prevent endothelial cells apoptosis. Methods A human umbilical vein endothelial cells (HUVECs) A/R injury model was used. A 30 minute desflurane treatment was initiated before anoxia. NF-κB inhibitor BAY11-7082 was administered in some experiments before desflurane preconditioning. Cells apoptosis was analyzed by flow cytometry using annexin V–fluorescein isothiocyanate staining and cell viability was evaluated by modified tertrozalium salt (MTT) assay. The cellular superoxide dismutases (SOD) activitiy were tested by water-soluble tetrazolium salt (WST-1) assay. NF-κB p65 subunit nuclear translocation was detected by immunofluorescence staining. Expression of inhibitor of NF-κB-α (IκBα), NF-κB p65 and cellular inhibitor of apoptosis 1 (c-IAP1), B-cell leukemia/lymphoma 2 (Bcl-2), cysteine containing aspartate specific protease 3 (caspases-3) and second mitochondrial-derived activator of caspase (SMAC/DIABLO) were determined by western blot. Results Desflurane preconditioning caused phosphorylation and nuclear translocation of NF-κB before anoxia, on the contrary, induced the synthesis of IκBα and inhibition of NF-κB after reoxygenation. Desflurane preconditioning up-regulated the expression of c-IAP1 and Bcl-2, blocked the cleavage of caspase-3 and reduced SMAC release, and decreased the cell death of HUVECs after A/R. The protective effect was abolished by BAY11-7082 administered before desflurane. Conclusions The results demonstrated that desflurane activated NF-κB during the preconditioning period and inhibited excessive activation of NF-κB in reperfusion. And the oscillation of NF-κB induced by desflurane preconditioning finally up-regulated antiapoptotic proteins expression and protected

  20. Mitochondria: the missing link between preconditioning and neuroprotection.

    PubMed

    Correia, Sónia C; Santos, Renato X; Perry, George; Zhu, Xiongwei; Moreira, Paula I; Smith, Mark A

    2010-01-01

    The quote "what does not kill you makes you stronger" perfectly describes the preconditioning phenomenon - a paradigm that affords robust brain tolerance in the face of neurodegenerative insults. Over the last few decades, many attempts have been made to identify the molecular mechanisms involved in preconditioning-induced protective responses, and recent data suggests that many of these mechanisms converge on the mitochondria, positing mitochondria as master regulators of preconditioning-triggered endogenous neuroprotection. In this review, we critically discuss evidence for the involvement of mitochondria within the preconditioning paradigm. We will highlight the crucial targets and mediators by which mitochondria are integrated into neuroprotective signaling pathways that underlie preconditioning, putting focus on mitochondrial respiratory chain and mitochondrial reactive oxygen species, mitochondrial ATP-sensitive potassium channels, mitochondrial permeability transition pore, uncoupling proteins, and mitochondrial antioxidant enzyme manganese superoxide dismutase. We also discuss the role of mitochondria in the induction of hypoxia-inducible factor-1, a transcription factor engaged in preconditioning-mediated neuroprotective effects. The identification of intrinsic mitochondrial mechanisms involved in preconditioning will provide new insights which can be translated into potential pharmacological interventions aimed at counteracting neurodegeneration. PMID:20463394

  1. Microtubule inhibitors block the morphological changes induced in Drosophila blood cells by a parasitoid wasp factor.

    PubMed

    Rizki, R M; Rizki, T M

    1990-03-15

    The shape change of Drosophila melanogaster blood cells (lamellocytes) from discoidal to bipolar that is caused by a factor from the female parasitoid Leptopilina heterotoma is blocked by the tubulin inhibitors vinblastine and vincristine in vitro. The actin inhibitor, cytochalasin B, causes arborization of Drosophila lamellocytes and acts synergistically with the wasp factor to alter lamellocyte morphology. Lamellocyte aborization induced by cytochalasin B is blocked by simultaneous treatment with vinblastine. These observations indicate that the changes in lamellocyte shape induced by both the wasp factor and cytochalasin B require microtubule assembly. PMID:2311722

  2. Fibroblast growth factors, old kids on the new block.

    PubMed

    Li, Xiaokun; Wang, Cong; Xiao, Jian; McKeehan, Wallace L; Wang, Fen

    2016-05-01

    The fibroblast growth factors (FGFs) are a family of cell intrinsic regulatory peptides that control a broad spectrum of cellular activities. The family includes canonic FGFs that elicit their activities by activating the FGF receptor (FGFR) tyrosine kinase and non-canonic members that elicit their activities intracellularly and via FGFR-independent mechanisms. The FGF signaling axis is highly complex due to the existence of multiple isoforms of both ligands and receptors, as well as cofactors that include the chemically heterogeneous heparan sulfate (HS) cofactors, and in the case of endocrine FGFs, the Klotho coreceptors. Resident FGF signaling controls embryonic development, maintains tissue homeostasis, promotes wound healing and tissue regeneration, and regulates functions of multiple organs. However, ectopic or aberrant FGF signaling is a culprit for various diseases, including congenital birth defects, metabolic disorder, and cancer. The molecular mechanisms by which the specificity of FGF signaling is achieved remain incompletely understood. Since its application as a druggable target has been gradually recognized by pharmaceutical companies and translational researchers, understanding the determinants of FGF signaling specificity has become even more important in order to get into the position to selectively suppress a particular pathway without affecting others to minimize side effects. PMID:26768548

  3. Some Experiences with Nonoverlapping Schur Complement Parallel Preconditioning for CFD Calculations

    NASA Technical Reports Server (NTRS)

    Barth, Timothy J.; Chan, Tony F.; Tang, Wei-Pai; Kwak, Dochan (Technical Monitor)

    1996-01-01

    In this work we consider solving matrices which arise from the discretization of advection-diffusion field equations on arbitrary triangulated domains using stabilized numerical methods. The talk will discuss several candidate matrix preconditioning algorithms based on the 2 x 2 block factorization induced by an apriori partitioning of the triangulated domain. Application of the 2 x 2 block preconditioner requires the formation and inversion of the Schur complement submatrix. We consider several strategies for simplifying this task: incomplete Schur complement factorizations, drop tolerance element filling, Schur complement probing, and localized Schur complement inversion. Numerical results will be shown comparing performance and efficiency of these approximations. The matrix preconditioner has also been embedded into a Newton algorithm for solving the nonlinear Euler and Navier-Stokes equations governing compressible flow. The remainder of the talk will show numerous examples in CFD to demonstrate the efficiency and robustness of the techniques.

  4. Task Parallel Incomplete Cholesky Factorization using 2D Partitioned-Block Layout

    SciTech Connect

    Kim, Kyungjoo; Rajamanickam, Sivasankaran; Stelle, George Widgery; Edwards, Harold C.; Olivier, Stephen Lecler

    2016-01-01

    We introduce a task-parallel algorithm for sparse incomplete Cholesky factorization that utilizes a 2D sparse partitioned-block layout of a matrix. Our factorization algorithm follows the idea of algorithms-by-blocks by using the block layout. The algorithm-byblocks approach induces a task graph for the factorization. These tasks are inter-related to each other through their data dependences in the factorization algorithm. To process the tasks on various manycore architectures in a portable manner, we also present a portable tasking API that incorporates different tasking backends and device-specific features using an open-source framework for manycore platforms i.e., Kokkos. A performance evaluation is presented on both Intel Sandybridge and Xeon Phi platforms for matrices from the University of Florida sparse matrix collection to illustrate merits of the proposed task-based factorization. Experimental results demonstrate that our task-parallel implementation delivers about 26.6x speedup (geometric mean) over single-threaded incomplete Choleskyby- blocks and 19.2x speedup over serial Cholesky performance which does not carry tasking overhead using 56 threads on the Intel Xeon Phi processor for sparse matrices arising from various application problems.

  5. Preconditioning methods for improved convergence rates in iterative reconstructions

    SciTech Connect

    Clinthorne, N.H.; Chiao, Pingchun; Rogers, W.L. . Div. of Nuclear Medicine); Pan, T.S. . Dept. of Nuclear Medicine); Stamos, J.A. . Dept. of Nuclear Engineering)

    1993-03-01

    Because of the characteristics of the tomographic inversion problem, iterative reconstruction techniques often suffer from poor convergence rates--especially at high spatial frequencies. By using preconditioning methods, the convergence properties of most iterative methods can be greatly enhanced without changing their ultimate solution. To increase reconstruction speed, the authors have applied spatially-invariant preconditioning filters that can be designed using the tomographic system response and implemented using 2-D frequency-domain filtering techniques. In a sample application, the authors performed reconstructions from noiseless, simulated projection data, using preconditioned and conventional steepest-descent algorithms. The preconditioned methods demonstrated residuals that were up to a factor of 30 lower than the unassisted algorithms at the same iteration. Applications of these methods to regularized reconstructions from projection data containing Poisson noise showed similar, although not as dramatic, behavior.

  6. Roles of thioredoxin in nitric oxide-dependent preconditioning-induced tolerance against MPTP neurotoxin

    SciTech Connect

    Chiueh, C.C. . E-mail: chiueh@tmu.edu.tw; Andoh, Tsugunobu; Chock, P. Boon

    2005-09-01

    Hormesis, a stress tolerance, can be induced by ischemic preconditioning stress. In addition to preconditioning, it may be induced by other means, such as gas anesthetics. Preconditioning mechanisms, which may be mediated by reprogramming survival genes and proteins, are obscure. A known neurotoxicant, 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), causes less neurotoxicity in the mice that are preconditioned. Pharmacological evidences suggest that the signaling pathway of {center_dot}NO-cGMP-PKG (protein kinase G) may mediate preconditioning phenomenon. We developed a human SH-SY5Y cell model for investigating {sup {center_dot}}NO-mediated signaling pathway, gene regulation, and protein expression following a sublethal preconditioning stress caused by a brief 2-h serum deprivation. Preconditioned human SH-SY5Y cells are more resistant against severe oxidative stress and apoptosis caused by lethal serum deprivation and 1-mehtyl-4-phenylpyridinium (MPP{sup +}). Both sublethal and lethal oxidative stress caused by serum withdrawal increased neuronal nitric oxide synthase (nNOS/NOS1) expression and {sup {center_dot}}NO levels to a similar extent. In addition to free radical scavengers, inhibition of nNOS, guanylyl cyclase, and PKG blocks hormesis induced by preconditioning. S-nitrosothiols and 6-Br-cGMP produce a cytoprotection mimicking the action of preconditioning tolerance. There are two distinct cGMP-mediated survival pathways: (i) the up-regulation of a redox protein thioredoxin (Trx) for elevating mitochondrial levels of antioxidant protein Mn superoxide dismutase (MnSOD) and antiapoptotic protein Bcl-2, and (ii) the activation of mitochondrial ATP-sensitive potassium channels [K(ATP)]. Preconditioning induction of Trx increased tolerance against MPP{sup +}, which was blocked by Trx mRNA antisense oligonucleotide and Trx reductase inhibitor. It is concluded that Trx plays a pivotal role in {sup {center_dot}}NO-dependent preconditioning hormesis against

  7. A Hybrid Parallel Preconditioning Algorithm For CFD

    NASA Technical Reports Server (NTRS)

    Barth,Timothy J.; Tang, Wei-Pai; Kwak, Dochan (Technical Monitor)

    1995-01-01

    A new hybrid preconditioning algorithm will be presented which combines the favorable attributes of incomplete lower-upper (ILU) factorization with the favorable attributes of the approximate inverse method recently advocated by numerous researchers. The quality of the preconditioner is adjustable and can be increased at the cost of additional computation while at the same time the storage required is roughly constant and approximately equal to the storage required for the original matrix. In addition, the preconditioning algorithm suggests an efficient and natural parallel implementation with reduced communication. Sample calculations will be presented for the numerical solution of multi-dimensional advection-diffusion equations. The matrix solver has also been embedded into a Newton algorithm for solving the nonlinear Euler and Navier-Stokes equations governing compressible flow. The full paper will show numerous examples in CFD to demonstrate the efficiency and robustness of the method.

  8. Preserving Symmetry in Preconditioned Krylov Subspace Methods

    NASA Technical Reports Server (NTRS)

    Chan, Tony F.; Chow, E.; Saad, Y.; Yeung, M. C.

    1996-01-01

    We consider the problem of solving a linear system Ax = b when A is nearly symmetric and when the system is preconditioned by a symmetric positive definite matrix M. In the symmetric case, one can recover symmetry by using M-inner products in the conjugate gradient (CG) algorithm. This idea can also be used in the nonsymmetric case, and near symmetry can be preserved similarly. Like CG, the new algorithms are mathematically equivalent to split preconditioning, but do not require M to be factored. Better robustness in a specific sense can also be observed. When combined with truncated versions of iterative methods, tests show that this is more effective than the common practice of forfeiting near-symmetry altogether.

  9. On polynomial preconditioning for indefinite Hermitian matrices

    NASA Technical Reports Server (NTRS)

    Freund, Roland W.

    1989-01-01

    The minimal residual method is studied combined with polynomial preconditioning for solving large linear systems (Ax = b) with indefinite Hermitian coefficient matrices (A). The standard approach for choosing the polynomial preconditioners leads to preconditioned systems which are positive definite. Here, a different strategy is studied which leaves the preconditioned coefficient matrix indefinite. More precisely, the polynomial preconditioner is designed to cluster the positive, resp. negative eigenvalues of A around 1, resp. around some negative constant. In particular, it is shown that such indefinite polynomial preconditioners can be obtained as the optimal solutions of a certain two parameter family of Chebyshev approximation problems. Some basic results are established for these approximation problems and a Remez type algorithm is sketched for their numerical solution. The problem of selecting the parameters such that the resulting indefinite polynomial preconditioners speeds up the convergence of minimal residual method optimally is also addressed. An approach is proposed based on the concept of asymptotic convergence factors. Finally, some numerical examples of indefinite polynomial preconditioners are given.

  10. Heart Block in Acute Myocardial Infarction: Prognostic Factors and Role of Transvenous Catheter Pacemaker

    PubMed Central

    Narvas, R. M.; Kilgour, J. M.; Basu, S. K.

    1970-01-01

    A prospective study was carried out to determine the prognostic factors in patients with second-degree and complete heart block following acute myocardial infarction and to re-examine the indications for artificial transvenous pacing. Of the 117 consecutive patients with proved acute myocardial infarction, 15 developed advanced heart block (second degree and complete). The presence of the following factors, either alone or in combinations, were attended with poor prognosis: preceding Stokes-Adams syndrome, cardiogenic shock, congestive heart failure, complications secondary to cardiac arrest, anterior infarction and wide QRS complex. In the nine cases requiring artificial transvenous pacemaker because of Stokes-Adams attacks, congestive heart failure or frequent multifocal ventricular ectopic beats, there were five deaths. The remaining six patients, who were without complications and were not paced, all survived; these patients had normal QRS duration with heart rates above 60 per minute. This study indicates that prophylactic transvenous catheter insertion in acute heart block does not appear justified unless specific indication(s) arise. Postmortem studies revealed significant narrowing of all the major coronary vessels in all five fatalities. The overall mortality in this series of cases of acute heart block was 33%. PMID:5410415

  11. Hybrid preconditioning for iterative diagonalization of ill-conditioned generalized eigenvalue problems in electronic structure calculations

    SciTech Connect

    Cai, Yunfeng; Bai, Zhaojun; Pask, John E.; Sukumar, N.

    2013-12-15

    The iterative diagonalization of a sequence of large ill-conditioned generalized eigenvalue problems is a computational bottleneck in quantum mechanical methods employing a nonorthogonal basis for ab initio electronic structure calculations. We propose a hybrid preconditioning scheme to effectively combine global and locally accelerated preconditioners for rapid iterative diagonalization of such eigenvalue problems. In partition-of-unity finite-element (PUFE) pseudopotential density-functional calculations, employing a nonorthogonal basis, we show that the hybrid preconditioned block steepest descent method is a cost-effective eigensolver, outperforming current state-of-the-art global preconditioning schemes, and comparably efficient for the ill-conditioned generalized eigenvalue problems produced by PUFE as the locally optimal block preconditioned conjugate-gradient method for the well-conditioned standard eigenvalue problems produced by planewave methods.

  12. Extremely Intense Magnetospheric Substorms : External Triggering? Preconditioning?

    NASA Astrophysics Data System (ADS)

    Tsurutani, Bruce; Echer, Ezequiel; Hajra, Rajkumar

    2016-07-01

    We study particularly intense substorms using a variety of near-Earth spacecraft data and ground observations. We will relate the solar cycle dependences of events, determine whether the supersubstorms are externally or internally triggered, and their relationship to other factors such as magnetospheric preconditioning. If time permits, we will explore the details of the events and whether they are similar to regular (Akasofu, 1964) substorms or not. These intense substorms are an important feature of space weather since they may be responsible for power outages.

  13. Towards bulk based preconditioning for quantum dotcomputations

    SciTech Connect

    Dongarra, Jack; Langou, Julien; Tomov, Stanimire; Channing,Andrew; Marques, Osni; Vomel, Christof; Wang, Lin-Wang

    2006-05-25

    This article describes how to accelerate the convergence of Preconditioned Conjugate Gradient (PCG) type eigensolvers for the computation of several states around the band gap of colloidal quantum dots. Our new approach uses the Hamiltonian from the bulk materials constituent for the quantum dot to design an efficient preconditioner for the folded spectrum PCG method. The technique described shows promising results when applied to CdSe quantum dot model problems. We show a decrease in the number of iteration steps by at least a factor of 4 compared to the previously used diagonal preconditioner.

  14. Oxidative stress effect on progesterone-induced blocking factor (PIBF) binding to PIBF-receptor in lymphocytes.

    PubMed

    de la Haba, Carlos; Palacio, José R; Palkovics, Tamas; Szekeres-Barthó, Júlia; Morros, Antoni; Martínez, Paz

    2014-01-01

    Receptor-ligand binding is an essential interaction for biological function. Oxidative stress can modify receptors and/or membrane lipid dynamics, thus altering cell physiological functions. The aim of this study is to analyze how oxidative stress may alter receptor-ligand binding and lipid domain distribution in the case of progesterone-induced blocking factor/progesterone-induced blocking factor-receptor. For membrane fluidity regionalization analysis of MEC-1 lymphocytes, two-photon microscopy was used in individual living cells. Lymphocytes were also double stained with AlexaFluor647/progesterone-induced blocking factor and Laurdan to evaluate -induced blocking factor/progesterone-induced blocking factor-receptor distribution in the different membrane domains, under oxidative stress. A new procedure has been developed which quantitatively analyzes the regionalization of a membrane receptor among the lipid domains of different fluidity in the plasma membrane. We have been able to establish a new tool which detects and evaluates lipid raft clustering from two-photon microscopy images of individual living cells. We show that binding of progesterone-induced blocking factor to progesterone-induced blocking factor-receptor causes a rigidification of plasma membrane which is related to an increase of lipid raft clustering. However, this clustering is inhibited under oxidative stress conditions. In conclusion, oxidative stress decreases membrane fluidity, impairs receptor-ligand binding and reduces lipid raft clustering. PMID:23954806

  15. A fast, preconditioned conjugate gradient Toeplitz solver

    NASA Technical Reports Server (NTRS)

    Pan, Victor; Schrieber, Robert

    1989-01-01

    A simple factorization is given of an arbitrary hermitian, positive definite matrix in which the factors are well-conditioned, hermitian, and positive definite. In fact, given knowledge of the extreme eigenvalues of the original matrix A, an optimal improvement can be achieved, making the condition numbers of each of the two factors equal to the square root of the condition number of A. This technique is to applied to the solution of hermitian, positive definite Toeplitz systems. Large linear systems with hermitian, positive definite Toeplitz matrices arise in some signal processing applications. A stable fast algorithm is given for solving these systems that is based on the preconditioned conjugate gradient method. The algorithm exploits Toeplitz structure to reduce the cost of an iteration to O(n log n) by applying the fast Fourier Transform to compute matrix-vector products. Matrix factorization is used as a preconditioner.

  16. Evaluation of emerging factors blocking filtration of high-adjunct-ratio wort.

    PubMed

    Ma, Ting; Zhu, Linjiang; Zheng, Feiyun; Li, Yongxian; Li, Qi

    2014-08-20

    Corn starch has become a common adjunct for beer brewing in Chinese breweries. However, with increasing ratio of corn starch, problems like poor wort filtration performance arise, which will decrease production capacity of breweries. To solve this problem, factors affecting wort filtration were evaluated, such as the size of corn starch particle, special yellow floats formed during liquefaction of corn starch, and residual substance after liquefaction. The effects of different enzyme preparations including β-amylase and β-glucanase on filtration rate were also evaluated. The results indicate that the emerging yellow floats do not severely block filtration, while the fine and uniform-shape corn starch particle and its incompletely hydrolyzed residue after liquefaction are responsible for filtration blocking. Application of β-amylase preparation increased the filtration rate of liquefied corn starch. This study is useful for our insight into the filtration blocking problem arising in the process of high-adjunct-ratio beer brewing and also provides a feasible solution using enzyme preparations. PMID:25088033

  17. Factors affecting magnitude and time course of neuromuscular block produced by suxamethonium.

    PubMed

    Vanlinthout, L E; van Egmond, J; de Boo, T; Lerou, J G; Wevers, R A; Booij, L H

    1992-07-01

    This study was designed to identify factors that significantly alter the magnitude and duration of suxamethonium-induced neuromuscular block in patients with an apparently normal genotype for pseudocholinesterase. One hundred and fifty-six adults (ages 18-65 yr) were allocated to 13 subgroups. Patients in each subgroup received suxamethonium 50-2000 micrograms kg-1. The mechanographic response of the adductor pollicis brevis muscle to ulnar nerve stimulation was recorded. The ED50 was found to be 167 micrograms kg-1, ED90 was 316 micrograms kg-1 and ED95 was 392 micrograms kg-1. The duration of action (delta t) was in agreement with earlier published results. The magnitude of block was dose-related and decreased with increasing onset time (ton) and pseudocholinesterase activity (PChA). Neither age nor gender affected the degree of suxamethonium-induced block. Delta t was dose-related, decreased with increasing PChA, and was shorter for women. Age and ton had no effect on delta t. PMID:1637599

  18. Orderings for conjugate gradient preconditionings

    NASA Technical Reports Server (NTRS)

    Ortega, James M.

    1991-01-01

    The effect of orderings on the rate of convergence of the conjugate gradient method with SSOR or incomplete Cholesky preconditioning is examined. Some results also are presented that help to explain why red/black ordering gives an inferior rate of convergence.

  19. Hyperbaric oxygen pretreatment and preconditioning.

    PubMed

    Camporesi, Enrico M; Bosco, Gerardo

    2014-01-01

    Exposure to hyperbaric oxygen (HBO2) before a crucial event, with the plan to create a preventing therapeutic situation, has been defined "preconditioning" and is emerging as a useful adjunct both in diving medicine as well before ischemic or inflammatory events. Oxygen pre-breathing before diving has been extensively documented in recreational, technical, commercial and military diving for tissue denitrogenation, resulting in reduced post-diving bubble loads, reduced decompression requirements and more rapid return to normal platelet function after a decompression. Preoxygenation at high atmospheric pressure has also been used in patients before exposure to clinical situations with beneficial effects, but the mechanisms of action have not yet been ascertained. During the reperfusion of ischemic tissue, oxygenated blood increases numbers and activities of oxidants generated in tissues. Previous reports showed that HBO2 preconditioning caused the activation of antioxidative enzymes and related genes in the central nervous system, including catalase (CAT), superoxide dismutase and heme oxygenase-1. Despite the increasing number of basic science publications on this issue, studies describing HBO2 preconditioning in the clinical practice remain scarce. To date, only a few studies have investigated the preconditioning effects of HBO2 in relation to the human brain and myocardium with robust and promising results. PMID:24984322

  20. Progesterone-induced blocking factor activates STAT6 via binding to a novel IL-4 receptor.

    PubMed

    Kozma, Noemi; Halasz, Melinda; Polgar, Beata; Poehlmann, Tobias G; Markert, Udo R; Palkovics, Tamas; Keszei, Marton; Par, Gabriella; Kiss, Katalin; Szeberenyi, Jozsef; Grama, Laszlo; Szekeres-Bartho, Julia

    2006-01-15

    Progesterone-induced blocking factor (PIBF) induces Th2-dominant cytokine production. Western blotting and EMSA revealed phosphorylation as well as nuclear translocation of STAT6 and inhibition of STAT4 phosphorylation in PIBF-treated cells. The silencing of STAT6 by small interfering RNA reduced the cytokine effects. Because the activation of the STAT6 pathway depends on the ligation of IL-4R, we tested the involvement of IL-4R in PIBF-induced STAT6 activation. Although PIBF does not bind to IL-4R, the blocking of the latter with an Ab abolished PIBF-induced STAT6 activation, whereas the blocking of the IL-13R had no effect. PIBF activated suppressor of cytokine signaling-3 and inhibited IL-12-induced suppressor of cytokine signaling-1 activation. The blocking of IL-4R counteracted all the described effects, suggesting that the PIBF receptor interacts with IL-4R alpha-chain, allowing PIBF to activate the STAT6 pathway. PIBF did not phosphorylate Jak3, suggesting that the gamma-chain is not needed for PIBF signaling. Confocal microscopic analysis revealed a colocalization and at 37 degrees C a cocapping of the FITC PIBF-activated PIBF receptor and PE anti-IL-4R-labeled IL-4R. After the digestion of the cells with phosphatidylinositol-specific phospholipase C, the STAT6-activating effect of PIBF was lost, whereas that of IL-4 remained unaltered. These data suggest the existence of a novel type of IL-4R composed of the IL-4R alpha-chain and the GPI-anchored PIBF receptor. PMID:16393965

  1. SCN5A variant that blocks fibroblast growth factor homologous factor regulation causes human arrhythmia.

    PubMed

    Musa, Hassan; Kline, Crystal F; Sturm, Amy C; Murphy, Nathaniel; Adelman, Sara; Wang, Chaojian; Yan, Haidun; Johnson, Benjamin L; Csepe, Thomas A; Kilic, Ahmet; Higgins, Robert S D; Janssen, Paul M L; Fedorov, Vadim V; Weiss, Raul; Salazar, Christina; Hund, Thomas J; Pitt, Geoffrey S; Mohler, Peter J

    2015-10-01

    Nav channels are essential for metazoan membrane depolarization, and Nav channel dysfunction is directly linked with epilepsy, ataxia, pain, arrhythmia, myotonia, and irritable bowel syndrome. Human Nav channelopathies are primarily caused by variants that directly affect Nav channel permeability or gating. However, a new class of human Nav channelopathies has emerged based on channel variants that alter regulation by intracellular signaling or cytoskeletal proteins. Fibroblast growth factor homologous factors (FHFs) are a family of intracellular signaling proteins linked with Nav channel regulation in neurons and myocytes. However, to date, there is surprisingly little evidence linking Nav channel gene variants with FHFs and human disease. Here, we provide, to our knowledge, the first evidence that mutations in SCN5A (encodes primary cardiac Nav channel Nav1.5) that alter FHF binding result in human cardiovascular disease. We describe a five*generation kindred with a history of atrial and ventricular arrhythmias, cardiac arrest, and sudden cardiac death. Affected family members harbor a novel SCN5A variant resulting in p.H1849R. p.H1849R is localized in the central binding core on Nav1.5 for FHFs. Consistent with these data, Nav1.5 p.H1849R affected interaction with FHFs. Further, electrophysiological analysis identified Nav1.5 p.H1849R as a gain-of-function for INa by altering steady-state inactivation and slowing the rate of Nav1.5 inactivation. In line with these data and consistent with human cardiac phenotypes, myocytes expressing Nav1.5 p.H1849R displayed prolonged action potential duration and arrhythmogenic afterdepolarizations. Together, these findings identify a previously unexplored mechanism for human Nav channelopathy based on altered Nav1.5 association with FHF proteins. PMID:26392562

  2. SCN5A variant that blocks fibroblast growth factor homologous factor regulation causes human arrhythmia

    PubMed Central

    Musa, Hassan; Kline, Crystal F.; Sturm, Amy C.; Murphy, Nathaniel; Adelman, Sara; Wang, Chaojian; Yan, Haidun; Johnson, Benjamin L.; Csepe, Thomas A.; Kilic, Ahmet; Higgins, Robert S. D.; Janssen, Paul M. L.; Fedorov, Vadim V.; Weiss, Raul; Salazar, Christina; Hund, Thomas J.; Pitt, Geoffrey S.; Mohler, Peter J.

    2015-01-01

    Nav channels are essential for metazoan membrane depolarization, and Nav channel dysfunction is directly linked with epilepsy, ataxia, pain, arrhythmia, myotonia, and irritable bowel syndrome. Human Nav channelopathies are primarily caused by variants that directly affect Nav channel permeability or gating. However, a new class of human Nav channelopathies has emerged based on channel variants that alter regulation by intracellular signaling or cytoskeletal proteins. Fibroblast growth factor homologous factors (FHFs) are a family of intracellular signaling proteins linked with Nav channel regulation in neurons and myocytes. However, to date, there is surprisingly little evidence linking Nav channel gene variants with FHFs and human disease. Here, we provide, to our knowledge, the first evidence that mutations in SCN5A (encodes primary cardiac Nav channel Nav1.5) that alter FHF binding result in human cardiovascular disease. We describe a five*generation kindred with a history of atrial and ventricular arrhythmias, cardiac arrest, and sudden cardiac death. Affected family members harbor a novel SCN5A variant resulting in p.H1849R. p.H1849R is localized in the central binding core on Nav1.5 for FHFs. Consistent with these data, Nav1.5 p.H1849R affected interaction with FHFs. Further, electrophysiological analysis identified Nav1.5 p.H1849R as a gain-of-function for INa by altering steady-state inactivation and slowing the rate of Nav1.5 inactivation. In line with these data and consistent with human cardiac phenotypes, myocytes expressing Nav1.5 p.H1849R displayed prolonged action potential duration and arrhythmogenic afterdepolarizations. Together, these findings identify a previously unexplored mechanism for human Nav channelopathy based on altered Nav1.5 association with FHF proteins. PMID:26392562

  3. Expression of Monocarboxylate Transporter Isoforms in Rat Skeletal Muscle Under Hypoxic Preconditioning and Endurance Training.

    PubMed

    Saxena, Saurabh; Shukla, Dhananjay; Bansal, Anju

    2016-03-01

    Previously, we have reported the regulation of monocarboxylate transporters (MCT)1 and MCT4 by physiological stimuli such as hypoxia and exercise. In the present study, we have evaluated the effect of hypoxic preconditioning and training on expression of different MCT isoforms in muscles. We found the increased mRNA expression of MCT1, MCT11, and MCT12 after hypoxic preconditioning with cobalt chloride and training. However, the expression of other MCT isoforms increased marginally or even reduced after hypoxic preconditioning. Only the protein expression of MCT1 increased after hypoxia preconditioning. MCT2 protein expression increased after training only and MCT4 protein expression decreased both in preconditioning and hypoxic training. Furthermore, we found decreased plasma lactate level during hypoxia preconditioning (0.74-fold), exercise (0.78-fold), and hypoxia preconditioning along with exercise (0.67-fold), which indicates increased lactate uptake by skeletal muscle. The protein-protein interactions with hypoxia inducible factor-1 and MCT isoforms were also evaluated, but no interaction was found. In conclusion, we say that almost all MCTs are expressed in red gastrocnemius muscle at the mRNA level and their expression is regulated differently under hypoxia preconditioning and exercise condition. PMID:26716978

  4. Salicylates Inhibit Flavivirus Replication Independently of Blocking Nuclear Factor Kappa B Activation

    PubMed Central

    Liao, Ching-Len; Lin, Yi-Ling; Wu, Bi-Ching; Tsao, Chang-Huei; Wang, Mei-Chuan; Liu, Chiu-I; Huang, Yue-Ling; Chen, Jui-Hui; Wang, Jia-Pey; Chen, Li-Kuang

    2001-01-01

    Flaviviruses comprise a positive-sense RNA genome that replicates exclusively in the cytoplasm of infected cells. Whether flaviviruses require an activated nuclear factor(s) to complete their life cycle and trigger apoptosis in infected cells remains elusive. Flavivirus infections quickly activate nuclear factor kappa B (NF-κB), and salicylates have been shown to inhibit NF-κB activation. In this study, we investigated whether salicylates suppress flavivirus replication and virus-induced apoptosis in cultured cells. In a dose-dependent inhibition, we found salicylates within a range of 1 to 5 mM not only restricted flavivirus replication but also abrogated flavivirus-triggered apoptosis. However, flavivirus replication was not affected by a specific NF-κB peptide inhibitor, SN50, and a proteosome inhibitor, lactacystin. Flaviviruses also replicated and triggered apoptosis in cells stably expressing IκBα-ΔN, a dominant-negative mutant that antagonizes NF-κB activation, as readily as in wild-type BHK-21 cells, suggesting that NF-κB activation is not essential for either flavivirus replication or flavivirus-induced apoptosis. Salicylates still diminished flavivirus replication and blocked apoptosis in the same IκBα-ΔN cells. This inhibition of flaviviruses by salicylates could be partially reversed by a specific p38 mitogen-activated protein (MAP) kinase inhibitor, SB203580. Together, these results show that the mechanism by which salicylates suppress flavivirus infection may involve p38 MAP kinase activity but is independent of blocking the NF-κB pathway. PMID:11483726

  5. Preconditioning Operators on Unstructured Grids

    NASA Technical Reports Server (NTRS)

    Nepomnyaschikh, S. V.

    1996-01-01

    We consider systems of mesh equations that approximate elliptic boundary value problems on arbitrary (unstructured) quasi-uniform triangulations and propose a method for constructing optimal preconditioning operators. The method is based upon two approaches: (1) the fictitious space method, i.e., the reduction of the original problem to a problem in an auxiliary (fictitious) space, and (2) the multilevel decomposition method, i.e., the construction of preconditioners by decomposing functions on hierarchical meshes. The convergence rate of the corresponding iterative process with the preconditioner obtained is independent of the mesh step. The preconditioner has an optimal computational cost: the number of arithmetic operations required for its implementation is proportional to the number of unknowns in the problem. The construction of the preconditioning operators for three dimensional problems can be done in the same way.

  6. Preconditioning for traumatic brain injury

    PubMed Central

    Yokobori, Shoji; Mazzeo, Anna T; Hosein, Khadil; Gajavelli, Shyam; Dietrich, W. Dalton; Bullock, M. Ross

    2016-01-01

    Traumatic brain injury (TBI) treatment is now focused on the prevention of primary injury and reduction of secondary injury. However, no single effective treatment is available as yet for the mitigation of traumatic brain damage in humans. Both chemical and environmental stresses applied before injury, have been shown to induce consequent protection against post-TBI neuronal death. This concept termed “preconditioning” is achieved by exposure to different pre-injury stressors, to achieve the induction of “tolerance” to the effect of the TBI. However, the precise mechanisms underlying this “tolerance” phenomenon are not fully understood in TBI, and therefore even less information is available about possible indications in clinical TBI patients. In this review we will summarize TBI pathophysiology, and discuss existing animal studies demonstrating the efficacy of preconditioning in diffuse and focal type of TBI. We will also review other non-TBI preconditionng studies, including ischemic, environmental, and chemical preconditioning, which maybe relevant to TBI. To date, no clinical studies exist in this field, and we speculate on possible futureclinical situation, in which pre-TBI preconditioning could be considered. PMID:24323189

  7. [Pharmacological preconditioning in carotid endarterectomy].

    PubMed

    Kuznetsov, M R; Karalkin, A V; Fedin, A I; Virganskii, A O; Kunitsyn, N V; Kholopova, E A; Yumin, S M

    2015-01-01

    The study was aimed at examining efficacy of preoperative preparation (pharmacological preconditioning) for carotid endarterectomy in patients with chronic cerebrovascular insufficiency. For this purpose, we analysed the outcomes of surgical treatment in a total of 80 patients presenting with haemodynamically significant unilateral and bilateral lesions of carotid arteries. Of these, 40 patients were operated on immediately and a further 40 patients underwent surgery after pharmacological preconditioning with Actovegin taken at a daily dose of 1,200 mg for 1.5 months. It was demonstrated that preoperative preparation prior to surgery increases cerebral perfusion which is determined by means of single-photon emission computed tomography, thus substantially improving the outcomes of surgical treatment. Statistically significant differences in cognitive function of these groups of patients were revealed 7 days and 6 months after the operation. Improvement of cognitive functions was associated with fewer symptom-free postoperative cerebral ischaemic foci in various regions of the brain. A conclusion was made on a positive role of pharmacological preconditioning with Actovegin in surgical management of cerebrovascular insufficiency, first of all in relation to more complete restoration of cognitive functions. PMID:26355920

  8. Inhibitors of hypoxia-inducible factor 1 block breast cancer metastatic niche formation and lung metastasis.

    PubMed

    Wong, Carmen Chak-Lui; Zhang, Huafeng; Gilkes, Daniele M; Chen, Jasper; Wei, Hong; Chaturvedi, Pallavi; Hubbi, Maimon E; Semenza, Gregg L

    2012-07-01

    Intratumoral hypoxia, a frequent finding in metastatic cancer, results in the activation of hypoxia-inducible factors (HIFs). HIFs are implicated in many steps of breast cancer metastasis, including metastatic niche formation through increased expression of lysyl oxidase (LOX) and lysyl oxidase-like (LOXL) proteins, enzymes that remodel collagen at the metastatic site and recruit bone marrow-derived cells (BMDCs) to the metastatic niche. We investigated the effect of two chemically and mechanistically distinct HIF inhibitors, digoxin and acriflavine, on breast cancer metastatic niche formation. Both drugs blocked the hypoxia-induced expression of LOX and LOXL proteins, collagen cross-linking, CD11b⁺ BMDC recruitment, and lung metastasis in an orthotopic breast cancer model. Patients with HIF-1 α-overexpressing breast cancers are at increased risk of metastasis and mortality and our results suggest that such patients may benefit from aggressive therapy that includes a HIF inhibitor. PMID:22231744

  9. Serum deprivation response inhibits breast cancer progression by blocking transforming growth factor-β signaling.

    PubMed

    Tian, Yao; Yu, Yue; Hou, Li-Kun; Chi, Jiang-Rui; Mao, Jie-Fei; Xia, Li; Wang, Xin; Wang, Ping; Cao, Xu-Chen

    2016-03-01

    Serum deprivation response (SDPR), a key substrate for protein kinase C, play a critical role in inducing membrane curvature and participate in the formation of caveolae. However, the function of SDPR in cancer development and progression is still not clear. Here, we found that SDPR is downregulated in human breast cancer. Overexpression of SDPR suppresses cell proliferation and invasion in MDA-MB-231 cells, while depletion of SDPR promotes cell proliferation and invasion in MCF10A cells. Subsequently, SDPR depletion induces epithelial-mesenchymal transition (EMT)-like phenotype. Finally, knockdown of SDPR activates transforming growth factor-β (TGF-β) signaling by upregulation of TGF-β1 expression. In conclusion, our results showed that SDPR inhibits breast cancer progression by blocking TGF-β signaling. Serum deprivation response suppresses cell proliferation and invasion in breast cancer cells. SDPR depletion induces epithelial-mesenchymal transition by activation of TGF-β signaling. PMID:26749136

  10. Argon Induces Protective Effects in Cardiomyocytes during the Second Window of Preconditioning

    PubMed Central

    Mayer, Britta; Soppert, Josefin; Kraemer, Sandra; Schemmel, Sabrina; Beckers, Christian; Bleilevens, Christian; Rossaint, Rolf; Coburn, Mark; Goetzenich, Andreas; Stoppe, Christian

    2016-01-01

    Increasing evidence indicates that argon has organoprotective properties. So far, the underlying mechanisms remain poorly understood. Therefore, we investigated the effect of argon preconditioning in cardiomyocytes within the first and second window of preconditioning. Primary isolated cardiomyocytes from neonatal rats were subjected to 50% argon for 1 h, and subsequently exposed to a sublethal dosage of hypoxia (<1% O2) for 5 h either within the first (0–3 h) or second window (24–48 h) of preconditioning. Subsequently, the cell viability and proliferation was measured. The argon-induced effects were assessed by evaluation of mRNA and protein expression after preconditioning. Argon preconditioning did not show any cardioprotective effects in the early window of preconditioning, whereas it leads to a significant increase of cell viability 24 h after preconditioning compared to untreated cells (p = 0.015) independent of proliferation. Argon-preconditioning significantly increased the mRNA expression of heat shock protein (HSP) B1 (HSP27) (p = 0.048), superoxide dismutase 2 (SOD2) (p = 0.001), vascular endothelial growth factor (VEGF) (p < 0.001) and inducible nitric oxide synthase (iNOS) (p = 0.001). No difference was found with respect to activation of pro-survival kinases in the early and late window of preconditioning. The findings provide the first evidence of argon-induced effects on the survival of cardiomyocytes during the second window of preconditioning, which may be mediated through the induction of HSP27, SOD2, VEGF and iNOS. PMID:27447611

  11. Argon Induces Protective Effects in Cardiomyocytes during the Second Window of Preconditioning.

    PubMed

    Mayer, Britta; Soppert, Josefin; Kraemer, Sandra; Schemmel, Sabrina; Beckers, Christian; Bleilevens, Christian; Rossaint, Rolf; Coburn, Mark; Goetzenich, Andreas; Stoppe, Christian

    2016-01-01

    Increasing evidence indicates that argon has organoprotective properties. So far, the underlying mechanisms remain poorly understood. Therefore, we investigated the effect of argon preconditioning in cardiomyocytes within the first and second window of preconditioning. Primary isolated cardiomyocytes from neonatal rats were subjected to 50% argon for 1 h, and subsequently exposed to a sublethal dosage of hypoxia (<1% O₂) for 5 h either within the first (0-3 h) or second window (24-48 h) of preconditioning. Subsequently, the cell viability and proliferation was measured. The argon-induced effects were assessed by evaluation of mRNA and protein expression after preconditioning. Argon preconditioning did not show any cardioprotective effects in the early window of preconditioning, whereas it leads to a significant increase of cell viability 24 h after preconditioning compared to untreated cells (p = 0.015) independent of proliferation. Argon-preconditioning significantly increased the mRNA expression of heat shock protein (HSP) B1 (HSP27) (p = 0.048), superoxide dismutase 2 (SOD2) (p = 0.001), vascular endothelial growth factor (VEGF) (p < 0.001) and inducible nitric oxide synthase (iNOS) (p = 0.001). No difference was found with respect to activation of pro-survival kinases in the early and late window of preconditioning. The findings provide the first evidence of argon-induced effects on the survival of cardiomyocytes during the second window of preconditioning, which may be mediated through the induction of HSP27, SOD2, VEGF and iNOS. PMID:27447611

  12. The effect of insulin-loaded linear poly(ethylene glycol)-brush-like poly(l-lysine) block copolymer on renal ischemia/reperfusion-induced lung injury through downregulating hypoxia-inducible factor

    PubMed Central

    Tong, Fei; Tang, Xiangyuan; Li, Xin; Xia, Wenquan; Liu, Daojun

    2016-01-01

    The aim of this study was to observe the therapeutic effect of insulin-loaded linear poly(ethylene glycol)-brush-like poly(l-lysine) block copolymer poly(ethylene glycol)-b-(poly(ethylenediamine l-glutamate)-g-poly(l-lysine)) (PEG-b-(PELG-g-PLL) on renal ischemia/reperfusion-induced lung injury through downregulating hypoxia-inducible factor (HIF) as compared to free insulin. Sprague Dawley rats were pretreated with 30 U/kg insulin or insulin/PEG-b-(PELG-g-PLL) complex, and then subjected to 45 minutes of ischemia and 24 hours of reperfusion. The blood and lungs were collected, the level of serum creatinine and blood urea nitrogen were measured, and the dry/wet lung ratios, the activity of superoxide dismutase and myeloperoxidase, the content of methane dicarboxylic aldehyde and tumor necrosis factor-α, and the expression of HIF-1α and vascular endothelial growth factor (VEGF) were measured in pulmonary tissues. Both insulin and insulin/PEG-b-(PELG-g-PLL) preconditioning improved the recovery of renal function, reduced pulmonary oxidative stress injury, restrained inflammatory damage, and downregulated the expression of HIF-1α and VEGF as compared to ischemia/reperfusion group, while insulin/PEG-b-(PELG-g-PLL) significantly improved this effect. PMID:27175073

  13. RNA Polymerase Sigma Factor That Blocks Morphological Differentiation by Streptomyces coelicolor

    PubMed Central

    Gehring, Amy M.; Yoo, Narie J.; Losick, Richard

    2001-01-01

    The filamentous bacterium Streptomyces coelicolor undergoes a complicated process of morphological differentiation that begins with the formation of an aerial mycelium and culminates in sporulation. Genes required for the initiation of aerial mycelium formation have been termed bld (bald), describing the smooth, undifferentiated colonies of mutant strains. By using an insertional mutagenesis protocol that relies on in vitro transposition, we have isolated a bld mutant harboring an insertion in a previously uncharacterized gene, SCE59.12c, renamed here rsuA. The insertion mutant exhibited no measurable growth defect but failed to produce an aerial mycelium and showed a significant delay in the production of the polyketide antibiotic actinorhodin. The rsuA gene encodes an apparent anti-sigma factor and is located immediately downstream of SCE59.13c, renamed here sigU, whose product is inferred to be a member of the extracytoplasmic function subfamily of RNA polymerase sigma factors. The absence of rsuA in a strain that contained sigU caused a block in development, and the overexpression of sigU in an otherwise wild-type strain caused a delay in aerial mycelium formation. However, a strain in which both rsuA and sigU had been deleted was able to undergo morphological differentiation normally. We conclude that the rsuA-encoded anti-sigma factor is responsible for antagonizing the function of the sigma factor encoded by sigU. We also conclude that the sigU-encoded sigma factor is not normally required for development but that its uncontrolled activity obstructs morphological differentiation at an early stage. PMID:11566999

  14. Preconditioned iterations to calculate extreme eigenvalues

    SciTech Connect

    Brand, C.W.; Petrova, S.

    1994-12-31

    Common iterative algorithms to calculate a few extreme eigenvalues of a large, sparse matrix are Lanczos methods or power iterations. They converge at a rate proportional to the separation of the extreme eigenvalues from the rest of the spectrum. Appropriate preconditioning improves the separation of the eigenvalues. Davidson`s method and its generalizations exploit this fact. The authors examine a preconditioned iteration that resembles a truncated version of Davidson`s method with a different preconditioning strategy.

  15. Blocking macrophage migration inhibitory factor activity alleviates mouse acute otitis media in vivo.

    PubMed

    Zhang, Jin; Xu, Min; Zheng, Qingyin; Zhang, Yan; Ma, Weijun; Zhang, Zhaoqiang

    2014-11-01

    This study was to investigate the role of macrophage migration inhibitory factor (MIF) in mouse acute otitis media (AOM), we hypothesize that blocking MIF activity will relieve mouse AOM. A mouse AOM model was constructed by injecting lipopolysaccharide (LPS) into the middle ear of C57BL/6 mice through the tympanic membrane (TM). MIF levels were measured by real-time PCR (RT-PCR) and ELISA after LPS application. Normal or AOM mice were given PBS or ISO-1 (MIF antagonist) every day for 10 days and the hearing levels were determined by measuring auditory brainstem response (ABR) threshold. After the ABR test finished, H&E staining was conducted and the inflammation was also measured by detecting interleukin (IL)-1β, tumor necrosis factor (TNF)-α and vascular endothelial growth factor (VEGF) levels with RT-PCR and ELISA. TLR-4 expression was determined by western blotting and NF-κB activation was determined by electrophoretic mobility shift assays. Compared with the normal control, MIF levels in the middle ear of LPS-induced AOM mice were significant increased. The ABR results showed that mean ABR thresholds in ISO-1 treated AOM mice were significantly reduced compared with PBS treated AOM mice since day 7, indicating that ISO-1 treatment potentially improved the hearing levels of AOM mice. H&E staining showed that ISO-1 treatment could reduce the mucosal thickness of AOM mice. In ISO-1 treated mice, TLR-4 expression and levels of IL-1β, TNF-α and VEGF were significantly lower compared with PBS treated AOM mice. ISO-1 treatment also significantly inhibited NF-κB activation in AOM mice compared with PBS treated AOM mice. These results suggested that blocking the activity of MIF by ISO-1 could reduce the inflammation in AOM mice in which process TLR-4 and NF-κB were involved. The reduction in MIF activity is conducive to alleviate mouse AOM, which may serve as a potential therapeutic target for the treatment of AOM. PMID:25108100

  16. Peroxiredoxin 1 interacts with and blocks the redox factor APE1 from activating interleukin-8 expression.

    PubMed

    Nassour, Hassan; Wang, Zhiqiang; Saad, Amine; Papaluca, Arturo; Brosseau, Nicolas; Affar, El Bachir; Alaoui-Jamali, Moulay A; Ramotar, Dindial

    2016-01-01

    APE1 is an essential DNA repair protein that also possesses the ability to regulate transcription. It has a unique cysteine residue C65, which maintains the reduce state of several transcriptional activators such as NF-κB. How APE1 is being recruited to execute the various biological functions remains unknown. Herein, we show that APE1 interacts with a novel partner PRDX1, a peroxidase that can also prevent oxidative damage to proteins by serving as a chaperone. PRDX1 knockdown did not interfere with APE1 expression level or its DNA repair activities. However, PRDX1 knockdown greatly facilitates APE1 detection within the nucleus by indirect immunofluorescence analysis, even though APE1 level was unchanged. The loss of APE1 interaction with PRDX1 promotes APE1 redox function to activate binding of the transcription factor NF-κB onto the promoter of a target gene, the proinflammatory chemokine IL-8 involved in cancer invasion and metastasis, resulting in its upregulation. Depletion of APE1 blocked the upregulation of IL-8 in the PRDX1 knockdown cells. Our findings suggest that the interaction of PRDX1 with APE1 represents a novel anti-inflammatory function of PRDX1, whereby the association safeguards APE1 from reducing transcription factors and activating superfluous gene expression, which otherwise could trigger cancer invasion and metastasis. PMID:27388124

  17. Peroxiredoxin 1 interacts with and blocks the redox factor APE1 from activating interleukin-8 expression

    PubMed Central

    Nassour, Hassan; Wang, Zhiqiang; Saad, Amine; Papaluca, Arturo; Brosseau, Nicolas; Affar, El Bachir; Alaoui-Jamali, Moulay A.; Ramotar, Dindial

    2016-01-01

    APE1 is an essential DNA repair protein that also possesses the ability to regulate transcription. It has a unique cysteine residue C65, which maintains the reduce state of several transcriptional activators such as NF-κB. How APE1 is being recruited to execute the various biological functions remains unknown. Herein, we show that APE1 interacts with a novel partner PRDX1, a peroxidase that can also prevent oxidative damage to proteins by serving as a chaperone. PRDX1 knockdown did not interfere with APE1 expression level or its DNA repair activities. However, PRDX1 knockdown greatly facilitates APE1 detection within the nucleus by indirect immunofluorescence analysis, even though APE1 level was unchanged. The loss of APE1 interaction with PRDX1 promotes APE1 redox function to activate binding of the transcription factor NF-κB onto the promoter of a target gene, the proinflammatory chemokine IL-8 involved in cancer invasion and metastasis, resulting in its upregulation. Depletion of APE1 blocked the upregulation of IL-8 in the PRDX1 knockdown cells. Our findings suggest that the interaction of PRDX1 with APE1 represents a novel anti-inflammatory function of PRDX1, whereby the association safeguards APE1 from reducing transcription factors and activating superfluous gene expression, which otherwise could trigger cancer invasion and metastasis. PMID:27388124

  18. Preconditioning for multidimensional TOMBO imaging.

    PubMed

    Horisaki, Ryoichi; Tanida, Jun

    2011-06-01

    In this Letter, we propose a preconditioning method to improve the convergence speed of iterative reconstruction algorithms in a compact, multidimensional, compound-eye imaging system called the thin observation module by bound optics. The condition number of the system matrix is improved by using a preconditioner matrix. To calculate the preconditioner matrix, the system model is expressed in the frequency domain. The proposed method is simulated by using a compressive sensing algorithm called the two-step iterative shrinkage/thresholding algorithm. The results showed improved reconstruction fidelity with a certain number of iterations for high signal-to-noise ratio measurements. PMID:21633452

  19. Preconditioning the bidomain model with almost linear complexity

    NASA Astrophysics Data System (ADS)

    Pierre, Charles

    2012-01-01

    The bidomain model is widely used in electro-cardiology to simulate spreading of excitation in the myocardium and electrocardiograms. It consists of a system of two parabolic reaction diffusion equations coupled with an ODE system. Its discretisation displays an ill-conditioned system matrix to be inverted at each time step: simulations based on the bidomain model therefore are associated with high computational costs. In this paper we propose a preconditioning for the bidomain model either for an isolated heart or in an extended framework including a coupling with the surrounding tissues (the torso). The preconditioning is based on a formulation of the discrete problem that is shown to be symmetric positive semi-definite. A block LU decomposition of the system together with a heuristic approximation (referred to as the monodomain approximation) are the key ingredients for the preconditioning definition. Numerical results are provided for two test cases: a 2D test case on a realistic slice of the thorax based on a segmented heart medical image geometry, a 3D test case involving a small cubic slab of tissue with orthotropic anisotropy. The analysis of the resulting computational cost (both in terms of CPU time and of iteration number) shows an almost linear complexity with the problem size, i.e. of type nlog α( n) (for some constant α) which is optimal complexity for such problems.

  20. Resveratrol preconditioning protects hepatocytes against hepatic ischemia reperfusion injury via Toll-like receptor 4/nuclear factor-κB signaling pathway in vitro and in vivo.

    PubMed

    He, Diao; Guo, Zhen; Pu, Jun-Liang; Zheng, Dao-Feng; Wei, Xu-Fu; Liu, Rui; Tang, Cheng-Yong; Wu, Zhong-Jun

    2016-06-01

    The purpose of this study was to investigate the protective effect of resveratrol against hepatic ischemia reperfusion injury (HIRI) and explore the potential underlying mechanism. Resveratrol-pretreated BRL-3A (rat liver) cells and rats underwent hypoxia/reoxygenation and hepatic ischemia/reperfusion, respectively. BRL-3A cell damage was evaluated, and the mRNA and protein expression of related signal molecules was assessed in cell model. The protein expression of related signal molecules was also assessed in rat model. Inflammatory cytokines levels were determined in the cell supernatant and rat serum while rat liver function and hepatocyte apoptosis were assessed. The results revealed that resveratrol significantly enhanced cell viability, inhibited cell apoptosis, and decreased levels of lactate dehydrogenase (LDH) and production of tumor necrosis factor-α (TNF-α) and interleukin-(IL)-1β in the cell supernatant. In addition, resveratrol ameliorated elevated Toll-like receptor 4 (TLR4) and nuclear factor (NF)-κB, and the depressed inhibitor of NF-κB (IκB)-α caused by hypoxia/reoxygenation stimulation in BRL-3A cells. Moreover, resveratrol inhibited the translocation of NF-κB p65 after the stimulation of hypoxia/reoxygenation in BRL-3A cells. In vivo assays revealed that resveratrol reduced levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and liver pathological changes, while it alleviated hepatocyte apoptosis, negatively mediated the production of TNF-α and IL-1β in serum, and reversed TLR4/NF-κB signaling pathway caused by hepatic ischemia/reperfusion stimulation in liver tissues. The results indicate that resveratrol protected hepatocytes against HIRI, which may be mediated in part via the TLR4/NF-κB signaling pathway. PMID:27064547

  1. 40 CFR 80.52 - Vehicle preconditioning.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... accordance with the “General vehicle handling requirements” per 40 CFR 86.132-96, up to and including the completion of the hot start exhaust test. (b) The preconditioning procedure prescribed at 40 CFR 86.132-96... 40 Protection of Environment 17 2013-07-01 2013-07-01 false Vehicle preconditioning. 80.52...

  2. Purification of a naturally produced, low molecular weight organic factor that reversibly blocks encystment of Blastocladiella emersonii zoospores.

    PubMed

    Gottschalk, W K; Sonneborn, D R

    1985-06-10

    The water mold Blastocladiella emersonii releases zoospore maintenance factor into the medium during zoosporogenesis. Extracellular factor mediates a reversible developmental block that maintains the motile, cell wall-less zoospore phenotype. A method for purifying the factor is reported that results in 75-120% recovery of biological activity. Analyses of purified factor by thin layer chromatography support the conclusion that factor activity resides in a single organic, low molecular weight molecular species. Other data (Gottschalk, W.K. & Sonneborn, D. R. (1985) J. Biol. Chem. 260, 6592-6599) independently support this conclusion and, in addition, support the conclusion that biological activity resides in an SH-containing cyclic ribotide. PMID:3997838

  3. Enteric pathogens deploy cell cycle inhibiting factors to block the bactericidal activity of Perforin-2

    PubMed Central

    McCormack, Ryan M; Lyapichev, Kirill; Olsson, Melissa L; Podack, Eckhard R; Munson, George P

    2015-01-01

    Perforin-2 (MPEG1) is an effector of the innate immune system that limits the proliferation and spread of medically relevant Gram-negative, -positive, and acid fast bacteria. We show here that a cullin-RING E3 ubiquitin ligase (CRL) complex containing cullin-1 and βTrCP monoubiquitylates Perforin-2 in response to pathogen associated molecular patterns such as LPS. Ubiquitylation triggers a rapid redistribution of Perforin-2 and is essential for its bactericidal activity. Enteric pathogens such as Yersinia pseudotuberculosis and enteropathogenic Escherichia coli disarm host cells by injecting cell cycle inhibiting factors (Cifs) into mammalian cells to deamidate the ubiquitin-like protein NEDD8. Because CRL activity is dependent upon NEDD8, Cif blocks ubiquitin dependent trafficking of Perforin-2 and thus, its bactericidal activity. Collectively, these studies further underscore the biological significance of Perforin-2 and elucidate critical molecular events that culminate in Perforin-2-dependent killing of both intracellular and extracellular, cell-adherent bacteria. DOI: http://dx.doi.org/10.7554/eLife.06505.001 PMID:26418746

  4. The factor XIIa blocking antibody 3F7: a safe anticoagulant with anti-inflammatory activities.

    PubMed

    Worm, Marie; Köhler, Elodie C; Panda, Rachita; Long, Andy; Butler, Lynn M; Stavrou, Evi X; Nickel, Katrin F; Fuchs, Tobias A; Renné, Thomas

    2015-10-01

    The plasma protein factor XII (FXII) is the initiating protease of the procoagulant and proinflammatory contact system. FXII activates both the bradykinin (BK) producing kallikrein-kinin system and the intrinsic pathway of coagulation. Contact with negatively charged surfaces induces auto-activation of zymogen FXII that results in activated FXII (FXIIa). Various in vivo activators of FXII have been identified including heparin, misfolded protein aggregates, nucleic acids and polyphosphate. Murine models have established a central role of FXII in arterial and venous thromboembolic diseases. Despite the central function of FXII in pathologic thrombosis, its deficiency does not impair hemostasis in animals or humans. The selective role of FXIIa in thrombosis, but not hemostasis, offers an exciting novel strategy for safe anticoagulation based on interference with FXIIa. We have generated the recombinant fully human FXIIa-blocking antibody 3F7, which abolished FXIIa enzymatic activity and prevented thrombosis in a cardiopulmonary bypass system in large animals, in the absence of increased therapy-associated bleeding. Furthermore, 3F7 also interfered with BK-driven edema in the severe swelling disorder hereditary angioedema (HAE) type III. Taken together, targeting FXIIa with 3F7 appears to be a promising approach to treat edema disorders and thrombosis. PMID:26605293

  5. The factor XIIa blocking antibody 3F7: a safe anticoagulant with anti-inflammatory activities

    PubMed Central

    Worm, Marie; Köhler, Elodie C.; Panda, Rachita; Long, Andy; Butler, Lynn M.; Stavrou, Evi X.; Nickel, Katrin F.; Fuchs, Tobias A.

    2015-01-01

    The plasma protein factor XII (FXII) is the initiating protease of the procoagulant and proinflammatory contact system. FXII activates both the bradykinin (BK) producing kallikrein-kinin system and the intrinsic pathway of coagulation. Contact with negatively charged surfaces induces auto-activation of zymogen FXII that results in activated FXII (FXIIa). Various in vivo activators of FXII have been identified including heparin, misfolded protein aggregates, nucleic acids and polyphosphate. Murine models have established a central role of FXII in arterial and venous thromboembolic diseases. Despite the central function of FXII in pathologic thrombosis, its deficiency does not impair hemostasis in animals or humans. The selective role of FXIIa in thrombosis, but not hemostasis, offers an exciting novel strategy for safe anticoagulation based on interference with FXIIa. We have generated the recombinant fully human FXIIa-blocking antibody 3F7, which abolished FXIIa enzymatic activity and prevented thrombosis in a cardiopulmonary bypass system in large animals, in the absence of increased therapy-associated bleeding. Furthermore, 3F7 also interfered with BK-driven edema in the severe swelling disorder hereditary angioedema (HAE) type III. Taken together, targeting FXIIa with 3F7 appears to be a promising approach to treat edema disorders and thrombosis. PMID:26605293

  6. Block-bordered diagonalization and parallel iterative solvers

    SciTech Connect

    Alvarado, F.; Dag, H.; Bruggencate, M. ten

    1994-12-31

    One of the most common techniques for enhancing parallelism in direct sparse matrix methods is the reorganization of a matrix into a blocked-bordered structure. Incomplete LDU factorization is a very good preconditioner for PCG in serial environments. However, the inherent sequential nature of the preconditioning step makes it less desirable in parallel environments. This paper explores the use of BBD (Blocked Bordered Diagonalization) in connection with ILU preconditioners. The paper shows that BBD-based ILU preconditioners are quite amenable to parallel processing. Neglecting entries from the entire border can result in a blocked diagonal matrix. The result is a great increase in parallelism at the expense of additional iterations. Experiments on the Sequent Symmetry shared memory machine using (mostly) power system that matrices indicate that the method is generally better than conventional ILU preconditioners and in many cases even better than partitioned inverse preconditioners, without the initial setup disadvantages of partitioned inverse preconditioners.

  7. Preconditioning matrices for the pseudospectral approximation of first-order operators

    NASA Technical Reports Server (NTRS)

    Funaro, D.; Rothman, E.

    1989-01-01

    The behavior of the eigenvalues of preconditioning matrices for the pseudospectral approximation to the derivative operator has been analyzed in one and two dimensions. The one-dimensional analysis resulted in real and positive eigenvalues for the selected tridiagonal matrices. In the two-dimensional analysis, the eigenvalues of the selected block-diagonal matrices behaved well, but the preconditioner is full and therefore not suitable for applications. The Richardson scheme has been applied in the unpreconditioned as well as the preconditioned version to find the solution of the model problem.

  8. Preconditioned conjugate gradient methods for the Navier-Stokes equations

    SciTech Connect

    Ajmani, K.; Ng, Wing Fai ); Liou, Meng Sing )

    1994-01-01

    A preconditioned Krylov subspace method (GMRES) is used to solve the linear systems of equations formed at each time-integration step of the unsteady, two-dimensional, compressible Navier-Stokes equations of fluid flow. The Navier-Stokes equations are cast in an implicit, upwind finite-volume, flux-split formulations. Several preconditioning techniques are investigated to enhance the efficiency and convergence rate of the implicit solver based on the GMRES algorithm. The superiority of the new solver is established by comparisons with a (LGSR). Computational test results for low-speed (incompressible flow over a backward-facing step at Mach 0.1), transonic flow (trailing edge flow in a transonic turbine cascade), and hypersonic flow (shock-on-shock interactions on a cylindrical leading edge at Mach 6.0) are presented. For the Mach 0.1 case, overall speedup factors of up to 17 (in terms of time-steps) and 15 (in terms of CPU times on a CRAY-YMP/8) are found in favor of the preconditioned GMRES solver, when compared with the LGSR solver. The corresponding speedup factors for the transonic flow cases are 17 and 23, respectively. The hypersonic flow case shows slightly lower speedup factors of 9 and 13, respectively. The study of preconditioners conducted in this research reveals that a new LUSGS-type preconditioner is much more efficient than a conventional incomplete LU-type preconditioner. 34 refs., 15 figs.

  9. Preconditioned conjugate gradient methods for the Navier-Stokes equations

    NASA Technical Reports Server (NTRS)

    Ajmani, Kumud; Ng, Wing-Fai; Liou, Meng-Sing

    1994-01-01

    A preconditioned Krylov subspace method (GMRES) is used to solve the linear systems of equations formed at each time-integration step of the unsteady, two-dimensional, compressible Navier-Stokes equations of fluid flow. The Navier-Stokes equations are cast in an implicit, upwind finite-volume, flux-split formulation. Several preconditioning techniques are investigated to enhance the efficiency and convergence rate of the implicit solver based on the GMRES algorithm. The superiority of the new solver is established by comparisons with a conventional implicit solver, namely line Gauss-Seidel relaxation (LGSR). Computational test results for low-speed (incompressible flow over a backward-facing step at Mach 0.1), transonic flow (trailing edge flow in a transonic turbine cascade), and hypersonic flow (shock-on-shock interactions on a cylindrical leading edge at Mach 6.0) are presented. For the Mach 0.1 case, overall speedup factors of up to 17 (in terms of time-steps) and 15 (in terms of CPU time on a CRAY-YMP/8) are found in favor of the preconditioned GMRES solver, when compared with the LGSR solver. The corresponding speedup factors for the transonic flow case are 17 and 23, respectively. The hypersonic flow case shows slightly lower speedup factors of 9 and 13, respectively. The study of preconditioners conducted in this research reveals that a new LUSGS-type preconditioner is much more efficient than a conventional incomplete LU-type preconditioner.

  10. Progesterone-induced blocking factor differentially regulates trophoblast and tumor invasion by altering matrix metalloproteinase activity.

    PubMed

    Halasz, Melinda; Polgar, Beata; Berta, Gergely; Czimbalek, Livia; Szekeres-Bartho, Julia

    2013-12-01

    Invasiveness is a common feature of trophoblast and tumors; however, while tumor invasion is uncontrolled, trophoblast invasion is strictly regulated. Both trophoblast and tumor cells express high levels of the immunomodulatory progesterone-induced blocking factor (PIBF), therefore, we aimed to test the possibility that PIBF might be involved in invasion. To this aim, we used PIBF-silenced or PIBF-treated trophoblast (HTR8/Svneo, and primary trophoblast) and tumor (HT-1080, A549, HCT116, PC3) cell lines. Silencing of PIBF increased invasiveness as well as MMP-2,-9 secretion of HTR8/SVneo, and decreased those of HT-1080 cells. PIBF induced immediate STAT6 activation in both cell lines. Silencing of IL-4Rα abrogated all the above effects of PIBF, suggesting that invasion-related signaling by PIBF is initiated through the IL-4Rα/PIBF-receptor complex. In HTR-8/SVneo, PIBF induced fast, but transient Akt and ERK phosphorylation, whereas in tumor cells, PIBF triggered sustained Akt, ERK, and late STAT3 activation. The late signaling events might be due to indirect action of PIBF. PIBF induced the expression of EGF and HB-EGF in HT-1080 cells. The STAT3-activating effect of PIBF was reduced in HB-EGF-deficient HT-1080 cells, suggesting that PIBF-induced HB-EGF contributes to late STAT3 activation. PIBF binds to the promoters of IL-6, EGF, and HB-EGF; however, the protein profile of the protein/DNA complex is different in the two cell lines. We conclude that in tumor cells, PIBF induces proteins, which activate invasion signaling, while-based on our previous data-PIBF might control trophoblast invasion by suppressing proinvasive genes. PMID:23807209

  11. Enhanced nucleotide excision repair capacity in lung cancer cells by preconditioning with DNA-damaging agents

    PubMed Central

    Choi, Ji Ye; Park, Jeong-Min; Yi, Joo Mi; Leem, Sun-Hee; Kang, Tae-Hong

    2015-01-01

    The capacity of tumor cells for nucleotide excision repair (NER) is a major determinant of the efficacy of and resistance to DNA-damaging chemotherapeutics, such as cisplatin. Here, we demonstrate that using lesion-specific monoclonal antibodies, NER capacity is enhanced in human lung cancer cells after preconditioning with DNA-damaging agents. Preconditioning of cells with a nonlethal dose of UV radiation facilitated the kinetics of subsequent cisplatin repair and vice versa. Dual-incision assay confirmed that the enhanced NER capacity was sustained for 2 days. Checkpoint activation by ATR kinase and expression of NER factors were not altered significantly by the preconditioning, whereas association of XPA, the rate-limiting factor in NER, with chromatin was accelerated. In preconditioned cells, SIRT1 expression was increased, and this resulted in a decrease in acetylated XPA. Inhibition of SIRT1 abrogated the preconditioning-induced predominant XPA binding to DNA lesions. Taking these data together, we conclude that upregulated NER capacity in preconditioned lung cancer cells is caused partly by an increased level of SIRT1, which modulates XPA sensitivity to DNA damage. This study provides some insights into the molecular mechanism of chemoresistance through acquisition of enhanced DNA repair capacity in cancer cells. PMID:26317794

  12. Preconditioning for edge-preserving image super resolution.

    PubMed

    Pelletier, Stéphane; Cooperstock, Jeremy R

    2012-01-01

    We propose a simple preconditioning method for accelerating the solution of edge-preserving image super-resolution (SR) problems in which a linear shift-invariant point spread function is employed. Our technique involves reordering the high-resolution (HR) pixels in a similar manner to what is done in preconditioning methods for quadratic SR formulations. However, due to the edge preserving requirements, the Hessian matrix of the cost function varies during the minimization process. We develop an efficient update scheme for the preconditioner in order to cope with this situation. Unlike some other acceleration strategies that round the displacement values between the low-resolution (LR) images on the HR grid, the proposed method does not sacrifice the optimality of the observation model. In addition, we describe a technique for preconditioning SR problems involving rational magnification factors. The use of such factors is motivated in part by the fact that, under certain circumstances, optimal SR zooms are nonintegers. We show that, by reordering the pixels of the LR images, the structure of the problem to solve is modified in such a way that preconditioners based on circulant operators can be used. PMID:21693419

  13. Parallel preconditioning for the solution of nonsymmetric banded linear systems

    SciTech Connect

    Amodio, P.; Mazzia, F.

    1994-12-31

    Many computational techniques require the solution of banded linear systems. Common examples derive from the solution of partial differential equations and of boundary value problems. In particular the authors are interested in the parallel solution of block Hessemberg linear systems Gx = f, arising from the solution of ordinary differential equations by means of boundary value methods (BVMs), even if the considered preconditioning may be applied to any block banded linear system. BVMs have been extensively investigated in the last few years and their stability properties give promising results. A new class of BVMs called Reverse Adams, which are BV-A-stable for orders up to 6, and BV-A{sub 0}-stable for orders up to 9, have been studied.

  14. Preconditioned Mixed Spectral Element Methods for Elasticity and Stokes Problems

    NASA Technical Reports Server (NTRS)

    Pavarino, Luca F.

    1996-01-01

    Preconditioned iterative methods for the indefinite systems obtained by discretizing the linear elasticity and Stokes problems with mixed spectral elements in three dimensions are introduced and analyzed. The resulting stiffness matrices have the structure of saddle point problems with a penalty term, which is associated with the Poisson ratio for elasticity problems or with stabilization techniques for Stokes problems. The main results of this paper show that the convergence rate of the resulting algorithms is independent of the penalty parameter, the number of spectral elements Nu and mildly dependent on the spectral degree eta via the inf-sup constant. The preconditioners proposed for the whole indefinite system are block-diagonal and block-triangular. Numerical experiments presented in the final section show that these algorithms are a practical and efficient strategy for the iterative solution of the indefinite problems arising from mixed spectral element discretizations of elliptic systems.

  15. First principles calculations of nucleon and pion form factors: understanding the building blocks of nuclear matter from lattice QCD

    SciTech Connect

    Constantia Alexandrou; Bojan Bistrovic; Robert Edwards; P de Forcrand; George Fleming; Philipp Haegler; John Negele; Konstantinos Orginos; Andrew Pochinsky; Dru Renner; David Richards; Wolfram Schroers; Antonios Tsapalis

    2005-10-01

    Lattice QCD is an essential complement to the current and anticipated DOE-supported experimental program in hadronic physics. In this poster we address several key questions central to our understanding of the building blocks of nuclear matter, nucleons and pions. Firstly, we describe progress at computing the electromagnetic form factors of the nucleon, describing the distribution of charge and current, before considering the role played by the strange quarks. We then describe the study of transition form factors to the Delta resonance. Finally, we present recent work to determine the pion form factor, complementary to the current JLab experimental determination and providing insight into the approach to asymptotic freedom.

  16. Phospholipids block nuclear factor-kappa B and tau phosphorylation and inhibit amyloid-beta secretion in human neuroblastoma cells.

    PubMed

    Pandey, N R; Sultan, K; Twomey, E; Sparks, D L

    2009-12-29

    Inflammation and oxidative stress have been shown to play a critical role in the pathophysiology that leads to neurodegeneration. Omega-6 phospholipids, e.g. dilinoleoylphosphatidylcholine (DLPC), have been shown to have anti-inflammatory properties and therefore experiments were undertaken to determine whether DLPC can prevent inflammatory neurodegenerative events in the model neuronal cell line, SH-SY5Y. Tumor necrosis factor (TNF-alpha) and H(2)O(2) activate mitogen-activated protein kinase (MAPK) in SH-SY5Y cells within 5 min and this activation is completely blocked by DLPC (12 microM). DLPC blocks IkappaBalpha phosphorylation in the SH-SY5Y cells and prevents the phosphorylation and activation of nuclear factor-kappa B (NF-kappaB). The phospholipid inhibits induction of MAPK and NF-kappaB in similar fashion to the MEK1/2-inhibitor, U0126 (10 microM). DLPC completely abolishes TNF-alpha, H(2)O(2) and lipopolysaccaride (LPS)-induced neuronal tau phosphorylation. Cellular amyloid precursor protein levels are reduced by DLPC and LPS-induced amyloid-beta expression and secretion in SH-SY5Y cells are completely blocked by DLPC. Taken together, these data suggest that DLPC can act through MAPK to block neuronal inflammatory cascades and prevent potential pathological consequences in the neuronal metabolism of amyloid and tau proteins. PMID:19788916

  17. Release of soluble "blocking" and "suppressor" factors from normal lymphocytes treated with RNA from spleens of tumour-bearing mice.

    PubMed Central

    Pennline, K. J.; Evans, S. B.; Nawrocki, J. F.; Rees, J. C.; Johnson, C. S.; Vallera, D. A.; Dodd, M. C.

    1979-01-01

    RNA extracted from the spleens of tumour-bearing (TLRNA) and tumour-immune (ILRNA) mice was shown to transfer to normal lymphocytes (NL) the ability to produce factors that blocked specific tumour-cell cytotoxicity and mediated specific antibody-dependent cell cytotoxicity (ADCC). Aliquots of normal C3H mouse lymphocytes were treated with TLRNA or ILRNA and cultured in vitro in the absence of tumour antigen. Supernatants were collected at 24h intervals and tested in a microcytotoxicity assay for blocking and ADCC activities. Factors that inhibited tumour destruction by specifically sensitized lymphocytes at the level of both the tumour cells and effector cells were demonstrable in culture supernatants of NL pretreated with TLRNA (50 or 100 microgram/4 X 10(6) cells) but not ILRNA. However, treatment of NL with either RNA resulted in the production factors that mediated tumour-specific ADCC. Cytotoxicity testing and absorption studies of the tumour cell and a control cell (LM) indicated that factors mediating ADCC and blocking at the target-cell level were specific for the tumour. Suppressor activity at the effector-cell level was not absorbed by tumour cells and represents a separate and distinct mechanism of immunosuppression. These data indicate that RNA faithfully transfers "suppressive" as well as "positive" types of immune responses that have been reported previously for lymphocytes obtained directly from tumour-bearing and tumour-immune animals. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 PMID:313804

  18. 40 CFR 80.52 - Vehicle preconditioning.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... accordance with the “General vehicle handling requirements” per 40 CFR 86.132-96, up to and including the completion of the hot start exhaust test. (b) The preconditioning procedure prescribed at 40 CFR...

  19. 40 CFR 80.52 - Vehicle preconditioning.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... accordance with the “General vehicle handling requirements” per 40 CFR 86.132-96, up to and including the completion of the hot start exhaust test. (b) The preconditioning procedure prescribed at 40 CFR...

  20. Laser thermal preconditioning enhances dermal wound repair

    NASA Astrophysics Data System (ADS)

    Wilmink, Gerald J.; Carter, Terry; Davidson, Jeffrey M.; Jansen, E. Duco

    2008-02-01

    Preconditioning tissues with an initial mild thermal stress, thereby eliciting a stress response, can serve to protect tissue from subsequent stresses. Patients at risk for impaired healing, such as diabetics, can benefit from therapeutic methods which enhance wound repair. We present a laser thermal preconditioning protocol that accelerates cutaneous wound repair in a murine model. A pulsed diode laser (λ = 1.86 μm, τ p = 2 ms, 50 Hz, H = 7.64 mJ/cm2) was used to precondition mouse skin before incisional wounds were made. The preconditioning protocol was optimized in vitro and in vivo using hsp70 expression, cell viability, and temperature measurements as benchmarks. Hsp70 expression was non-invasively monitored using a transgenic mouse strain with the hsp70 promoter driving luciferase expression. Tissue temperature recordings were acquired in real time using an infrared camera. Wound repair was assessed by measuring hsp70 expression, biomechanical properties, and wound histology for up to 24 d. Bioluminescence (BLI) was monitored with the IVIS 200 System (Xenogen) and tensile properties with a tensiometer (BTC-2000). The in vivo BLI studies indicated that the optimized laser preconditioning protocol increased hsp70 expression by 15-fold. The tensiometer data revealed that laser preconditioned wounds are ~40% stronger than control wounds at 10 days post surgery. Similar experiments in a diabetic mouse model also enhanced wound repair strength. These results indicate that 1) noninvasive imaging methods can aid in the optimization of novel laser preconditioning methods; 2) that optimized preconditioning with a 1.86 μm diode laser enhances early wound repair.

  1. Bradykinin mediates cardiac preconditioning at a distance.

    PubMed

    Schoemaker, R G; van Heijningen, C L

    2000-05-01

    Preconditioning the heart by brief coronary (CAO) or mesenteric artery occlusion (MAO) can protect against damage during subsequent prolonged CAO and reperfusion. The role of bradykinin (BK) in remote cardiac preconditioning by MAO is investigated by antagonizing the BK B(2) receptor [Hoechst 140 (HOE-140)] or simulating local BK release by mesenteric intra-arterial infusion. Anesthetized male Wistar rats (n = 6-8) were treated with HOE-140 or saline before starting the preconditioning protocol, CAO, MAO, or non-preconditioned control. Infarct size related to risk area [ratio of infarct area to area at risk (IA/AR)] was determined after 3 h of reperfusion following a 60-min CAO. IA/AR was 62 +/- 5% in controls and not affected by HOE-140 (58 +/- 6%). CAO as well as MAO significantly protected the heart (IA/AR, 37 +/- 3 and 35 +/- 5%), which was prevented by HOE-140 (IA/AR, 71 +/- 6 and 65 +/- 7%, respectively). Brief intramesenteric BK infusion mimicked MAO (IA/AR, 26 +/- 3%). Pretreatment with hexamethonium could abolish this protection (IA/AR, 67 +/- 4%). These data indicate an important role for BK in remote preconditioning by MAO. Results support the hypothesis that remote preconditioning acts through sensory nerve stimulation in the ischemic organ. PMID:10775135

  2. The evolving concept of physiological ischemia training vs. ischemia preconditioning.

    PubMed

    Ni, Jun; Lu, Hongjian; Lu, Xiao; Jiang, Minghui; Peng, Qingyun; Ren, Caili; Xiang, Jie; Mei, Chengyao; Li, Jianan

    2015-11-01

    Ischemic heart diseases are the leading cause of death with increasing numbers of patients worldwide. Despite advances in revascularization techniques, angiogenic therapies remain highly attractive. Physiological ischemia training, which is first proposed in our laboratory, refers to reversible ischemia training of normal skeletal muscles by using a tourniquet or isometric contraction to cause physiologic ischemia for about 4 weeks for the sake of triggering molecular and cellular mechanisms to promote angiogenesis and formation of collateral vessels and protect remote ischemia areas. Physiological ischemia training therapy augments angiogenesis in the ischemic myocardium by inducing differential expression of proteins involved in energy metabolism, cell migration, protein folding, and generation. It upregulates the expressions of vascular endothelial growth factor, and induces angiogenesis, protects the myocardium when infarction occurs by increasing circulating endothelial progenitor cells and enhancing their migration, which is in accordance with physical training in heart disease rehabilitation. These findings may lead to a new approach of therapeutic angiogenesis for patients with ischemic heart diseases. On the basis of the promising results in animal studies, studies were also conducted in patients with coronary artery disease without any adverse effect in vivo, indicating that physiological ischemia training therapy is a safe, effective and non-invasive angiogenic approach for cardiovascular rehabilitation. Preconditioning is considered to be the most protective intervention against myocardial ischemia-reperfusion injury to date. Physiological ischemia training is different from preconditioning. This review summarizes the preclinical and clinical data of physiological ischemia training and its difference from preconditioning. PMID:26664354

  3. Preconditioned conjugate gradient wave-front reconstructors for multiconjugate adaptive optics

    NASA Astrophysics Data System (ADS)

    Gilles, Luc; Ellerbroek, Brent L.; Vogel, Curtis R.

    2003-09-01

    Multiconjugate adaptive optics (MCAO) systems with 104-105 degrees of freedom have been proposed for future giant telescopes. Using standard matrix methods to compute, optimize, and implement wave-front control algorithms for these systems is impractical, since the number of calculations required to compute and apply the reconstruction matrix scales respectively with the cube and the square of the number of adaptive optics degrees of freedom. We develop scalable open-loop iterative sparse matrix implementations of minimum variance wave-front reconstruction for telescope diameters up to 32 m with more than 104 actuators. The basic approach is the preconditioned conjugate gradient method with an efficient preconditioner, whose block structure is defined by the atmospheric turbulent layers very much like the layer-oriented MCAO algorithms of current interest. Two cost-effective preconditioners are investigated: a multigrid solver and a simpler block symmetric Gauss-Seidel (BSGS) sweep. Both options require off-line sparse Cholesky factorizations of the diagonal blocks of the matrix system. The cost to precompute these factors scales approximately as the three-halves power of the number of estimated phase grid points per atmospheric layer, and their average update rate is typically of the order of 10-2 Hz, i.e., 4-5 orders of magnitude lower than the typical 103 Hz temporal sampling rate. All other computations scale almost linearly with the total number of estimated phase grid points. We present numerical simulation results to illustrate algorithm convergence. Convergence rates of both preconditioners are similar, regardless of measurement noise level, indicating that the layer-oriented BSGS sweep is as effective as the more elaborated multiresolution preconditioner.

  4. Preconditioned conjugate gradient wave-front reconstructors for multiconjugate adaptive optics.

    PubMed

    Gilles, Luc; Ellerbroek, Brent L; Vogel, Curtis R

    2003-09-10

    Multiconjugate adaptive optics (MCAO) systems with 10(4)-10(5) degrees of freedom have been proposed for future giant telescopes. Using standard matrix methods to compute, optimize, and implement wavefront control algorithms for these systems is impractical, since the number of calculations required to compute and apply the reconstruction matrix scales respectively with the cube and the square of the number of adaptive optics degrees of freedom. We develop scalable open-loop iterative sparse matrix implementations of minimum variance wave-front reconstruction for telescope diameters up to 32 m with more than 10(4) actuators. The basic approach is the preconditioned conjugate gradient method with an efficient preconditioner, whose block structure is defined by the atmospheric turbulent layers very much like the layer-oriented MCAO algorithms of current interest. Two cost-effective preconditioners are investigated: a multigrid solver and a simpler block symmetric Gauss-Seidel (BSGS) sweep. Both options require off-line sparse Cholesky factorizations of the diagonal blocks of the matrix system. The cost to precompute these factors scales approximately as the three-halves power of the number of estimated phase grid points per atmospheric layer, and their average update rate is typically of the order of 10(-2) Hz, i.e., 4-5 orders of magnitude lower than the typical 10(3) Hz temporal sampling rate. All other computations scale almost linearly with the total number of estimated phase grid points. We present numerical simulation results to illustrate algorithm convergence. Convergence rates of both preconditioners are similar, regardless of measurement noise level, indicating that the layer-oriented BSGS sweep is as effective as the more elaborated multiresolution preconditioner. PMID:14503692

  5. Weighted graph based ordering techniques for preconditioned conjugate gradient methods

    NASA Technical Reports Server (NTRS)

    Clift, Simon S.; Tang, Wei-Pai

    1994-01-01

    We describe the basis of a matrix ordering heuristic for improving the incomplete factorization used in preconditioned conjugate gradient techniques applied to anisotropic PDE's. Several new matrix ordering techniques, derived from well-known algorithms in combinatorial graph theory, which attempt to implement this heuristic, are described. These ordering techniques are tested against a number of matrices arising from linear anisotropic PDE's, and compared with other matrix ordering techniques. A variation of RCM is shown to generally improve the quality of incomplete factorization preconditioners.

  6. Responsive corneosurfametry following in vivo skin preconditioning.

    PubMed

    Uhoda, E; Goffin, V; Pierard, G E

    2003-12-01

    Skin is subjected to many environmental threats, some of which altering the structure and function of the stratum corneum. Among them, surfactants are recognized factors that may influence irritant contact dermatitis. The present study was conducted to compare the variations in skin capacitance and corneosurfametry (CSM) reactivity before and after skin exposure to repeated subclinical injuries by 2 hand dishwashing liquids. A forearm immersion test was performed on 30 healthy volunteers. 2 daily soak sessions were performed for 5 days. At inclusion and the day following the last soak session, skin capacitance was measured and cyanoacrylate skin-surface strippings were harvested. The latter specimens were used for the ex vivo microwave CSM. Both types of assessments clearly differentiated the 2 hand dishwashing liquids. The forearm immersion test allowed the discriminant sensitivity of CSM to increase. Intact skin capacitance did not predict CSM data. By contrast, a significant correlation was found between the post-test conductance and the corresponding CSM data. In conclusion, a forearm immersion test under realistic conditions can discriminate the irritation potential between surfactant-based products by measuring skin conductance and performing CSM. In vivo skin preconditioning by surfactants increases CSM sensitivity to the same surfactants. PMID:15025702

  7. Remote ischemic preconditioning for kidney protection: GSK3β-centric insights into the mechanism of action.

    PubMed

    Liu, Zhangsuo; Gong, Rujun

    2015-11-01

    Preventing acute kidney injury (AKI) in high-risk patients following medical interventions is a paramount challenge for clinical practice. Recent data from animal experiments and clinical trials indicate that remote ischemic preconditioning, represented by limb ischemic preconditioning, confers a protective action on the kidney. Ischemic preconditioning is effective in reducing the risk for AKI following cardiovascular interventions and the use of iodinated radiocontrast media. Nevertheless, the underlying mechanisms for this protective effect are elusive. A protective signal is conveyed from the remote site undergoing ischemic preconditioning, such as the limb, to target organs, such as the kidney, by multiple potential communication pathways, which may involve humoral, neuronal, and systemic mechanisms. Diverse transmitting pathways trigger a variety of signaling cascades, including the reperfusion injury salvage kinase and survivor activating factor enhancement pathways, all of which converge on glycogen synthase kinase 3β (GSK3β). Inhibition of GSK3β subsequent to ischemic preconditioning reinforces the Nrf2-mediated antioxidant defense, diminishes the nuclear factor-κB-dependent proinflammatory response, and exerts prosurvival effects ensuing from the desensitized mitochondria permeability transition. Thus, therapeutic targeting of GSK3β by ischemic preconditioning or by pharmacologic preconditioning with existing US Food and Drug Administration-approved drugs having GSK3β-inhibitory activities might represent a pragmatic and cost-effective adjuvant strategy for kidney protection and prophylaxis against AKI. PMID:26271146

  8. Fibrinogen blocks the autoactivation and thrombin-mediated activation of factor XI on dextran sulfate.

    PubMed Central

    Scott, C F; Colman, R W

    1992-01-01

    The intrinsic pathway of blood coagulation is activated when factor XIa, one of the three contact-system enzymes, is generated and then activates factor IX. Factor XI has been shown to be efficiently activated in vitro by surface-bound factor XIIa after factor XI is transported to the surface by its cofactor, high molecular weight kininogen (HK). However, individuals lacking any of the three contact-system proteins--namely, factor XII, prekallikrein, and HK--do not suffer from bleeding abnormalities. This mystery has led several investigators to search for an "alternate" activation pathway for factor XI. Recently, factor XI has been reported to be autoactivated on the soluble "surface" dextran sulfate, and thrombin was shown to accelerate the autoactivation. However, it was also reported that HK, the cofactor for factor XIIa-mediated activation of factor XI, actually diminishes the thrombin-catalyzed activation rate of factor XI. Nonetheless, it was suggested that thrombin was a more efficient activator than factor XIIa. In this report we investigated the effect of fibrinogen, the major coagulation protein in plasma, on the activation rate of factor XI. Fibrinogen, the preferred substrate for thrombin in plasma, virtually prevented autoactivation of factor XI as well as the thrombin-mediated activation of factor XI, while having no effect on factor XIIa-catalyzed activation. HK dramatically curtailed the autoactivation of factor XI in addition to the thrombin-mediated activation. These data indicate that factor XI would not be autoactivated in a plasma environment, and thrombin would, therefore, be unlikely to potentiate the activation. We believe that the "missing pathway" for factor XI activation remains an enigma that warrants further investigation. PMID:1454798

  9. Polynomial preconditioning for conjugate gradient methods

    SciTech Connect

    Ashby, S.F.

    1987-12-01

    The solution of a linear system of equations, Ax = b, arises in many scientific applications. If A is large and sparse, an iterative method is required. When A is hermitian positive definite (hpd), the conjugate gradient method of Hestenes and Stiefel is popular. When A is hermitian indefinite (hid), the conjugate residual method may be used. If A is ill-conditioned, these methods may converge slowly, in which case a preconditioner is needed. In this thesis we examine the use of polynomial preconditioning in CG methods for both hermitian positive definite and indefinite matrices. Such preconditioners are easy to employ and well-suited to vector and/or parallel architectures. We first show that any CG method is characterized by three matrices: an hpd inner product matrix B, a preconditioning matrix C, and the hermitian matrix A. The resulting method, CG(B,C,A), minimizes the B-norm of the error over a Krylov subspace. We next exploit the versatility of polynomial preconditioners to design several new CG methods. To obtain an optimum preconditioner, we solve a constrained minimax approximation problem. The preconditioning polynomial, C(lambda), is optimum in that it minimizes a bound on the condition number of the preconditioned matrix, p/sub m/(A). An adaptive procedure for dynamically determining the optimum preconditioner is also discussed. Finally, in a variety of numerical experiments, conducted on a Cray X-MP/48, we demonstrate the effectiveness of polynomial preconditioning. 66 ref., 19 figs., 39 tabs.

  10. Minimal residual method stronger than polynomial preconditioning

    SciTech Connect

    Faber, V.; Joubert, W.; Knill, E.

    1994-12-31

    Two popular methods for solving symmetric and nonsymmetric systems of equations are the minimal residual method, implemented by algorithms such as GMRES, and polynomial preconditioning methods. In this study results are given on the convergence rates of these methods for various classes of matrices. It is shown that for some matrices, such as normal matrices, the convergence rates for GMRES and for the optimal polynomial preconditioning are the same, and for other matrices such as the upper triangular Toeplitz matrices, it is at least assured that if one method converges then the other must converge. On the other hand, it is shown that matrices exist for which restarted GMRES always converges but any polynomial preconditioning of corresponding degree makes no progress toward the solution for some initial error. The implications of these results for these and other iterative methods are discussed.

  11. Projection preconditioning for Lanczos-type methods

    SciTech Connect

    Bielawski, S.S.; Mulyarchik, S.G.; Popov, A.V.

    1996-12-31

    We show how auxiliary subspaces and related projectors may be used for preconditioning nonsymmetric system of linear equations. It is shown that preconditioned in such a way (or projected) system is better conditioned than original system (at least if the coefficient matrix of the system to be solved is symmetrizable). Two approaches for solving projected system are outlined. The first one implies straightforward computation of the projected matrix and consequent using some direct or iterative method. The second approach is the projection preconditioning of conjugate gradient-type solver. The latter approach is developed here in context with biconjugate gradient iteration and some related Lanczos-type algorithms. Some possible particular choices of auxiliary subspaces are discussed. It is shown that one of them is equivalent to using colorings. Some results of numerical experiments are reported.

  12. Inhibition of pyrimidine synthesis reverses viral virulence factor-mediated block of mRNA nuclear export

    PubMed Central

    Zhang, Liang; Das, Priyabrata; Schmolke, Mirco; Manicassamy, Balaji; Wang, Yaming; Deng, Xiaoyi; Cai, Ling; Tu, Benjamin P.; Forst, Christian V.; Roth, Michael G.; Levy, David E.; García-Sastre, Adolfo; de Brabander, Jef; Phillips, Margaret A.

    2012-01-01

    The NS1 protein of influenza virus is a major virulence factor essential for virus replication, as it redirects the host cell to promote viral protein expression. NS1 inhibits cellular messenger ribonucleic acid (mRNA) processing and export, down-regulating host gene expression and enhancing viral gene expression. We report in this paper the identification of a nontoxic quinoline carboxylic acid that reverts the inhibition of mRNA nuclear export by NS1, in the absence or presence of the virus. This quinoline carboxylic acid directly inhibited dihydroorotate dehydrogenase (DHODH), a host enzyme required for de novo pyrimidine biosynthesis, and partially reduced pyrimidine levels. This effect induced NXF1 expression, which promoted mRNA nuclear export in the presence of NS1. The release of NS1-mediated mRNA export block by DHODH inhibition also occurred in the presence of vesicular stomatitis virus M (matrix) protein, another viral inhibitor of mRNA export. This reversal of mRNA export block allowed expression of antiviral factors. Thus, pyrimidines play a necessary role in the inhibition of mRNA nuclear export by virulence factors. PMID:22312003

  13. Hypoxic preconditioning with cobalt ameliorates hypobaric hypoxia induced pulmonary edema in rat.

    PubMed

    Shukla, Dhananjay; Saxena, Saurabh; Purushothaman, Jayamurthy; Shrivastava, Kalpana; Singh, Mrinalini; Shukla, Shirish; Malhotra, Vineet Kumar; Mustoori, Sairam; Bansal, Anju

    2011-04-10

    Exposure to high altitude results in hypobaric hypoxia which is considered as an acute physiological stress and often leads to high altitude maladies such as high altitude pulmonary edema (HAPE) and high altitude cerebral edema (HACE). The best way to prevent high altitude injuries is hypoxic preconditioning which has potential clinical usefulness and can be mimicked by cobalt chloride. Preconditioning with cobalt has been reported to provide protection in various tissues against ischemic injury. However, the effect of preconditioning with cobalt against high altitude induced pulmonary edema has not been investigated in vivo. Therefore, in the present study, rats pretreated with saline or cobalt (12.5mg/kg body weight) for 7days were exposed to hypobaric hypoxia of 9142m for 5h at 24°C. Formation of pulmonary edema was assessed by measuring transvascular leakage of sodium fluorescein dye and lung water content. Total protein content, albumin content, vascular endothelial growth factor (VEGF) and cytokine levels were measured in bronchoalveolar lavage fluid. Expression of HO-1, MT, NF-κB DNA binding activity and lung tissue pathology were evaluated to determine the effect of preconditioning on HAPE. Hypobaric hypoxia induced increase in transvascular leakage of sodium fluorescein dye, lung water content, lavage total protein, albumin, VEGF levels, pro-inflammatory cytokine levels, tissue expression of cell adhesion molecules and NF-κB DNA binding activity were reduced significantly after hypoxic preconditioning with cobalt. Expression of anti-inflammatory protein HO-1, MT, TGF-β and IL-6 were increased after hypoxic preconditioning. These data suggest that hypoxic preconditioning with cobalt has protective effect against HAPE. PMID:21296072

  14. Integrated Assessment of Behavioral and Environmental Risk Factors for Lyme Disease Infection on Block Island, Rhode Island

    PubMed Central

    Krause, Peter J.; Niccolai, Linda; Steeves, Tanner; O’Keefe, Corrine Folsom; Diuk-Wasser, Maria A.

    2014-01-01

    Peridomestic exposure to Borrelia burgdorferi-infected Ixodes scapularis nymphs is considered the dominant means of infection with black-legged tick-borne pathogens in the eastern United States. Population level studies have detected a positive association between the density of infected nymphs and Lyme disease incidence. At a finer spatial scale within endemic communities, studies have focused on individual level risk behaviors, without accounting for differences in peridomestic nymphal density. This study simultaneously assessed the influence of peridomestic tick exposure risk and human behavior risk factors for Lyme disease infection on Block Island, Rhode Island. Tick exposure risk on Block Island properties was estimated using remotely sensed landscape metrics that strongly correlated with tick density at the individual property level. Behavioral risk factors and Lyme disease serology were assessed using a longitudinal serosurvey study. Significant factors associated with Lyme disease positive serology included one or more self-reported previous Lyme disease episodes, wearing protective clothing during outdoor activities, the average number of hours spent daily in tick habitat, the subject’s age and the density of shrub edges on the subject’s property. The best fit multivariate model included previous Lyme diagnoses and age. The strength of this association with previous Lyme disease suggests that the same sector of the population tends to be repeatedly infected. The second best multivariate model included a combination of environmental and behavioral factors, namely hours spent in vegetation, subject’s age, shrub edge density (increase risk) and wearing protective clothing (decrease risk). Our findings highlight the importance of concurrent evaluation of both environmental and behavioral factors to design interventions to reduce the risk of tick-borne infections. PMID:24416278

  15. Preconditioned Conjugate Gradient methods for low speed flow calculations

    NASA Technical Reports Server (NTRS)

    Ajmani, Kumud; Ng, Wing-Fai; Liou, Meng-Sing

    1993-01-01

    An investigation is conducted into the viability of using a generalized Conjugate Gradient-like method as an iterative solver to obtain steady-state solutions of very low-speed fluid flow problems. Low-speed flow at Mach 0.1 over a backward-facing step is chosen as a representative test problem. The unsteady form of the two dimensional, compressible Navier-Stokes equations are integrated in time using discrete time-steps. The Navier-Stokes equations are cast in an implicit, upwind finite-volume, flux split formulation. The new iterative solver is used to solve a linear system of equations at each step of the time-integration. Preconditioning techniques are used with the new solver to enhance the stability and the convergence rate of the solver and are found to be critical to the overall success of the solver. A study of various preconditioners reveals that a preconditioner based on the lower-upper (L-U)-successive symmetric over-relaxation iterative scheme is more efficient than a preconditioner based on incomplete L-U factorizations of the iteration matrix. The performance of the new preconditioned solver is compared with a conventional line Gauss-Seidel relaxation (LGSR) solver. Overall speed-up factors of 28 (in terms of global time-steps required to converge to a steady-state solution) and 20 (in terms of total CPU time on one processor of a CRAY-YMP) are found in favor of the new preconditioned solver, when compared with the LGSR solver.

  16. Drug Repurposing Approach Identifies Inhibitors of the Prototypic Viral Transcription Factor IE2 that Block Human Cytomegalovirus Replication.

    PubMed

    Mercorelli, Beatrice; Luganini, Anna; Nannetti, Giulio; Tabarrini, Oriana; Palù, Giorgio; Gribaudo, Giorgio; Loregian, Arianna

    2016-03-17

    New targets for antiviral strategies are needed against human cytomegalovirus (HCMV), a major human pathogen. A cell-based screen aimed at finding inhibitors of the viral transcription factor Immediate-Early 2 (IE2) was performed in HCMV-infected cells expressing EGFP under the control of an IE2-inducible viral promoter. Screening of a library of bioactive small molecules led to the identification of several compounds able to inhibit EGFP expression and also HCMV replication with potency in the low-micromolar range. Follow-up studies with four selected hits indicated that they all block viral DNA synthesis as well as viral Early and Late gene expression. Furthermore, mechanistic studies confirmed that the compounds specifically act via inhibition of IE2 transactivating activity, thus blocking viral Early gene expression and the progression of virus replication. These results provide proof of concept for identifying small molecules that modulate the activity of a microbial transcription factor to control pathogen replication. PMID:26877023

  17. The TCP4 transcription factor of Arabidopsis blocks cell division in yeast at G1 {yields} S transition

    SciTech Connect

    Aggarwal, Pooja; Padmanabhan, Bhavna; Bhat, Abhay; Sarvepalli, Kavitha; Sadhale, Parag P.; Nath, Utpal

    2011-07-01

    Highlights: {yields} TCP4 is a class II TCP transcription factor, that represses cell division in Arabidopsis. {yields} TCP4 expression in yeast retards cell division by blocking G1 {yields} S transition. {yields} Genome-wide expression studies and Western analysis reveals stabilization of cell cycle inhibitor Sic1, as possible mechanism. -- Abstract: The TCP transcription factors control important aspects of plant development. Members of class I TCP proteins promote cell cycle by regulating genes directly involved in cell proliferation. In contrast, members of class II TCP proteins repress cell division. While it has been postulated that class II proteins induce differentiation signal, their exact role on cell cycle has not been studied. Here, we report that TCP4, a class II TCP protein from Arabidopsis that repress cell proliferation in developing leaves, inhibits cell division by blocking G1 {yields} S transition in budding yeast. Cells expressing TCP4 protein with increased transcriptional activity fail to progress beyond G1 phase. By analyzing global transcriptional status of these cells, we show that expression of a number of cell cycle genes is altered. The possible mechanism of G1 {yields} S arrest is discussed.

  18. Resveratrol and ischemic preconditioning in the brain.

    PubMed

    Raval, Ami P; Lin, Hung Wen; Dave, Kunjan R; Defazio, R Anthony; Della Morte, David; Kim, Eun Joo; Perez-Pinzon, Miguel A

    2008-01-01

    Cardiovascular pathologies in the French are not prevalent despite high dietary saturated fat consumption. This is commonly referred to as the "French Paradox" attributing its anti-lipidemic effects to moderate consumption of red wine. Resveratrol, a phytoalexin found in red wine, is currently the focus of intense research both in the cardiovascular system and the brain. Current research suggests resveratrol may enhance prognosis of neurological disorders such as, Parkinson's, Huntington's, Alzheimer's diseases and stroke. The beneficial effects of resveratrol include: antioxidation, free radical scavenger, and modulation of neuronal energy homeostasis and glutamatergic receptors/ion channels. Resveratrol directly increases sirtuin 1 (SIRT1) activity, a NAD(+) (oxidized form of nicotinamide adenine dinucleotide)-dependent histone deacetylase related to increased lifespan in various species similar to calorie restriction. We recently demonstrated that brief resveratrol pretreatment conferred neuroprotection against cerebral ischemia via SIRT1 activation. This neuroprotective effect produced by resveratrol was similar to ischemic preconditioning-induced neuroprotection, which protects against lethal ischemic insults in the brain and other organ systems. Inhibition of SIRT1 abolished ischemic preconditioning-induced neuroprotection in CA1 region of the hippocampus. Since resveratrol and ischemic preconditioning-induced neuroprotection require activation of SIRT1, this common signaling pathway may provide targeted therapeutic treatment modalities as it relates to stroke and other brain pathologies. In this review, we will examine common signaling pathways, cellular targets of resveratrol, and ischemic preconditioning-induced neuroprotection as it relates to the brain. PMID:18537630

  19. Health and Nutrition: Preconditions for Educational Achievement.

    ERIC Educational Resources Information Center

    Negussie, Birgit

    This paper discusses the importance of maternal and infant health for children's educational achievement. Education, health, and nutrition are so closely related that changes in one causes changes in the others. Improvement of maternal and preschooler health and nutrition is a precondition for improved educational achievement. Although parental…

  20. Preconditioning matrices for Chebyshev derivative operators

    NASA Technical Reports Server (NTRS)

    Rothman, Ernest E.

    1986-01-01

    The problem of preconditioning the matrices arising from pseudo-spectral Chebyshev approximations of first order operators is considered in both one and two dimensions. In one dimension a preconditioner represented by a full matrix which leads to preconditioned eigenvalues that are real, positive, and lie between 1 and pi/2, is already available. Since there are cases in which it is not computationally convenient to work with such a preconditioner, a large number of preconditioners were studied which were more sparse (in particular three and four diagonal matrices). The eigenvalues of such preconditioned matrices are compared. The results were applied to the problem of finding the steady state solution to an equation of the type u sub t = u sub x + f, where the Chebyshev collocation is used for the spatial variable and time discretization is performed by the Richardson method. In two dimensions different preconditioners are proposed for the matrix which arises from the pseudo-spectral discretization of the steady state problem. Results are given for the CPU time and the number of iterations using a Richardson iteration method for the unpreconditioned and preconditioned cases.

  1. Revealing Preconditions for Trustful Collaboration in CSCL

    ERIC Educational Resources Information Center

    Gerdes, Anne

    2010-01-01

    This paper analyses preconditions for trust in virtual learning environments. The concept of trust is discussed with reference to cases reporting trust in cyberspace and through a philosophical clarification holding that trust in the form of self-surrender is a common characteristic of all human co-existence. In virtual learning environments,…

  2. 40 CFR 1065.518 - Engine preconditioning.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ..., such as with a diesel engine that relies on urea-based selective catalytic reduction. Note that § 1065... cycle specified in 40 CFR 1039.505(b)(1), the second half of the cycle consists of modes three through... 40 Protection of Environment 33 2014-07-01 2014-07-01 false Engine preconditioning....

  3. A Framework for Batched and GPU-Resident Factorization Algorithms Applied to Block Householder Transformations

    SciTech Connect

    Dong, Tingzing Tim; Tomov, Stanimire Z; Luszczek, Piotr R; Dongarra, Jack J

    2015-01-01

    As modern hardware keeps evolving, an increasingly effective approach to developing energy efficient and high-performance solvers is to design them to work on many small size and independent problems. Many applications already need this functionality, especially for GPUs, which are currently known to be about four to five times more energy efficient than multicore CPUs. We describe the development of one-sided factorizations that work for a set of small dense matrices in parallel, and we illustrate our techniques on the QR factorization based on Householder transformations. We refer to this mode of operation as a batched factorization. Our approach is based on representing the algorithms as a sequence of batched BLAS routines for GPU-only execution. This is in contrast to the hybrid CPU-GPU algorithms that rely heavily on using the multicore CPU for specific parts of the workload. But for a system to benefit fully from the GPU's significantly higher energy efficiency, avoiding the use of the multicore CPU must be a primary design goal, so the system can rely more heavily on the more efficient GPU. Additionally, this will result in the removal of the costly CPU-to-GPU communication. Furthermore, we do not use a single symmetric multiprocessor(on the GPU) to factorize a single problem at a time. We illustrate how our performance analysis, and the use of profiling and tracing tools, guided the development and optimization of our batched factorization to achieve up to a 2-fold speedup and a 3-fold energy efficiency improvement compared to our highly optimized batched CPU implementations based on the MKL library(when using two sockets of Intel Sandy Bridge CPUs). Compared to a batched QR factorization featured in the CUBLAS library for GPUs, we achieved up to 5x speedup on the K40 GPU.

  4. Snow precipitation at four ice core sites in East Antarctica: provenance, seasonality and blocking factors

    NASA Astrophysics Data System (ADS)

    Scarchilli, Claudio; Frezzotti, Massimo; Ruti, Paolo Michele

    2011-11-01

    Snow precipitation is the primary mass input to the Antarctic ice sheet and is one of the most direct climatic indicators, with important implications for paleoclimatic reconstruction from ice cores. Provenance of precipitation and the dynamic conditions that force these precipitation events at four deep ice core sites (Dome C, Law Dome, Talos Dome, and Taylor Dome) in East Antarctica were analysed with air mass back trajectories calculated using the Lagrangian model and the mean composite data for precipitation, geopotential height and wind speed field data from the European Centre for Medium Range Weather Forecast from 1980 to 2001. On an annual basis, back trajectories showed that the Atlantic-Indian and Ross-Pacific Oceans were the main provenances of precipitation in Wilkes Land (80%) and Victoria Land (40%), respectively, whereas the greatest influence of the ice sheet was on the interior near the Vostok site (80%) and in the Southwest Ross Sea (50%), an effect that decreased towards the coast and along the Antarctic slope. Victoria Land received snowfall atypically with respect to other Antarctica areas in terms of pathway (eastern instead of western), seasonality (summer instead of winter) and velocity (old air age). Geopotential height patterns at 500 hPa at low (>10 days) and high (2-6 days) frequencies during snowfall cycles at two core sites showed large positive anomalies at low frequencies developing in the Tasman Sea-Eastern Indian Ocean at higher latitudes (60-70°S) than normal. This could be considered part of an atmospheric blocking event, with transient eddies acting to decelerate westerlies in a split region area and accelerate the flow on the flanks of the low-frequency positive anomalies.

  5. Condition number estimation of preconditioned matrices.

    PubMed

    Kushida, Noriyuki

    2015-01-01

    The present paper introduces a condition number estimation method for preconditioned matrices. The newly developed method provides reasonable results, while the conventional method which is based on the Lanczos connection gives meaningless results. The Lanczos connection based method provides the condition numbers of coefficient matrices of systems of linear equations with information obtained through the preconditioned conjugate gradient method. Estimating the condition number of preconditioned matrices is sometimes important when describing the effectiveness of new preconditionerers or selecting adequate preconditioners. Operating a preconditioner on a coefficient matrix is the simplest method of estimation. However, this is not possible for large-scale computing, especially if computation is performed on distributed memory parallel computers. This is because, the preconditioned matrices become dense, even if the original matrices are sparse. Although the Lanczos connection method can be used to calculate the condition number of preconditioned matrices, it is not considered to be applicable to large-scale problems because of its weakness with respect to numerical errors. Therefore, we have developed a robust and parallelizable method based on Hager's method. The feasibility studies are curried out for the diagonal scaling preconditioner and the SSOR preconditioner with a diagonal matrix, a tri-daigonal matrix and Pei's matrix. As a result, the Lanczos connection method contains around 10% error in the results even with a simple problem. On the other hand, the new method contains negligible errors. In addition, the newly developed method returns reasonable solutions when the Lanczos connection method fails with Pei's matrix, and matrices generated with the finite element method. PMID:25816331

  6. Condition Number Estimation of Preconditioned Matrices

    PubMed Central

    Kushida, Noriyuki

    2015-01-01

    The present paper introduces a condition number estimation method for preconditioned matrices. The newly developed method provides reasonable results, while the conventional method which is based on the Lanczos connection gives meaningless results. The Lanczos connection based method provides the condition numbers of coefficient matrices of systems of linear equations with information obtained through the preconditioned conjugate gradient method. Estimating the condition number of preconditioned matrices is sometimes important when describing the effectiveness of new preconditionerers or selecting adequate preconditioners. Operating a preconditioner on a coefficient matrix is the simplest method of estimation. However, this is not possible for large-scale computing, especially if computation is performed on distributed memory parallel computers. This is because, the preconditioned matrices become dense, even if the original matrices are sparse. Although the Lanczos connection method can be used to calculate the condition number of preconditioned matrices, it is not considered to be applicable to large-scale problems because of its weakness with respect to numerical errors. Therefore, we have developed a robust and parallelizable method based on Hager’s method. The feasibility studies are curried out for the diagonal scaling preconditioner and the SSOR preconditioner with a diagonal matrix, a tri-daigonal matrix and Pei’s matrix. As a result, the Lanczos connection method contains around 10% error in the results even with a simple problem. On the other hand, the new method contains negligible errors. In addition, the newly developed method returns reasonable solutions when the Lanczos connection method fails with Pei’s matrix, and matrices generated with the finite element method. PMID:25816331

  7. Blocking Fibroblast Growth Factor Receptor Signaling Inhibits Tumor Growth, Lymphangiogenesis, and Metastasis

    PubMed Central

    Larrieu-Lahargue, Frédéric; Welm, Alana L.; Bouchecareilh, Marion; Alitalo, Kari; Li, Dean Y.; Bikfalvi, Andreas; Auguste, Patrick

    2012-01-01

    Fibroblast Growth Factor receptor (FGFR) activity plays crucial roles in tumor growth and patient survival. However, FGF (Fibroblast Growth Factor) signaling as a target for cancer therapy has been under-investigated compared to other receptor tyrosine kinases. Here, we studied the effect of FGFR signaling inhibition on tumor growth, metastasis and lymphangiogenesis by expressing a dominant negative FGFR (FGFR-2DN) in an orthotopic mouse mammary 66c14 carcinoma model. We show that FGFR-2DN-expressing 66c14 cells proliferate in vitro slower than controls. 66c14 tumor outgrowth and lung metastatic foci are reduced in mice implanted with FGFR-2DN-expressing cells, which also exhibited better overall survival. We found 66c14 cells in the lumen of tumor lymphatic vessels and in lymph nodes. FGFR-2DN-expressing tumors exhibited a decrease in VEGFR-3 (Vascular Endothelial Growth Factor Receptor-3) or podoplanin-positive lymphatic vessels, an increase in isolated intratumoral lymphatic endothelial cells and a reduction in VEGF-C (Vascular Endothelial Growth Factor-C) mRNA expression. FGFs may act in an autocrine manner as the inhibition of FGFR signaling in tumor cells suppresses VEGF-C expression in a COX-2 (cyclooxygenase-2) or HIF1-α (hypoxia-inducible factor-1 α) independent manner. FGFs may also act in a paracrine manner on tumor lymphatics by inducing expression of pro-lymphangiogenic molecules such as VEGFR-3, integrin α9, prox1 and netrin-1. Finally, in vitro lymphangiogenesis is impeded in the presence of FGFR-2DN 66c14 cells. These data confirm that both FGF and VEGF signaling are necessary for the maintenance of vascular morphogenesis and provide evidence that targeting FGFR signaling may be an interesting approach to inhibit tumor lymphangiogenesis and metastatic spread. PMID:22761819

  8. Dexmedetomidine preconditioning ameliorates kidney ischemia-reperfusion injury

    PubMed Central

    Lempiäinen, Juha; Finckenberg, Piet; Mervaala, Elina E; Storvik, Markus; Kaivola, Juha; Lindstedt, Ken; Levijoki, Jouko; Mervaala, Eero M

    2014-01-01

    Kidney ischemia-reperfusion (I/R) injury is a common cause of acute kidney injury. We tested whether dexmedetomidine (Dex), an alpha2 adrenoceptor (α2-AR) agonist, protects against kidney I/R injury. Sprague–Dawley rats were divided into four groups: (1) Sham-operated group; (2) I/R group (40 min ischemia followed by 24 h reperfusion); (3) I/R group + Dex (1 μg/kg i.v. 60 min before the surgery), (4) I/R group + Dex (10 μg/kg). The effects of Dex postconditiong (Dex 1 or 10 μg/kg i.v. after reperfusion) as well as the effects of peripheral α2-AR agonism with fadolmidine were also examined. Hemodynamic effects were monitored, renal function measured, and acute tubular damage along with monocyte/macrophage infiltration scored. Kidney protein kinase B, toll like receptor 4, light chain 3B, p38 mitogen-activated protein kinase (p38 MAPK), sirtuin 1, adenosine monophosphate kinase (AMPK), and endothelial nitric oxide synthase (eNOS) expressions were measured, and kidney transciptome profiles analyzed. Dex preconditioning, but not postconditioning, attenuated I/R injury-induced renal dysfunction, acute tubular necrosis and inflammatory response. Neither pre- nor postconditioning with fadolmidine protected kidneys. Dex decreased blood pressure more than fadolmidine, ameliorated I/R-induced impairment of autophagy and increased renal p38 and eNOS expressions. Dex downregulated 245 and upregulated 61 genes representing 17 enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, in particular, integrin pathway and CD44. Ingenuity analysis revealed inhibition of Rac and nuclear factor (erythroid-derived 2)-like 2 pathways, whereas aryl hydrocarbon receptor (AHR) pathway was activated. Dex preconditioning ameliorates kidney I/R injury and inflammatory response, at least in part, through p38-CD44-pathway and possibly also through ischemic preconditioning. PMID:25505591

  9. Preconditioning 2D Integer Data for Fast Convex Hull Computations.

    PubMed

    Cadenas, José Oswaldo; Megson, Graham M; Luengo Hendriks, Cris L

    2016-01-01

    In order to accelerate computing the convex hull on a set of n points, a heuristic procedure is often applied to reduce the number of points to a set of s points, s ≤ n, which also contains the same hull. We present an algorithm to precondition 2D data with integer coordinates bounded by a box of size p × q before building a 2D convex hull, with three distinct advantages. First, we prove that under the condition min(p, q) ≤ n the algorithm executes in time within O(n); second, no explicit sorting of data is required; and third, the reduced set of s points forms a simple polygonal chain and thus can be directly pipelined into an O(n) time convex hull algorithm. This paper empirically evaluates and quantifies the speed up gained by preconditioning a set of points by a method based on the proposed algorithm before using common convex hull algorithms to build the final hull. A speedup factor of at least four is consistently found from experiments on various datasets when the condition min(p, q) ≤ n holds; the smaller the ratio min(p, q)/n is in the dataset, the greater the speedup factor achieved. PMID:26938221

  10. Preconditioning 2D Integer Data for Fast Convex Hull Computations

    PubMed Central

    2016-01-01

    In order to accelerate computing the convex hull on a set of n points, a heuristic procedure is often applied to reduce the number of points to a set of s points, s ≤ n, which also contains the same hull. We present an algorithm to precondition 2D data with integer coordinates bounded by a box of size p × q before building a 2D convex hull, with three distinct advantages. First, we prove that under the condition min(p, q) ≤ n the algorithm executes in time within O(n); second, no explicit sorting of data is required; and third, the reduced set of s points forms a simple polygonal chain and thus can be directly pipelined into an O(n) time convex hull algorithm. This paper empirically evaluates and quantifies the speed up gained by preconditioning a set of points by a method based on the proposed algorithm before using common convex hull algorithms to build the final hull. A speedup factor of at least four is consistently found from experiments on various datasets when the condition min(p, q) ≤ n holds; the smaller the ratio min(p, q)/n is in the dataset, the greater the speedup factor achieved. PMID:26938221

  11. Harnessing high density lipoproteins to block transforming growth factor beta and to inhibit the growth of liver tumor metastases.

    PubMed

    Medina-Echeverz, José; Fioravanti, Jessica; Díaz-Valdés, Nancy; Frank, Kathrin; Aranda, Fernando; Gomar, Celia; Ardaiz, Nuria; Dotor, Javier; Umansky, Viktor; Prieto, Jesús; Berraondo, Pedro

    2014-01-01

    Transforming growth factor β (TGF-β) is a powerful promoter of cancer progression and a key target for antitumor therapy. As cancer cells exhibit active cholesterol metabolism, high density lipoproteins (HDLs) appear as an attractive delivery system for anticancer TGFβ-inhibitory molecules. We constructed a plasmid encoding a potent TGF-β-blocking peptide (P144) linked to apolipoprotein A-I (ApoA-I) through a flexible linker (pApoLinkerP144). The ApoLinkerP144 sequence was then incorporated into a hepatotropic adeno-associated vector (AAVApoLinkerP144). The aim was to induce hepatocytes to produce HDLs containing a modified ApoA-I capable of blocking TGF-β. We observed that transduction of the murine liver with pApoLinkerP144 led to the appearance of a fraction of circulating HDL containing the fusion protein. These HDLs were able to attenuate TGF-β signaling in the liver and to enhance IL-12 -mediated IFN-γ production. Treatment of liver metastasis of MC38 colorectal cancer with AAVApoLinkerP144 resulted in a significant reduction of tumor growth and enhanced expression of IFN-γ and GM-CSF in cancerous tissue. ApoLinkerP144 also delayed MC38 liver metastasis in Rag2-/-IL2rγ-/- immunodeficient mice. This effect was associated with downregulation of TGF-β target genes essential for metastatic niche conditioning. Finally, in a subset of ret transgenic mice, a model of aggressive spontaneous metastatic melanoma, AAVApoLinkerP144 delayed tumor growth in association with increased CD8+ T cell numbers in regional lymph nodes. In conclusion, modification of HDLs to transport TGF-β-blocking molecules is a novel and promising approach to inhibit the growth of liver metastases by immunological and non-immunological mechanisms. PMID:24797128

  12. Harnessing High Density Lipoproteins to Block Transforming Growth Factor Beta and to Inhibit the Growth of Liver Tumor Metastases

    PubMed Central

    Medina-Echeverz, José; Fioravanti, Jessica; Díaz-Valdés, Nancy; Frank, Kathrin; Aranda, Fernando; Gomar, Celia; Ardaiz, Nuria; Dotor, Javier; Umansky, Viktor; Prieto, Jesús; Berraondo, Pedro

    2014-01-01

    Transforming growth factor β (TGF-β) is a powerful promoter of cancer progression and a key target for antitumor therapy. As cancer cells exhibit active cholesterol metabolism, high density lipoproteins (HDLs) appear as an attractive delivery system for anticancer TGFβ-inhibitory molecules. We constructed a plasmid encoding a potent TGF-β-blocking peptide (P144) linked to apolipoprotein A-I (ApoA-I) through a flexible linker (pApoLinkerP144). The ApoLinkerP144 sequence was then incorporated into a hepatotropic adeno-associated vector (AAVApoLinkerP144). The aim was to induce hepatocytes to produce HDLs containing a modified ApoA-I capable of blocking TGF-β. We observed that transduction of the murine liver with pApoLinkerP144 led to the appearance of a fraction of circulating HDL containing the fusion protein. These HDLs were able to attenuate TGF-β signaling in the liver and to enhance IL-12 -mediated IFN-γ production. Treatment of liver metastasis of MC38 colorectal cancer with AAVApoLinkerP144 resulted in a significant reduction of tumor growth and enhanced expression of IFN-γ and GM-CSF in cancerous tissue. ApoLinkerP144 also delayed MC38 liver metastasis in Rag2−/−IL2rγ−/− immunodeficient mice. This effect was associated with downregulation of TGF-β target genes essential for metastatic niche conditioning. Finally, in a subset of ret transgenic mice, a model of aggressive spontaneous metastatic melanoma, AAVApoLinkerP144 delayed tumor growth in association with increased CD8+ T cell numbers in regional lymph nodes. In conclusion, modification of HDLs to transport TGF-β-blocking molecules is a novel and promising approach to inhibit the growth of liver metastases by immunological and non-immunological mechanisms. PMID:24797128

  13. Antibodies against amino acids 1-15 of tumor necrosis factor block its binding to cell-surface receptor.

    PubMed Central

    Socher, S H; Riemen, M W; Martinez, D; Friedman, A; Tai, J; Quintero, J C; Garsky, V; Oliff, A

    1987-01-01

    Human tumor necrosis factor (hTNF) mediates a variety of biologic activities, which are dependent on the attachment of hTNF to cell-surface receptors. To identify regions of the hTNF protein involved in binding hTNF to its receptor, we prepared five synthetic peptides [hTNF-(1-15), hTNF-(1-31), hTNF-(65-79), hTNF-(98-111), and hTNF-(124-141)] and two hydroxylamine cleavage fragments [hTNF-(1-39) and hTNF-(40-157)] of hTNF. The hTNF-synthetic peptides and hTNF fragments were tested in hTNF receptor binding assays and in two biologic assays: cytolysis of tumor cells and suppression of lipoprotein lipase in adipocytes. Neither the synthetic peptides nor hTNF fragments were active agonists or antagonists in these assays. The synthetic peptides were also conjugated to thyroglobulin, and peptide-specific antisera were raised. All five peptide-thyroglobulin conjugates induced antibody responses to the immunizing peptide and to hTNF. Each antiserum was tested for antagonist activity in hTNF binding assays. Only antisera raised against hTNF-(1-15) or hTNF-(1-31) and antisera against whole hTNF blocked binding. IgGs purified from these three antisera also block hTNF-induced cytolysis and lipoprotein lipase suppression. We conclude that antibodies that recognize the N-terminus of hTNF block the attachment of hTNF to its cellular receptor and inhibit the biologic effects of hTNF. PMID:2827156

  14. [Positive influence on cardiovascular risk factor by blocking the endocannabinoid system].

    PubMed

    Chatterjee, T; Ritz, A; Ince, H; Nienaber, Ch A; Rehders, T C

    2008-05-28

    Intra-abdominal fat mass, or central adiposity, and cardiovascular risk are strongly correlated. Adipose tissue is an endocrine organ that secretes hormones and cytokines influencing appetite, energy metabolism, and atherosclerosis. Rimonabant is the first selective blocker of the cannabinoid-1 receptor in development for the treatment of obesity, diabetes mellitus typ 2, and cardiometabolic risk factors. This article provides an review of efficacy of rimonabant the first selective blocker of the cannabinoid-1 receptor. PMID:18592956

  15. Identification of flavopiridol analogues that selectively inhibit positive transcription elongation factor (P-TEFb) and block HIV-1 replication.

    PubMed

    Ali, Akbar; Ghosh, Animesh; Nathans, Robin S; Sharova, Natalia; O'Brien, Siobhan; Cao, Hong; Stevenson, Mario; Rana, Tariq M

    2009-08-17

    The positive transcription elongation factor (P-TEFb; CDK9/cyclin T1) regulates RNA polymerase II-dependent transcription of cellular and integrated viral genes. It is an essential cofactor for HIV-1 Tat transactivation, and selective inhibition of P-TEFb blocks HIV-1 replication without affecting cellular transcription; this indicates that P-TEFb could be a potential target for developing anti-HIV-1 therapeutics. Flavopiridol, a small molecule CDK inhibitor, blocks HIV-1 Tat transactivation and viral replication by inhibiting P-TEFb kinase activity, but it is highly cytotoxic. In the search for selective and less cytotoxic P-TEFb inhibitors, we prepared a series of flavopiridol analogues and evaluated their kinase inhibitory activity against P-TEFb and CDK2/cyclin A, and tested their cellular antiviral potency and cytotoxicity. We identified several analogues that selectively inhibit P-TEFb kinase activity in vitro and show antiviral potency comparable to that of flavopiridol, but with significantly reduced cytotoxicity. These compounds are valuable molecular probes for understanding P-TEFb-regulated cellular and HIV-1 gene transcription and provide potential anti-HIV-1 therapeutics. PMID:19603446

  16. A Robust Locally Preconditioned Semi-Coarsening Multigrid Algorithm for the 2-D Navier-Stokes Equations

    NASA Technical Reports Server (NTRS)

    Cain, Michael D.

    1999-01-01

    The goal of this thesis is to develop an efficient and robust locally preconditioned semi-coarsening multigrid algorithm for the two-dimensional Navier-Stokes equations. This thesis examines the performance of the multigrid algorithm with local preconditioning for an upwind-discretization of the Navier-Stokes equations. A block Jacobi iterative scheme is used because of its high frequency error mode damping ability. At low Mach numbers, the performance of a flux preconditioner is investigated. The flux preconditioner utilizes a new limiting technique based on local information that was developed by Siu. Full-coarsening and-semi-coarsening are examined as well as the multigrid V-cycle and full multigrid. The numerical tests were performed on a NACA 0012 airfoil at a range of Mach numbers. The tests show that semi-coarsening with flux preconditioning is the most efficient and robust combination of coarsening strategy, and iterative scheme - especially at low Mach numbers.

  17. Functional Genomic Screen Identifies Klebsiella pneumoniae Factors Implicated in Blocking Nuclear Factor κB (NF-κB) Signaling*

    PubMed Central

    Tomás, Anna; Lery, Leticia; Regueiro, Verónica; Pérez-Gutiérrez, Camino; Martínez, Verónica; Moranta, David; Llobet, Enrique; González-Nicolau, Mar; Insua, Jose L.; Tomas, Juan M.; Sansonetti, Philippe J.; Tournebize, Régis; Bengoechea, José A.

    2015-01-01

    Klebsiella pneumoniae is an etiologic agent of community-acquired and nosocomial pneumonia. It has been shown that K. pneumoniae infections are characterized by reduced early inflammatory response. Recently our group has shown that K. pneumoniae dampens the activation of inflammatory responses by antagonizing the activation of the NF-κB canonical pathway. Our results revealed that K. pneumoniae capsule polysaccharide (CPS) was necessary but not sufficient to attenuate inflammation. To identify additional Klebsiella factors required to dampen inflammation, we standardized and applied a high-throughput gain-of-function screen to examine a Klebsiella transposon mutant library. We identified 114 mutants that triggered the activation of NF-κB. Two gene ontology categories accounted for half of the loci identified in the screening: metabolism and transport genes (32% of the mutants) and envelope-related genes (17%). Characterization of the mutants revealed that the lack of the enterobactin siderophore was linked to a reduced CPS expression, which in turn underlined the NF-κB activation induced by the mutant. The lipopolysaccharide (LPS) O-polysaccharide and the pullulanase (PulA) type 2 secretion system (T2SS) are required for full effectiveness of the immune evasion. Importantly, these factors do not play a redundant role. The fact that LPS O-polysaccharide and T2SS mutant-induced responses were dependent on TLR2-TLR4-MyD88 activation suggested that LPS O-polysaccharide and PulA perturbed Toll-like receptor (TLR)-dependent recognition of K. pneumoniae. Finally, we demonstrate that LPS O-polysaccharide and pulA mutants are attenuated in the pneumonia mouse model. We propose that LPS O-polysaccharide and PulA T2SS could be new targets for the design of new antimicrobials. Increasing TLR-governed defense responses might provide also selective alternatives for the management of K. pneumoniae pneumonia. PMID:25971969

  18. Functional Genomic Screen Identifies Klebsiella pneumoniae Factors Implicated in Blocking Nuclear Factor κB (NF-κB) Signaling.

    PubMed

    Tomás, Anna; Lery, Leticia; Regueiro, Verónica; Pérez-Gutiérrez, Camino; Martínez, Verónica; Moranta, David; Llobet, Enrique; González-Nicolau, Mar; Insua, Jose L; Tomas, Juan M; Sansonetti, Philippe J; Tournebize, Régis; Bengoechea, José A

    2015-07-01

    Klebsiella pneumoniae is an etiologic agent of community-acquired and nosocomial pneumonia. It has been shown that K. pneumoniae infections are characterized by reduced early inflammatory response. Recently our group has shown that K. pneumoniae dampens the activation of inflammatory responses by antagonizing the activation of the NF-κB canonical pathway. Our results revealed that K. pneumoniae capsule polysaccharide (CPS) was necessary but not sufficient to attenuate inflammation. To identify additional Klebsiella factors required to dampen inflammation, we standardized and applied a high-throughput gain-of-function screen to examine a Klebsiella transposon mutant library. We identified 114 mutants that triggered the activation of NF-κB. Two gene ontology categories accounted for half of the loci identified in the screening: metabolism and transport genes (32% of the mutants) and envelope-related genes (17%). Characterization of the mutants revealed that the lack of the enterobactin siderophore was linked to a reduced CPS expression, which in turn underlined the NF-κB activation induced by the mutant. The lipopolysaccharide (LPS) O-polysaccharide and the pullulanase (PulA) type 2 secretion system (T2SS) are required for full effectiveness of the immune evasion. Importantly, these factors do not play a redundant role. The fact that LPS O-polysaccharide and T2SS mutant-induced responses were dependent on TLR2-TLR4-MyD88 activation suggested that LPS O-polysaccharide and PulA perturbed Toll-like receptor (TLR)-dependent recognition of K. pneumoniae. Finally, we demonstrate that LPS O-polysaccharide and pulA mutants are attenuated in the pneumonia mouse model. We propose that LPS O-polysaccharide and PulA T2SS could be new targets for the design of new antimicrobials. Increasing TLR-governed defense responses might provide also selective alternatives for the management of K. pneumoniae pneumonia. PMID:25971969

  19. Corticotropin-releasing factor antagonist blocks microwave-induced decreases in high-affinity choline uptake in the rat brain

    SciTech Connect

    Lai, H.; Carino, M.A.; Horita, A.; Guy, A.W. )

    1990-10-01

    Acute (45-min) irradiation with pulsed low-level microwaves (2450-MHz, 2 microseconds pulses at 500 pps, average power density of 1 mW/cm2, whole-body average specific absorption rate of 0.6 W/kg) decreased sodium-dependent high-affinity choline uptake (HACU) activity in the frontal cortex and hippocampus of the rat. These effects were blocked by pretreating the animals before exposure with intracerebroventricular injection of the specific corticotropin-releasing factor (CRF) receptor antagonist, alpha-helical-CRF9-41 (25 micrograms). Similar injection of the antagonist had no significant effect on HACU in the brain of the sham-exposed rats. These data suggest that low-level microwave irradiation activates CRF in the brain, which in turn causes the changes in central HACU.

  20. Solving block linear systems with low-rank off-diagonal blocks is easily parallelizable

    SciTech Connect

    Menkov, V.

    1996-12-31

    An easily and efficiently parallelizable direct method is given for solving a block linear system Bx = y, where B = D + Q is the sum of a non-singular block diagonal matrix D and a matrix Q with low-rank blocks. This implicitly defines a new preconditioning method with an operation count close to the cost of calculating a matrix-vector product Qw for some w, plus at most twice the cost of calculating Qw for some w. When implemented on a parallel machine the processor utilization can be as good as that of those operations. Order estimates are given for the general case, and an implementation is compared to block SSOR preconditioning.

  1. Heart Block

    MedlinePlus

    ... Block Explore Heart Block What Is... Electrical System & EKG Results Types Causes Who Is at Risk Signs & ... heart block. Doctors use a test called an EKG (electrocardiogram) to help diagnose heart block. This test ...

  2. Cardioprotection Acquired Through Exercise: The Role of Ischemic Preconditioning

    PubMed Central

    Marongiu, Elisabetta; Crisafulli, Antonio

    2014-01-01

    A great bulk of evidence supports the concept that regular exercise training can reduce the incidence of coronary events and increase survival chances after myocardial infarction. These exercise-induced beneficial effects on the myocardium are reached by means of the reduction of several risk factors relating to cardiovascular disease, such as high cholesterol, hypertension, obesity etc. Furthermore, it has been demonstrated that exercise can reproduce the “ischemic preconditioning” (IP), which refers to the capacity of short periods of ischemia to render the myocardium more resistant to subsequent ischemic insult and to limit infarct size during prolonged ischemia. However, IP is a complex phenomenon which, along with infarct size reduction, can also provide protection against arrhythmia and myocardial stunning due to ischemia-reperfusion. Several clues demonstrate that preconditioning may be directly induced by exercise, thus inducing a protective phenotype at the heart level without the necessity of causing ischemia. Exercise appears to act as a physiological stress that induces beneficial myocardial adaptive responses at cellular level. The purpose of the present paper is to review the latest data on the role played by exercise in triggering myocardial preconditioning. PMID:24720421

  3. Development of an epidermal growth factor derivative with EGFR blocking activity.

    PubMed

    Panosa, Clara; Tebar, Francesc; Ferrer-Batallé, Montserrat; Fonge, Humphrey; Seno, Masaharu; Reilly, Raymond M; Massaguer, Anna; De Llorens, Rafael

    2013-01-01

    The members of the epidermal growth factor (EGF)/ErbB family are prime targets for cancer therapy. However, the therapeutic efficiency of the existing anti-ErbB agents is limited. Thus, identifying new molecules that inactivate the ErbB receptors through novel strategies is an important goal on cancer research. In this study we have developed a shorter form of human EGF (EGFt) with a truncated C-terminal as a novel EGFR inhibitor. EGFt was designed based on the superimposition of the three-dimensional structures of EGF and the Potato Carboxypeptidase Inhibitor (PCI), an EGFR blocker previously described by our group. The peptide was produced in E. coli with a high yield of the correctly folded peptide. EGFt showed specificity and high affinity for EGFR but induced poor EGFR homodimerization and phosphorylation. Interestingly, EGFt promoted EGFR internalization and translocation to the cell nucleus although it did not stimulate the cell growth. In addition, EGFt competed with EGFR native ligands, inhibiting the proliferation of cancer cells. These data indicate that EGFt may be a potential EGFR blocker for cancer therapy. In addition, the lack of EGFR-mediated growth-stimulatory activity makes EGFt an excellent delivery agent to target toxins to tumours over-expressing EGFR. PMID:23935985

  4. Small Molecule Inhibitors Targeting Tec Kinase Block Unconventional Secretion of Fibroblast Growth Factor 2.

    PubMed

    La Venuta, Giuseppe; Wegehingel, Sabine; Sehr, Peter; Müller, Hans-Michael; Dimou, Eleni; Steringer, Julia P; Grotwinkel, Mareike; Hentze, Nikolai; Mayer, Matthias P; Will, David W; Uhrig, Ulrike; Lewis, Joe D; Nickel, Walter

    2016-08-19

    Fibroblast growth factor 2 (FGF2) is a potent mitogen promoting both tumor cell survival and tumor-induced angiogenesis. It is secreted by an unconventional secretory mechanism that is based upon direct translocation across the plasma membrane. Key steps of this process are (i) phosphoinositide-dependent membrane recruitment, (ii) FGF2 oligomerization and membrane pore formation, and (iii) extracellular trapping mediated by membrane-proximal heparan sulfate proteoglycans. Efficient secretion of FGF2 is supported by Tec kinase that stimulates membrane pore formation based upon tyrosine phosphorylation of FGF2. Here, we report the biochemical characterization of the direct interaction between FGF2 and Tec kinase as well as the identification of small molecules that inhibit (i) the interaction of FGF2 with Tec, (ii) tyrosine phosphorylation of FGF2 mediated by Tec in vitro and in a cellular context, and (iii) unconventional secretion of FGF2 from cells. We further demonstrate the specificity of these inhibitors for FGF2 because tyrosine phosphorylation of a different substrate of Tec is unaffected in their presence. Building on previous evidence using RNA interference, the identified compounds corroborate the role of Tec kinase in unconventional secretion of FGF2. In addition, they are valuable lead compounds with great potential for drug development aiming at the inhibition of FGF2-dependent tumor growth and metastasis. PMID:27382052

  5. A Note on Substructuring Preconditioning for Nonconforming Finite Element Approximations of Second Order Elliptic Problems

    NASA Technical Reports Server (NTRS)

    Maliassov, Serguei

    1996-01-01

    In this paper an algebraic substructuring preconditioner is considered for nonconforming finite element approximations of second order elliptic problems in 3D domains with a piecewise constant diffusion coefficient. Using a substructuring idea and a block Gauss elimination, part of the unknowns is eliminated and the Schur complement obtained is preconditioned by a spectrally equivalent very sparse matrix. In the case of quasiuniform tetrahedral mesh an appropriate algebraic multigrid solver can be used to solve the problem with this matrix. Explicit estimates of condition numbers and implementation algorithms are established for the constructed preconditioner. It is shown that the condition number of the preconditioned matrix does not depend on either the mesh step size or the jump of the coefficient. Finally, numerical experiments are presented to illustrate the theory being developed.

  6. Isoflurane Preconditioning Confers Cardioprotection by Activation of ALDH2

    PubMed Central

    Lang, Xiao-E; Wang, Xiong; Zhang, Ke-Rang; Lv, Ji-Yuan; Jin, Jian-Hua; Li, Qing-Shan

    2013-01-01

    The volatile anesthetic, isoflurane, protects the heart from ischemia/reperfusion (I/R) injury. Aldehyde dehydrogenase 2 (ALDH2) is thought to be an endogenous mechanism against ischemia-reperfusion injury possibly through detoxification of toxic aldehydes. We investigated whether cardioprotection by isoflurane depends on activation of ALDH2.Anesthetized rats underwent 40 min of coronary artery occlusion followed by 120 min of reperfusion and were randomly assigned to the following groups: untreated controls, isoflurane preconditioning with and without an ALDH2 inhibitor, the direct activator of ALDH2 or a protein kinase C (PKCε) inhibitor. Pretreatment with isoflurane prior to ischemia reduced LDH and CK-MB levels and infarct size, while it increased phosphorylation of ALDH2, which could be blocked by the ALDH2 inhibitor, cyanamide. Isolated neonatal cardiomyocytes were treated with hypoxia followed by reoxygenation. Hypoxia/reoxygenation (H/R) increased cardiomyocyte apoptosis and injury which were attenuated by isoflurane and forced the activation of ALDH2. In contrast, the effect of isoflurane-induced protection was almost abolished by knockdown of ALDH2. Activation of ALDH2 and cardioprotection by isoflurane were substantially blocked by the PKCε inhibitor. Activation of ALDH2 by mitochondrial PKCε plays an important role in the cardioprotection of isoflurane in myocardium I/R injury. PMID:23468836

  7. Preconditioning Stem Cells for In Vivo Delivery

    PubMed Central

    Sart, Sébastien; Ma, Teng

    2014-01-01

    Abstract Stem cells have emerged as promising tools for the treatment of incurable neural and heart diseases and tissue damage. However, the survival of transplanted stem cells is reported to be low, reducing their therapeutic effects. The major causes of poor survival of stem cells in vivo are linked to anoikis, potential immune rejection, and oxidative damage mediating apoptosis. This review investigates novel methods and potential molecular mechanisms for stem cell preconditioning in vitro to increase their retention after transplantation in damaged tissues. Microenvironmental preconditioning (e.g., hypoxia, heat shock, and exposure to oxidative stress), aggregate formation, and hydrogel encapsulation have been revealed as promising strategies to reduce cell apoptosis in vivo while maintaining biological functions of the cells. Moreover, this review seeks to identify methods of optimizing cell dose preparation to enhance stem cell survival and therapeutic function after transplantation. PMID:25126478

  8. Hypoxic preconditioning increases the protective effect of bone marrow mesenchymal stem cells on spinal cord ischemia/reperfusion injury.

    PubMed

    Wang, Zhilin; Fang, Bo; Tan, Zhibin; Zhang, Dong; Ma, Hong

    2016-03-01

    Transplantation of bone marrow mesenchymal stem cells (BMSCs) protect against spinal cord ischemia/reperfusion injury (SCIRI). However, a large number of transplanted BMSCs often undergo apoptosis, which severely affects the treatment outcome. Previous studies have demonstrated that hypoxic preconditioning effectively increases the survival rate of BMSCs following transplantation, and increases their protective effect on injured tissues. However, there have been few reports regarding roles of hypoxic preconditioning in SCIRI. The present study isolated rat BMSCs and separately transplanted hypoxia‑ and non‑hypoxia‑preconditioned BMSCs into the spinal cord tissues of rats with SCIRI. The role of hypoxic preconditioning in the promotion of the protective effect of BMSCs on SCIRI was investigated using neurological function scores, Evans blue staining, hematoxylin and eosin staining and terminal deoxynucleotidyl transferase dUTP nick end labeling. In addition, reverse transcription‑quantitative polymerase chain reaction and western blotting were used to detect the expression levels of hypoxia‑inducible factor 1α (HIF‑1α), and to investigate its possible underlying mechanism of action. The results indicated that hypoxic preconditioning effectively increased the protective effects of BMSCs on neurological function, blood spinal cord barrier and tissue damage following SCIRI, and inhibited apoptosis. Furthermore, hypoxic preconditioned BMSCs upregulated the expression of HIF‑1α in spinal cord tissues. Therefore, hypoxic preconditioning effectively increased the protective effect of BMSCs on SCIRI and may be associated with upregulation of the expression of HIF‑1α. Hypoxic preconditioning may serve as an effective means of increasing the protective effect of BMSCs on SCIRI. PMID:26783161

  9. M-step preconditioned conjugate gradient methods

    NASA Technical Reports Server (NTRS)

    Adams, L.

    1983-01-01

    Preconditioned conjugate gradient methods for solving sparse symmetric and positive finite systems of linear equations are described. Necessary and sufficient conditions are given for when these preconditioners can be used and an analysis of their effectiveness is given. Efficient computer implementations of these methods are discussed and results on the CYBER 203 and the Finite Element Machine under construction at NASA Langley Research Center are included.

  10. Institutionalized ignorance as a precondition for rational risk expertise.

    PubMed

    Merkelsen, Henrik

    2011-07-01

    The present case study seeks to explain the conditions for experts' rational risk perception by analyzing the institutional contexts that constitute a field of food safety expertise in Denmark. The study highlights the role of risk reporting and how contextual factors affect risk reporting from the lowest organizational level, where concrete risks occur, to the highest organizational level, where the body of professional risk expertise is situated. The article emphasizes the role of knowledge, responsibility, loyalty, and trust as risk-attenuation factors and concludes by suggesting that the preconditions for the expert's rationality may rather be a lack of risk-specific knowledge due to poor risk reporting than a superior level of risk knowledge. PMID:21284683

  11. The antiabortive effect of progesterone-induced blocking factor in mice is manifested by modulating NK activity.

    PubMed

    Szekeres-Bartho, J; Par, G; Dombay, G y; Smart, Y C; Volgyi, Z

    1997-05-01

    Immunologic effects of progesterone are mediated by a protein named the progesterone-induced blocking factor (PIBF), which inhibits NK activity and displays an antiabortive effect in mice. Our previous data provide indirect evidence for the importance of PIBF in the maintenance of normal gestation. This study was aimed at investigating whether neutralization of endogenous PIBF production influences pregnancy outcome and if so, what are the mechanisms that participate in this process. Syngeneically pregnant Balb/c mice on Day 8.5 of pregnancy were injected ip with 0.3 mg/kg of RU 486 or with 0.5 mg of rabbit anti-PIBF IgG alone, or together with anti-NK monoclonal antibodies. Mice treated with the same amount of normal rabbit serum or untreated mice of similar gestational age were used as controls. On Day 10.5 the ratio of living and resorbed embryos and NK activity of the spleen cells were determined. In mice treated with anti-PIBF the ratio of resorbed fetuses was significantly higher than that in untreated controls. In RU 486-treated mice we also observed significantly increased resorption rate, which was associated with the inability of spleen cells to produce PIBF. Both anti-PIBF treatment and that with progesterone receptor blocker resulted in increased splenic NK activity. There was a positive relationship between NK activity and the rate of resorptions. All the above effects were corrected by simultaneous treatment with anti-NK or anti-NC (natural cytotoxic) antibodies. These data allow the conclusion that PIBF contributes to normal gestation in mice and that the effect of PIBF is manifested via blocking NK and/or NC activity. PMID:9178647

  12. Seismic responses and controlling factors of Miocene deepwater gravity-flow deposits in Block A, Lower Congo Basin

    NASA Astrophysics Data System (ADS)

    Wang, Linlin; Wang, Zhenqi; Yu, Shui; Ngia, Ngong Roger

    2016-08-01

    The Miocene deepwater gravity-flow sedimentary system in Block A of the southwestern part of the Lower Congo Basin was identified and interpreted using high-resolution 3-D seismic, drilling and logging data to reveal development characteristics and main controlling factors. Five types of deepwater gravity-flow sedimentary units have been identified in the Miocene section of Block A, including mass transport, deepwater channel, levee, abandoned channel and sedimentary lobe deposits. Each type of sedimentary unit has distinct external features, internal structures and lateral characteristics in seismic profiles. Mass transport deposits (MTDs) in particular correspond to chaotic low-amplitude reflections in contact with mutants on both sides. The cross section of deepwater channel deposits in the seismic profile is in U- or V-shape. The channel deposits change in ascending order from low-amplitude, poor-continuity, chaotic filling reflections at the bottom, to high-amplitude, moderate to poor continuity, chaotic or sub-parallel reflections in the middle section and to moderate-weak amplitude, good continuity, parallel or sub-parallel reflections in the upper section. The sedimentary lobes are laterally lobate, which corresponds to high-amplitude, good-continuity, moundy reflection signatures in the seismic profile. Due to sediment flux, faults, and inherited terrain, few mass transport deposits occur in the northeastern part of the study area. The front of MTDs is mainly composed of channel-levee complex deposits, while abandoned-channel and lobe-deposits are usually developed in high-curvature channel sections and the channel terminals, respectively. The distribution of deepwater channel, levee, abandoned channel and sedimentary lobe deposits is predominantly controlled by relative sea level fluctuations and to a lesser extent by tectonism and inherited terrain.

  13. Brimonidine Blocks Glutamate Excitotoxicity-Induced Oxidative Stress and Preserves Mitochondrial Transcription Factor A in Ischemic Retinal Injury

    PubMed Central

    Lee, Dongwook; Kim, Keun-Young; Noh, You Hyun; Chai, Stephen; Lindsey, James D.; Ellisman, Mark H.; Weinreb, Robert N.; Ju, Won-Kyu

    2012-01-01

    Glutamate excitotoxicity-induced oxidative stress have been linked to mitochondrial dysfunction in retinal ischemia and optic neuropathies including glaucoma. Brimonindine (BMD), an alpha 2-adrenergic receptor agonist, contributes to the neuroprotection of retinal ganglion cells (RGCs) against glutamate excitotoxicity or oxidative stress. However, the molecular mechanisms of BMD-associated mitochondrial preservation in RGC protection against glutamate excitotoxicity-induced oxidative stress following retinal ischemic injury remain largely unknown. Here, we tested whether activation of alpha 2 adrenergic receptor by systemic BMD treatment blocks glutamate excitotoxicity-induced oxidative stress, and preserves the expression of mitochondrial transcription factor A (Tfam) and oxidative phosphorylation (OXPHOS) complex in ischemic retina. Sprague-Dawley rats received BMD (1 mg/kg/day) or vehicle (0.9% saline) systemically and then transient ischemia was induced by acute intraocular pressure elevation. Systemic BMD treatment significantly increased RGC survival at 4 weeks after ischemia. At 24 hours, BMD significantly decreased Bax expression but increased Bcl-xL and phosphorylated Bad protein expression in ischemic retina. Importantly. BMD significantly blocked the upregulations of N-methyl-D-aspartate receptors 1 and 2A protein expression, as well as of SOD2 protein expression in ischemic retina at 24 hours. During the early neurodegeneration following ischemic injury (12–72 hours), Tfam and OXPHOS complex protein expression were significantly increased in vehicle-treated retina. At 24 hours after ischemia, Tfam immunoreactivity was increased in the outer plexiform layer, inner nuclear layer, inner plexiform layer and ganglion cell layer. Further, Tfam protein was expressed predominantly in RGCs. Finally, BMD preserved Tfam immunoreactivity in RGCs as well as Tfam/OXPHOS complex protein expression in the retinal extracts against ischemic injury. Our findings suggest

  14. Is longer sevoflurane preconditioning neuroprotective in permanent focal cerebral ischemia?

    PubMed

    Qiu, Caiwei; Sheng, Bo; Wang, Shurong; Liu, Jin

    2013-08-15

    Sevoflurane preconditioning has neuroprotective effects in the cerebral ischemia/reperfusion model. However, its influence on permanent cerebral ischemia remains unclear. In the present study, the rats were exposed to sevoflurane for 15, 30, 60, and 120 minutes, followed by induction of permanent cerebral ischemia. Results demonstrated that 30- and 60-minute sevoflurane preconditioning significantly reduced the infarct volume at 24 hours after cerebral ischemia, and 60-minute lurane preconditioning additionally reduced the number of TUNEL- and caspase-3-positive cells in the ischemic penumbra. However, 120-minute sevoflurane preconditioning did not show evident neuroprotective effects. Moreover, 60-minute sevoflurane preconditioning significantly attenuated neurological deficits and infarct volume in rats at 4 days after cerebral ischemia. These findings indicated that 60-minute sevoflurane preconditioning can induce the best neuroprotective effects in rats with permanent cerebral ischemia through the inhibition of apoptosis. PMID:25206521

  15. Remote Ischemic Preconditioning Reduces Cerebral Oxidative Stress Following Hypothermic Circulatory Arrest in a Porcine Model.

    PubMed

    Arvola, Oiva; Haapanen, Henri; Herajärvi, Johanna; Anttila, Tuomas; Puistola, Ulla; Karihtala, Peeter; Tuominen, Hannu; Anttila, Vesa; Juvonen, Tatu

    2016-01-01

    Remote ischemic precondition has become prominent as one of the most promising methods to mitigate neurological damage following ischemic insult. The purpose of this study was to investigate whether the effects of remote ischemic preconditioning can be seen in the markers of oxidative stress or in redox-regulating enzymes in a porcine model. A total of 12 female piglets were randomly assigned to 2 groups. The study group underwent an intervention of 4 cycles of 5-minute ischemic preconditioning on the right hind leg. All piglets underwent 60-minute hypothermic circulatory arrest. Oxidative stress marker 8-hydroxydeoxyguanosine (8-OHdG) was measured from blood samples with enzyme-linked immunosorbent assay. After 7 days of follow-up, samples from the brain, heart, kidney, and ovary were harvested for histopathologic examination. The immunohistochemical stainings of hypoxia marker hypoxia-inducible factor-1-α, oxidative stress marker 8-OHdG, DNA repair enzyme 8-oxoguanine glycosylase, and antioxidant response regulators nuclear factor erythroid 2-related factor 2 and protein deglycase were analyzed. The level of 8-OHdG referred to baseline was decreased in the sagittal sinus׳ blood samples in the study group after a prolonged deep hypothermic circulatory arrest at 360 minutes after reperfusion. Total histopathologic score was 3.8 (1.8-6.0) in the study group and was 4.4 (2.5-6.5) in the control group (P = 0.72), demonstrating no statistically significant difference in cerebral injury. Our findings demonstrate that the positive effects of remote ischemic preconditioning can be seen in cellular oxidative balance regulators in an animal model after 7 days of preconditioned ischemic insult. PMID:27568144

  16. Transforming Growth Factor-β1 Induced Epithelial Mesenchymal Transition is blocked by a chemical antagonist of translation factor eIF4E

    PubMed Central

    Smith, K. A.; Zhou, B.; Avdulov, S.; Benyumov, A.; Peterson, M.; Liu, Y.; Okon, A.; Hergert, P.; Braziunas, J.; Wagner, C. R.; Borok, Z.; Bitterman, P. B.

    2015-01-01

    The epithelial to mesenchymal transition (EMT) imparts disease-defining properties to epithelial cells in cancer and organ fibrosis. Prior studies identify EMT control points at the level of transcription and translation, and indicate that activation of translation initiation factor 4E (eIF4E) is involved in the mechanisms coordinating these two levels of control. Here we show that 4Ei-1, a specific chemical antagonist of the eIF4E-mRNA cap interaction, potently inhibits transforming growth factor beta 1 (TGF-β1) mediated EMT in lung epithelial cells. Upon treatment with TGF-β1, we observed a rapid recruitment of Snail1 mRNA into the actively translated polysome pool accompanied by accumulation of the EMT transcription factor Snail1 in the nucleus. 4Ei-1 blocks ribosome recruitment to the Snail1 transcript thereby preventing accumulation of the Snail1 protein in the nucleus. Our findings establish an obligatory role for upstream translational control of downstream Snail1-mediated transcriptional events in TGF-β1 induced EMT, and provide proof of concept for efforts to pharmacologically modulate the eIF4E-cap interaction as a means to inhibit pathological EMT in the setting of cancer and organ fibrosis. PMID:26678431

  17. Implicit preconditioned WENO scheme for steady viscous flow computation

    NASA Astrophysics Data System (ADS)

    Huang, Juan-Chen; Lin, Herng; Yang, Jaw-Yen

    2009-02-01

    A class of lower-upper symmetric Gauss-Seidel implicit weighted essentially nonoscillatory (WENO) schemes is developed for solving the preconditioned Navier-Stokes equations of primitive variables with Spalart-Allmaras one-equation turbulence model. The numerical flux of the present preconditioned WENO schemes consists of a first-order part and high-order part. For first-order part, we adopt the preconditioned Roe scheme and for the high-order part, we employ preconditioned WENO methods. For comparison purpose, a preconditioned TVD scheme is also given and tested. A time-derivative preconditioning algorithm is devised and a discriminant is devised for adjusting the preconditioning parameters at low Mach numbers and turning off the preconditioning at intermediate or high Mach numbers. The computations are performed for the two-dimensional lid driven cavity flow, low subsonic viscous flow over S809 airfoil, three-dimensional low speed viscous flow over 6:1 prolate spheroid, transonic flow over ONERA-M6 wing and hypersonic flow over HB-2 model. The solutions of the present algorithms are in good agreement with the experimental data. The application of the preconditioned WENO schemes to viscous flows at all speeds not only enhances the accuracy and robustness of resolving shock and discontinuities for supersonic flows, but also improves the accuracy of low Mach number flow with complicated smooth solution structures.

  18. Ischemic preconditioning protects against gap junctional uncoupling in cardiac myofibroblasts.

    PubMed

    Sundset, Rune; Cooper, Marie; Mikalsen, Svein-Ole; Ytrehus, Kirsti

    2004-01-01

    Ischemic preconditioning increases the heart's tolerance to a subsequent longer ischemic period. The purpose of this study was to investigate the role of gap junction communication in simulated preconditioning in cultured neonatal rat cardiac myofibroblasts. Gap junctional intercellular communication was assessed by Lucifer yellow dye transfer. Preconditioning preserved intercellular coupling after prolonged ischemia. An initial reduction in coupling in response to the preconditioning stimulus was also observed. This may protect neighboring cells from damaging substances produced during subsequent regional ischemia in vivo, and may preserve gap junctional communication required for enhanced functional recovery during subsequent reperfusion. PMID:16247851

  19. Preconditioning and the limit to the incompressible flow equations

    NASA Technical Reports Server (NTRS)

    Turkel, E.; Fiterman, A.; Vanleer, B.

    1993-01-01

    The use of preconditioning methods to accelerate the convergence to a steady state for both the incompressible and compressible fluid dynamic equations are considered. The relation between them for both the continuous problem and the finite difference approximation is also considered. The analysis relies on the inviscid equations. The preconditioning consists of a matrix multiplying the time derivatives. Hence, the steady state of the preconditioned system is the same as the steady state of the original system. For finite difference methods the preconditioning can change and improve the steady state solutions. An application to flow around an airfoil is presented.

  20. Vertical ridge augmentation using an equine block infused with recombinant human platelet-derived growth factor-BB: a histologic study in a canine model.

    PubMed

    Simion, Massimo; Nevins, Myron; Rocchietta, Isabella; Fontana, Filippo; Maschera, Emilio; Schupbach, Peter; Kim, David M

    2009-06-01

    This preclinical study evaluated the efficacy of purified recombinant human platelet-derived growth factor (rhPDGF-BB), combined with a novel equine hydroxyapatite and collagen (eHAC) bone block, in providing vertical bone regeneration in critical-size defects simulating localized mandibular alveolar bone atrophy. In addition, the impact of barrier membrane placement in growth factor-mediated bone regeneration was also studied. Bilateral posterior mandibular defects simulating severe localized bony atrophy were created in 12 adult foxhounds following removal of all four mandibular premolars. Three months later, the defects were grafted as follows: group A: eHAC block alone; group B: eHAC block + collagen membrane; group C: eHAC block + rhPDGF-BB; group D: eHAC block + rhPDGF-BB + membrane. The animals were sacrificed after 5 months and the grafted areas were examined histologically, radiographically, and clinically. Groups A and B (controls) exhibited little to no vertical bone regeneration. Group C demonstrated significant vertical bone regeneration, with dense, well-vascularized bone, high bone-to-implant contact, and accelerated replacement of graft particles with newly formed bone. In group D, with the imposition of a barrier membrane, robust bone regeneration was less evident when compared to group C. As in the first study in this series, the importance of the periosteum as a source of osteoprogenitor cells in growth factor-mediated regenerative procedures is examined. PMID:19537464

  1. Amlexanox Blocks the Interaction between S100A4 and Epidermal Growth Factor and Inhibits Cell Proliferation.

    PubMed

    Cho, Ching Chang; Chou, Ruey-Hwang; Yu, Chin

    2016-01-01

    The human S100A4 protein binds calcium, resulting in a change in its conformation to promote the interaction with its target protein. Human epidermal growth factor (EGF) is the target protein of S100A4 and a critical ligand of the receptor EGFR. The EGF/EGFR system promotes cell survival, differentiation, and growth by activating several signaling pathways. Amlexanox is an anti-inflammatory and anti-allergic drug that is used to treat recurrent aphthous ulcers. In the present study, we determined that amlexanox interacts with S100A4 using heteronuclear single quantum correlation titration. We elucidated the interactions of S100A4 with EGF and amlexanox using fluorescence and nuclear magnetic resonance spectroscopy. We generated two binary models (for the S100A4-EGF and S100A4-amlexanox complexes) and observed that amlexanox and EGF share a similar binding region in mS100A4. We also used a WST-1 assay to investigate the bioactivity of S100A4, EGF, and amlexanox, and found that amlexanox blocks the binding between S100A4 and EGF, and is therefore useful for the development of new anti-proliferation drugs. PMID:27559743

  2. Amlexanox Blocks the Interaction between S100A4 and Epidermal Growth Factor and Inhibits Cell Proliferation

    PubMed Central

    Cho, Ching Chang; Chou, Ruey-Hwang; Yu, Chin

    2016-01-01

    The human S100A4 protein binds calcium, resulting in a change in its conformation to promote the interaction with its target protein. Human epidermal growth factor (EGF) is the target protein of S100A4 and a critical ligand of the receptor EGFR. The EGF/EGFR system promotes cell survival, differentiation, and growth by activating several signaling pathways. Amlexanox is an anti-inflammatory and anti-allergic drug that is used to treat recurrent aphthous ulcers. In the present study, we determined that amlexanox interacts with S100A4 using heteronuclear single quantum correlation titration. We elucidated the interactions of S100A4 with EGF and amlexanox using fluorescence and nuclear magnetic resonance spectroscopy. We generated two binary models (for the S100A4-EGF and S100A4-amlexanox complexes) and observed that amlexanox and EGF share a similar binding region in mS100A4. We also used a WST-1 assay to investigate the bioactivity of S100A4, EGF, and amlexanox, and found that amlexanox blocks the binding between S100A4 and EGF, and is therefore useful for the development of new anti-proliferation drugs. PMID:27559743

  3. Creating functional sophistication from simple protein building blocks, exemplified by factor H and the regulators of complement activation.

    PubMed

    Makou, Elisavet; Herbert, Andrew P; Barlow, Paul N

    2015-10-01

    Complement control protein modules (CCPs) occur in numerous functionally diverse extracellular proteins. Also known as short consensus repeats (SCRs) or sushi domains each CCP contains approximately 60 amino acid residues, including four consensus cysteines participating in two disulfide bonds. Varying in length and sequence, CCPs adopt a β-sandwich type fold and have an overall prolate spheroidal shape with N- and C-termini lying close to opposite poles of the long axis. CCP-containing proteins are important as cytokine receptors and in neurotransmission, cell adhesion, blood clotting, extracellular matrix formation, haemoglobin metabolism and development, but CCPs are particularly well represented in the vertebrate complement system. For example, factor H (FH), a key soluble regulator of the alternative pathway of complement activation, is made up entirely from a chain of 20 CCPs joined by short linkers. Collectively, therefore, the 20 CCPs of FH must mediate all its functional capabilities. This is achieved via collaboration and division of labour among these modules. Structural studies have illuminated the dynamic architectures that allow FH and other CCP-rich proteins to perform their biological functions. These are largely the products of a highly varied set of intramolecular interactions between CCPs. The CCP can act as building block, spacer, highly versatile recognition site or dimerization mediator. Tandem CCPs may form composite binding sites or contribute to flexible, rigid or conformationally 'switchable' segments of the parent proteins. PMID:26517887

  4. Blocking Endogenous Leukemia Inhibitory Factor During Placental Development in Mice Leads to Abnormal Placentation and Pregnancy Loss

    PubMed Central

    Winship, Amy; Correia, Jeanne; Krishnan, Tara; Menkhorst, Ellen; Cuman, Carly; Zhang, Jian-Guo; Nicola, Nicos A.; Dimitriadis, Evdokia

    2015-01-01

    The placenta forms the interface between the maternal and fetal circulation and is critical for the establishment of a healthy pregnancy. Specialized trophoblast cells derived from the embryonic trophectoderm play a pivotal role in the establishment of the placenta. Leukemia inhibitory factor (LIF) is one of the predominant cytokines present in the placenta during early pregnancy. LIF has been shown to regulate trophoblast adhesion and invasion in vitro, however its precise role in vivo is unknown. We hypothesized that LIF would be required for normal placental development in mice. LIF and LIFRα were immunolocalized to placental trophoblasts and fetal vessels in mouse implantation sites during mid-gestation. Temporally blocking LIF action during specific periods of placental development via intraperitoneal administration of our specific LIFRα antagonist, PEGLA, resulted in abnormal placental trophoblast and vascular morphology and reduced activated STAT3 but not ERK. Numerous genes regulating angiogenesis and oxidative stress were altered in the placenta in response to LIF inhibition. Pregnancy viability was also significantly compromised in PEGLA treated mice. Our data suggest that LIF plays an important role in placentation in vivo and the maintenance of healthy pregnancy. PMID:26272398

  5. Exercise preconditioning of the myocardium.

    PubMed

    Kavazis, Andreas N

    2009-01-01

    Diseases of the heart (e.g. myocardial ischaemia reperfusion injury) remain the major cause of death in the industrialized world. Therefore, developing a pragmatic countermeasure to reduce myocardial ischaemia reperfusion injury is vital. In this regard, a plethora of evidence indicates that regular exercise can protect the heart during an ischaemia reperfusion insult (i.e. cardioprotection). This review summarizes studies indicating that both short-term (i.e. 1-5 days) and long-term (i.e. weeks to months) endurance exercise provides cardioprotection. Data are presented showing that exercise duration and exercise intensity are both important factors in achieving a cardioprotective phenotype. Importantly, it appears that the exercise duration of a single exercise session should last for 60 minutes and should be performed at about 75% maximum oxygen consumption in order to achieve exercise-induced cardioprotection. Furthermore, data are presented showing that exercise-induced cardioprotection against myocardial stunning can persist for at least 9 days after the cessation of exercise training, but is lost 18 days after exercise. This review also summarizes the exercise-induced adaptations that occur to the myocardium. In particular, extrinsic changes observed in human and animal models include neural, hormonal, humoral, vascular and reduced body fat. Other anatomical and biochemical/molecular changes that have been studied as putative mechanisms in exercise-induced cardioprotection include alterations in anatomic coronary arteries, induction of myocardial heat shock proteins, increased myocardial cyclooxygenase-2 activity, elevated endoplasmic reticulum stress proteins, nitric oxide production, improved function of sarcolemmal and/or mitochondrial adenosine triphosphate (ATP)-sensitive potassium channels and increased myocardial antioxidant capacity. However, the most compelling evidence for exercise-induced cardioprotection is the fact that exercise training

  6. Interleukin 10 inhibits macrophage microbicidal activity by blocking the endogenous production of tumor necrosis factor alpha required as a costimulatory factor for interferon gamma-induced activation.

    PubMed Central

    Oswald, I P; Wynn, T A; Sher, A; James, S L

    1992-01-01

    Interleukin 10 (IL-10) inhibits interferon gamma-induced macrophage activation for cytotoxicity against larvae of the human parasite Schistosoma mansoni by suppressing production of the toxic effector molecule nitric oxide (NO). In this study, the mechanism of IL-10 action was identified as inhibition of endogenous tumor necrosis factor alpha (TNF-alpha) production by interferon gamma-activated macrophages. TNF-alpha appears to serve as a cofactor for interferon gamma-mediated activation, since both schistosomulum killing and NO production were inhibited by anti-TNF-alpha antibody, whereas TNF-alpha alone was unable to stimulate these macrophage functions. IL-10 blocked TNF-alpha production by interferon gamma-treated macrophages at the levels of both protein and mRNA synthesis. Addition of exogenous TNF-alpha reversed IL-10-mediated suppression of macrophage cytotoxic activity as well as NO production. Likewise, addition of a macrophage-triggering agent (bacterial lipopolysaccharide or muramyl dipeptide), which induced the production of TNF-alpha, also reversed the suppressive effect of IL-10 on cytotoxic function. In contrast to IL-10, two other cytokines, IL-4 and transforming growth factor beta, which also inhibit macrophage activation for schistosomulum killing and NO production, did not substantially suppress endogenous TNF-alpha production. These results, therefore, describe a separate pathway by which macrophage microbicidal function is inhibited by the down-regulatory cytokine IL-10. Images PMID:1528880

  7. Parallel preconditioning techniques for sparse CG solvers

    SciTech Connect

    Basermann, A.; Reichel, B.; Schelthoff, C.

    1996-12-31

    Conjugate gradient (CG) methods to solve sparse systems of linear equations play an important role in numerical methods for solving discretized partial differential equations. The large size and the condition of many technical or physical applications in this area result in the need for efficient parallelization and preconditioning techniques of the CG method. In particular for very ill-conditioned matrices, sophisticated preconditioner are necessary to obtain both acceptable convergence and accuracy of CG. Here, we investigate variants of polynomial and incomplete Cholesky preconditioners that markedly reduce the iterations of the simply diagonally scaled CG and are shown to be well suited for massively parallel machines.

  8. Domain-decomposed preconditionings for transport operators

    NASA Technical Reports Server (NTRS)

    Chan, Tony F.; Gropp, William D.; Keyes, David E.

    1991-01-01

    The performance was tested of five different interface preconditionings for domain decomposed convection diffusion problems, including a novel one known as the spectral probe, while varying mesh parameters, Reynolds number, ratio of subdomain diffusion coefficients, and domain aspect ratio. The preconditioners are representative of the range of practically computable possibilities that have appeared in the domain decomposition literature for the treatment of nonoverlapping subdomains. It is shown that through a large number of numerical examples that no single preconditioner can be considered uniformly superior or uniformly inferior to the rest, but that knowledge of particulars, including the shape and strength of the convection, is important in selecting among them in a given problem.

  9. H(curl) Auxiliary Mesh Preconditioning

    SciTech Connect

    Kolev, T V; Pasciak, J E; Vassilevski, P S

    2006-08-31

    This paper analyzes a two-level preconditioning scheme for H(curl) bilinear forms. The scheme utilizes an auxiliary problem on a related mesh that is more amenable for constructing optimal order multigrid methods. More specifically, we analyze the case when the auxiliary mesh only approximately covers the original domain. The latter assumption is important since it allows for easy construction of nested multilevel spaces on regular auxiliary meshes. Numerical experiments in both two and three space dimensions illustrate the optimal performance of the method.

  10. Deflation-accelerated preconditioning of the Poisson-Neumann Schur problem on long domains with a high-order discontinuous element-based collocation method

    NASA Astrophysics Data System (ADS)

    Joshi, Sumedh M.; Thomsen, Greg N.; Diamessis, Peter J.

    2016-05-01

    A combination of block-Jacobi and deflation preconditioning is used to solve a high-order discontinuous element-based collocation discretization of the Schur complement of the Poisson-Neumann system as arises in the operator splitting of the incompressible Navier-Stokes equations. The preconditioners and deflation vectors are chosen to mitigate the effects of ill-conditioning due to highly-elongated domains typical of simulations of strongly non-hydrostatic environmental flows, and to achieve Generalized Minimum RESidual method (GMRES) convergence independent of the size of the number of elements in the long direction. The ill-posedness of the Poisson-Neumann system manifests as an inconsistency of the Schur complement problem, but it is shown that this can be accounted for with appropriate projections out of the null space of the Schur complement matrix without affecting the accuracy of the solution. The block-Jacobi preconditioner is shown to yield GMRES convergence independent of the polynomial order and only weakly dependent on the number of elements within a subdomain in the decomposition. The combined deflation and block-Jacobi preconditioning is compared with two-level non-overlapping block-Jacobi preconditioning of the Schur problem, and while both methods achieve convergence independent of the grid size, deflation is shown to require half as many GMRES iterations and 25% less wall-clock time for a variety of grid sizes and domain aspect ratios. The deflation methods shown to be effective for the two-dimensional Poisson-Neumann problem are extensible to the three-dimensional problem assuming a Fourier discretization in the third dimension. A Fourier discretization results in a two-dimensional Helmholtz problem for each Fourier component that is solved using deflated block-Jacobi preconditioning on its Schur complement. Here again deflation is shown to be superior to two-level non-overlapping block-Jacobi preconditioning, requiring about half as many GMRES

  11. 40 CFR 86.132-00 - Vehicle preconditioning.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... tested for the SFTP supplemental tests of aggressive driving (US06) and air conditioning (SC03). Section...) Air Conditioning Test (SC03) Preconditioning. (1) If the SC03 test follows the exhaust emission FTP or... preconditioning cycles for the SC03 air conditioning test and the 10 minute soak are conducted at the same...

  12. 40 CFR 1066.407 - Vehicle preparation and preconditioning.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ...) Prepare the vehicle for testing as described in 40 CFR 86.131. (b) If testing will include measurement of refueling emissions, perform the vehicle preconditioning steps as described in 40 CFR 86.153. Otherwise, perform the vehicle preconditioning steps as described in 40 CFR 86.132....

  13. 40 CFR 1066.407 - Vehicle preparation and preconditioning.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ...) Prepare the vehicle for testing as described in 40 CFR 86.131. (b) If testing will include measurement of refueling emissions, perform the vehicle preconditioning steps as described in 40 CFR 86.153. Otherwise, perform the vehicle preconditioning steps as described in 40 CFR 86.132....

  14. [STRESS AND INFARCT LIMITING EFFECTS OF EARLY HYPOXIC PRECONDITIONING].

    PubMed

    Lishmanov, Yu B; Maslov, L N; Sementsov, A S; Naryzhnaya, N V; Tsibulnikov, S Yu

    2015-09-01

    It was established that early hypoxic preconditioning is an adaptive state different from eustress and distress. Hypoxic preconditioning has the cross effects, increasing the tolerance of the heart to ischemia-reperfusion and providing antiulcerogenic effect during immobilization stress. PMID:26672158

  15. 40 CFR 86.532-78 - Vehicle preconditioning.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 18 2011-07-01 2011-07-01 false Vehicle preconditioning. 86.532-78... (CONTINUED) CONTROL OF EMISSIONS FROM NEW AND IN-USE HIGHWAY VEHICLES AND ENGINES Emission Regulations for 1978 and Later New Motorcycles; Test Procedures § 86.532-78 Vehicle preconditioning. (a) The...

  16. 40 CFR 86.532-78 - Vehicle preconditioning.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 19 2013-07-01 2013-07-01 false Vehicle preconditioning. 86.532-78... (CONTINUED) CONTROL OF EMISSIONS FROM NEW AND IN-USE HIGHWAY VEHICLES AND ENGINES Emission Regulations for 1978 and Later New Motorcycles; Test Procedures § 86.532-78 Vehicle preconditioning. (a) The...

  17. 40 CFR 86.532-78 - Vehicle preconditioning.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 18 2010-07-01 2010-07-01 false Vehicle preconditioning. 86.532-78... (CONTINUED) CONTROL OF EMISSIONS FROM NEW AND IN-USE HIGHWAY VEHICLES AND ENGINES Emission Regulations for 1978 and Later New Motorcycles; Test Procedures § 86.532-78 Vehicle preconditioning. (a) The...

  18. Solving large test-day models by iteration on data and preconditioned conjugate gradient.

    PubMed

    Lidauer, M; Strandén, I; Mäntysaari, E A; Pösö, J; Kettunen, A

    1999-12-01

    A preconditioned conjugate gradient method was implemented into an iteration on a program for data estimation of breeding values, and its convergence characteristics were studied. An algorithm was used as a reference in which one fixed effect was solved by Gauss-Seidel method, and other effects were solved by a second-order Jacobi method. Implementation of the preconditioned conjugate gradient required storing four vectors (size equal to number of unknowns in the mixed model equations) in random access memory and reading the data at each round of iteration. The preconditioner comprised diagonal blocks of the coefficient matrix. Comparison of algorithms was based on solutions of mixed model equations obtained by a single-trait animal model and a single-trait, random regression test-day model. Data sets for both models used milk yield records of primiparous Finnish dairy cows. Animal model data comprised 665,629 lactation milk yields and random regression test-day model data of 6,732,765 test-day milk yields. Both models included pedigree information of 1,099,622 animals. The animal model ¿random regression test-day model¿ required 122 ¿305¿ rounds of iteration to converge with the reference algorithm, but only 88 ¿149¿ were required with the preconditioned conjugate gradient. To solve the random regression test-day model with the preconditioned conjugate gradient required 237 megabytes of random access memory and took 14% of the computation time needed by the reference algorithm. PMID:10629827

  19. Reduced-order preconditioning for bidomain simulations.

    PubMed

    Deo, Makarand; Bauer, Steffen; Plank, Gernot; Vigmond, Edward

    2007-05-01

    Simulations of the bidomain equations involve solving large, sparse, linear systems of the form Ax = b. Being an initial value problems, it is solved at every time step. Therefore, efficient solvers are essential to keep simulations tractable. Iterative solvers, especially the preconditioned conjugate gradient (PCG) method, are attractive since memory demands are minimized compared to direct methods, albeit at the cost of solution speed. However, a proper preconditioner can drastically speed up the solution process by reducing the number of iterations. In this paper, a novel preconditioner for the PCG method based on system order reduction using the Arnoldi method (A-PCG) is proposed. Large order systems, generated during cardiac bidomain simulations employing a finite element method formulation, are solved with the A-PCG method. Its performance is compared with incomplete LU (ILU) preconditioning. Results indicate that the A-PCG estimates an approximate solution considerably faster than the ILU, often within a single iteration. To reduce the computational demands in terms of memory and run time, the use of a cascaded preconditioner was suggested. The A-PCG was applied to quickly obtain an approximate solution, and subsequently a cheap iterative method such as successive overrelaxation (SOR) is applied to further refine the solution to arrive at a desired accuracy. The memory requirements are less than those of direct LU but more than ILU method. The proposed scheme is shown to yield significant speedups when solving time evolving systems. PMID:17518292

  20. The multigrid preconditioned conjugate gradient method

    NASA Technical Reports Server (NTRS)

    Tatebe, Osamu

    1993-01-01

    A multigrid preconditioned conjugate gradient method (MGCG method), which uses the multigrid method as a preconditioner of the PCG method, is proposed. The multigrid method has inherent high parallelism and improves convergence of long wavelength components, which is important in iterative methods. By using this method as a preconditioner of the PCG method, an efficient method with high parallelism and fast convergence is obtained. First, it is considered a necessary condition of the multigrid preconditioner in order to satisfy requirements of a preconditioner of the PCG method. Next numerical experiments show a behavior of the MGCG method and that the MGCG method is superior to both the ICCG method and the multigrid method in point of fast convergence and high parallelism. This fast convergence is understood in terms of the eigenvalue analysis of the preconditioned matrix. From this observation of the multigrid preconditioner, it is realized that the MGCG method converges in very few iterations and the multigrid preconditioner is a desirable preconditioner of the conjugate gradient method.

  1. Insulin-like growth factor II blocks apoptosis of N-myc2-expressing woodchuck liver epithelial cells.

    PubMed Central

    Yang, D; Faris, R; Hixson, D; Affigne, S; Rogler, C E

    1996-01-01

    N-myc2 and insulin-like growth factor II (IGF-II) are coordinately overexpressed in the great majority of altered hepatic foci, which are the earliest precancerous lesions observed in the liver of woodchuck hepatitis virus carrier woodchucks, and these genes continue to be overexpressed in hepatocellular carcinomas (HCCs). We have investigated the function of these genes in woodchuck hepatocarcinogenesis by using a woodchuck liver epithelial cell line (WC-3). WC-3 cells react positively with a monoclonal antibody (12.8.5) against woodchuck oval cells, suggesting a lineage relationship with oval cells. Overexpression of N-myc2 in three WC-3 cell lines caused their morphological transformation and increased their growth rate and saturation density in medium containing 10% serum. Removal of serum from the medium increased cell death of the N-myc2-expressing lines, whereas cell death in control lines was minimal. The death of N-myc2-expressing WC-3 cells was accompanied by nucleosomal fragmentation of cellular DNA, and DAPI (4',6-diamidino-2-phenylindole) staining revealed condensation and fragmentation of the nuclei, suggesting that N-myc2-expressing WC-3 cells undergo apoptosis in the absence of serum. In colony regression assays, conducted in the absence of serum, control colonies were stable, while N-myc2-expressing colonies regressed to various degrees. Addition of recombinant human IGF-II to the serum-free medium blocked both cell death and colony regression in all the N-myc2-expressing lines. Therefore, coordinate overexpression of N-myc2 and IGF-II in woodchuck altered hepatic foci may allow cells which otherwise might die to survive and progress to hepatocellular carcinoma. PMID:8709253

  2. TIGAR contributes to ischemic tolerance induced by cerebral preconditioning through scavenging of reactive oxygen species and inhibition of apoptosis.

    PubMed

    Zhou, Jun-Hao; Zhang, Tong-Tong; Song, Dan-Dan; Xia, Yun-Fei; Qin, Zheng-Hong; Sheng, Rui

    2016-01-01

    Previous study showed that TIGAR (TP53-induced glycolysis and apoptosis regulator) protected ischemic brain injury via enhancing pentose phosphate pathway (PPP) flux and preserving mitochondria function. This study was aimed to study the role of TIGAR in cerebral preconditioning. The ischemic preconditioning (IPC) and isoflurane preconditioning (ISO) models were established in primary cultured cortical neurons and in mice. Both IPC and ISO increased TIGAR expression in cortical neurons. Preconditioning might upregulate TIGAR through SP1 transcription factor. Lentivirus mediated knockdown of TIGAR significantly abolished the ischemic tolerance induced by IPC and ISO. ISO also increased TIGAR in mouse cortex and hippocampus and alleviated subsequent brain ischemia-reperfusion injury, while the ischemic tolerance induced by ISO was eliminated with TIGAR knockdown in mouse brain. ISO increased the production of NADPH and glutathione (GSH), and scavenged reactive oxygen species (ROS), while TIGAR knockdown decreased GSH and NADPH production and increased the level of ROS. Supplementation of ROS scavenger NAC and PPP product NADPH effectively rescue the neuronal injury caused by TIGAR deficiency. Notably, TIGAR knockdown inhibited ISO-induced anti-apoptotic effects in cortical neurons. These results suggest that TIGAR participates in the cerebral preconditioning through reduction of ROS and subsequent cell apoptosis. PMID:27256465

  3. TIGAR contributes to ischemic tolerance induced by cerebral preconditioning through scavenging of reactive oxygen species and inhibition of apoptosis

    PubMed Central

    Zhou, Jun-Hao; Zhang, Tong-Tong; Song, Dan-Dan; Xia, Yun-Fei; Qin, Zheng-Hong; Sheng, Rui

    2016-01-01

    Previous study showed that TIGAR (TP53-induced glycolysis and apoptosis regulator) protected ischemic brain injury via enhancing pentose phosphate pathway (PPP) flux and preserving mitochondria function. This study was aimed to study the role of TIGAR in cerebral preconditioning. The ischemic preconditioning (IPC) and isoflurane preconditioning (ISO) models were established in primary cultured cortical neurons and in mice. Both IPC and ISO increased TIGAR expression in cortical neurons. Preconditioning might upregulate TIGAR through SP1 transcription factor. Lentivirus mediated knockdown of TIGAR significantly abolished the ischemic tolerance induced by IPC and ISO. ISO also increased TIGAR in mouse cortex and hippocampus and alleviated subsequent brain ischemia-reperfusion injury, while the ischemic tolerance induced by ISO was eliminated with TIGAR knockdown in mouse brain. ISO increased the production of NADPH and glutathione (GSH), and scavenged reactive oxygen species (ROS), while TIGAR knockdown decreased GSH and NADPH production and increased the level of ROS. Supplementation of ROS scavenger NAC and PPP product NADPH effectively rescue the neuronal injury caused by TIGAR deficiency. Notably, TIGAR knockdown inhibited ISO-induced anti-apoptotic effects in cortical neurons. These results suggest that TIGAR participates in the cerebral preconditioning through reduction of ROS and subsequent cell apoptosis. PMID:27256465

  4. Increased BDNF protein expression after ischemic or PKC epsilon preconditioning promotes electrophysiologic changes that lead to neuroprotection

    PubMed Central

    Neumann, Jake T; Thompson, John W; Raval, Ami P; Cohan, Charles H; Koronowski, Kevin B; Perez-Pinzon, Miguel A

    2015-01-01

    Ischemic preconditioning (IPC) via protein kinase C epsilon (PKCɛ) activation induces neuroprotection against lethal ischemia. Brain-derived neurotrophic factor (BDNF) is a pro-survival signaling molecule that modulates synaptic plasticity and neurogenesis. Interestingly, BDNF mRNA expression increases after IPC. In this study, we investigated whether IPC or pharmacological preconditioning (PKCɛ activation) promoted BDNF-induced neuroprotection, if neuroprotection by IPC or PKCɛ activation altered neuronal excitability, and whether these changes were BDNF-mediated. We used both in vitro (hippocampal organotypic cultures and cortical neuronal-glial cocultures) and in vivo (acute hippocampal slices 48 hours after preconditioning) models of IPC or PKCɛ activation. BDNF protein expression increased 24 to 48 hours after preconditioning, where inhibition of the BDNF Trk receptors abolished neuroprotection against oxygen and glucose deprivation (OGD) in vitro. In addition, there was a significant decrease in neuronal firing frequency and increase in threshold potential 48 hours after preconditioning in vivo, where this threshold modulation was dependent on BDNF activation of Trk receptors in excitatory cortical neurons. In addition, 48 hours after PKCɛ activation in vivo, the onset of anoxic depolarization during OGD was significantly delayed in hippocampal slices. Overall, these results suggest that after IPC or PKCɛ activation, there are BDNF-dependent electrophysiologic modifications that lead to neuroprotection. PMID:25370861

  5. Essential involvement of the NMDA receptor in ethanol preconditioning-dependent neuroprotection from amyloid-betain vitro.

    PubMed

    Mitchell, Robert M; Neafsey, Edward J; Collins, Michael A

    2009-10-01

    In several epidemiological studies, moderate ethanol consumption has been associated with reduced risks of cognitive decline or Alzheimer's dementia. Of potential relevance is that brain cultures preconditioned with moderate ethanol concentrations are resistant to neurotoxic Alzheimer's amyloid-beta (Abeta) peptides. Using rat cerebellar mixed cultures we investigated whether certain membrane receptors were early 'sensors' in moderate ethanol preconditioning (MEP). In a 6-day MEP protocol (30 mM ethanol), neuroprotection from Abeta25-35 was undiminished by antagonism during the first 3 days of either adenosine A(1) or Galpha(i/o) protein-coupled receptors. However, similar cotreatment with memantine or DL-2-amino-5-phosphono-pentanoic acid (AP-5), antagonists of NMDA receptors (NMDAR), abolished neuroprotection, indicating key early involvement of this ionotropic glutamate receptor. Also in these cultures, directly activating NMDAR using subexcitotoxic NMDA preconditioning prevented Abeta neurotoxicity. By day 2 of MEP, we observed increased levels of NMDAR subunits NR1, NR2B, and NR2C that persisted through day 6. Interestingly, memantine co-exposure blocked elevations in the obligatory NR1 subunit. Furthermore, 2 days of MEP significantly increased two indicators of synaptic NMDAR localization, NR2B phospho-Tyr1472, and post-synaptic density 95 scaffolding protein. The results indicate that ethanol preconditioning-dependent neuroprotection is associated with early increases in NR subunits concomitant with enhancement of synaptic localization and activity of NMDAR. PMID:19694907

  6. Iterative image restoration using approximate inverse preconditioning.

    PubMed

    Nagy, J G; Plemmons, R J; Torgersen, T C

    1996-01-01

    Removing a linear shift-invariant blur from a signal or image can be accomplished by inverse or Wiener filtering, or by an iterative least-squares deblurring procedure. Because of the ill-posed characteristics of the deconvolution problem, in the presence of noise, filtering methods often yield poor results. On the other hand, iterative methods often suffer from slow convergence at high spatial frequencies. This paper concerns solving deconvolution problems for atmospherically blurred images by the preconditioned conjugate gradient algorithm, where a new approximate inverse preconditioner is used to increase the rate of convergence. Theoretical results are established to show that fast convergence can be expected, and test results are reported for a ground-based astronomical imaging problem. PMID:18285203

  7. Hyperbaric oxygen preconditioning protects rats against CNS oxygen toxicity.

    PubMed

    Arieli, Yehuda; Kotler, Doron; Eynan, Mirit; Hochman, Ayala

    2014-06-15

    We examined the hypothesis that repeated exposure to non-convulsive hyperbaric oxygen (HBO) as preconditioning provides protection against central nervous system oxygen toxicity (CNS-OT). Four groups of rats were used in the study. Rats in the control and the negative control (Ctl-) groups were kept in normobaric air. Two groups of rats were preconditioned to non-convulsive HBO at 202 kPa for 1h once every other day for a total of three sessions. Twenty-four hours after preconditioning, one of the preconditioned groups and the control rats were exposed to convulsive HBO at 608 kPa, and latency to CNS-OT was measured. Ctl- rats and the second preconditioned group (PrC-) were not subjected to convulsive HBO exposure. Tissues harvested from the hippocampus and frontal cortex were evaluated for enzymatic activity and nitrotyrosine levels. In the group exposed to convulsive oxygen at 608 kPa, latency to CNS-OT increased from 12.8 to 22.4 min following preconditioning. A significant decrease in the activity of glutathione reductase and glucose-6-phosphate dehydrogenase, and a significant increase in glutathione peroxidase activity, was observed in the hippocampus of preconditioned rats. Nitrotyrosine levels were significantly lower in the preconditioned animals, the highest level being observed in the control rats. In the cortex of the preconditioned rats, a significant increase was observed in glutathione S-transferase and glutathione peroxidase activity. Repeated exposure to non-convulsive HBO provides protection against CNS-OT. The protective mechanism involves alterations in the enzymatic activity of the antioxidant system and lower levels of peroxynitrite, mainly in the hippocampus. PMID:24675062

  8. Ouabain triggers preconditioning through activation of the Na+,K+-ATPase signaling cascade in rat hearts

    PubMed Central

    Pierre, Sandrine V.; Yang, Changjun; Yuan, Zhaokan; Seminerio, Jennifer; Mouas, Christian; Garlid, Keith D.; Dos-Santos, Pierre; Xie, Zijian

    2007-01-01

    Objective Because ouabain activates several pathways that are critical to cardioprotective mechanisms such as ischemic preconditioning, we tested if this digitalis compound could protect the heart against ischemia-reperfusion injury through activation of the Na+,K+-ATPase/c-Src receptor complex. Methods and Results In Langendorff-perfused rat hearts, a short (4 min) administration of ouabain 10 μM followed by an 8-minute washout before 30 minutes of global ischemia and reperfusion improved cardiac function, decreased lactate dehydrogenase release and reduced infarct size by 40%. Western blot analysis revealed that ouabain activated the cardioprotective phospholipase Cγ1/protein kinase Cε (PLC-γ1/PKCε) pathway. Pre-treatment of the hearts with the Src kinase family inhibitor 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolol[3,4-d]pyrimidine (PP2) blocked not only ouabain-induced activation of PLC-γ1/PKCε pathway, but also cardiac protection. This protection was also blocked by a PKCε translocation inhibitor peptide (PKCε TIP). Conclusion Short exposure to a low concentration of ouabain protects the heart against ischemia/reperfusion injury. This effect of ouabain on the heart is most likely due to the activation of the Na+,K+-ATPase/c-Src receptor complex and subsequent stimulation of key mediators of preconditioning, namely PLC-γ1 and PKCε. PMID:17157283

  9. Preconditioning Vaccine Sites for mRNA-Transfected Dendritic Cell Therapy and Antitumor Efficacy.

    PubMed

    Batich, Kristen A; Swartz, Adam M; Sampson, John H

    2016-01-01

    Messenger RNA (mRNA)-transfected dendritic cell (DC) vaccines have been shown to be a powerful modality for eliciting antitumor immune responses in mice and humans; however, their application has not been fully optimized since many of the factors that contribute to their efficacy remain poorly understood. Work stemming from our laboratory has recently demonstrated that preconditioning the vaccine site with a recall antigen prior to the administration of a dendritic cell vaccine creates systemic recall responses and resultantly enhances dendritic cell migration to the lymph nodes with improved antitumor efficacy. This chapter describes the generation of murine mRNA-transfected DC vaccines, as well as a method for vaccine site preconditioning with protein antigen formulations that create potent recall responses. PMID:27076169

  10. Voluntary Exercise Preconditioning Activates Multiple Antiapoptotic Mechanisms and Improves Neurological Recovery after Experimental Traumatic Brain Injury

    PubMed Central

    Zhao, Zaorui; Sabirzhanov, Boris; Wu, Junfang; Faden, Alan I.

    2015-01-01

    Abstract Physical activity can attenuate neuronal loss, reduce neuroinflammation, and facilitate recovery after brain injury. However, little is known about the mechanisms of exercise-induced neuroprotection after traumatic brain injury (TBI) or its modulation of post-traumatic neuronal cell death. Voluntary exercise, using a running wheel, was conducted for 4 weeks immediately preceding (preconditioning) moderate-level controlled cortical impact (CCI), a well-established experimental TBI model in mice. Compared to nonexercised controls, exercise preconditioning (pre-exercise) improved recovery of sensorimotor performance in the beam walk task, as well as cognitive/affective functions in the Morris water maze, novel object recognition, and tail-suspension tests. Further, pre-exercise reduced lesion size, attenuated neuronal loss in the hippocampus, cortex, and thalamus, and decreased microglial activation in the cortex. In addition, exercise preconditioning activated the brain-derived neurotrophic factor pathway before trauma and amplified the injury-dependent increase in heat shock protein 70 expression, thus attenuating key apoptotic pathways. The latter include reduction in CCI-induced up-regulation of proapoptotic B-cell lymphoma 2 (Bcl-2)-homology 3–only Bcl-2 family molecules (Bid, Puma), decreased mitochondria permeabilization with attenuated release of cytochrome c and apoptosis-inducing factor (AIF), reduced AIF translocation to the nucleus, and attenuated caspase activation. Given these neuroprotective actions, voluntary physical exercise may serve to limit the consequences of TBI. PMID:25419789

  11. Blocking Infralimbic Basic Fibroblast Growth Factor (bFGF or FGF2) Facilitates Extinction of Drug Seeking After Cocaine Self-Administration.

    PubMed

    Hafenbreidel, Madalyn; Twining, Robert C; Rafa Todd, Carolynn; Mueller, Devin

    2015-12-01

    Drug exposure results in structural and functional changes in brain regions that regulate reward and these changes may underlie the persistence of compulsive drug seeking and relapse. Neurotrophic factors, such as basic fibroblast growth factor (bFGF or FGF2), are necessary for neuronal survival, growth, and differentiation, and may contribute to these drug-induced changes. Following cocaine exposure, bFGF is increased in addiction-related brain regions, including the infralimbic medial prefrontal cortex (IL-mPFC). The IL-mPFC is necessary for extinction, but whether drug-induced overexpression of bFGF in this region affects extinction of drug seeking is unknown. Thus, we determined whether blocking bFGF in IL-mPFC would facilitate extinction following cocaine self-administration. Rats were trained to lever press for intravenous infusions of cocaine before extinction. Blocking bFGF in IL-mPFC before four extinction sessions resulted in facilitated extinction. In contrast, blocking bFGF alone was not sufficient to facilitate extinction, as blocking bFGF and returning rats to their home cage had no effect on subsequent extinction. Furthermore, bFGF protein expression increased in IL-mPFC following cocaine self-administration, an effect reversed by extinction. These results suggest that cocaine-induced overexpression of bFGF inhibits extinction, as blocking bFGF during extinction permits rapid extinction. Therefore, targeted reductions in bFGF during therapeutic interventions could enhance treatment outcomes for addiction. PMID:25994078

  12. A projected preconditioned conjugate gradient algorithm for computing many extreme eigenpairs of a Hermitian matrix

    SciTech Connect

    Vecharynski, Eugene; Yang, Chao; Pask, John E.

    2015-06-01

    We present an iterative algorithm for computing an invariant subspace associated with the algebraically smallest eigenvalues of a large sparse or structured Hermitian matrix A. We are interested in the case in which the dimension of the invariant subspace is large (e.g., over several hundreds or thousands) even though it may still be small relative to the dimension of A. These problems arise from, for example, density functional theory (DFT) based electronic structure calculations for complex materials. The key feature of our algorithm is that it performs fewer Rayleigh–Ritz calculations compared to existing algorithms such as the locally optimal block preconditioned conjugate gradient or the Davidson algorithm. It is a block algorithm, and hence can take advantage of efficient BLAS3 operations and be implemented with multiple levels of concurrency. We discuss a number of practical issues that must be addressed in order to implement the algorithm efficiently on a high performance computer.

  13. Population Blocks.

    ERIC Educational Resources Information Center

    Smith, Martin H.

    1992-01-01

    Describes an educational game called "Population Blocks" that is designed to illustrate the concept of exponential growth of the human population and some potential effects of overpopulation. The game material consists of wooden blocks; 18 blocks are painted green (representing land), 7 are painted blue (representing water); and the remaining…

  14. Essential Role of the Redox Sensitive Kinase p66shc in Determining Energetic and Oxidative Status and Cell Fate in Neuronal Preconditioning

    PubMed Central

    Brown, Jacquelynn E.; Zeiger, Stephanie L.H.; Hettinger, Jane C.; Brooks, Joshua D.; Holt, Benjamin; Morrow, Jason D.; Musiek, Erik S.; Milne, Ginger; McLaughlin, BethAnn

    2010-01-01

    Ischemic preconditioning is a phenomenon in which low level stressful stimuli upregulate endogenous defensive programs resulting in subsequent resistance to otherwise lethal injuries. We previously observed that signal transduction systems typically associated with neurodegeneration such as caspase activation are requisite events for the expression of tolerance and induction of HSP70. In this work, we sought to determine the extent and duration of oxidative and energetic dysfunction as well as the role of effector kinases on metabolic function in preconditioned cells. Using an in vitro neuronal culture model, we observed a robust increase in Raf and p66Shc activation within 1h of preconditioning. Total ATP content decreased by 25% 3h after preconditioning but returned to baseline by 24h. Use of a free radical spin trap or p66shc inhibitor increased ATP content whereas a Raf inhibitor had no effect. Phosphorylated p66shc rapidly relocalized to the mitochondria and in the absence of activated p66shc, autophagic processing increased. The constitutively expressed chaperone HSC70 relocalized to autophagosomes. Preconditioned cells experience significant total oxidative stress measured by F2-isoprostanes and neuronal stress evaluated by F4-neuroprostane measurement. Neuroprostane levels were enhanced in the presence of Shc inhibitors. Finally, we found that inhibiting either p66shc or Raf blocked neuroprotection afforded by preconditioning as well as upregulation of HSP70 suggesting both kinases. This is the first work to demonstrate the essential role of p66shc in mediating requisite mitochondrial and energetic compensation following preconditioning and suggests a mechanism by which protein and organelle damage mediated by ROS can increase HSP70. PMID:20392947

  15. Upstream signaling of protein kinase C-epsilon in xenon-induced pharmacological preconditioning. Implication of mitochondrial adenosine triphosphate dependent potassium channels and phosphatidylinositol-dependent kinase-1.

    PubMed

    Weber, Nina C; Toma, Octavian; Damla, Halil; Wolter, Jessica I; Schlack, Wolfgang; Preckel, Benedikt

    2006-06-01

    Xenon elicits preconditioning of the myocardium via protein kinase C-epsilon. We determined the implication of (1) the mitochondrial adenosinetriphosphate dependent potassium (K(ATP)) channels and (2) the 3'phosphatidylinositol-dependent kinase-1 (PDK-1) in activating protein kinase C-epsilon. For infarct size measurements, anaesthetized rats were subjected to 25 min of coronary artery occlusion followed by 120 min of reperfusion. Rats received xenon 70% during three 5-min periods before ischaemia with or without the K(ATP) channel blocker 5-hydroxydecanoate or Wortmannin as PI3K/PDK-1 inhibitor. For Western blot, hearts were excised at five time points after xenon preconditioning (Control, 15, 25, 35, 45 min). Infarct size was reduced from 42+/-6% (mean+/-S.D.) to 27+/-8% after xenon preconditioning (P<0.05). Western blot revealed an increased activation of PKC-epsilon after 45 min and of PDK-1 after 25 min during xenon preconditioning. 5-hydroxydecanoate and Wortmannin blocked both effects. PKC-epsilon is activated downstream of mitochondrial K(ATP) channels and PDK-1. Both pathways are functionally involved in xenon preconditioning. PMID:16716295

  16. Preconditioning of endoplasmic reticulum stress protects against acrylonitrile-induced cytotoxicity in primary rat astrocytes: The role of autophagy.

    PubMed

    Yu, Bai; Wenjun, Zhao; Changsheng, Yin; Yuntao, Fang; Jing, Ma; Ben, Li; Hai, Qian; Guangwei, Xing; Suhua, Wang; Fang, Li; Aschner, Michael; Rongzhu, Lu

    2016-07-01

    This study explored the protective effects of endoplasmic reticulum (ER) stress preconditioning induced by 2-deoxy-d-glucose (2-DG) or oxidized dithiothreitol (DTTox) on acrylonitrile (AN)-induced cytotocity in primary rat astrocytes. Cells were pretreated with 2-DG or DTTox for different times at various concentration. Next, astrocytes were treated with 2.5mM AN for an additional 12h. Cell viability and cytotoxicity were assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction and lactate dehydrogenase (LDH) leakage, respectively. Reactive oxygen species (ROS) and mitochondrial membrane potential (ΔΨm) were determined. Expression of glucose-regulated protein 78 (GRP78), phosphorylated-eukaryotic translation initiation factor 2α (p-eIF2α), microtubule-associated protein light chain 3 (LC3), P62, and Beclin1 were used to assess autophagy. In addition, 3-methyadenine (3-MA), an autophagy-specific inhibitor, was used to assess the role of autophagy in ER stress preconditioning-induced protection against AN cytotoxicity. The results showed that AN alone significantly decreased astrocytic viability and enhanced cytotoxicity. Compared to the AN-alone group, preconditioning with 2-DG or DTTox significantly increased cell viability and reduced cytotoxicity to indistinguishable levels. Decreased ROS generation and increased ΔΨm were also inherent to ER stress preconditioning with these compounds. Furthermore, autophagy was activated by both 2-DG and DTTox. Blockage of autophagy attenuated the protection afforded by 2-DG or DTTox preconditioning in AN-treated astrocytes. These results establish that ER stress preconditioning affords cellular protection against AN, and that activation of autophagy mediates the cytoprotection. Modulation of ER stress and resultant activation of autophagy may be a novel target for to ameliorate AN toxicity. PMID:27260289

  17. An overview of NSPCG: A nonsymmetric preconditioned conjugate gradient package

    NASA Astrophysics Data System (ADS)

    Oppe, Thomas C.; Joubert, Wayne D.; Kincaid, David R.

    1989-05-01

    The most recent research-oriented software package developed as part of the ITPACK Project is called "NSPCG" since it contains many nonsymmetric preconditioned conjugate gradient procedures. It is designed to solve large sparse systems of linear algebraic equations by a variety of different iterative methods. One of the main purposes for the development of the package is to provide a common modular structure for research on iterative methods for nonsymmetric matrices. Another purpose for the development of the package is to investigate the suitability of several iterative methods for vector computers. Since the vectorizability of an iterative method depends greatly on the matrix structure, NSPCG allows great flexibility in the operator representation. The coefficient matrix can be passed in one of several different matrix data storage schemes. These sparse data formats allow matrices with a wide range of structures from highly structured ones such as those with all nonzeros along a relatively small number of diagonals to completely unstructured sparse matrices. Alternatively, the package allows the user to call the accelerators directly with user-supplied routines for performing certain matrix operations. In this case, one can use the data format from an application program and not be required to copy the matrix into one of the package formats. This is particularly advantageous when memory space is limited. Some of the basic preconditioners that are available are point methods such as Jacobi, Incomplete LU Decomposition and Symmetric Successive Overrelaxation as well as block and multicolor preconditioners. The user can select from a large collection of accelerators such as Conjugate Gradient (CG), Chebyshev (SI, for semi-iterative), Generalized Minimal Residual (GMRES), Biconjugate Gradient Squared (BCGS) and many others. The package is modular so that almost any accelerator can be used with almost any preconditioner.

  18. The hyperbaric oxygen preconditioning-induced brain protection is mediated by a reduction of early apoptosis after transient global cerebral ischemia

    PubMed Central

    Ostrowski, Robert P.; Graupner, Gerhart; Titova, Elena; Zhang, Jennifer; Chiu, Jeffrey; Dach, Neal; Corleone, Dalia; Tang, Jiping; Zhang, John H.

    2008-01-01

    We hypothesized that the brain-protective effect of hyperbaric oxygen (HBO) preconditioning in a transient global cerebral ischemia rat model is mediated by the inhibition of early apoptosis. One hundred ten male Sprague Dawley (SD) rats (300–350 g body weight) were allocated to the sham group and three other groups with 10 minutes of four-vessel occlusion, untreated or preconditioned with either 3 or 5 hyperbaric oxygenations. HBO preconditioning improved neurobehavioral scores and reduced mortality, decreased ischemic cell change, reduced the number of early apoptotic cells and hampered a conversion of early to late apoptotic alterations. HBO preconditioning reduced the immunoreactivity of phosphorylated p38 in vulnerable neurons and increased the expression of brain derived neurotrophic factor (BDNF) in early stage post-ischemia. However, preconditioning with 3 HBO treatments proved less beneficial than with 5 HBO treatments. We conclude that HBO preconditioning may be neuroprotective by reducing early apoptosis and inhibition of the conversion of early to late apoptosis, possibly through an increase in brain BDNF level and the suppression of p38 activation. PMID:17822911

  19. The Galvanotactic Migration of Keratinocytes is Enhanced by Hypoxic Preconditioning

    PubMed Central

    Guo, Xiaowei; Jiang, Xupin; Ren, Xi; Sun, Huanbo; Zhang, Dongxia; Zhang, Qiong; Zhang, Jiaping; Huang, Yuesheng

    2015-01-01

    The endogenous electric field (EF)-directed migration of keratinocytes (galvanotaxis) into wounds is an essential step in wound re-epithelialization. Hypoxia, which occurs immediately after injury, acts as an early stimulus to initiate the healing process; however, the mechanisms for this effect, remain elusive. We show here that the galvanotactic migration of keratinocytes was enhanced by hypoxia preconditioning as a result of the increased directionality rather than the increased motility of keratinocytes. This enhancement was both oxygen tension- and preconditioning time-dependent, with the maximum effects achieved using 2% O2 preconditioning for 6 hours. Hypoxic preconditioning (2% O2, 6 hours) decreased the threshold voltage of galvanotaxis to < 25 mV/mm, whereas this value was between 25 and 50 mV/mm in the normal culture control. In a scratch-wound monolayer assay in which the applied EF was in the default healing direction, hypoxic preconditioning accelerated healing by 1.38-fold compared with the control conditions. Scavenging of the induced ROS by N-acetylcysteine (NAC) abolished the enhanced galvanotaxis and the accelerated healing by hypoxic preconditioning. Our data demonstrate a novel and unsuspected role of hypoxia in supporting keratinocyte galvanotaxis. Enhancing the galvanotactic response of cells might therefore be a clinically attractive approach to induce improved wound healing. PMID:25988491

  20. Parathyroid hormone blocks the stimulatory effect of insulin-like growth factor-I on collagen synthesis in cultured 21-day fetal rat calvariae

    SciTech Connect

    Kream, B.E.; Petersen, D.N.; Raisz, L.G. )

    1990-01-01

    We examined the interaction of parathyroid hormone (PTH) and recombinant human insulin-like growth factor I (IGF-I) on collagen synthesis in 21-day fetal rat calvariae as assessed by measuring the incorporation of ({sup 3}H)proline into collagenase-digestible protein. After 96 hours of culture, 10 nM PTH antagonized the stimulation of collagen synthesis and partially blocked the increase in dry weight produced by 10 nM IGF-I. The effect of PTH to block IGF-I stimulated collagen synthesis was observed in the central bone of calvariae and was mimicked by forskolin and phorbol 12-myristate 13-acetate, but not by 1,25-dihydroxyvitamin D3, transforming growth factor-alpha or dexamethasone. Our data are consistent with the concept that the direct effect of PTH is to inhibit basal CDP labeling and fully oppose IGF-I stimulated CDP labeling. The finding that this effect of PTH is mimicked by forskolin and PMA suggests that this block in IGF-I stimulation of CDP labeling involves both cAMP and protein kinase C mediated pathways.

  1. Pre-Conditioning with Low-Level Laser (Light) Therapy: Light Before the Storm

    PubMed Central

    Agrawal, Tanupriya; Gupta, Gaurav K.; Rai, Vikrant; Carroll, James D.; Hamblin, Michael R.

    2014-01-01

    Pre-conditioning by ischemia, hyperthermia, hypothermia, hyperbaric oxygen (and numerous other modalities) is a rapidly growing area of investigation that is used in pathological conditions where tissue damage may be expected. The damage caused by surgery, heart attack, or stroke can be mitigated by pre-treating the local or distant tissue with low levels of a stress-inducing stimulus, that can induce a protective response against subsequent major damage. Low-level laser (light) therapy (LLLT) has been used for nearly 50 years to enhance tissue healing and to relieve pain, inflammation and swelling. The photons are absorbed in cytochrome(c) oxidase (unit four in the mitochondrial respiratory chain), and this enzyme activation increases electron transport, respiration, oxygen consumption and ATP production. A complex signaling cascade is initiated leading to activation of transcription factors and up- and down-regulation of numerous genes. Recently it has become apparent that LLLT can also be effective if delivered to normal cells or tissue before the actual insult or trauma, in a pre-conditioning mode. Muscles are protected, nerves feel less pain, and LLLT can protect against a subsequent heart attack. These examples point the way to wider use of LLLT as a pre-conditioning modality to prevent pain and increase healing after surgical/medical procedures and possibly to increase athletic performance. PMID:25552961

  2. Impact of preconditioning pulse on lesion formation during high-intensity focused ultrasound histotripsy.

    PubMed

    Xu, Jin; Bigelow, Timothy A; Riesberg, Grant M

    2012-11-01

    Therapeutic applications with high-intensity focused ultrasound (HIFU) fall into two classifications-one using thermal effect for coagulation or ablation while generally avoiding cavitation and the other using cavitation-mediated mechanical effects while suppressing heating. Representative of the latter, histotripsy uses HIFU at low duty factor to create energetic bubble clouds inside tissue to liquefy a region and has the advantages in real-time monitoring and lesion fidelity to treatment planning. We explored the impact of a preconditioning/heating pulse on histotripsy lesion formation in porcine muscle samples. During sonication, a targeted square region 9 mm wide (lateral to the focal plane) was scanned in a raster pattern with a step size of 0.75 mm. The 20-s exposure at each treatment location consisted of a 5-s duration preconditioning burst at spatial-peak intensities from 0-1386 W/cm² followed by 5000 tone bursts at high intensity (with spatial-peak pulse-average intensity of 47.34 kW/cm², spatial-peak temporal-average intensity of 284 W/cm², peak compressional pressure of 102 MPa and peak rarefactional pressure of 17 MPa). The temperature increase for all exposures was measured using a thermal imager immediately after each exposure. Lesion volume increased with increasing amplitude of the preconditioning pulse until coagulation was observed, but lesion width/area did not change significantly with the amplitude. In addition, the lesion dimensions became smaller when the global tissue temperature was raised before applying the histotripsy pulsing sequence. Therefore, the benefit of the preconditioning pulse was not caused by global heating. PMID:22929656

  3. Effect of zinc supplements in the attenuated cardioprotective effect of ischemic preconditioning in hyperlipidemic rat heart.

    PubMed

    Kansal, Sunil Kumar; Jyoti, Uma; Sharma, Samridhi; Kaura, Arun; Deshmukh, Rahul; Goyal, Sandeep

    2015-06-01

    Hyperlipidemia is regarded as independent risk factor in the development of ischemic heart disease, and it can increase the myocardial susceptibility to ischemia-/reperfusion (I/R)-induced injury. Hyperlipidemia attenuates the cardioprotective response of ischemic preconditioning (IPC). The present study investigated the effect of zinc supplements in the attenuated cardioprotective effect of ischemic preconditioning in hyperlipidemic rat hearts. Hyperlipidemia was induced in rat by feeding high-fat diet (HFD) for 6 weeks then the serum lipid profile was observed. In experiment, the isolated Langendorff rat heart preparation was subjected to 4 cycles of ischemic preconditioning (IPC), then 30 min of ischemia followed by 120 min of reperfusion. Myocardial infarct size was elaborated morphologically by triphenyltetrazolium chloride (TTC) staining and biochemically by lactate dehydrogenase (LDH) and creatine kinase-MB (CK-MB) release from coronary effluent and left ventricular collagen content. However, the effect of zinc supplement, i.e., zinc pyrithione (10 μM) perfused during reperfusion for 120 min, significantly abrogated the attenuated cardioprotective effect of ischemic preconditioning in hyperlipidemic rat heart whereas administration of chelator of this zinc ionophore, i.e., N,N,N',N'-tetrakis(2-pyridylmethyl)ethylene diamine (TPEN; 10 μM), perfused during reperfusion 2 min before the perfusion of zinc pyrithione abrogated the cardioprotective effect of zinc supplement during experiment in hyperlipidemic rat heart. Thus, the administration of zinc supplements limits the infarct size, LDH, and CK-MB and enhanced the collagen level which suggests that the attenuated cardioprotective effect of IPC in hyperlipidemic rat is due to zinc loss during reperfusion caused by ischemia/reperfusion. PMID:25743572

  4. Progressive Evaluation of Apoptosis, Proliferation, and Angiogenesis in Fresh Rat Ovarian Autografts Under Remote Ischemic Preconditioning.

    PubMed

    Damous, Luciana Lamarão; Silva, Sônia Maria da; Carbonel, Adriana Aparecida Ferraz; Simões, Manuel de Jesus; Baracat, Edmund Chada; Montero, Edna Frasson de Souza

    2016-06-01

    This study evaluated the remote ischemic preconditioning (R-IPC) early and late repercussion on fresh ovarian transplants, aiming to assess a probable protective effect in ovarian follicular pool. Sixty Wistar EPM-1 rats were used, divided in 2 study groups: ovarian transplantation (Tx) and Tx + R-IPC, submitted to ovary transplant with or without R-IPC, respectively. These groups were subdivided according to the date for euthanasia: 4th, 7th, 14th, 21st, and 30th days of the postoperatory period. Morphology, morphometry, neoangiogenesis (vascular endothelial growth factor [VEGF]), proliferative activity (Ki-67), and apoptosis (cleaved caspase-3) were evaluated. Remote ischemic preconditioning was performed in the common iliac artery. Fresh autologous ovarian tissue was implanted integrally in the retroperitoneum. All animals showed resumption of estrous phase after ovary transplantation. Remote ischemic preconditioning attenuated the lesions progressively from the 7th day, with greater number of the immature follicles (14 days, P < .05), but didn't affect mature follicles and corpora lutea (P > .05). Immunohistochemical analyzes, taken as a whole, show that R-IPC benefic effect is more evident in the later periods of evaluation, when a greater proliferative activity (14, 21, and 30 days, P < .05) and lesser cell apoptotic activity (21 and 30 days, P < .05). The VEGF expression was similar in all times (P > .05). Remote ischemic preconditioning could have a benefic effect in the progressive evaluation of freshly grafted ovarian, especially on the latest phases of the posttransplant period. The 14th day was a landmark in the recuperation of the graft. Further investigations are necessary to determine the role of R-IPC in this scenario and its effect in frozen-thawed ovarian tissue. PMID:26674322

  5. A Weakest Precondition Approach to Robustness

    NASA Astrophysics Data System (ADS)

    Balliu, Musard; Mastroeni, Isabella

    With the increasing complexity of information management computer systems, security becomes a real concern. E-government, web-based financial transactions or military and health care information systems are only a few examples where large amount of information can reside on different hosts distributed worldwide. It is clear that any disclosure or corruption of confidential information in these contexts can result fatal. Information flow controls constitute an appealing and promising technology to protect both data confidentiality and data integrity. The certification of the security degree of a program that runs in untrusted environments still remains an open problem in the area of language-based security. Robustness asserts that an active attacker, who can modify program code in some fixed points (holes), is unable to disclose more private information than a passive attacker, who merely observes unclassified data. In this paper, we extend a method recently proposed for checking declassified non-interference in presence of passive attackers only, in order to check robustness by means of weakest precondition semantics. In particular, this semantics simulates the kind of analysis that can be performed by an attacker, i.e., from public output towards private input. The choice of semantics allows us to distinguish between different attacks models and to characterize the security of applications in different scenarios.

  6. Concepts of hypoxic NO signaling in remote ischemic preconditioning

    PubMed Central

    Totzeck, Matthias; Hendgen-Cotta, Ulrike; Rassaf, Tienush

    2015-01-01

    Acute coronary syndromes remain a leading single cause of death worldwide. Therapeutic strategies to treat cardiomyocyte threatening ischemia/reperfusion injury are urgently needed. Remote ischemic preconditioning (rIPC) applied by brief ischemic episodes to heart-distant organs has been tested in several clinical studies, and the major body of evidence points to beneficial effects of rIPC for patients. The underlying signaling, however, remains incompletely understood. This relates particularly to the mechanism by which the protective signal is transferred from the remote site to the target organ. Many pathways have been forwarded but none can explain the protective effects completely. In light of recent experimental studies, we here outline the current knowledge relating to the generation of the protective signal in the remote organ, the signal transfer to the target organ and the transduction of the transferred signal into cardioprotection. The majority of studies favors a humoral factor that activates cardiomyocyte downstream signaling - receptor-dependent and independently. Cellular targets include deleterious calcium (Ca2+) signaling, reactive oxygen species, mitochondrial function and structure, and cellular apoptosis and necrosis. Following an outline of the existing evidence, we will furthermore characterize the existing knowledge and discuss future perspectives with particular emphasis on the interaction between the recently discovered hypoxic nitrite-nitric oxide signaling in rIPC. This refers to the protective role of nitrite, which can be activated endogenously using rIPC and which then contributes to cardioprotection by rIPC. PMID:26516418

  7. Fetal asphyctic preconditioning alters the transcriptional response to perinatal asphyxia

    PubMed Central

    2014-01-01

    Background Genomic reprogramming is thought to be, at least in part, responsible for the protective effect of brain preconditioning. Unraveling mechanisms of this endogenous neuroprotection, activated by preconditioning, is an important step towards new clinical strategies for treating asphyctic neonates. Therefore, we investigated whole-genome transcriptional changes in the brain of rats which underwent perinatal asphyxia (PA), and rats where PA was preceded by fetal asphyctic preconditioning (FAPA). Offspring were sacrificed 6 h and 96 h after birth, and whole-genome transcription was investigated using the Affymetrix Gene1.0ST chip. Microarray data were analyzed with the Bioconductor Limma package. In addition to univariate analysis, we performed Gene Set Enrichment Analysis (GSEA) in order to derive results with maximum biological relevance. Results We observed minimal, 25% or less, overlap of differentially regulated transcripts across different experimental groups which leads us to conclude that the transcriptional phenotype of these groups is largely unique. In both the PA and FAPA group we observe an upregulation of transcripts involved in cellular stress. Contrastingly, transcripts with a function in the cell nucleus were mostly downregulated in PA animals, while we see considerable upregulation in the FAPA group. Furthermore, we observed that histone deacetylases (HDACs) are exclusively regulated in FAPA animals. Conclusions This study is the first to investigate whole-genome transcription in the neonatal brain after PA alone, and after perinatal asphyxia preceded by preconditioning (FAPA). We describe several genes/pathways, such as ubiquitination and proteolysis, which were not previously linked to preconditioning-induced neuroprotection. Furthermore, we observed that the majority of upregulated genes in preconditioned animals have a function in the cell nucleus, including several epigenetic players such as HDACs, which suggests that epigenetic

  8. Reduction in postsystolic wall thickening during late preconditioning.

    PubMed

    Monnet, Xavier; Lucats, Laurence; Colin, Patrice; Derumeaux, Geneviève; Dubois-Rande, Jean-Luc; Hittinger, Luc; Ghaleh, Bijan; Berdeaux, Alain

    2007-01-01

    Brief coronary artery occlusion (CAO) and reperfusion induce myocardial stunning and late preconditioning. Postsystolic wall thickening (PSWT) also develops with CAO and reperfusion. However, the time course of PSWT during stunning and the regional function pattern of the preconditioned myocardium remain unknown. The goal of this study was to investigate the evolution of PSWT during myocardial stunning and its modifications during late preconditioning. Dogs were chronically instrumented to measure (sonomicrometry) systolic wall thickening (SWT), PSWT, total wall thickening (TWT = SWT + PSWT), and maximal rate of thickening (dWT/dt(max)). Two 10-min CAO (circumflex artery) were performed 24 h apart (day 0 and day 1, n = 7). At day 0, CAO decreased SWT and increased PSWT. During the first hours of the subsequent stunning, evolution of PSWT was symmetrical to that of SWT. At day 1, baseline SWT was similar to day 0, but PSWT was reduced (-66%), while dWT/dt(max) and SWT/TWT ratio increased (+48 and +14%, respectively). After CAO at day 1, stunning was reduced, indicating late preconditioning. Simultaneously vs. day 0, PSWT was significantly reduced, and dWT/dt(max) as well as SWT/TWT ratio were increased, i.e., a greater part of TWT was devoted to ejection. Similar decrease in PSWT was observed with a nonischemic preconditioning stimulus (rapid ventricular pacing, n = 4). In conclusion, a major contractile adaptation occurs during late preconditioning, i.e., the rate of wall thickening is enhanced and PWST is almost abolished. These phenotype adaptations represent potential approaches for characterizing stunning and late preconditioning with repetitive ischemia in humans. PMID:16920813

  9. Ionic Blocks

    ERIC Educational Resources Information Center

    Sevcik, Richard S.; Gamble, Rex; Martinez, Elizabet; Schultz, Linda D.; Alexander, Susan V.

    2008-01-01

    "Ionic Blocks" is a teaching tool designed to help middle school students visualize the concepts of ions, ionic compounds, and stoichiometry. It can also assist high school students in reviewing their subject mastery. Three dimensional blocks are used to represent cations and anions, with color indicating charge (positive or negative) and size…

  10. Nuclear mutations that block group II RNA splicing in maize chloroplasts reveal several intron classes with distinct requirements for splicing factors.

    PubMed Central

    Jenkins, B D; Kulhanek, D J; Barkan, A

    1997-01-01

    To elucidate mechanisms that regulate chloroplast RNA splicing in multicellular plants, we sought nuclear mutations in maize that result in chloroplast splicing defects. Evidence is presented for two nuclear genes whose function is required for the splicing of group II introns in maize chloroplasts. A mutation in the crs1 (for chloroplast RNA splicing 1) gene blocks the splicing of only the atpF intron, whereas a mutation in the crs2 gene blocks the splicing of many chloroplast introns. In addition, a correlation was observed between the absence of plastid ribosomes and the failure to splice several chloroplast introns. Our results suggest that a chloroplast-encoded factor and a nuclear-encoded factor whose activity requires crs2 function facilitate the splicing of distinct sets of group II introns. These two genetically defined intron sets also differ with regard to intron structure: one set consists of only subgroup IIA introns and the other of only subgroup IIB introns. Therefore, it is likely that distinct splicing factors recognize subgroup-specific features of intron structure or facilitate subgroup-specific aspects of the splicing reaction. Of the 12 pre-mRNA introns in the maize chloroplast genome, only one is normally spliced in both crs2 mutants and in mutants lacking plastid ribosomes, indicating that few, if any, of the group II introns in the chloroplast genome undergo autocatalytic splicing in vivo. PMID:9090875

  11. Autologous preconditioned mesenchymal stem cell sheets improve left ventricular function in a rabbit old myocardial infarction model

    PubMed Central

    Tanaka, Yuya; Shirasawa, Bungo; Takeuchi, Yuriko; Kawamura, Daichi; Nakamura, Tamami; Samura, Makoto; Nishimoto, Arata; Ueno, Koji; Morikage, Noriyasu; Hosoyama, Tohru; Hamano, Kimikazu

    2016-01-01

    Mesenchymal stem cells (MSCs) constitute one of the most powerful tools for therapeutic angiogenesis in infarcted hearts. However, conventional MSC transplantation approaches result in insufficient therapeutic effects due to poor retention of graft cells in severe ischemic diseases. Cell sheet technology has been developed as a new method to prolong graft cell retention even in ischemic tissue. Recently, we demonstrated that hypoxic pretreatment enhances the therapeutic efficacy of cell sheet implantation in infarcted mouse hearts. In this study, we investigated whether hypoxic pretreatment activates the therapeutic functions of bone marrow-derived MSC (BM-MSC) sheets and improves cardiac function in rabbit infarcted hearts following autologous transplantation. Production of vascular endothelial growth factor (VEGF) was increased in BM-MSC monolayer sheets and it peaked at 48 h under hypoxic culture conditions (2% O2). To examine in vivo effects, preconditioned autologous BM-MSC sheets were implanted into a rabbit old myocardial infarction model. Implantation of preconditioned BM-MSC sheets accelerated angiogenesis in the peri-infarcted area and decreased the infarcted area, leading to improvement of the left ventricular function of the infarcted heart. Importantly, the therapeutic efficacy of the preconditioned BM-MSC sheets was higher than that of standardly cultured sheets. Thus, implantation of autologous preconditioned BM-MSC sheets is a feasible approach for enhancing therapeutic angiogenesis in chronically infarcted hearts. PMID:27347329

  12. Ischemic Preconditioning Increases the Tolerance of Fatty Liver to Hepatic Ischemia-Reperfusion Injury in the Rat

    PubMed Central

    Serafín, Anna; Roselló-Catafau, Joan; Prats, Neus; Xaus, Carme; Gelpí, Emilio; Peralta, Carmen

    2002-01-01

    Hepatic steatosis is a major risk factor in ischemia-reperfusion. The present study evaluates whether preconditioning, demonstrated to be effective in normal livers, could also confer protection in the presence of steatosis and investigates the potential underlying protective mechanisms. Fatty rats had increased hepatic injury and decreased survival after 60 minutes of ischemia compared with lean rats. Fatty livers showed a degree of neutrophil accumulation and microcirculatory alterations similar to that of normal livers. However, in presence of steatosis, an increased lipid peroxidation that could be reduced with glutathione-ester pretreatment was observed after hepatic reperfusion. Ischemic preconditioning reduced hepatic injury and increased animal survival. Both in normal and fatty livers, this endogenous protective mechanism was found to control lipid peroxidation, hepatic microcirculation failure, and neutrophil accumulation, reducing the subsequent hepatic injury. These beneficial effects could be mediated by nitric oxide, because the inhibition of nitric oxide synthesis and nitric oxide donor pretreatment abolished and simulated, respectively, the benefits of preconditioning. Thus, ischemic preconditioning could be an effective surgical strategy to reduce the hepatic ischemia-reperfusion injury in normal and fatty livers under normothermic conditions, including hepatic resections, and liver transplantation. PMID:12163383

  13. TLR9 bone marrow chimeric mice define a role for cerebral TNF in neuroprotection induced by CpG preconditioning.

    PubMed

    Packard, Amy E B; Leung, Philberta Y; Vartanian, Keri B; Stevens, Susan L; Bahjat, Frances R; Stenzel-Poore, Mary P

    2012-12-01

    Systemic preconditioning with the TLR9 ligand CpG induces neuroprotection against brain ischemic injury through a tumor necrosis factor (TNF)-dependent mechanism. It is unclear how systemic administration of CpG engages the brain to induce the protective phenotype. To address this, we created TLR9-deficient reciprocal bone marrow chimeric mice lacking TLR9 on either hematopoietic cells or radiation-resistant cells of nonhematopoietic origin. We report that wild-type mice reconstituted with TLR9-deficient hematopoietic cells failed to show neuroprotection after systemic CpG preconditioning. Further, while hematopoietic expression of TLR9 is required for CpG-induced neuroprotection it is not sufficient to restore protection to TLR9-deficient mice that are reconstituted with hematopoietic cells bearing TLR9. To determine whether the absence of protection was associated with TNF, we examined TNF levels in the systemic circulation and the brain. We found that although TNF is required for CpG preconditioning, systemic TNF levels did not correlate with the protective phenotype. However, induction of cerebral TNF mRNA required expression of TLR9 on both hematopoietic and nonhematopoietic cells and correlated with neuroprotection. In accordance with these results, we show the therapeutic potential of intranasal CpG preconditioning, which induces brain TNF mRNA and robust neuroprotection with no concomitant increase in systemic levels of TNF. PMID:23010947

  14. Hydrogen sulfide preconditioning protects against myocardial ischemia/reperfusion injury in rats through inhibition of endo/sarcoplasmic reticulum stress

    PubMed Central

    Li, Changyong; Hu, Min; Wang, Yuan; Lu, Huan; Deng, Jing; Yan, Xiaohong

    2015-01-01

    Ischemia reperfusion (I/R) injury is a major cause of myocardial damage. Hydrogen sulfide (H2S), a gaseous signal molecule, has drawn considerable attention for its role in various pathophysiological processes. Multiple lines of evidence reveal the protective effects of H2S in various models of cardiac injury, however, the exact mechanism underlying this protective effect of H2S against myocardial I/R injury is not fully understood. The present study was designed to investigate whether H2S preconditioning attenuates myocardial I/R injury in rats and whether the observed protection is associated with reduced endo/sarcoplasmic reticulum (ER/SR) stress. We found that H2S preconditioning significantly reduced myocardial infarct size, preserved left ventricular function, and inhibited I/R-induced cardiomyocyte apoptosis in vivo. Furthermore, H2S preconditioning significantly attenuated I/R-induced ER/SR stress responses, including the increased expression of glucose-regulated protein 78, C/EBP homologous protein, and activate transcription factor in myocardium. Additionally, we demonstrate that H2S preconditioning attenuates ER/SR stress and inhibits cardiomyocyte apoptosis in an in vitro model of hypoxia/reoxygenation in rat H9c2 cardiac myocytes. In conclusion, these results suggest that H2S-attenuated ER/SR stress plays an important role in its protective effects against I/R-induced myocardial injury. PMID:26339339

  15. A Clinical Experimental Model to Evaluate Analgesic Effect of Remote Ischemic Preconditioning in Acute Postoperative Pain

    PubMed Central

    Pereira, Francisco Elano Carvalho; Mello, Irene Lopes; Pimenta, Fernando Heladio de Oliveira Medeiros; Costa, Debora Maia; Wong, Deysi Viviana Tenazoa; Fernandes, Claudia Regina; Lima Junior, Roberto César; Gomes, Josenília M. Alves

    2016-01-01

    This study aims to evaluate the viability of a clinical model of remote ischemic preconditioning (RIPC) and its analgesic effects. It is a prospective study with twenty (20) patients randomly divided into two groups: control group and RIPC group. The opioid analgesics consumption in the postoperative period, the presence of secondary mechanical hyperalgesia, the scores of postoperative pain by visual analog scale, and the plasma levels interleukins (IL-6) were evaluated. The tourniquet applying after spinal anesthetic block was safe, producing no pain for all patients in the tourniquet group. The total dose of morphine consumption in 24 hours was significantly lower in RIPC group than in the control group (p = 0.0156). The intensity analysis of rest pain, pain during coughing and pain in deep breathing, showed that visual analogue scale (VAS) scores were significantly lower in RIPC group compared to the control group: p = 0.0087, 0.0119, and 0.0015, respectively. There were no differences between groups in the analysis of presence or absence of mechanical hyperalgesia (p = 0.0704) and in the serum levels of IL-6 dosage over time (p < 0.0001). This clinical model of remote ischemic preconditioning promoted satisfactory analgesia in patients undergoing conventional cholecystectomy, without changing serum levels of IL-6. PMID:27446611

  16. A Clinical Experimental Model to Evaluate Analgesic Effect of Remote Ischemic Preconditioning in Acute Postoperative Pain.

    PubMed

    Pereira, Francisco Elano Carvalho; Mello, Irene Lopes; Pimenta, Fernando Heladio de Oliveira Medeiros; Costa, Debora Maia; Wong, Deysi Viviana Tenazoa; Fernandes, Claudia Regina; Lima Junior, Roberto César; Gomes, Josenília M Alves

    2016-01-01

    This study aims to evaluate the viability of a clinical model of remote ischemic preconditioning (RIPC) and its analgesic effects. It is a prospective study with twenty (20) patients randomly divided into two groups: control group and RIPC group. The opioid analgesics consumption in the postoperative period, the presence of secondary mechanical hyperalgesia, the scores of postoperative pain by visual analog scale, and the plasma levels interleukins (IL-6) were evaluated. The tourniquet applying after spinal anesthetic block was safe, producing no pain for all patients in the tourniquet group. The total dose of morphine consumption in 24 hours was significantly lower in RIPC group than in the control group (p = 0.0156). The intensity analysis of rest pain, pain during coughing and pain in deep breathing, showed that visual analogue scale (VAS) scores were significantly lower in RIPC group compared to the control group: p = 0.0087, 0.0119, and 0.0015, respectively. There were no differences between groups in the analysis of presence or absence of mechanical hyperalgesia (p = 0.0704) and in the serum levels of IL-6 dosage over time (p < 0.0001). This clinical model of remote ischemic preconditioning promoted satisfactory analgesia in patients undergoing conventional cholecystectomy, without changing serum levels of IL-6. PMID:27446611

  17. Ischemic Preconditioning in White Matter: Magnitude and Mechanism

    PubMed Central

    Hamner, Margaret A.; Ye, Zucheng; Lee, Richard V.; Colman, Jamie R.; Le, Thu; Gong, Davin C.; Weinstein, Jonathan R.

    2015-01-01

    Ischemic preconditioning (IPC) is a robust neuroprotective phenomenon whereby brief ischemic exposure confers tolerance to a subsequent ischemic challenge. IPC has not been studied selectively in CNS white matter (WM), although stroke frequently involves WM. We determined whether IPC is present in WM and, if so, its mechanism. We delivered a brief in vivo preconditioning ischemic insult (unilateral common carotid artery ligation) to 12- to 14-week-old mice and determined WM ischemic vulnerability [oxygen–glucose deprivation (OGD)] 72 h later, using acutely isolated optic nerves (CNS WM tracts) from the preconditioned (ipsilateral) and control (contralateral) hemispheres. Functional and structural recovery was assessed by quantitative measurement of compound action potentials (CAPs) and immunofluorescent microscopy. Preconditioned mouse optic nerves (MONs) showed better functional recovery after OGD than the non-preconditioned MONs (31 ± 3 vs 17 ± 3% normalized CAP area, p < 0.01). Preconditioned MONs also showed improved axon integrity and reduced oligodendrocyte injury compared with non-preconditioned MONs. Toll-like receptor-4 (TLR4) and type 1 interferon receptor (IFNAR1), key receptors in innate immune response, are implicated in gray matter preconditioning. Strikingly, IPC-mediated WM protection was abolished in both TLR4−/− and IFNAR1−/− mice. In addition, IPC-mediated protection in WM was also abolished in IFNAR1fl/fl LysMcre, but not in IFNAR1fl/fl control, mice. These findings demonstrated for the first time that IPC was robust in WM, the phenomenon being intrinsic to WM itself. Furthermore, WM IPC was dependent on innate immune cell signaling pathways. Finally, these data demonstrated that microglial-specific expression of IFNAR1 plays an indispensable role in WM IPC. SIGNIFICANCE STATEMENT Ischemic preconditioning (IPC) has been studied predominantly in gray matter, but stroke in humans frequently involves white matter (WM) as well. Here we

  18. Heat shock proteins, end effectors of myocardium ischemic preconditioning?

    PubMed Central

    Guisasola, María Concepcion; Desco, Maria del Mar; Gonzalez, Fernanda Silvana; Asensio, Fernando; Dulin, Elena; Suarez, Antonio; Garcia Barreno, Pedro

    2006-01-01

    The purpose of this study was to investigate (1) whether ischemia-reperfusion increased the content of heat shock protein 72 (Hsp72) transcripts and (2) whether myocardial content of Hsp72 is increased by ischemic preconditioning so that they can be considered as end effectors of preconditioning. Twelve male minipigs (8 protocol, 4 sham) were used, with the following ischemic preconditioning protocol: 3 ischemia and reperfusion 5-minute alternative cycles and last reperfusion cycle of 3 hours. Initial and final transmural biopsies (both in healthy and ischemic areas) were taken in all animals. Heat shock protein 72 messenger ribonucleic acid (mRNA) expression was measured by a semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR) method using complementary DNA normalized against the housekeeping gene cyclophilin. The identification of heat shock protein 72 was performed by immunoblot. In our “classic” preconditioning model, we found no changes in mRNA hsp72 levels or heat shock protein 72 content in the myocardium after 3 hours of reperfusion. Our experimental model is valid and the experimental techniques are appropriate, but the induction of heat shock proteins 72 as end effectors of cardioprotection in ischemic preconditioning does not occur in the first hours after ischemia, but probably at least 24 hours after it, in the so-called “second protection window.” PMID:17009598

  19. Implementation of Preconditioned Dual-Time Procedures in OVERFLOW

    NASA Technical Reports Server (NTRS)

    Pandya, Shishir A.; Venkateswaran, Sankaran; Pulliam, Thomas H.; Kwak, Dochan (Technical Monitor)

    2003-01-01

    Preconditioning methods have become the method of choice for the solution of flowfields involving the simultaneous presence of low Mach and transonic regions. It is well known that these methods are important for insuring accurate numerical discretization as well as convergence efficiency over various operating conditions such as low Mach number, low Reynolds number and high Strouhal numbers. For unsteady problems, the preconditioning is introduced within a dual-time framework wherein the physical time-derivatives are used to march the unsteady equations and the preconditioned time-derivatives are used for purposes of numerical discretization and iterative solution. In this paper, we describe the implementation of the preconditioned dual-time methodology in the OVERFLOW code. To demonstrate the performance of the method, we employ both simple and practical unsteady flowfields, including vortex propagation in a low Mach number flow, flowfield of an impulsively started plate (Stokes' first problem) arid a cylindrical jet in a low Mach number crossflow with ground effect. All the results demonstrate that the preconditioning algorithm is responsible for improvements to both numerical accuracy and convergence efficiency and, thereby, enables low Mach number unsteady computations to be performed at a fraction of the cost of traditional time-marching methods.

  20. Fourier analysis of parallel inexact Block-Jacobi splitting with transport synthetic acceleration in slab geometry

    SciTech Connect

    Rosa, M.; Warsa, J. S.; Chang, J. H.

    2006-07-01

    A Fourier analysis is conducted for the discrete-ordinates (SN) approximation of the neutron transport problem solved with Richardson iteration (Source Iteration) and Richardson iteration preconditioned with Transport Synthetic Acceleration (TSA), using the Parallel Block-Jacobi (PBJ) algorithm. Both 'traditional' TSA (TTSA) and a 'modified' TSA (MTSA), in which only the scattering in the low order equations is reduced by some non-negative factor {beta} and < 1, are considered. The results for the un-accelerated algorithm show that convergence of the PBJ algorithm can degrade. The PBJ algorithm with TTSA can be effective provided the {beta} parameter is properly tuned for a given scattering ratio c, but is potentially unstable. Compared to TTSA, MTSA is less sensitive to the choice of {beta}, more effective for the same computational effort (c'), and it is unconditionally stable. (authors)

  1. Resveratrol preconditioning protects against cerebral ischemic injury via Nrf2

    PubMed Central

    Narayanan, Srinivasan V.; Dave, Kunjan R.; Saul, Isa; Perez-Pinzon, Miguel A.

    2015-01-01

    Background and Purpose Nuclear erythroid 2 related factor 2 (Nrf2) is an astrocyte-enriched transcription factor that has previously been shown to upregulate cellular antioxidant systems in response to ischemia. While resveratrol preconditioning (RPC) has emerged as a potential neuroprotective therapy, the involvement of Nrf2 in RPC-induced neuroprotection and mitochondrial reactive oxygen species (ROS) production following cerebral ischemia remains unclear. The goal of our study was to study the contribution of Nrf2 to RPC and its effects on mitochondrial function. Methods We used rodent astrocyte cultures and an in vivo stroke model with RPC. An Nrf2 DNA-binding ELISA and protein analysis via Western blotting of downstream Nrf2 targets were performed to determine RPC-induced activation of Nrf2 in rat and mouse astrocytes. Following RPC, mitochondrial function was determined by measuring ROS production and mitochondrial respiration in both wild-type (WT) and Nrf2−/− mice. Infarct volume was measured to determine neuroprotection, while protein levels were measured by immunoblotting. Results We report that Nrf2 is activated by RPC in rodent astrocyte cultures, and that loss of Nrf2 reduced RPC-mediated neuroprotection in a mouse model of focal cerebral ischemia. In addition, we observed that wild-type and Nrf2−/− cortical mitochondria exhibited increased uncoupling and ROS production following RPC treatments, Finally, Nrf2−/− astrocytes exhibited decreased mitochondrial antioxidant expression and were unable to upregulate cellular antioxidants following RPC treatment. Conclusion Nrf2 contributes to RPC-induced neuroprotection through maintaining mitochondrial coupling and antioxidant protein expression. PMID:25908459

  2. Cucurbitacin I blocks cerebrospinal fluid and platelet derived growth factor-BB stimulation of leptomeningeal and meningioma DNA synthesis

    PubMed Central

    2013-01-01

    Background Currently, there are no consistently effective chemotherapies for recurrent and inoperable meningiomas. Recently, cucurbitacin I (JSI-124), a naturally occurring tetracyclic triterpenoid compound used as folk medicines has been found to have cytoxic and anti-proliferative properties in several malignancies thru inhibition of activator of transcription (STAT3) activation. Previously, we have found STAT3 to be activated in meningiomas, particularly higher grade tumors. Methods Primary leptomeningeal cultures were established from 17, 20 and 22 week human fetuses and meningioma cell cultures were established from 6 World Health Organization (WHO) grade I or II meningiomas. Cells were treated with cerebrospinal fluid from patients without neurologic disease. The effects of cucurbitacin I on cerebrospinal fluid stimulation of meningioma cell DNA synthesis phosphorylation/activation of JAK1, STAT3, pMEK1/2, p44/42MAPK, Akt, mTOR, Rb and caspase 3 activation were analyzed in human leptomeningeal and meningioma cells. Results Cerebrospinal fluid significantly stimulated DNA synthesis in leptomeningeal cells. Co-administration of cucurbitacin I (250 nM) produces a significant blockade of this effect. Cucurbitacin I alone also produced a significant reduction in basal DNA synthesis. In grade I and II meningiomas, cerebrospinal fluid also significantly stimulated DNA synthesis. Co-administration of cucurbitacin I (250 nM) blocked this effect. In the leptomeningeal cultures, cerebrospinal fluid stimulated STAT3 phosphorylation but not p44/42MAPK, Akt or mTOR. Cucurbitacin I had no effect on basal STAT3 phosphorylation but co-administration with cerebrospinal fluid blocked cerebrospinal fluid stimulation of STAT3 phosphorylation in each. In the grade I meningiomas, cerebrospinal fluid stimulated phosphorylation of STAT3 and decreased MEK1/2 and cucurbitacin I had no effect on basal STAT3, p44/42MAPK, Akt, JAK1, mTOR, or Rb phosphorylation. In the grade II

  3. Beta-elemene blocks epithelial-mesenchymal transition in human breast cancer cell line MCF-7 through Smad3-mediated down-regulation of nuclear transcription factors.

    PubMed

    Zhang, Xian; Li, Yinghua; Zhang, Yang; Song, Jincheng; Wang, Qimin; Zheng, Luping; Liu, Dan

    2013-01-01

    Epithelial-mesenchymal transition (EMT) is the first step required for breast cancer to initiate metastasis. However, the potential of drugs to block and reverse the EMT process are not well explored. In the present study, we investigated the inhibitory effect of beta-elemene (ELE), an active component of a natural plant-derived anti-neoplastic agent in an established EMT model mediated by transforming growth factor-beta1 (TGF-β1). We found that ELE (40 µg/ml ) blocked the TGF-β1-induced phenotypic transition in the human breast cancer cell line MCF-7. ELE was able to inhibit TGF-β1-mediated upregulation of mRNA and protein expression of nuclear transcription factors (SNAI1, SNAI2, TWIST and SIP1), potentially through decreasing the expression and phosphorylation of Smad3, a central protein mediating the TGF-β1 signalling pathway. These findings suggest a potential therapeutic benefit of ELE in treating basal-like breast cancer. PMID:23516540

  4. R + C Factors and Sacro Occipital Technique Orthopedic Blocking: a pilot study using pre and post VAS assessment

    PubMed Central

    Blum, Charles L.

    2015-01-01

    Introduction: The concept of a systematic or predictive relationship between distant vertebral levels distinct from accumulative functional compensatory mechanisms, such as in scoliosis, has been perpetuated within chiropractic technique systems based on clinical observation and experience. This study seeks to investigate this relationship between the cervical and lumbar vertebrae. Methods: Patients (experimental group n=26 and control group n=12) were selected from the patient base of one office, and were limited to patients that had sensitivity at specific cervical reflex points. Using a pre and post outcome measurement and sacro occipital technique R + C protocols, the related lumbar vertebra was adjusted in the direction indicated by the cervical vertebral sensitivity. Results: Statistical analysis revealed there was a statistically significant difference between pre- and post-VAS measurements and found that the notable difference in mean change in VAS scores were statistically significantly different between the experimental and control groups (p < .001). Conclusion: The findings of this study suggest that further research into cervical and lumbar vertebra interrelationships, and the efficacy of orthopedic block treatment, may be warranted. Further studies are needed to confirm whether a causal relationship exists between lumbar manipulation and decreased cervical spine sensitivity. PMID:26136605

  5. Gpu Implementation of Preconditioning Method for Low-Speed Flows

    NASA Astrophysics Data System (ADS)

    Zhang, Jiale; Chen, Hongquan

    2016-06-01

    An improved preconditioning method for low-Mach-number flows is implemented on a GPU platform. The improved preconditioning method employs the fluctuation of the fluid variables to weaken the influence of accuracy caused by the truncation error. The GPU parallel computing platform is implemented to accelerate the calculations. Both details concerning the improved preconditioning method and the GPU implementation technology are described in this paper. Then a set of typical low-speed flow cases are simulated for both validation and performance analysis of the resulting GPU solver. Numerical results show that dozens of times speedup relative to a serial CPU implementation can be achieved using a single GPU desktop platform, which demonstrates that the GPU desktop can serve as a cost-effective parallel computing platform to accelerate CFD simulations for low-Speed flows substantially.

  6. Operator-Based Preconditioning of Stiff Hyperbolic Systems

    SciTech Connect

    Reynolds, Daniel R.; Samtaney, Ravi; Woodward, Carol S.

    2009-02-09

    We introduce an operator-based scheme for preconditioning stiff components encoun- tered in implicit methods for hyperbolic systems of partial differential equations posed on regular grids. The method is based on a directional splitting of the implicit operator, followed by a char- acteristic decomposition of the resulting directional parts. This approach allows for solution to any number of characteristic components, from the entire system to only the fastest, stiffness-inducing waves. We apply the preconditioning method to stiff hyperbolic systems arising in magnetohydro- dynamics and gas dynamics. We then present numerical results showing that this preconditioning scheme works well on problems where the underlying stiffness results from the interaction of fast transient waves with slowly-evolving dynamics, scales well to large problem sizes and numbers of processors, and allows for additional customization based on the specific problems under study.

  7. Liquid hydrogen turbopump rapid start program. [thermal preconditioning using coatings

    NASA Technical Reports Server (NTRS)

    Wong, G. S.

    1973-01-01

    This program was to analyze, test, and evaluate methods of achieving rapid-start of a liquid hydrogen feed system (inlet duct and turbopump) using a minimum of thermal preconditioning time and propellant. The program was divided into four tasks. Task 1 includes analytical studies of the testing conducted in the other three tasks. Task 2 describes the results from laboratory testing of coating samples and the successful adherence of a KX-635 coating to the internal surfaces of the feed system tested in Task 4. Task 3 presents results of testing an uncoated feed system. Tank pressure was varied to determine the effect of flowrate on preconditioning. The discharge volume and the discharge pressure which initiates opening of the discharge valve were varied to determine the effect on deadhead (no through-flow) start transients. Task 4 describes results of testing a similar, internally coated feed system and illustrates the savings in preconditioning time and propellant resulting from the coatings.

  8. On adaptive weighted polynomial preconditioning for Hermitian positive definite matrices

    NASA Technical Reports Server (NTRS)

    Fischer, Bernd; Freund, Roland W.

    1992-01-01

    The conjugate gradient algorithm for solving Hermitian positive definite linear systems is usually combined with preconditioning in order to speed up convergence. In recent years, there has been a revival of polynomial preconditioning, motivated by the attractive features of the method on modern architectures. Standard techniques for choosing the preconditioning polynomial are based only on bounds for the extreme eigenvalues. Here a different approach is proposed, which aims at adapting the preconditioner to the eigenvalue distribution of the coefficient matrix. The technique is based on the observation that good estimates for the eigenvalue distribution can be derived after only a few steps of the Lanczos process. This information is then used to construct a weight function for a suitable Chebyshev approximation problem. The solution of this problem yields the polynomial preconditioner. In particular, we investigate the use of Bernstein-Szego weights.

  9. Preconditioning boosts regenerative programmes in the adult zebrafish heart

    PubMed Central

    de Preux Charles, Anne-Sophie; Bise, Thomas; Baier, Felix; Sallin, Pauline; Jaźwińska, Anna

    2016-01-01

    During preconditioning, exposure to a non-lethal harmful stimulus triggers a body-wide increase of survival and pro-regenerative programmes that enable the organism to better withstand the deleterious effects of subsequent injuries. This phenomenon has first been described in the mammalian heart, where it leads to a reduction of infarct size and limits the dysfunction of the injured organ. Despite its important clinical outcome, the actual mechanisms underlying preconditioning-induced cardioprotection remain unclear. Here, we describe two independent models of cardiac preconditioning in the adult zebrafish. As noxious stimuli, we used either a thoracotomy procedure or an induction of sterile inflammation by intraperitoneal injection of immunogenic particles. Similar to mammalian preconditioning, the zebrafish heart displayed increased expression of cardioprotective genes in response to these stimuli. As zebrafish cardiomyocytes have an endogenous proliferative capacity, preconditioning further elevated the re-entry into the cell cycle in the intact heart. This enhanced cycling activity led to a long-term modification of the myocardium architecture. Importantly, the protected phenotype brought beneficial effects for heart regeneration within one week after cryoinjury, such as a more effective cell-cycle reentry, enhanced reactivation of embryonic gene expression at the injury border, and improved cell survival shortly after injury. This study reveals that exposure to antecedent stimuli induces adaptive responses that render the fish more efficient in the activation of the regenerative programmes following heart damage. Our results open a new field of research by providing the adult zebrafish as a model system to study remote cardiac preconditioning. PMID:27440423

  10. Targeted Disruption of Heparan Sulfate Interaction with Hepatocyte and Vascular Endothelial Growth Factors Blocks Normal and Oncogenic Signaling

    PubMed Central

    Cecchi, Fabiola; Pajalunga, Deborah; Fowler, C. Andrew; Uren, Aykut; Rabe, Daniel C.; Peruzzi, Benedetta; MacDonald, Nicholas J.; Blackman, Davida K.; Stahl, Stephen J.; Byrd, R. Andrew; Bottaro, Donald P.

    2012-01-01

    Summary Hepatocyte growth factor (HGF) and vascular endothelial cell growth factor (VEGF) regulate normal development and homeostasis, and drive disease progression in many forms of cancer. Both proteins signal by binding to receptor tyrosine kinases and heparan sulfate (HS) proteoglycans on target cell surfaces. Basic residues comprising the primary HS binding sites on HGF and VEGF provide similar surface charge distributions without underlying structural similarity. Combining three acidic amino acid substitutions in these sites in the HGF isoform NK1 or the VEGF isoform VEGF165 transformed each into potent, selective competitive antagonists of their respective normal and oncogenic signaling pathways. Our findings illustrate the importance of HS in growth factor driven cancer progression and reveal an efficient strategy for therapeutic antagonist development. PMID:22897854

  11. Ethanol preconditioning of rat cerebellar cultures targets NMDA receptors to the synapse and enhances peroxiredoxin 2 expression.

    PubMed

    Mitchell, Robert M; Tajuddin, Nuzhath; Campbell, Edward M; Neafsey, Edward J; Collins, Michael A

    2016-07-01

    Epidemiological studies indicate that light-moderate alcohol (ethanol) consumers tend to have reduced risks of cognitive impairment and progression to dementia during aging. Exploring possible mechanisms, we previously found that moderate ethanol preconditioning (MEP, 20-30mM) of rat brain cultures for several days instigated neuroprotection against β-amyloid peptides. Our biochemical evidence implicated the NMDA receptor (NMDAR) as a potential neuroprotective "sensor", specifically via synaptic NMDAR signaling. It remains unclear how ethanol modulates the receptor and its downstream targets to engender neuroprotection. Here we confirm with deconvolution microscopy that MEP of rat mixed cerebellar cultures robustly increases synaptic NMDAR localization. Phospho-activation of the non-receptor tyrosine kinases Src and Pyk2, known to be linked to synaptic NMDAR, is also demonstrated. Additionally, the preconditioning enhances levels of an antioxidant protein, peroxiredoxin 2 (Prx2), reported to be downstream of synaptic NMDAR signaling, and NMDAR antagonism with memantine (earlier found to abrogate MEP neuroprotection) blocks the Prx2 elevations. To further link Prx2 with antioxidant-based neuroprotection, we circumvented the ethanol preconditioning-NMDAR pathway by pharmacologically increasing Prx2 with the naturally-occurring cruciferous compound, 3H-1,2-dithiole-3-thione (D3T). Thus, D3T pretreatment elevated Prx2 expression to a similar extent as MEP, while concomitantly preventing β-amyloid neurotoxicity; D3T also protected the cultures from hydrogen peroxide toxicity. The findings support a mechanism that couples synaptic NMDAR signaling, Prx2 expression and augmented antioxidant defenses in ethanol preconditioning-induced neuroprotection. That this mechanism can be emulated by a cruciferous vegetable constituent suggests that such naturally-occurring "neutraceuticals" may be useful in therapy for oxidative stress-related dementias. PMID:27021955

  12. Choice of Variables and Preconditioning for Time Dependent Problems

    NASA Technical Reports Server (NTRS)

    Turkel, Eli; Vatsa, Verr N.

    2003-01-01

    We consider the use of low speed preconditioning for time dependent problems. These are solved using a dual time step approach. We consider the effect of this dual time step on the parameter of the low speed preconditioning. In addition, we compare the use of two sets of variables, conservation and primitive variables, to solve the system. We show the effect of these choices on both the convergence to a steady state and the accuracy of the numerical solutions for low Mach number steady state and time dependent flows.

  13. Fourier analysis of finite element preconditioned collocation schemes

    NASA Technical Reports Server (NTRS)

    Deville, Michel O.; Mund, Ernest H.

    1990-01-01

    The spectrum of the iteration operator of some finite element preconditioned Fourier collocation schemes is investigated. The first part of the paper analyses one-dimensional elliptic and hyperbolic model problems and the advection-diffusion equation. Analytical expressions of the eigenvalues are obtained with use of symbolic computation. The second part of the paper considers the set of one-dimensional differential equations resulting from Fourier analysis (in the tranverse direction) of the 2-D Stokes problem. All results agree with previous conclusions on the numerical efficiency of finite element preconditioning schemes.

  14. Preconditioning for multiplexed imaging with spatially coded PSFs.

    PubMed

    Horisaki, Ryoichi; Tanida, Jun

    2011-06-20

    We propose a preconditioning method to improve the convergence of iterative reconstruction algorithms in multiplexed imaging based on convolution-based compressive sensing with spatially coded point spread functions (PSFs). The system matrix is converted to improve the condition number with a preconditioner matrix. The preconditioner matrix is calculated by Tikhonov regularization in the frequency domain. The method was demonstrated with simulations and an experiment involving a range detection system with a grating based on the multiplexed imaging framework. The results of the demonstrations showed improved reconstruction fidelity by using the proposed preconditioning method. PMID:21716495

  15. A subspace preconditioning algorithm for eigenvector/eigenvalue computation

    SciTech Connect

    Bramble, J.H.; Knyazev, A.V.; Pasciak, J.E.

    1996-12-31

    We consider the problem of computing a modest number of the smallest eigenvalues along with orthogonal bases for the corresponding eigen-spaces of a symmetric positive definite matrix. In our applications, the dimension of a matrix is large and the cost of its inverting is prohibitive. In this paper, we shall develop an effective parallelizable technique for computing these eigenvalues and eigenvectors utilizing subspace iteration and preconditioning. Estimates will be provided which show that the preconditioned method converges linearly and uniformly in the matrix dimension when used with a uniform preconditioner under the assumption that the approximating subspace is close enough to the span of desired eigenvectors.

  16. A Parallel, Fully Coupled, Fully Implicit Solution to Reactive Transport in Porous Media Using the Preconditioned Jacobian-Free Newton-Krylov Method

    SciTech Connect

    Luanjing Guo; Hai Huang; Derek Gaston; Cody Permann; David Andrs; George Redden; Chuan Lu; Don Fox; Yoshiko Fujita

    2013-03-01

    Modeling large multicomponent reactive transport systems in porous media is particularly challenging when the governing partial differential algebraic equations (PDAEs) are highly nonlinear and tightly coupled due to complex nonlinear reactions and strong solution-media interactions. Here we present a preconditioned Jacobian-Free Newton-Krylov (JFNK) solution approach to solve the governing PDAEs in a fully coupled and fully implicit manner. A well-known advantage of the JFNK method is that it does not require explicitly computing and storing the Jacobian matrix during Newton nonlinear iterations. Our approach further enhances the JFNK method by utilizing physics-based, block preconditioning and a multigrid algorithm for efficient inversion of the preconditioner. This preconditioning strategy accounts for self- and optionally, cross-coupling between primary variables using diagonal and off-diagonal blocks of an approximate Jacobian, respectively. Numerical results are presented demonstrating the efficiency and massive scalability of the solution strategy for reactive transport problems involving strong solution-mineral interactions and fast kinetics. We found that the physics-based, block preconditioner significantly decreases the number of linear iterations, directly reducing computational cost; and the strongly scalable algebraic multigrid algorithm for approximate inversion of the preconditioner leads to excellent parallel scaling performance.

  17. The Protective Effect of Remote Renal Preconditioning Against Hippocampal Ischemia Reperfusion Injury: Role of KATP Channels.

    PubMed

    Mehrjerdi, Fatemeh Zare; Aboutaleb, Nahid; Pazoki-Toroudi, Hamidreza; Soleimani, Mansoureh; Ajami, Marjan; Khaksari, Mehdi; Safari, Fatemeh; Habibey, Rouhollah

    2015-12-01

    Remote ischemic preconditioning (RIPC), which consists of several brief ischemia/reperfusion applied at the remote site of lethal ischemia reperfusion, can, through activating different mechanisms, increase the ability of the body's endogenous protection against prolonged ischemia/reperfusion. Recent studies have shown that RIPC has neuroprotective effects, but its mechanisms are not well elucidated. The present study aimed to determine whether activation of KATP channels in remote renal preconditioning decreases hippocampus damage induced by global cerebral ischemia. RIPC was induced by ischemia of the left renal artery (IPC); 24 h later, global cerebral ischemia reperfusion (IR) was induced by common carotid arteries occlusion. 5hydroxydecanoate (5HD) and glibenclamide (Gli) were injected before of IPC. The levels of malondialdehyde (MDA) and catalase (CAT) activity were assessed in hippocampus. Terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) was assessed to detect apoptotic cells in hippocampus. RIPC inhibited apoptosis by decreasing positive TUNEL cells (P < 0.05). KATP channels blocking with 5HD and Gli markedly increased apoptosis in hippocampal cells in RIPC group (P < 0.001). RIPC decreased MDA level and increased CAT activity in ischemic hippocampus (P < 0.01). Also, 5HD and Gli inhibited the effect of RIPC on MDA level and CAT activity (P < 0.05). The present study shows that RIPC can effectively attenuate programmed cell death, increase activity of CAT, and reduce MDA levels. Blocking of KATP channels inhibited the protective effects of RIPC. PMID:26254913

  18. Preconditioned conjugate-gradient methods for low-speed flow calculations

    NASA Technical Reports Server (NTRS)

    Ajmani, Kumud; Ng, Wing-Fai; Liou, Meng-Sing

    1993-01-01

    An investigation is conducted into the viability of using a generalized Conjugate Gradient-like method as an iterative solver to obtain steady-state solutions of very low-speed fluid flow problems. Low-speed flow at Mach 0.1 over a backward-facing step is chosen as a representative test problem. The unsteady form of the two dimensional, compressible Navier-Stokes equations is integrated in time using discrete time-steps. The Navier-Stokes equations are cast in an implicit, upwind finite-volume, flux split formulation. The new iterative solver is used to solve a linear system of equations at each step of the time-integration. Preconditioning techniques are used with the new solver to enhance the stability and convergence rate of the solver and are found to be critical to the overall success of the solver. A study of various preconditioners reveals that a preconditioner based on the Lower-Upper Successive Symmetric Over-Relaxation iterative scheme is more efficient than a preconditioner based on Incomplete L-U factorizations of the iteration matrix. The performance of the new preconditioned solver is compared with a conventional Line Gauss-Seidel Relaxation (LGSR) solver. Overall speed-up factors of 28 (in terms of global time-steps required to converge to a steady-state solution) and 20 (in terms of total CPU time on one processor of a CRAY-YMP) are found in favor of the new preconditioned solver, when compared with the LGSR solver.

  19. Climate preconditioning on submarine landslides at IODP site C0018 (Nankai Trough)

    NASA Astrophysics Data System (ADS)

    Kremer, Katrina; Usman, Muhammed O.; Satoguchi, Yasufumi; Nagahashi, Yoshitaka; Vadakkepuliyambatta, Sunil; Panieri, Giuliana; Strasser, Michael

    2016-04-01

    Submarine landslides are major agents in sediment-mass transfer from shallow to deep sea. Due to their rapid emplacement and tsunamigenic potential, they pose significant geohazards for society and to off- and on-shore infrastructures. Dating of the respective deposits, often referred to as mass-transport deposits (MTDs), remains an important step in order to study the frequency of such large MTDs and to better understand their trigger mechanism and preconditioning factors. Although MTDs can be imaged by seismic surveys, characterization and dating of their deposits, which are mostly buried deeper than what can be reached by standard coring techniques from conventional research vessels, require scientific ocean drilling. The aim of this study is to reconstruct the timing of large MTDs at site C0018 (IODP Exp. 333) within a slope-basin in the outer fore arc of the Nankai subduction zone, off the coast of SW Japan. Although, this margin is characterized by magnitude 8+ earthquake occurring every 150 years, only six large landslide deposits are identified in the sediment record spanning nearly 1 Million years. This suggests that long term processes other than short-term earthquake trigger mechanism must precondition the slope for infrequent failure. In this study, the existing age model of C0018 has been refined with new tephra ages and oxygen isotope stratigraphy on planctonic foraminiferas. Following this new data set, the MTDs at C0018 seem to occur during warm phases of interglacials suggesting that climate act as preconditioning factor of submarine slope instabilities in this tectonic active region.

  20. Developing a correlation index and U disequilibrium factor for the exploratory boreholes in Wahkut block of West Khasi Hills district, Meghalaya (India).

    PubMed

    Kukreti, B M; Kumar, Pramod

    2013-02-01

    With the objective to affirm the apparent uranium ore zone grade/thickness with good confidence for the non-cored as well as those boreholes with poor core recovery in the sedimentary environment of Wahkut block, West Khasi Hills district of Meghalaya, a systematic study between the in situ measured γ-ray logs under field conditions and laboratory analyzed core assay under controlled conditions has been carried out. The study area spans 2 sqkm having 33 cored and 39 non-cored boreholes with a cumulative drilled depth of about 11,000 m. On this available cored borehole database, simultaneous uranium ore zone continuity, both for in situ γ-ray logs and radiometric core assay, was evaluated with the experimental parameters of 1.0m ore zone thickness at 0.010% eU(3)O(8) cut off grade. A population of 18 such simultaneous qualifying zone (borehole log and core assay) across the 15 cored boreholes gave a grade thickness continuity index of 0.92 with a moderately strong relationship between the radiometric core assay and the in situ γ-ray logs. After validation of an in situ uranium ore zone, study boreholes were examined for their uranium disequilibrium status by fitting regression equations for the radiometric U(3)O(8)(β/γ) and spectrometric radium measurements, done on the borehole core samples. A parent favoring uranium disequilibrium was observed in the sedimentary environment of Wahkut block, with a log normal distribution. An average uranium disequilibrium factor 1.46 ± 0.245 was estimated for the 19 study boreholes, across the block. PMID:23202436

  1. Characterization of inhibitory anti-insulin-like growth factor receptor antibodies with different epitope specificity and ligand-blocking properties: implications for mechanism of action in vivo.

    PubMed

    Doern, Adam; Cao, Xianjun; Sereno, Arlene; Reyes, Christopher L; Altshuler, Angelina; Huang, Flora; Hession, Cathy; Flavier, Albert; Favis, Michael; Tran, Hon; Ailor, Eric; Levesque, Melissa; Murphy, Tracey; Berquist, Lisa; Tamraz, Susan; Snipas, Tracey; Garber, Ellen; Shestowsky, William S; Rennard, Rachel; Graff, Christilyn P; Wu, Xiufeng; Snyder, William; Cole, Lindsay; Gregson, David; Shields, Michael; Ho, Steffan N; Reff, Mitchell E; Glaser, Scott M; Dong, Jianying; Demarest, Stephen J; Hariharan, Kandasamy

    2009-04-10

    Therapeutic antibodies directed against the type 1 insulin-like growth factor receptor (IGF-1R) have recently gained significant momentum in the clinic because of preliminary data generated in human patients with cancer. These antibodies inhibit ligand-mediated activation of IGF-1R and the resulting down-stream signaling cascade. Here we generated a panel of antibodies against IGF-1R and screened them for their ability to block the binding of both IGF-1 and IGF-2 at escalating ligand concentrations (>1 microm) to investigate allosteric versus competitive blocking mechanisms. Four distinct inhibitory classes were found as follows: 1) allosteric IGF-1 blockers, 2) allosteric IGF-2 blockers, 3) allosteric IGF-1 and IGF-2 blockers, and 4) competitive IGF-1 and IGF-2 blockers. The epitopes of representative antibodies from each of these classes were mapped using a purified IGF-1R library containing 64 mutations. Most of these antibodies bound overlapping surfaces on the cysteine-rich repeat and L2 domains. One class of allosteric IGF-1 and IGF-2 blocker was identified that bound a separate epitope on the outer surface of the FnIII-1 domain. Using various biophysical techniques, we show that the dual IGF blockers inhibit ligand binding using a spectrum of mechanisms ranging from highly allosteric to purely competitive. Binding of IGF-1 or the inhibitory antibodies was associated with conformational changes in IGF-1R, linked to the ordering of dynamic or unstructured regions of the receptor. These results suggest IGF-1R uses disorder/order within its polypeptide sequence to regulate its activity. Interestingly, the activity of representative allosteric and competitive inhibitors on H322M tumor cell growth in vitro was reflective of their individual ligand-blocking properties. Many of the antibodies in the clinic likely adopt one of the inhibitory mechanisms described here, and the outcome of future clinical studies may reveal whether a particular inhibitory mechanism

  2. Late preconditioning against myocardial stunning. An endogenous protective mechanism that confers resistance to postischemic dysfunction 24 h after brief ischemia in conscious pigs.

    PubMed

    Sun, J Z; Tang, X L; Knowlton, A A; Park, S W; Qiu, Y; Bolli, R

    1995-01-01

    Conscious pigs underwent a sequence of 10 2-min coronary occlusions, each separated by 2 min of reperfusion, for three consecutive days (days 1, 2, and 3 of stage I). The recovery of systolic wall thickening (WTh) after the 10th reperfusion was markedly improved on days 2 and 3 compared with day 1, indicating that the myocardium had become preconditioned against "stunning." 10 d after stage I, pigs underwent again a sequence of 10 2-min coronary occlusions for two consecutive days (days 1 and 2 of stage II). On day 1 of stage II, the recovery of WTh after the 10th reperfusion was similar to that noted on day 1 of stage I; on day 2 of stage II, however, the recovery of WTh was again markedly improved compared with day 1. Blockade of adenosine receptors with 8-p-sulfophenyl theophylline failed to prevent the development of preconditioning against stunning. Northern blot analysis demonstrated an increase in heat stress protein (HSP) 70 mRNA 2 h after the preconditioning ischemia; at this same time point, immunohistochemical analysis revealed a concentration of HSP70 in the nucleus and an overall increase in staining for HSP70. 24 h after the preconditioning ischemia, Western dot blot analysis demonstrated an increase in HSP70. This study indicates the existence of a new, previously unrecognized cardioprotective phenomenon. The results demonstrate that a brief ischemic stress induces a powerful, long-lasting (at least 48 h) adaptive response that renders the myocardium relatively resistant to stunning 24 h later (late preconditioning against stunning). This adaptive response disappears within 10 d after the last ischemic stress but can be reinduced by another ischemic stress. Unlike early and late preconditioning against infarction, late preconditioning against stunning is not blocked by adenosine receptor antagonists, and therefore appears to involve a mechanism different from that of other forms of preconditioning currently known. The increase in myocardial HSP70 is

  3. The U.S. Geological Survey Modular Ground-Water Model - PCGN: A Preconditioned Conjugate Gradient Solver with Improved Nonlinear Control

    USGS Publications Warehouse

    Naff, Richard L.; Banta, Edward R.

    2008-01-01

    The preconditioned conjugate gradient with improved nonlinear control (PCGN) package provides addi-tional means by which the solution of nonlinear ground-water flow problems can be controlled as compared to existing solver packages for MODFLOW. Picard iteration is used to solve nonlinear ground-water flow equations by iteratively solving a linear approximation of the nonlinear equations. The linear solution is provided by means of the preconditioned conjugate gradient algorithm where preconditioning is provided by the modi-fied incomplete Cholesky algorithm. The incomplete Cholesky scheme incorporates two levels of fill, 0 and 1, in which the pivots can be modified so that the row sums of the preconditioning matrix and the original matrix are approximately equal. A relaxation factor is used to implement the modified pivots, which determines the degree of modification allowed. The effects of fill level and degree of pivot modification are briefly explored by means of a synthetic, heterogeneous finite-difference matrix; results are reported in the final section of this report. The preconditioned conjugate gradient method is coupled with Picard iteration so as to efficiently solve the nonlinear equations associated with many ground-water flow problems. The description of this coupling of the linear solver with Picard iteration is a primary concern of this document.

  4. Protein Kinase Cδ Blocks Immediate-Early Gene Expression in Senescent Cells by Inactivating Serum Response Factor

    PubMed Central

    Wheaton, Keith; Riabowol, Karl

    2004-01-01

    Fibroblasts lose the ability to replicate in response to growth factors and become unable to express growth-associated immediate-early genes, including c-fos and egr-1, as they become senescent. The serum response factor (SRF), a major transcriptional activator of immediate-early gene promoters, loses the ability to bind to the serum response element (SRE) and becomes hyperphosphorylated in senescent cells. We identify protein kinase C delta (PKCδ) as the kinase responsible for inactivation of SRF both in vitro and endogenously in senescent cells. This is due to a higher level of PKCδ activity as cells age, production of the PKCδ catalytic fragment, and its nuclear localization in senescent but not in low-passage-number cells. The phosphorylation of T160 of SRF by PKCδ in vitro and in vivo led to loss of SRF DNA binding activity. Both the PKCδ inhibitor rottlerin and ectopic expression of a dominant negative form of PKCδ independently restored SRE-dependent transcription and immediate-early gene expression in senescent cells. Modulation of PKCδ activity in vivo with rottlerin or bistratene A altered senescent- and young-cell morphology, respectively. These observations support the idea that the coordinate transcriptional inhibition of several growth-associated genes by PKCδ contributes to the senescent phenotype. PMID:15282327

  5. 40 CFR 86.132-00 - Vehicle preconditioning.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 19 2014-07-01 2014-07-01 false Vehicle preconditioning. 86.132-00 Section 86.132-00 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) CONTROL OF EMISSIONS FROM NEW AND IN-USE HIGHWAY VEHICLES AND ENGINES Emission Regulations for 1977 and Later Model Year New...

  6. 40 CFR 86.132-00 - Vehicle preconditioning.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 19 2013-07-01 2013-07-01 false Vehicle preconditioning. 86.132-00 Section 86.132-00 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) CONTROL OF EMISSIONS FROM NEW AND IN-USE HIGHWAY VEHICLES AND ENGINES Emission Regulations for 1977 and Later Model Year New...

  7. 40 CFR 1066.405 - Vehicle preparation and preconditioning.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 33 2014-07-01 2014-07-01 false Vehicle preparation and preconditioning. 1066.405 Section 1066.405 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR POLLUTION CONTROLS VEHICLE-TESTING PROCEDURES Preparing Vehicles and Running an Exhaust...

  8. 40 CFR 86.132-00 - Vehicle preconditioning.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 19 2012-07-01 2012-07-01 false Vehicle preconditioning. 86.132-00 Section 86.132-00 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) CONTROL OF EMISSIONS FROM NEW AND IN-USE HIGHWAY VEHICLES AND ENGINES Emission Regulations for 1977 and Later Model Year New...

  9. 33 CFR 183.220 - Preconditioning for tests.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 33 Navigation and Navigable Waters 2 2010-07-01 2010-07-01 false Preconditioning for tests. 183.220 Section 183.220 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) BOATING SAFETY BOATS AND ASSOCIATED EQUIPMENT Flotation Requirements for Outboard Boats Rated for Engines of More Than 2 Horsepower General...

  10. 33 CFR 183.320 - Preconditioning for tests.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 33 Navigation and Navigable Waters 2 2010-07-01 2010-07-01 false Preconditioning for tests. 183.320 Section 183.320 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) BOATING SAFETY BOATS AND ASSOCIATED EQUIPMENT Flotation Requirements for Outboard Boats Rated for Engines of 2 Horsepower or Less General §...

  11. 40 CFR 1065.516 - Sample system decontamination and preconditioning.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 33 2014-07-01 2014-07-01 false Sample system decontamination and preconditioning. 1065.516 Section 1065.516 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR POLLUTION CONTROLS ENGINE-TESTING PROCEDURES Performing an Emission Test Over Specified Duty Cycles § 1065.516 Sample...

  12. Combustion of coal/water mixtures with thermal preconditioning

    SciTech Connect

    Novack, M.; Roffe, G.; Miller, G.

    1987-01-01

    Thermal preconditioning is a process in which coal/water mixtures are vaporized to produce coal/steam suspensions, and then superheated to allow the coal to devolitalize producing suspensions of char particles in hydrocarbon gases and steam. This final product of the process can be injected without atomization, and burned directly in a gas turbine combustor. This paper reports on the results of an experimental program in which thermally preconditioned coal/water mixture was successfully burned with a stable flame in a gas turbine combustor test rig. Tests were performed at a mixture flowrate of 300 1b/hr and combustor pressure of 8 atmospheres. The coal/water mixture was thermally preconditioned and injected into the combustor over a temperature range from 350/sup 0/F to 600/sup 0/F, and combustion air was supplied at between 600/sup 0/F to 725/sup 0/F. Test durations varied between 10 to 20 minutes. The original mean coal particle size for these tests, prior to preconditioning was 25 microns. Results of additional tests showed that one-third of the sulfur contained in the solids of a coal/water mixture with 3 percent sulfur were evolved in gaseous form (under mild thermolized conditions) mainly as H/sub 2/S with the remainder as light mercaptans.

  13. Improvement in computational fluid dynamics through boundary verification and preconditioning

    NASA Astrophysics Data System (ADS)

    Folkner, David E.

    This thesis provides improvements to computational fluid dynamics accuracy and efficiency through two main methods: a new boundary condition verification procedure and preconditioning techniques. First, a new verification approach that addresses boundary conditions was developed. In order to apply the verification approach to a large range of arbitrary boundary conditions, it was necessary to develop unifying mathematical formulation. A framework was developed that allows for the application of Dirichlet, Neumann, and extrapolation boundary condition, or in some cases the equations of motion directly. Verification of boundary condition techniques was performed using exact solutions from canonical fluid dynamic test cases. Second, to reduce computation time and improve accuracy, preconditioning algorithms were applied via artificial dissipation schemes. A new convective upwind and split pressure (CUSP) scheme was devised and was shown to be more effective than traditional preconditioning schemes in certain scenarios. The new scheme was compared with traditional schemes for unsteady flows for which both convective and acoustic effects dominated. Both boundary conditions and preconditioning algorithms were implemented in the context of a "strand grid" solver. While not the focus of this thesis, strand grids provide automatic viscous quality meshing and are suitable for moving mesh overset problems.

  14. 40 CFR 86.132-96 - Vehicle preconditioning.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 18 2010-07-01 2010-07-01 false Vehicle preconditioning. 86.132-96 Section 86.132-96 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) CONTROL OF EMISSIONS FROM NEW AND IN-USE HIGHWAY VEHICLES AND ENGINES Emission Regulations for 1977 and Later Model Year New...

  15. 40 CFR 86.1774-99 - Vehicle preconditioning.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 19 2011-07-01 2011-07-01 false Vehicle preconditioning. 86.1774-99... (CONTINUED) CONTROL OF EMISSIONS FROM NEW AND IN-USE HIGHWAY VEHICLES AND ENGINES (CONTINUED) General Provisions for the Voluntary National Low Emission Vehicle Program for Light-Duty Vehicles and...

  16. 40 CFR 86.1774-99 - Vehicle preconditioning.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 19 2010-07-01 2010-07-01 false Vehicle preconditioning. 86.1774-99... (CONTINUED) CONTROL OF EMISSIONS FROM NEW AND IN-USE HIGHWAY VEHICLES AND ENGINES (CONTINUED) General Provisions for the Voluntary National Low Emission Vehicle Program for Light-Duty Vehicles and...

  17. 40 CFR 86.1774-99 - Vehicle preconditioning.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 20 2013-07-01 2013-07-01 false Vehicle preconditioning. 86.1774-99... (CONTINUED) CONTROL OF EMISSIONS FROM NEW AND IN-USE HIGHWAY VEHICLES AND ENGINES (CONTINUED) General Provisions for the Voluntary National Low Emission Vehicle Program for Light-Duty Vehicles and...

  18. The Role of Preconditioning on Thermosphere Mass Density (Invited)

    NASA Astrophysics Data System (ADS)

    Thayer, J. P.; Liu, X.

    2013-12-01

    The ability to determine the amount of change expected in thermosphere mass density at a specific altitude in response to solar and geomagnetic disturbances is of major importance in predicting how low-earth orbiting satellites will be affected by atmospheric drag. It is also of importance in understanding how energy deposited in the thermosphere results in a certain change in thermosphere mass density. The response at a particular altitude will depend on the type of energy input, the altitude distribution of energy input, the internal processing of the energy input, and the state properties of the thermosphere gas (i.e. density, temperature, composition, winds) prior to the energy input - that is, the preconditioned state. As an example of preconditioning, the mass density at an altitude a few scale heights above the altitude where a fixed amount of energy is deposited will have a greater relative change when the initial state of the thermosphere exospheric temperature is cold. Thus, the preconditioned state of the thermosphere must be described properly in order to adequately predict the mass density response to a given energy input. Furthermore, the preconditioned composition structure will be important and can also cause the level of response in mass density to vary with altitude. The solar EUV flux is the major contributor in establishing the preconditioned state of thermosphere and the recent solar cycle with its extreme solar minimum EUV flux has resulted in an unprecedented cold and contracted thermosphere. High-resolution mass density observations inferred from accelerometer measurements on the CHAMP and GRACE satellites are used to demonstrate the role of preconditioning in mass density response to geomagnetic disturbances. Temperature and composition conditions are evaluated to explain observed changes in mass density. In particular, the dynamic action of the oxygen to helium transition region in both latitude and altitude is used to explain complex

  19. Thermal preconditioning of coal/water mixtures. Final report

    SciTech Connect

    Roffe, G.; Miller, G.

    1984-10-01

    Thermal preconditioning of coal/water mixtures is a process proposed for use with stationary gas turbine engines in which the CWM is heated before delivery to the combustor in order to accomplish the water vaporization and coal pyrolysis/devolatilization steps prior to injection. The process offers a number of potential advantages such as the ability to start the engine without the use of an auxiliary fuel system, the elimination of atomizing nozzles, increased flame stability for proper turndown, compatibility with NO/sub x/-control techniques such as rich-burn-quick quench combustors, and potentially faster char burnout. The objective of the program was to obtain information which will allow the feasibility of thermal preconditioning to be evaluated. The economics of the process and its impact on a combined cycle system have been addressed. The slurry heating and boiling processes have been studied and the relationships between fuel properties, temperature and residence time in the processing apparatus and the evolution of combustible gases have been measured. A special apparatus was designed and constructed for the experimental portion of the program. Results indicate that at temperatures above 900/sup 0/F significant devolatilization can be accomplished in residence times on the order of one second. A preliminary economic and performance analysis has been completed for the thermal preconditioning process. Four gas turbine power plant concepts incorporating thermal preconditioning of CWS have been investigated. These concepts differ from one another in the source of heat used for the preconditioning process. Heat paths have been defined and the relationships between the efficiencies and operating conditions of the various components on heat rate and plant output have been determined. The analysis indicates that increases in heat rate of less than 5% can be expected. 4 refs., 10 figs., 2 tabs.

  20. Combustion of coal/water mixtures with thermal preconditioning

    SciTech Connect

    Novack, M.; Roffe, G.; Miller, G.

    1987-07-01

    Thermal preconditioning is a process in which coal/water mixtures are vaporized to produce coal/steam suspensions, and then superheated to allow the coal to devolatilize producing suspensions of char particles in hydrocarbon gases and steam. This final product of the process can be injected without atomization, and burned directly in a gas turbine combustor. This paper reports on the results of an experimental program in which thermally preconditioned coal/water mixture was successfully burned with a stable flame in a gas turbine combustor test rig. Tests were performed at a mixture flowrate of 300 lb/hr and combustor pressure of 8 atm. The coal/water mixture was thermally preconditioned and injected into the combustor over a temperature range from 340/sup 0/F to 600/sup 0/F, and combustion air was supplied at between 600/sup 0/F to 725/sup 0/F. Test durations varied between 10 and 20 min. Major results of the combustion testing were that: A stable flame was maintained over a wide equivalence ratio range, between phi = 2.2 (rich) and 0.2 (lean); and combustion efficiency of over 99 percent was achieved when the mixture was preconditioned to 600/sup 0/F and the combustion air preheated to 725/sup 0/F. Measurements of ash particulates, captured in the exhaust sampling probe located 20 in. from the injector face, show typical sizes collected to be about 1 ..mu..m, with agglomerates of these particulates to be not more than 8 ..mu..m. The original mean coal particle size for these tests, prior to preconditioning, was 25 ..mu..m. Results of additional tests showed that one third of the sulfur contained in the solids of a coal/water mixture with 3 percent sulfur was evolved in gaseous form (under mild thermolized conditions) mainly as H/sub 2/S with the remainder as light mercaptans.

  1. Hyperbaric oxygen preconditioning promotes neovascularization of transplanted skin flaps in rats

    PubMed Central

    Liu, Xuehua; Yang, Jing; Li, Zhuo; Yang, Lin; Wang, Cong; Gao, Chunjin; Liang, Fang

    2014-01-01

    To determine whether Hyperbaric oxygen preconditioning (HBO-PC) promotes neovascularization by increasing Stromal cell derived factor-1 (SDF-1) and CXC chemokine receptor 4 (CXCR4) in transplanted skin flaps of rats. The epigastric pedicle skin flap was established in a rat model. Rats were randomly assigned to the following five groups: 1) sham-operated group (SH); 2) ischemia followed by reperfusion 3 days postoperatively group (IR3d); 3) ischemia followed by reperfusion 5 days postoperatively group (IR5d); 4) hyperbaric oxygen preconditioning and ischemia followed by reperfusion 3 days postoperatively group (HBO-PC3d); and 5) hyperbaric oxygen preconditioning and ischemia followed by reperfusion 5 days postoperatively group(HBO-PC5d). For the groups receiving HBO-PC, animals underwent 1 hour of HBO at 2.0 ATA in 100% O2 twice per day for 3 days consecutively prior to surgery. After perfusion, Laser Doppler perfusion imaging (LDPI) was performed, and skin flap tissue samples were harvested for histological evaluation and western blot analysis. Perfusion was significantly improved in the HBO-PC groups compared with the IR groups on postoperative 3 and 5. Microvessel density (MVD) was significantly increased by HBO-PC compared with IR groups postoperatively. Western blot analysis revealed that SDF-1 and CXCR4 expression in the HBO-PC groups was significantly increased compared with IR groups. HBO-PC promoted neovascularization via increasing expression levels of SDF-1 and CXCR4 in transplanted skin flaps of rats. PMID:25197344

  2. The key role of meteorological preconditions in triggering large-scale floods in Germany

    NASA Astrophysics Data System (ADS)

    Mühr, Bernhard; Kunz, Michael

    2016-04-01

    The key role of meteorological preconditions in triggering large-scale floods in Germany Central Europe has seen some major flood events over recent year. In Germany, for example, the severe flooding in 2002 caused total loss amounting to 11.2 Billion Euros, representing the costliest natural disaster ever. In 2013, another disastrous flood event was responsible for losses of 8 Billion Euros. In November 2015, an exceptional heavy rain event affected mainly southern Germany with widespread rain amounts between 50 and 200 mm within 36 hours across an area of roughly 100.000 km² (federal states of Bavaria and Baden-Württemberg). Usually such a rain event inevitably would trigger several floods, but in that case, surprisingly only a few gauges exceeded flood stages and only marginal damage has been caused. Due to exceptional dry weather conditions in the previous months, most of the precipitation drained with the consequence that surface runoff was very low. Within CEDIM's (Center for Disaster Management and Risk Reduction Technology) forensic disaster analysis Task Force we examined the relation between event precipitation, preconditions, and water levels for that and other events in Germany. Such information helps to rapidly evaluate ongoing flood events and to assess their potential severity as an important component of disaster response activities. Furthermore, closely monitoring and documenting the hydro-meteorological factors that are most decisive for the generation and triggering of flood events is one part of CEDIM's approach. The investigation of meteorological preconditions (e.g., Antecedent Precipitation Index) and the combination with expected rain amounts provides a valuable basis for the in-depth analysis and improved understanding and forecasting of floods and their key drivers.

  3. Pertussis toxin treatment does not block inhibition by atrial natriuretic factor of aldosterone secretion in cultured bovine zona glomerulosa cells

    SciTech Connect

    De Lean, A.; Cantin, M.

    1986-03-05

    The authors have previously reported that atrial natriuretic factor (ANF) potently inhibits PGE or forskolin-stimulation aldosterone secretion in bovine zona glomerulosa (ZG) by acting through specific high affinity receptors. In order to evaluate the functional role of the regulatory protein N/sub i/ and the inhibition of adenylate cyclase activity (AC) in ZG, the authors have studied the effect of treatment with PT on inhibition by ANF of aldosterone production. Primary cultures of ZG were treated for 18 hours in serum-free F12 medium with (0-100 ng/ml PT). No effect of PT pretreatment was observed either on basal, PGE-stimulated or ANF-inhibited levels of steroidogenesis. When membranes prepared from control ZG were ADP-ribosylated with (/sup 32/P) NAD in the presence of PT, two toxin-specific bands with 39 Kd and 41 Kd were documented on SDS gel. Cell pretreatment with as low as 1 ng/ml drastically reduced further labelling of these two bands while higher doses completely abolished them. Since PT treatment covalently modifies completely the toxin substrate without altering ANF inhibition of adrenal steroidogenesis, the authors conclude that N/sub i/ is not involved in the mode of action of ANF on aldosterone production.

  4. Metalloproteinase Inhibitors, Nonantimicrobial Chemically Modified Tetracyclines, and Ilomastat Block Bacillus anthracis Lethal Factor Activity in Viable Cells

    PubMed Central

    Kocer, Salih S.; Walker, Stephen G.; Zerler, Brad; Golub, Lorne M.; Simon, Sanford R.

    2005-01-01

    Lethal toxin, produced by the bacterium Bacillus anthracis, is a major contributor to morbidity and mortality in animals and humans who have contracted anthrax. One component of this toxin, lethal factor (LF), proteolytically inactivates members of the mitogen-activated protein kinase kinase (MAPKK or MEK) family. In this study we show that CMT-300, CMT-308, and Ilomastat, agents initially characterized as matrix metalloproteinase inhibitors which are in early stages of development as pharmaceuticals, effectively inhibit the zinc metalloproteinase activity of LF. All three inhibitors, CMT-300, CMT-308, and Ilomastat, inhibit LF-mediated cleavage of a synthetic peptide substrate based on the N-terminal domain of MEKs. Inhibition of LF-mediated MEK proteolysis by all three agents was also achieved using lysates of the human monocytoid line MonoMac 6 as sources of MAPKKs and visualization of the extent of cleavage after separation by sodium dodecyl sulfate-polyacrylamide gel electrophoresis followed by detection by Western blotting. Finally, we have demonstrated inhibition of intracellular MEKs in viable human monocytes and MonoMac 6 cells by these agents after incubation of the cells with a reconstituted preparation of recombinant lethal toxin. All three agents are effective inhibitors when incubated with LF prior to exposure to cells, while the CMTs, but not Ilomastat, are also effective when added after LF has already entered the viable cell targets. These results offer promise for strategies to combat effects of the lethal toxin of B. anthracis. PMID:16239558

  5. Attributes and Preconditions of Collaboration between and among Schools, Institutions of Higher Education, and State Education Agencies. Instructional Leadership and School Improvement.

    ERIC Educational Resources Information Center

    Reed, Patricia; Cejda, Brent

    Recognizing that successful collaboration among schools, institutes of higher education, and state education agencies to is an important factor in the professional development of education personnel, this document examines existing knowledge of interorganizational collaboration and identifies organizational preconditions conducive to the…

  6. MueLu Multigrid Preconditioning Package

    SciTech Connect

    2012-09-11

    MueLu is intended for the research and development of multigrid algorithms used in the solution of sparse linear systems arising from systems of partial differential equations. The software provides multigrid source code, test programs, and short example programs to demonstrate the various interfaces for creating, accessing, and applying the solvers. MueLu currently provides an implementation of smoothed aggregation algebraic multigrid method and interfaces to many commonly used smoothers. However, the software is intended to be extensible, and new methods can be incorporated easily. MueLu also allows for advanced usage, such as combining multiple methods and segregated solves. The library supports point and block access to matrix data. All algorithms and methods in MueLu have been or will be published in the open scientific literature.

  7. MueLu Multigrid Preconditioning Package

    Energy Science and Technology Software Center (ESTSC)

    2012-09-11

    MueLu is intended for the research and development of multigrid algorithms used in the solution of sparse linear systems arising from systems of partial differential equations. The software provides multigrid source code, test programs, and short example programs to demonstrate the various interfaces for creating, accessing, and applying the solvers. MueLu currently provides an implementation of smoothed aggregation algebraic multigrid method and interfaces to many commonly used smoothers. However, the software is intended to bemore » extensible, and new methods can be incorporated easily. MueLu also allows for advanced usage, such as combining multiple methods and segregated solves. The library supports point and block access to matrix data. All algorithms and methods in MueLu have been or will be published in the open scientific literature.« less

  8. Protective effects of remote ischemic preconditioning in rat hindlimb on ischemia- reperfusion injury★

    PubMed Central

    Zhang, Ying; Liu, Xiangrong; Yan, Feng; Min, Lianqiu; Ji, Xunming; Luo, Yumin

    2012-01-01

    Three cycles of remote ischemic pre-conditioning induced by temporarily occluding the bilateral femoral arteries (10 minutes) prior to 10 minutes of reperfusion were given once a day for 3 days before the animal received middle artery occlusion and reperfusion surgery. The results showed that brain infarct volume was significantly reduced after remote ischemic pre-conditioning. Scores in the forelimb placing test and the postural reflex test were significantly lower in rats having undergone remote ischemic pre-conditioning compared with those who did not receive remote ischemic pre-conditioning. Thus, neurological function was better in rats having undergone remote ischemic pre-conditioning compared with those who did not receive remote ischemic pre-conditioning. These results indicate that remote ischemic pre-conditioning in rat hindlimb exerts protective effects in ischemia-reperfusion injury. PMID:25745448

  9. Optimization of Blocked Designs in fMRI Studies

    ERIC Educational Resources Information Center

    Maus, Barbel; van Breukelen, Gerard J. P.; Goebel, Rainer; Berger, Martijn P. F.

    2010-01-01

    Blocked designs in functional magnetic resonance imaging (fMRI) are useful to localize functional brain areas. A blocked design consists of different blocks of trials of the same stimulus type and is characterized by three factors: the length of blocks, i.e., number of trials per blocks, the ordering of task and rest blocks, and the time between…

  10. Aurintricarboxylic acid blocks in vitro and in vivo activity of YopH, an essential virulent factor of Yersinia pestis, the agent of plague.

    PubMed

    Liang, Fubo; Huang, Zhonghui; Lee, Seung-Yub; Liang, Jiao; Ivanov, Maya I; Alonso, Andres; Bliska, James B; Lawrence, David S; Mustelin, Tomas; Zhang, Zhong-Yin

    2003-10-24

    Yersinia are causative agents in human diseases ranging from gastrointestinal syndromes to Bubonic Plague. There is increasing risk of misuse of infectious agents, such as Yersinia pestis, as weapons of terror as well as instruments of warfare for mass destruction. YopH is an essential virulence factor whose protein-tyrosine phosphatase (PTP) activity is required for Yersinia pathogenicity. Consequently, there is considerable interest in developing potent and selective YopH inhibitors as novel anti-plague agents. We have screened a library of 720 structurally diverse commercially available carboxylic acids and identified 26 YopH inhibitors with IC50 values below 100 mum. The most potent and specific YopH inhibitor is aurintricarboxylic acid (ATA), which exhibits a Ki value of 5 nm for YopH and displays 6-120-fold selectivity in favor of YopH against a panel of mammalian PTPs. To determine whether ATA can block the activity of YopH in a cellular context, we have examined the effect of ATA on T-cell signaling in human Jurkat cells transfected with YopH. We show that YopH severely decreases the T-cell receptor-induced cellular tyrosine phosphorylation, ERK1/2 activity, and interleukin-2 transcriptional activity. We demonstrate that ATA can effectively block the inhibitory activity of YopH and restore normal T-cell function. These results provide a proof-of-concept for the hypothesis that small molecule inhibitors that selectively target YopH may be therapeutically useful. In addition, it is expected that potent and selective YopH inhibitors, such as ATA, should be useful reagents to delineate YopH's cellular targets in plague and other pathogenic conditions caused by Yersinia infection. PMID:12888560

  11. Pigment epithelium-derived factor inhibits advanced glycation end product-elicited mesangial cell damage by blocking NF-kappaB activation.

    PubMed

    Ide, Yuichiro; Matsui, Takanori; Ishibashi, Yuji; Takeuchi, Masayoshi; Yamagishi, Sho-ichi

    2010-09-01

    Advanced glycation end products (AGE), senescent macroprotein derivatives formed at an accelerated rate under hyperglycemic conditions, elicit oxidative stress generation and inflammatory reactions, thus being involved in the development and progression of diabetic nephropathy. Recently, we, along with others, have found that pigment epithelium-derived factor (PEDF), a glycoprotein with potent neuronal differentiating activity, inhibits AGE-elicited endothelial cell damage through its anti-oxidative properties and blocks the progression of experimental diabetic retinopathy. However, a role of PEDF in diabetic nephropathy is not fully understood. In this study, we investigated whether and how PEDF could protect against AGE-elicited mesangial cell damage in vitro. PEDF mRNA and protein levels were decreased by the treatments of AGE. PEDF or neutralizing antibody raised against RAGE (receptor for AGE) was found to inhibit the AGE-induced oxidative stress generation and subsequent NF-kappaB activation in mesangial cells. Further, AGE increased mRNA levels of monocyte chemoattractant protein-1 (MCP-1), vascular cell adhesion molecule-1 (VCAM-1) and plasminogen activator inhibitor-1 (PAI-1) in mesangial cells, all of which were prevented by the treatments with PEDF, RAGE antibody or pyrrolidine dithiocarbamate, a NF-kappaB inhibitor. The present results demonstrated for the first time that PEDF blocked the AGE-RAGE-mediated mesangial cell injury by inhibiting NF-kappaB activation via suppression of reactive oxygen species generation. Our present study suggests that substitution of PEDF proteins may be a promising strategy for the treatment of diabetic nephropathy. PMID:20381502

  12. Single-domain antibodies that compete with the natural ligand fibroblast growth factor block the internalization of the fibroblast growth factor receptor 1

    SciTech Connect

    Veggiani, Gianluca; Ossolengo, Giuseppe; Aliprandi, Marisa; Cavallaro, Ugo; Marco, Ario de

    2011-05-20

    Highlights: {yields} Recombinant antibodies for FGFR1 were isolated from a llama naive library in VHH format. {yields} These antibodies compete with the natural ligand FGF-2 for the same epitope on FGFR1. {yields} The antibody competition inhibits the FGF-2-dependent internalization of FGFR1. -- Abstract: Single-domain antibodies in VHH format specific for fibroblast growth factor receptor 1 (FGFR1) were isolated from a phage-display llama naive library. In particular, phage elution in the presence of the natural receptor ligand fibroblast growth factor (FGF) allowed for the identification of recombinant antibodies that compete with FGF for the same region on the receptor surface. These antibodies posses a relatively low affinity for FGFR1 and were never identified when unspecific elution conditions favoring highly affine binders were applied to panning procedures. Two populations of competitive antibodies were identified that labeled specifically the receptor-expressing cells in immunofluorescence and recognize distinct epitopes. Antibodies from both populations effectively prevented FGF-dependent internalization and nuclear accumulation of the receptor in cultured cells. This achievement indicates that these antibodies have a capacity to modulate the receptor physiology and, therefore, constitute powerful reagents for basic research and a potential lead for therapeutic applications.

  13. Lymphoid enhancer factor-1 blocks adenomatous polyposis coli-mediated nuclear export and degradation of beta-catenin. Regulation by histone deacetylase 1.

    PubMed

    Henderson, Beric R; Galea, Melanie; Schuechner, Stefan; Leung, Louie

    2002-07-01

    The oncogenic protein beta-catenin is overexpressed in many cancers, frequently accumulating in nuclei where it forms active complexes with lymphoid enhancer factor-1 (LEF-1)/T-cell transcription factors, inducing genes such as c-myc and cyclin D1. In normal cells, nuclear beta-catenin levels are controlled by the adenomatous polyposis coli (APC) protein through nuclear export and cytoplasmic degradation. Transient expression of LEF-1 is known to increase nuclear beta-catenin levels by an unknown mechanism. Here, we show that APC and LEF-1 compete for nuclear beta-catenin with opposing consequences. APC can export nuclear beta-catenin to the cytoplasm for degradation. In contrast, LEF-1 anchors beta-catenin in the nucleus by blocking APC-mediated nuclear export. LEF-1 also prevented the APC/CRM1-independent nuclear export of beta-catenin as revealed by in vitro assays. Importantly, LEF-1-bound beta-catenin was protected from degradation by APC and axin in SW480 colon cancer cells. The ability of LEF-1 to trap beta-catenin in the nucleus was down-regulated by histone deacetylase 1, and this correlated with a decrease in LEF1 transcription activity. Our findings identify LEF-1 as key regulator of beta-catenin nuclear localization and stability and suggest that overexpression of LEF-1 in colon cancer and melanoma cells may contribute to the accumulation of oncogenic beta-catenin in the nucleus. PMID:11986304

  14. Mechanisms of Heart Block after Transcatheter Aortic Valve Replacement – Cardiac Anatomy, Clinical Predictors and Mechanical Factors that Contribute to Permanent Pacemaker Implantation

    PubMed Central

    Young Lee, Mark; Chilakamarri Yeshwant, Srinath; Chava, Sreedivya; Lawrence Lustgarten, Daniel

    2015-01-01

    Transcatheter aortic valve replacement (TAVR) has emerged as a valuable, minimally invasive treatment option in patients with symptomatic severe aortic stenosis at prohibitive or increased risk for conventional surgical replacement. Consequently, patients undergoing TAVR are prone to peri-procedural complications including cardiac conduction disturbances, which is the focus of this review. Atrioventricular conduction disturbances and arrhythmias before, during or after TAVR remain a matter of concern for this high-risk group of patients, as they have important consequences on hospital duration, short- and long-term medical management and finally on decisions of device-based treatment strategies (pacemaker or defibrillator implantation). We discuss the mechanisms of atrioventricular disturbances and characterise predisposing factors. Using validated clinical predictors, we discuss strategies to minimise the likelihood of creating permanent high-grade heart block, and identify factors to expedite the decision to implant a permanent pacemaker when the latter is unavoidable. We also discuss optimal pacing strategies to mitigate the possibility of pacing-induced cardiomyopathy. PMID:26835105

  15. A pre-conditioned implicit direct forcing based immersed boundary method for incompressible viscous flows

    NASA Astrophysics Data System (ADS)

    Park, Hyunwook; Pan, Xiaomin; Lee, Changhoon; Choi, Jung-Il

    2016-06-01

    A novel immersed boundary (IB) method based on an implicit direct forcing (IDF) scheme is developed for incompressible viscous flows. The key idea for the present IDF method is to use a block LU decomposition technique in momentum equations with Taylor series expansion to construct the implicit IB forcing in a recurrence form, which imposes more accurate no-slip boundary conditions on the IB surface. To accelerate the IB forcing convergence during the iterative procedure, a pre-conditioner matrix is introduced in the recurrence formulation of the IB forcing. A Jacobi-type parameter is determined in the pre-conditioner matrix by minimizing the Frobenius norm of the matrix function representing the difference between the IB forcing solution matrix and the pre-conditioner matrix. In addition, the pre-conditioning parameter is restricted due to the numerical stability in the recurrence formulation. Consequently, the present pre-conditioned IDF (PIDF) enables accurate calculation of the IB forcing within a few iterations. We perform numerical simulations of two-dimensional flows around a circular cylinder and three-dimensional flows around a sphere for low and moderate Reynolds numbers. The result shows that PIDF yields a better imposition of no-slip boundary conditions on the IB surfaces for low Reynolds number with a fairly larger time step than IB methods with different direct forcing schemes due to the implicit treatment of the diffusion term for determining the IB forcing. Finally, we demonstrate the robustness of the present PIDF scheme by numerical simulations of flow around a circular array of cylinders, flows around a falling sphere, and two sedimenting spheres in gravity.

  16. Polyethylene Glycol Preconditioning: An Effective Strategy to Prevent Liver Ischemia Reperfusion Injury

    PubMed Central

    Pantazi, Eirini; Calvo, Maria; Folch-Puy, Emma; Serafín, Anna; Panisello, Arnau; Adam, René; Roselló-Catafau, Joan

    2016-01-01

    Hepatic ischemia reperfusion injury (IRI) is an inevitable clinical problem for liver surgery. Polyethylene glycols (PEGs) are water soluble nontoxic polymers that have proven their effectiveness in various in vivo and in vitro models of tissue injury. The present study aims to investigate whether the intravenous administration of a high molecular weight PEG of 35 kDa (PEG 35) could be an effective strategy for rat liver preconditioning against IRI. PEG 35 was intravenously administered at 2 and 10 mg/kg to male Sprague Dawley rats. Then, rats were subjected to one hour of partial ischemia (70%) followed by two hours of reperfusion. The results demonstrated that PEG 35 injected intravenously at 10 mg/kg protected efficiently rat liver against the deleterious effects of IRI. This was evidenced by the significant decrease in transaminases levels and the better preservation of mitochondrial membrane polarization. Also, PEG 35 preserved hepatocyte morphology as reflected by an increased F-actin/G-actin ratio and confocal microscopy findings. In addition, PEG 35 protective mechanisms were correlated with the activation of the prosurvival kinase Akt and the cytoprotective factor AMPK and the inhibition of apoptosis. Thus, PEG may become a suitable agent to attempt pharmacological preconditioning against hepatic IRI. PMID:26981166

  17. Trends in the use of preconditioning to hypoxia for early prevention of future life diseases.

    PubMed

    Basovich, Simon N

    2013-02-01

    Environmental factors during fetal life program the health outcomes regarding many diseases in future life. This idea has been supported by worldwide epidemiological studies, but the underlying mechanisms are still poorly understood. Three questions should be answered. (i) Does a common underlying cause of ordinary pathological fetal development exist? (ii) If such a cause exists, which mechanism might develop disease in later life? (iii) Is it possible to prevent this underlying cause and therefore the associated obstetric complications to primarily prevent future life diseases? The objective of this review is to attempt to answer these three questions by using PubMed (extending to October 2012) and other sources. Three data-based answers corresponding to these questions were found: (i) hypoxia, (ii) excessive stimulation of neurogenesis, and (iii) preconditioning/adaptation to hypoxia. The method for such preconditioning/adaptation is intermittent hypoxic training (IHT), in which air with low oxygen concentration is breathed through a mask to protect against subsequent strong adverse influences. Data are cited for IHT applications for the prevention/treatment of diseases in different fields, particularly in obstetrics. Data suggested that all common fetal origins of adult diseases are likely predetermined by changes in the fetal brain; therefore, early detection of these changes must be very important. The use of IHT may be a real means to primarily prevent obstetric complications and therefore, prevent future life diseases. PMID:23524890

  18. Protective effect of carbon monoxide pre-conditioning on LPS-induced endothelial cell stress

    PubMed Central

    Zannoni, Augusta; Bacci, Maria Laura; Forni, Monica

    2009-01-01

    Increasing evidence indicates that carbon monoxide (CO) may protect against several diseases including sepsis. The ability of CO pre-treatment to provide good pre-conditioning against lipopolysaccharide (LPS)-induced injury was tested using an in vitro model of primary culture of porcine aortic endothelial cells (pAEC). pAEC were exposed to CO (250 ppm) or air for 1 h prior to the addition of LPS (10 μg/ml). Hsp70, HO-1, and Egr-1 protein levels were determined as well as vascular endothelial growth factor (VEGF) secretion after 4, 7, and 15 h. The effect of CO on LPS-induced apoptosis was also detected at 15 h. CO pre-treatment before the addition of LPS, significantly reduced LPS-induced apoptosis. LPS induced an increase in the level of VEGF in culture media after 7 and 15 h, and a larger increase was detected in CO pre-treated cells. In addition, CO pre-treatment reduced LPS-induced Hsp70, HO-1, and Egr-1 protein expression. In conclusion, CO treatment seems to provide a good pre-conditioning for the prevention of LPS-induced endothelial injury. PMID:19693705

  19. In vivo inhibition of the mitochondrial H+-ATP synthase in neurons promotes metabolic preconditioning

    PubMed Central

    Formentini, Laura; Pereira, Marta P; Sánchez-Cenizo, Laura; Santacatterina, Fulvio; Lucas, José J; Navarro, Carmen; Martínez-Serrano, Alberto; Cuezva, José M

    2014-01-01

    A key transducer in energy conservation and signaling cell death is the mitochondrial H+-ATP synthase. The expression of the ATPase inhibitory factor 1 (IF1) is a strategy used by cancer cells to inhibit the activity of the H+-ATP synthase to generate a ROS signal that switches on cellular programs of survival. We have generated a mouse model expressing a mutant of human IF1 in brain neurons to assess the role of the H+-ATP synthase in cell death in vivo. The expression of hIF1 inhibits the activity of oxidative phosphorylation and mediates the shift of neurons to an enhanced aerobic glycolysis. Metabolic reprogramming induces brain preconditioning affording protection against quinolinic acid-induced excitotoxicity. Mechanistically, preconditioning involves the activation of the Akt/p70S6K and PARP repair pathways and Bcl-xL protection from cell death. Overall, our findings provide the first in vivo evidence highlighting the H+-ATP synthase as a target to prevent neuronal cell death. PMID:24521670

  20. Plant Translation Elongation Factor 1Bβ Facilitates Potato Virus X (PVX) Infection and Interacts with PVX Triple Gene Block Protein 1.

    PubMed

    Hwang, JeeNa; Lee, Seonhee; Lee, Joung-Ho; Kang, Won-Hee; Kang, Jin-Ho; Kang, Min-Young; Oh, Chang-Sik; Kang, Byoung-Cheorl

    2015-01-01

    The eukaryotic translation elongation factor 1 (eEF1) has two components: the G-protein eEF1A and the nucleotide exchange factor eEF1B. In plants, eEF1B is itself composed of a structural protein (eEF1Bγ) and two nucleotide exchange subunits (eEF1Bα and eEF1Bβ). To test the effects of elongation factors on virus infection, we isolated eEF1A and eEF1B genes from pepper (Capsicum annuum) and suppressed their homologs in Nicotiana benthamiana using virus-induced gene silencing (VIGS). The accumulation of a green fluorescent protein (GFP)-tagged Potato virus X (PVX) was significantly reduced in the eEF1Bβ- or eEF1Bɣ-silenced plants as well as in eEF1A-silenced plants. Yeast two-hybrid and co-immunoprecipitation analyses revealed that eEF1Bα and eEF1Bβ interacted with eEF1A and that eEF1A and eEF1Bβ interacted with triple gene block protein 1 (TGBp1) of PVX. These results suggest that both eEF1A and eEF1Bβ play essential roles in the multiplication of PVX by physically interacting with TGBp1. Furthermore, using eEF1Bβ deletion constructs, we found that both N- (1-64 amino acids) and C-terminal (150-195 amino acids) domains of eEF1Bβ are important for the interaction with PVX TGBp1 and that the C-terminal domain of eEF1Bβ is involved in the interaction with eEF1A. These results suggest that eEF1Bβ could be a potential target for engineering virus-resistant plants. PMID:26020533

  1. Hypoxic preconditioning: effect, mechanism and clinical implication (Part 1).

    PubMed

    Lu, Guo-wei; Shao, Guo

    2014-11-01

    Hypoxic preconditioning (HPC) refers to exposure of organisms, systems, organs, tissues or cells to moderate hypoxia/ischemia that is able to result in a resistance to subsequent severe hypoxia/ischemia in tissues and cells. The effects exerted by HPC are well documented. The original local in situ (LiHPC) is now broadened to remote ectopic organs-tissues (ReHPC) and extended crossly to cross pluripotential HPC(CpHPC) induced by a variety of stresses other than hypoxia/ischemia, including cancer, for example. We developed a unique animal model of repetitive autohypoxia in adult mice, and studied systematically on the effects and mechanisms of HPC on the model in our laboratory since the early 1960s. The tolerances to hypoxia and protection from injury increased significantly in this model. The adult mice behave like hypoxia-intolerant mammalian newborns and hypoxia-tolerant adult animals during their exposure to repetitive autohypoxia. The overall energy supply and demand decreased, the microorganization of the brain maintained and the spacial learning and memory ability improved but not impaired, the detrimental neurochemicals such as free radicals down-regulated and the beneficial neurochemicals such as adenosine(ADO) and antihypoxic gene(s)/factor(s) (AHGs/AHFs) up-regulated. Accordingly, we hypothesize that mechanisms for the tolerance/protective effects of HPC are fundamentally depending on energy saving and brain plasticity in particular. It is thought that these two major mechanisms are triggered by exposure to hypoxia/ischemia via oxygen sensing-transduction pathways and HIF-1 initiation cascades. We suggest that HPC is an intrinsic mechanism developed in biological evolution and is a novel potential strategy for fighting against hypoxia-ischemia and other stresses. Motivation of endogenous antihypoxic potential, activation of oxygen sensing--signal transduction systems and supplement of exogenous antihypoxic substances as well as development of HPC

  2. Shape reanalysis and sensitivities utilizing preconditioned iterative boundary solvers

    NASA Technical Reports Server (NTRS)

    Guru Prasad, K.; Kane, J. H.

    1992-01-01

    The computational advantages associated with the utilization of preconditined iterative equation solvers are quantified for the reanalysis of perturbed shapes using continuum structural boundary element analysis (BEA). Both single- and multi-zone three-dimensional problems are examined. Significant reductions in computer time are obtained by making use of previously computed solution vectors and preconditioners in subsequent analyses. The effectiveness of this technique is demonstrated for the computation of shape response sensitivities required in shape optimization. Computer times and accuracies achieved using the preconditioned iterative solvers are compared with those obtained via direct solvers and implicit differentiation of the boundary integral equations. It is concluded that this approach employing preconditioned iterative equation solvers in reanalysis and sensitivity analysis can be competitive with if not superior to those involving direct solvers.

  3. Combined incomplete LU and strongly implicit procedure preconditioning

    SciTech Connect

    Meese, E.A.

    1996-12-31

    For the solution of large sparse linear systems of equations, the Krylov-subspace methods have gained great merit. Their efficiency are, however, largely dependent upon preconditioning of the equation-system. A family of matrix factorisations often used for preconditioning, is obtained from a truncated Gaussian elimination, ILU(p). Less common, supposedly due to it`s restriction to certain sparsity patterns, is factorisations generated by the strongly implicit procedure (SIP). The ideas from ILU(p) and SIP are used in this paper to construct a generalized strongly implicit procedure, applicable to matrices with any sparsity pattern. The new algorithm has been run on some test equations, and efficiency improvements over ILU(p) was found.

  4. Investigation of Reperfusion Injury and Ischemic Preconditioning in Microsurgry

    PubMed Central

    Wang, Wei Zhong

    2008-01-01

    Ischemia/reperfusion (I/R) is inevitable in many vascular and musculoskeletal traumas, diseases, free tissue transfers, and during time-consuming reconstructive surgeries in the extremities. Salvage of a prolonged ischemic extremity or flap still remains a challenge for the microvascular surgeon. One of the common complications after microsurgery is I/R-induced tissue death or I/R injury. Twenty years after the discovery, ischemic preconditioning (IPC) has emerged as a powerful method for attenuating I/R injury in a variety of organs or tissues. However, its therapeutic expectations still need to be fulfilled. In this article, the author reviews some important experimental evidences of I/R injury as well as preconditioning-induced protection in the fields relevant to microsurgery. PMID:18946882

  5. Finding Chemical Reaction Paths with a Multilevel Preconditioning Protocol

    PubMed Central

    2015-01-01

    Finding transition paths for chemical reactions can be computationally costly owing to the level of quantum-chemical theory needed for accuracy. Here, we show that a multilevel preconditioning scheme that was recently introduced (Tempkin et al. J. Chem. Phys.2014, 140, 184114) can be used to accelerate quantum-chemical string calculations. We demonstrate the method by finding minimum-energy paths for two well-characterized reactions: tautomerization of malonaldehyde and Claissen rearrangement of chorismate to prephanate. For these reactions, we show that preconditioning density functional theory (DFT) with a semiempirical method reduces the computational cost for reaching a converged path that is an optimum under DFT by several fold. The approach also shows promise for free energy calculations when thermal noise can be controlled. PMID:25516726

  6. Finding Chemical Reaction Paths with a Multilevel Preconditioning Protocol

    DOE PAGESBeta

    Kale, Seyit; Sode, Olaseni; Weare, Jonathan; Dinner, Aaron R.

    2014-11-07

    Finding transition paths for chemical reactions can be computationally costly owing to the level of quantum-chemical theory needed for accuracy. Here, we show that a multilevel preconditioning scheme that was recently introduced (Tempkin et al. J. Chem. Phys. 2014, 140, 184114) can be used to accelerate quantum-chemical string calculations. We demonstrate the method by finding minimum-energy paths for two well-characterized reactions: tautomerization of malonaldehyde and Claissen rearrangement of chorismate to prephanate. For these reactions, we show that preconditioning density functional theory (DFT) with a semiempirical method reduces the computational cost for reaching a converged path that is an optimum undermore » DFT by several fold. In conclusion, the approach also shows promise for free energy calculations when thermal noise can be controlled.« less

  7. Reconstructing Clusters for Preconditioned Short-term Load Forecasting

    NASA Astrophysics Data System (ADS)

    Itagaki, Tadahiro; Mori, Hiroyuki

    This paper presents a new preconditioned method for short-term load forecasting that focuses on more accurate predicted value. In recent years, the deregulated and competitive power market increases the degree of uncertainty. As a result, more sophisticated short-term load forecasting techniques are required to deal with more complicated load behavior. To alleviate the complexity of load behavior, this paper presents a new preconditioned model. In this paper, clustering results are reconstructed to equalize the number of learning data after clustering with the Kohonen-based neural network. That enhances a short-term load forecasting model at each reconstructed cluster. The proposed method is successfully applied to real data of one-step ahead daily maximum load forecasting.

  8. Finding Chemical Reaction Paths with a Multilevel Preconditioning Protocol

    SciTech Connect

    Kale, Seyit; Sode, Olaseni; Weare, Jonathan; Dinner, Aaron R.

    2014-11-07

    Finding transition paths for chemical reactions can be computationally costly owing to the level of quantum-chemical theory needed for accuracy. Here, we show that a multilevel preconditioning scheme that was recently introduced (Tempkin et al. J. Chem. Phys. 2014, 140, 184114) can be used to accelerate quantum-chemical string calculations. We demonstrate the method by finding minimum-energy paths for two well-characterized reactions: tautomerization of malonaldehyde and Claissen rearrangement of chorismate to prephanate. For these reactions, we show that preconditioning density functional theory (DFT) with a semiempirical method reduces the computational cost for reaching a converged path that is an optimum under DFT by several fold. In conclusion, the approach also shows promise for free energy calculations when thermal noise can be controlled.

  9. Remote ischemic preconditioning improves post resuscitation cerebral function via overexpressing neuroglobin after cardiac arrest in rats.

    PubMed

    Fan, Ran; Yu, Tao; Lin, Jia-Li; Ren, Guang-Dong; Li, Yi; Liao, Xiao-Xing; Huang, Zi-Tong; Jiang, Chong-Hui

    2016-10-01

    In this study, we investigated the effects of remote ischemic preconditioning on post resuscitation cerebral function in a rat model of cardiac arrest and resuscitation. The animals were randomized into six groups: 1) sham operation, 2) lateral ventricle injection and sham operation, 3) cardiac arrest induced by ventricular fibrillation, 4) lateral ventricle injection and cardiac arrest, 5) remote ischemic preconditioning initiated 90min before induction of ventricular fibrillation, and 6) lateral ventricle injection and remote ischemic preconditioning before cardiac arrest. Reagent of Lateral ventricle injection is neuroglobin antisense oligodeoxynucleotides which initiated 24h before sham operation, cardiac arrest or remote ischemic preconditioning. Remote ischemic preconditioning was induced by four cycles of 5min of limb ischemia, followed by 5min of reperfusion. Ventricular fibrillation was induced by current and lasted for 6min. Defibrillation was attempted after 6min of cardiopulmonary resuscitation. The animals were then monitored for 2h and observed for an additionally maximum 70h. Post resuscitation cerebral function was evaluated by neurologic deficit score at 72h after return of spontaneous circulation. Results showed that remote ischemic preconditioning increased neurologic deficit scores. To investigate the neuroprotective effects of remote ischemic preconditioning, we observed neuronal injury at 48 and 72h after return of spontaneous circulation and found that remote ischemic preconditioning significantly decreased the occurrence of neuronal apoptosis and necrosis. To further comprehend mechanism of neuroprotection induced by remote ischemic preconditioning, we found expression of neuroglobin at 24h after return of spontaneous circulation was enhanced. Furthermore, administration of neuroglobin antisense oligodeoxynucleotides before induction of remote ischemic preconditioning showed that the level of neuroglobin was decreased then partly abrogated

  10. Parallel Domain Decomposition Preconditioning for Computational Fluid Dynamics

    NASA Technical Reports Server (NTRS)

    Barth, Timothy J.; Chan, Tony F.; Tang, Wei-Pai; Kutler, Paul (Technical Monitor)

    1998-01-01

    This viewgraph presentation gives an overview of the parallel domain decomposition preconditioning for computational fluid dynamics. Details are given on some difficult fluid flow problems, stabilized spatial discretizations, and Newton's method for solving the discretized flow equations. Schur complement domain decomposition is described through basic formulation, simplifying strategies (including iterative subdomain and Schur complement solves, matrix element dropping, localized Schur complement computation, and supersparse computations), and performance evaluation.

  11. Object-oriented design of preconditioned iterative methods

    SciTech Connect

    Bruaset, A.M.

    1994-12-31

    In this talk the author discusses how object-oriented programming techniques can be used to develop a flexible software package for preconditioned iterative methods. The ideas described have been used to implement the linear algebra part of Diffpack, which is a collection of C++ class libraries that provides high-level tools for the solution of partial differential equations. In particular, this software package is aimed at rapid development of PDE-based numerical simulators, primarily using finite element methods.

  12. Preconditioned Alternating Projection Algorithms for Maximum a Posteriori ECT Reconstruction.

    PubMed

    Krol, Andrzej; Li, Si; Shen, Lixin; Xu, Yuesheng

    2012-11-01

    We propose a preconditioned alternating projection algorithm (PAPA) for solving the maximum a posteriori (MAP) emission computed tomography (ECT) reconstruction problem. Specifically, we formulate the reconstruction problem as a constrained convex optimization problem with the total variation (TV) regularization. We then characterize the solution of the constrained convex optimization problem and show that it satisfies a system of fixed-point equations defined in terms of two proximity operators raised from the convex functions that define the TV-norm and the constrain involved in the problem. The characterization (of the solution) via the proximity operators that define two projection operators naturally leads to an alternating projection algorithm for finding the solution. For efficient numerical computation, we introduce to the alternating projection algorithm a preconditioning matrix (the EM-preconditioner) for the dense system matrix involved in the optimization problem. We prove theoretically convergence of the preconditioned alternating projection algorithm. In numerical experiments, performance of our algorithms, with an appropriately selected preconditioning matrix, is compared with performance of the conventional MAP expectation-maximization (MAP-EM) algorithm with TV regularizer (EM-TV) and that of the recently developed nested EM-TV algorithm for ECT reconstruction. Based on the numerical experiments performed in this work, we observe that the alternating projection algorithm with the EM-preconditioner outperforms significantly the EM-TV in all aspects including the convergence speed, the noise in the reconstructed images and the image quality. It also outperforms the nested EM-TV in the convergence speed while providing comparable image quality. PMID:23271835

  13. Preconditioned Alternating Projection Algorithms for Maximum a Posteriori ECT Reconstruction

    PubMed Central

    Krol, Andrzej; Li, Si; Shen, Lixin; Xu, Yuesheng

    2012-01-01

    We propose a preconditioned alternating projection algorithm (PAPA) for solving the maximum a posteriori (MAP) emission computed tomography (ECT) reconstruction problem. Specifically, we formulate the reconstruction problem as a constrained convex optimization problem with the total variation (TV) regularization. We then characterize the solution of the constrained convex optimization problem and show that it satisfies a system of fixed-point equations defined in terms of two proximity operators raised from the convex functions that define the TV-norm and the constrain involved in the problem. The characterization (of the solution) via the proximity operators that define two projection operators naturally leads to an alternating projection algorithm for finding the solution. For efficient numerical computation, we introduce to the alternating projection algorithm a preconditioning matrix (the EM-preconditioner) for the dense system matrix involved in the optimization problem. We prove theoretically convergence of the preconditioned alternating projection algorithm. In numerical experiments, performance of our algorithms, with an appropriately selected preconditioning matrix, is compared with performance of the conventional MAP expectation-maximization (MAP-EM) algorithm with TV regularizer (EM-TV) and that of the recently developed nested EM-TV algorithm for ECT reconstruction. Based on the numerical experiments performed in this work, we observe that the alternating projection algorithm with the EM-preconditioner outperforms significantly the EM-TV in all aspects including the convergence speed, the noise in the reconstructed images and the image quality. It also outperforms the nested EM-TV in the convergence speed while providing comparable image quality. PMID:23271835

  14. Protection by ozone preconditioning is mediated by the antioxidant system in cisplatin-induced nephrotoxicity in rats.

    PubMed Central

    Borrego, Aluet; Zamora, Zullyt B; González, Ricardo; Romay, Cheyla; Menéndez, Silvia; Hernández, Frank; Montero, Teresita; Rojas, Enys

    2004-01-01

    BACKGROUND: Acute renal failure is a dose-limiting factor of cisplatin chemotherapy. Here, we show the protective effect of ozone oxidative preconditioning against cisplatin-induced renal dysfunction in rats. Ozone oxidative preconditioning is a prophylactic approach, which favors the antioxidant-pro-oxidant balance for preservation of the cell redox state by increasing antioxidant endogenous systems in various in vivo and in vitro experimental models. AIMS: To analyze the protective role of ozone oxidative preconditioning against cisplatin-induced nephrotoxicity. METHODS: Male Sprague-Dawley rats were pretreated with 15 intrarectal applications of ozone/oxygen mixture at 0.36, 0.72, 1.1, 1.8 and 2.5 mg/kg before cisplatin intraperitoneal injection (6 mg/kg). Serum and kidneys were extracted and analyzed 5 days after cisplatin treatment for determinations of the renal content of glutathione, thiobarbituric acid-reactive substances, renal concentration and enzymatic activities of catalase, superoxide dismutase and glutathione peroxidase. RESULTS: Ozone pretreatment prevented the increase in serum creatinine levels, the glutathione depletion and the inhibition of superoxide dismutase, catalase and glutathione peroxidase activities induced by cisplatin in the rat kidney. Also, the renal content of thiobarbituric acid-reactive substances was decreased by ozone therapy. These protective effects of ozone were dose dependent. CONCLUSIONS: Intrarectal ozone therapy prevented effectively the renal antioxidant unbalance induced by cisplatin treatment. PMID:15203559

  15. Transient expression of Nxf, a bHLH-PAS transactivator induced by neuronal preconditioning, confers neuroprotection in cultured cells.

    PubMed

    Hester, Ian; McKee, Sarah; Pelletier, Phillip; Thompson, Charles; Storbeck, Christopher; Mears, Alan; Schulz, Jörg B; Hakim, Antoine A; Sabourin, Luc A

    2007-03-01

    Cortical spreading depression (CSD) induces waves of neuronal depolarization that confer neuroprotection to subsequent ischemic events in the rat brain. To gain insights into the molecular mechanisms elicited by CSD, we used representational difference analysis (RDA) to identify mRNAs induced by potassium depolarization in vivo. Using this approach, we have isolated a cDNA encoding the SIM2-related bHLH-PAS protein Nxf. Our results confirm that Nxf mRNA and protein are rapidly and transiently expressed in cortical neurons following CSD. Reporter assays show that Nxf is a transcriptional activator that associates with the bHLH-PAS sub-class co-factor ARNT2. Adenovirus-mediated expression of epitope-tagged Nxf results in cell death and the direct activation of the Bax gene in cultured cells. However, RNA interference studies show that endogenous Nxf is required for optimal neuroprotection by preconditioning in cultured F-11 cells. Together, our data indicate that Nxf is a novel bHLH-PAS transactivator transiently induced by preconditioning and that its sustained expression is detrimental. The identification of Nxf may represent an important step in our understanding of the molecular mechanisms of brain preconditioning and injury. PMID:17214977

  16. Concentrated Hypoxia-Preconditioned Adipose Mesenchymal Stem Cell-Conditioned Medium Improves Wounds Healing in Full-Thickness Skin Defect Model.

    PubMed

    Sun, Biao; Guo, Shilei; Xu, Fei; Wang, Bin; Liu, Xiujuan; Zhang, Yuanyuan; Xu, Yan

    2014-01-01

    In recent years, the bioactive factors were utilized in exercise and athletic skin injuries. In this research, the concentrated conditioned medium of hypoxia-preconditioned adipose mesenchymal stem cells, which is rich in bioactive factor, is applied in full-thickness skin defect model to evaluate the therapeutic efficacy. Adipose mesenchymal stem cells were harvested from the abdominal subcutaneous adipose tissues. The surface markers and the potential of differentiation were analyzed. The conditioned medium of hypoxia-preconditioned stem cells was collected and freeze-dried and then applied on the rat full-thickness skin defect model, and the healing time of each group was recorded. Haematoxylin and eosin staining of skin was assessed by microscope. The characteristics of adipose mesenchymal stem cells were similar to those of other mesenchymal stem cells. The concentration of protein in freeze-dried conditioned medium in 1 mL water was about 15 times higher than in the normal condition medium. In vivo, the concentrated hypoxia-preconditioned conditioned medium can reduce the wound size and accelerate the skin wound healing. The concentrated hypoxia-preconditioned adipose mesenchymal stem cell-conditioned medium has great effect on rat model of wound healing, and it would be an ideal agent for wound care in clinical application. PMID:27433483

  17. Concentrated Hypoxia-Preconditioned Adipose Mesenchymal Stem Cell-Conditioned Medium Improves Wounds Healing in Full-Thickness Skin Defect Model

    PubMed Central

    Sun, Biao; Guo, Shilei; Xu, Fei; Wang, Bin; Liu, Xiujuan; Zhang, Yuanyuan

    2014-01-01

    In recent years, the bioactive factors were utilized in exercise and athletic skin injuries. In this research, the concentrated conditioned medium of hypoxia-preconditioned adipose mesenchymal stem cells, which is rich in bioactive factor, is applied in full-thickness skin defect model to evaluate the therapeutic efficacy. Adipose mesenchymal stem cells were harvested from the abdominal subcutaneous adipose tissues. The surface markers and the potential of differentiation were analyzed. The conditioned medium of hypoxia-preconditioned stem cells was collected and freeze-dried and then applied on the rat full-thickness skin defect model, and the healing time of each group was recorded. Haematoxylin and eosin staining of skin was assessed by microscope. The characteristics of adipose mesenchymal stem cells were similar to those of other mesenchymal stem cells. The concentration of protein in freeze-dried conditioned medium in 1 mL water was about 15 times higher than in the normal condition medium. In vivo, the concentrated hypoxia-preconditioned conditioned medium can reduce the wound size and accelerate the skin wound healing. The concentrated hypoxia-preconditioned adipose mesenchymal stem cell-conditioned medium has great effect on rat model of wound healing, and it would be an ideal agent for wound care in clinical application. PMID:27433483

  18. A Shifted Block Lanczos Algorithm 1: The Block Recurrence

    NASA Technical Reports Server (NTRS)

    Grimes, Roger G.; Lewis, John G.; Simon, Horst D.

    1990-01-01

    In this paper we describe a block Lanczos algorithm that is used as the key building block of a software package for the extraction of eigenvalues and eigenvectors of large sparse symmetric generalized eigenproblems. The software package comprises: a version of the block Lanczos algorithm specialized for spectrally transformed eigenproblems; an adaptive strategy for choosing shifts, and efficient codes for factoring large sparse symmetric indefinite matrices. This paper describes the algorithmic details of our block Lanczos recurrence. This uses a novel combination of block generalizations of several features that have only been investigated independently in the past. In particular new forms of partial reorthogonalization, selective reorthogonalization and local reorthogonalization are used, as is a new algorithm for obtaining the M-orthogonal factorization of a matrix. The heuristic shifting strategy, the integration with sparse linear equation solvers and numerical experience with the code are described in a companion paper.

  19. Comparative Effects of Periarticular Multimodal Drug Injection and Single-Shot Femoral Nerve Block on Pain Following Total Knee Arthroplasty and Factors Influencing Their Effectiveness

    PubMed Central

    Nakagawa, Shuji; Inoue, Hiroaki; Kan, Hiroyuki; Hino, Manabu; Ichimaru, Shohei; Ikoma, Kazuya; Fujiwara, Hiroyoshi; Amaya, Fumimasa; Sawa, Teiji; Kubo, Toshikazu

    2016-01-01

    Purpose This study compared the analgesic effects of local infiltration analgesia (LIA) and femoral nerve block (FNB) after total knee arthroplasty (TKA) and assessed factors associated with analgesia obtained by these two methods. Materials and Methods Study subjects included 66 patients (72 knees) who underwent TKA for osteoarthritis of the knee. Pain visual analogue scale (VAS), the amount of analgesics used, number of days to achieve 90° of flexion of the knee joint, date of initiating parallel-bar walking, range of motion of the knee joint at discharge, and adverse events were investigated. Results The VAS scores did not differ significantly between two groups, whereas the amount of analgesics used was significantly lower in the LIA group. Preoperative flexion contracture was significantly more severe in the LIA group with high VAS compared with low VAS. No serious adverse event occurred in the LIA or FNB group. Conclusions The lower analgesic usage in the LIA group than the FNB group indicates that the analgesic effect of LIA was greater than that of singleshot FNB after TKA. There were no serious complications in either group. The postoperative analgesic effect of LIA was smaller in patients with severe than less severe preoperative flexion contracture. PMID:27595078

  20. Passive cigarette smoke exposure inhibits ultraviolet light B-induced skin tumors in SKH-1 hairless mice by blocking the nuclear factor kappa B signalling pathway.

    PubMed

    Gottipati, Koteswara R; Poulsen, Henrik; Starcher, Barry

    2008-09-01

    Chronic exposure to sunlight [ultraviolet light B (UVB) irradiation] is the most common cause of non-melanoma skin tumors. In the present study, we investigated the effects of passive cigarette smoke superimposed over UVB irradiation, on tumor development, skin pathology and matrix changes in SKH-1 hairless mice. Groups of mice were exposed to 0.1 J/cm(2) of UVB five times per week for 20 weeks and/or exposure to passive cigarette smoke from 40 cigarettes a day over the same time period. UVB exposure resulted in an average of four large squamous cell carcinomas (SCC) and 15 smaller papillomas per mouse, whereas exposing the mice to both UVB + passive cigarette smoke completely prevented SCC formation and averaged less than one small papilloma per mouse. Oxidative DNA damage was investigated and there were no significant changes in the levels of urinary DNA adducts between control, smoke, UV and UV + smoke groups with the exception of 8-oxo guanine which was significantly reduced in the presence of passive cigarette smoke. Immunohistochemistry results revealed that tumor necrosis factor receptor 2 (TNF-R2), glycogen synthase kinase-3 beta, nuclear factor kappa B (NF-kappaB)/p65, KI-67 and cyclooxygenase 2 (COX-2) were markedly up-regulated in the epithelium by UVB exposure, whereas passive smoke exposure combined with the UVB irradiation completely blocked the expression of these proteins. Our results suggest that passive smoke exposure prevents UVB-induced SCC in mice and dramatically reduces the incidence of non-malignant papillomas by altering the NF-kappaB signalling pathway of tumorigenesis. PMID:18312384

  1. Suspended sediment behavior in a coastal dry-summer subtropical catchment: Effects of hydrologic preconditions

    NASA Astrophysics Data System (ADS)

    Gray, A. B.; Warrick, J. A.; Pasternack, G. B.; Watson, E. B.; Goñi, M. A.

    2014-06-01

    Variation in fluvial suspended sediment-discharge behavior is generally thought to be the product of changes in processes governing the delivery of sediment and water to the channel. The objective of this study was to infer sediment supply dynamics from the response of suspended sediment behavior to antecedent hydrologic factors. The Salinas River (California) is seasonally active, moderately sized, and potentially susceptible to lasting impacts of hydrologic event history because of aridity, high discharge variability, and in-channel terminating flows. Forty-five years of suspended sediment data from the lower Salinas and 80 years of hydrologic data were used to construct hydrologic descriptors of basin preconditioning and to test the effects of these preconditions on suspended sediment behavior. Hydrologic precondition factors - including change in mean daily discharge and increasing elapsed time since the last moderate discharge event (~ 10-20 times mean discharge (Qmean)) - were found to have significant positive effects on discharge-corrected, fine suspended-sediment concentrations. Conversely, increased elapsed time since the last low discharge event (~ 0.1-0.4 times Qmean), and the sum of low flow conditions over interannual time scales were found to cause significant negative trends in fine suspended sediment concentration residuals. Suspended sand concentrations are suppressed by increased elapsed time after threshold discharges of ~ 0.1-2 and 5-100 times Qmean, and increased low to no flow days over time scales from 1 to 2000 days. Current and previous year water yield and precipitation magnitudes correlate positively with sand concentration. Addition of fine sediment from lower Salinas hillslope or channel sources on the rising limb of the hydrograph is the major mechanism behind an overall positive hysteretic pattern, which was forensically supported by the annual occurrence of in-channel suspended sediment deposition by early season, channel

  2. Mononuclear phagocyte system depletion blocks interstitial tonicity-responsive enhancer binding protein/vascular endothelial growth factor C expression and induces salt-sensitive hypertension in rats.

    PubMed

    Machnik, Agnes; Dahlmann, Anke; Kopp, Christoph; Goss, Jennifer; Wagner, Hubertus; van Rooijen, Nico; Eckardt, Kai-Uwe; Müller, Dominik N; Park, Joon-Keun; Luft, Friedrich C; Kerjaschki, Dontscho; Titze, Jens

    2010-03-01

    We showed recently that mononuclear phagocyte system (MPS) cells provide a buffering mechanism for salt-sensitive hypertension by driving interstitial lymphangiogenesis, modulating interstitial Na(+) clearance, and increasing endothelial NO synthase protein expression in response to very high dietary salt via a tonicity-responsive enhancer binding protein/vascular endothelial growth factor C regulatory mechanism. We now tested whether isotonic saline and deoxycorticosterone acetate (DOCA)-salt treatment leads to a similar regulatory response in Sprague-Dawley rats. Male rats were fed a low-salt diet and received tap water (low-salt diet LSD), 1.0% saline (high-salt diet HSD), or DOCA+1.0% saline (DOCA-HSD). To test the regulatory role of interstitial MPS cells, we further depleted MPS cells with clodronate liposomes. HSD and DOCA-HSD led to Na(+) accumulation in the skin, MPS-driven tonicity-responsive enhancer binding protein/vascular endothelial growth factor C-mediated hyperplasia of interstitial lymph capillaries, and increased endothelial NO synthase protein expression in skin interstitium. Clodronate liposome MPS cell depletion blocked MPS infiltration in the skin interstitium, resulting in unchanged tonicity-responsive enhance binding protein/vascular endothelial growth factor C levels and absent hyperplasia of the lymph capillary network. Moreover, no increased skin endothelial NO synthase protein expression occurred in either clodronate liposome-treated HSD or DOCA-salt rats. Thus, absence of the MPS-cell regulatory response converted a salt-resistant blood-pressure state to a salt-sensitive state in HSD rats. Furthermore, salt-sensitive hypertension in DOCA-salt rats was aggravated. We conclude that MPS cells act as onsite controllers of interstitial volume and blood pressure homeostasis, providing a local regulatory salt-sensitive tonicity-responsive enhancer binding protein/vascular endothelial growth factor C-mediated mechanism in the skin to maintain

  3. [Preconditioning impact on coronary perfusion during ischemia and reperfusion of heart].

    PubMed

    Maslov, L N; Lishmanov, Iu B; Oeltgen, P; Peĭ, J-M; Krylatov, A V; Barzakh, E I; Portnichenko, A G; Meshoulam, R

    2012-04-01

    Recent studies have confirmed that ischemic preconditioning prevents appearance of reperfusion endothelial dysfunction. However, the issue of preconditioning impact on no-reflow phenomenon remains unresolved. The receptor mechanisms involved in the cardioprotective and vasoprotective effects of preconditioning are different. The ability of preconditioning in preventing reperfusion endothelial dysfunction is dependent upon bradykinin B2-receptor activation and not dependent upon adenosine receptor stimulation. The vasoprotective effect of preconditioning is mediated via mechanisms relying in part on activation of protein kinase C, NO-synthase, cyclooxygenase, mitochondrial K(ATP)-channel opening and an enhancement of antioxidative protection of the heart. The delayed preconditioning also exerts endothelium-protective effect. Peroxynitrite, NO* and O2* are the triggers of this effect but a possible end-effector involves endothelial NO-synthase. PMID:22834333

  4. Electrochemical immunosensor for detection of epidermal growth factor reaching lower detection limit: toward oxidized glutathione as a more efficient blocking reagent for the antibody functionalized silver nanoparticles and antigen interaction.

    PubMed

    Lin, Yuqing; Liu, Kangyu; Wang, Chao; Li, Linbo; Liu, Yuxin

    2015-08-18

    Blocking reagent is of vital importance for an immunosensor because it ensures the antifouling of the sensing interface and thus selective determination of the target. This Letter investigates a small inactive peptide, oxidized glutathione (GSSG), to replace the commonly used bovine serum albumin (BSA) as blocking reagent for immunosensor fabrication to lower the detection limit of electrochemical immunosensors. The EGF (epidermal growth factor) detection as an example is used here to compare the blocking effects from GSSG and BSA, respectively. The relatively big size of BSA sterically hinders EGF and antibody functionalized silver nanoparticles (Ab-AgNPs) binding. By comparison, GSSG cannot hinder EGF and Ab-AgNPs binding since it is much smaller than EGF, verified by scanning electron microscopy (SEM) results. The established GSSG blocking-based immunosensor for EGF reaches a very low detection limit of 0.01 pM, exhibits wide linearity range between 0.1 pM and 0.1 μM and is more sensitive than the BSA blocking strategy. The proposed GSSG-blocking strategy in the immunoassay paves an attractive platform for other biomolecules to reach a lower detection limit. PMID:26204199

  5. Morphine-Induced Preconditioning: Involvement of Protein Kinase A and Mitochondrial Permeability Transition Pore

    PubMed Central

    Dorsch, Marianne; Behmenburg, Friederike; Raible, Miriam; Blase, Dominic; Grievink, Hilbert; Hollmann, Markus W.; Heinen, André; Huhn, Ragnar

    2016-01-01

    Background Morphine induces myocardial preconditioning (M-PC) via activation of mitochondrial large conductance Ca2+-sensitive potassium (mKCa) channels. An upstream regulator of mKCa channels is protein kinase A (PKA). Furthermore, mKCa channel activation regulates mitochondrial bioenergetics and thereby prevents opening of the mitochondrial permeability transition pore (mPTP). Here, we investigated in the rat heart in vivo whether 1) M-PC is mediated by activation of PKA, and 2) pharmacological opening of the mPTP abolishes the cardioprotective effect of M-PC and 3) M-PC is critically dependent on STAT3 activation, which is located upstream of mPTP within the signalling pathway. Methods Male Wistar rats were randomised to six groups (each n = 6). All animals underwent 25 minutes of regional myocardial ischemia and 120 minutes of reperfusion. Control animals (Con) were not further treated. Morphine preconditioning was initiated by intravenous administration of 0.3 mg/kg morphine (M-PC). The PKA blocker H-89 (10 μg/kg) was investigated with and without morphine (H-89+M-PC, H-89). We determined the effect of mPTP opening with atractyloside (5 mg/kg) with and without morphine (Atr+M-PC, Atr). Furthermore, the effect of morphine on PKA activity was tested in isolated adult rat cardiomyocytes. In further experiments in isolated hearts we tested the protective properties of morphine in the presence of STAT3 inhibition, and whether pharmacological prevention of the mPTP-opening by cyclosporine A (CsA) is cardioprotective in the presence of STAT3 inhibition. Results Morphine reduced infarct size from 64±5% to 39±9% (P<0.05 vs. Con). H-89 completely blocked preconditioning by morphine (64±9%; P<0.05 vs. M-PC), but H-89 itself had not effect on infarct size (61±10%; P>0.05 vs. Con). Also, atractyloside abolished infarct size reduction of morphine completely (65±9%; P<0.05 vs. M-PC) but had no influence on infarct size itself (64±5%; P>0.05 vs. Con). In isolated

  6. Preconditioned iterative methods for space-time fractional advection-diffusion equations

    NASA Astrophysics Data System (ADS)

    Zhao, Zhi; Jin, Xiao-Qing; Lin, Matthew M.

    2016-08-01

    In this paper, we propose practical numerical methods for solving a class of initial-boundary value problems of space-time fractional advection-diffusion equations. First, we propose an implicit method based on two-sided Grünwald formulae and discuss its stability and consistency. Then, we develop the preconditioned generalized minimal residual (preconditioned GMRES) method and preconditioned conjugate gradient normal residual (preconditioned CGNR) method with easily constructed preconditioners. Importantly, because resulting systems are Toeplitz-like, fast Fourier transform can be applied to significantly reduce the computational cost. We perform numerical experiments to demonstrate the efficiency of our preconditioners, even in cases with variable coefficients.

  7. Hypothermic Preconditioning Reverses Tau Ontogenesis in Human Cortical Neurons and is Mimicked by Protein Phosphatase 2A Inhibition

    PubMed Central

    Rzechorzek, Nina M.; Connick, Peter; Livesey, Matthew R.; Borooah, Shyamanga; Patani, Rickie; Burr, Karen; Story, David; Wyllie, David J.A.; Hardingham, Giles E.; Chandran, Siddharthan

    2015-01-01

    Hypothermia is potently neuroprotective, but the molecular basis of this effect remains obscure. Changes in neuronal tau protein are of interest, since tau becomes hyperphosphorylated in injury-resistant, hypothermic brains. Noting inter-species differences in tau isoforms, we have used functional cortical neurons differentiated from human pluripotent stem cells (hCNs) to interrogate tau modulation during hypothermic preconditioning at clinically-relevant temperatures. Key tau developmental transitions (phosphorylation status and splicing shift) are recapitulated during hCN differentiation and subsequently reversed by mild (32 °C) to moderate (28 °C) cooling — conditions which reduce oxidative and excitotoxic stress-mediated injury in hCNs. Blocking a major tau kinase decreases hCN tau phosphorylation and abrogates hypothermic neuroprotection, whilst inhibition of protein phosphatase 2A mimics cooling-induced tau hyperphosphorylation and protects normothermic hCNs from oxidative stress. These findings indicate a possible role for phospho-tau in hypothermic preconditioning, and suggest that cooling drives human tau towards an earlier ontogenic phenotype whilst increasing neuronal resilience to common neurotoxic insults. This work provides a critical step forward in understanding how we might exploit the neuroprotective benefits of cooling without cooling patients. PMID:26870825

  8. Hypothermic Preconditioning Reverses Tau Ontogenesis in Human Cortical Neurons and is Mimicked by Protein Phosphatase 2A Inhibition.

    PubMed

    Rzechorzek, Nina M; Connick, Peter; Livesey, Matthew R; Borooah, Shyamanga; Patani, Rickie; Burr, Karen; Story, David; Wyllie, David J A; Hardingham, Giles E; Chandran, Siddharthan

    2016-01-01

    Hypothermia is potently neuroprotective, but the molecular basis of this effect remains obscure. Changes in neuronal tau protein are of interest, since tau becomes hyperphosphorylated in injury-resistant, hypothermic brains. Noting inter-species differences in tau isoforms, we have used functional cortical neurons differentiated from human pluripotent stem cells (hCNs) to interrogate tau modulation during hypothermic preconditioning at clinically-relevant temperatures. Key tau developmental transitions (phosphorylation status and splicing shift) are recapitulated during hCN differentiation and subsequently reversed by mild (32 °C) to moderate (28 °C) cooling--conditions which reduce oxidative and excitotoxic stress-mediated injury in hCNs. Blocking a major tau kinase decreases hCN tau phosphorylation and abrogates hypothermic neuroprotection, whilst inhibition of protein phosphatase 2A mimics cooling-induced tau hyperphosphorylation and protects normothermic hCNs from oxidative stress. These findings indicate a possible role for phospho-tau in hypothermic preconditioning, and suggest that cooling drives human tau towards an earlier ontogenic phenotype whilst increasing neuronal resilience to common neurotoxic insults. This work provides a critical step forward in understanding how we might exploit the neuroprotective benefits of cooling without cooling patients. PMID:26870825

  9. REACTIVE TRANSPORT MODELING USING A PARALLEL FULLY-COUPLED SIMULATOR BASED ON PRECONDITIONED JACOBIAN-FREE NEWTON-KRYLOV

    SciTech Connect

    Luanjing Guo; Chuan Lu; Hai Huang; Derek R. Gaston

    2012-06-01

    Systems of multicomponent reactive transport in porous media that are large, highly nonlinear, and tightly coupled due to complex nonlinear reactions and strong solution-media interactions are often described by a system of coupled nonlinear partial differential algebraic equations (PDAEs). A preconditioned Jacobian-Free Newton-Krylov (JFNK) solution approach is applied to solve the PDAEs in a fully coupled, fully implicit manner. The advantage of the JFNK method is that it avoids explicitly computing and storing the Jacobian matrix during Newton nonlinear iterations for computational efficiency considerations. This solution approach is also enhanced by physics-based blocking preconditioning and multigrid algorithm for efficient inversion of preconditioners. Based on the solution approach, we have developed a reactive transport simulator named RAT. Numerical results are presented to demonstrate the efficiency and massive scalability of the simulator for reactive transport problems involving strong solution-mineral interactions and fast kinetics. It has been applied to study the highly nonlinearly coupled reactive transport system of a promising in situ environmental remediation that involves urea hydrolysis and calcium carbonate precipitation.

  10. Endometrial expression of progesterone-induced blocking factor and galectins-1, -3, -9, and -3 binding protein in the luteal phase and early pregnancy in cattle.

    PubMed

    Okumu, L A; Fair, T; Szekeres-Bartho, J; O'Doherty, A M; Crowe, M A; Roche, J F; Lonergan, P; Forde, N

    2011-07-27

    Progesterone-induced blocking factor (PIBF) and galectins modulate the maternal immune response during pregnancy. We hypothesized that the relative transcript abundance of the above genes would be different during the luteal phase/early pregnancy and would be affected by progesterone supplementation. To further test this, hypothesis protein expression analyses were carried out to evaluate the abundance and localization of LGALS9 and PIBF. Following estrus synchronization, heifers were inseminated (n = 140) or not (n = 70). Half the heifers in each status (cyclic or potentially pregnant) were randomly assigned to receive a progesterone-releasing intravaginal device (PRID) on day 3 after estrus, which elevated progesterone concentrations from day 3.5 to 8 (P < 0.05), resulting in four treatment groups: cyclic and pregnant heifers, each with normal and high progesterone. After confirmation of pregnancy status in inseminated animals, uterine tissue was collected on days 5, 7, 13, or 16 of the luteal phase of the cycle/pregnancy. Gene and protein expression was determined using Q-RT-PCR and IHC, respectively, on 5 heifers per treatment per time point (i.e., 80 in total). Progesterone concentrations did not affect expression of any of the genes (P > 0.05). LGALS9 and LGALS3BP were expressed at low levels in both cyclic and pregnant endometria until day 13. On day 16, expression increased only in the pregnant heifers (P < 0.0001). LGALS1 and LGALS3 decreased on day 7 (P < 0.0001) and remained low until day 16. Pregnancy had no effect on the expression of LGALS1, LGALS3, and PIBF. Additionally, LGALS9 and PIBF proteins were expressed in distinct uterine cell types. These results indicate that the galectins may be involved in uterine receptivity and/or implantation in heifers. PMID:21610087

  11. Lufaxin, a Novel Factor Xa Inhibitor from the Salivary Gland of the sand fly Lutzomyia longipalpis, Blocks PAR2 Activation and Inhibits Inflammation and Thrombosis in Vivo

    PubMed Central

    Collin, Nicolas; Assumpção, Teresa C. F.; Mizurini, Daniella M.; Gilmore, Dana; Dutra-Oliveira, Angélica; Kotsyfakis, Michalis; Sá-Nunes, Anderson; Teixeira, Clarissa; Ribeiro, José M. C.; Monteiro, Robson Q.; Valenzuela, Jesus G.; Francischetti, Ivo M. B.

    2012-01-01

    Objective Blood-sucking arthropods salivary glands (SGs) contain a remarkable diversity of antihemostatics. The aim of this study was to identify the unique salivary anticoagulant of the sand fly Lutzomyia longipalpis, which remained elusive for decades. Methods and Results Several L. longipalpis salivary proteins were expressed in HEK293 cells and screened for inhibition of blood coagulation. A novel 32.4-kDa molecule, named Lufaxin, was identified as a slow, tight, non-competitive, and reversible inhibitor of Factor Xa (FXa). Notably, Lufaxin primary sequence does not share similarity to any physiological or salivary inhibitors of coagulation reported to date. Lufaxin is specific for FXa and does not interact with FX, DEGR- FXa, or 15 other enzymes. In addition, Lufaxin blocks prothrombinase and increases both PT and aPTT. Surface plasmon resonance experiments revealed that FXa binds Lufaxin with a KD ~3 nM, and isothermal titration calorimetry determined a stoichiometry of 1:1. Lufaxin also prevents PAR2 activation by FXa in the MDA-MB-231 cell line and abrogates edema formation triggered by injection of FXa in the paw of mice. Moreover, Lufaxin prevents FeCl3-induced carotid artery thrombus formation and prolongs aPTT ex vivo, implying that it works as an anticoagulant in vivo. Finally, SG of sandflies was found to inhibit FXa and to interact with the enzyme. Conclusion Lufaxin belongs to a novel family of slow-tight FXa inhibitors, which display antithrombotic and antiinflamatory activities. It is a useful tool to understand FXa structural features and its role in pro-hemostatic and pro-inflammatory events. PMID:22796577

  12. Histone Deacetylase Inhibitors Enhance the Apoptotic Activity of Insulin-Like Growth Factor Binding Protein-3 by Blocking PKC-Induced IGFBP-3 Degradation

    PubMed Central

    Oh, Seung Hyun; Whang, Young Mi; Min, Hye-Young; Han, Seung Ho; Kang, Ju-Hee; Song, Ki-Hoon; Glisson, Bonnie S.; Kim, Yeul Hong; Lee, Ho-Young

    2012-01-01

    Overexpression of insulin-like growth factor binding protein (IGFBP)-3 induces apoptosis of cancer cells. However, preexisting resistance to IGFBP-3 could limit its antitumor activities. This study characterizes the efficacy and mechanism of the combination of recombinant IGFBP-3 (rIGFBP-3) and HDAC inhibitors to overcome IGFBP-3 resistance in a subset of non-small cell lung cancer (NSCLC) and head and neck squamous cell carcinoma (HNSCC) cells. The effects of the combination of rIGFBP-3 and a number of HDAC inhibitors on cell proliferation and apoptosis were assessed in vitro and in vivo by using the MTT assay, a flow cytometry-based TUNEL assay, western blot analyses, and the NSCLC xenograft tumor model. Combined treatment with HDAC inhibitors and rIGFBP-3 had synergistic antiproliferative effects accompanied by increased apoptosis rates in a subset of NSCLC and HNSCC cell lines in vitro. Moreover, combined treatment with depsipeptide and rIGFBP-3 completely suppressed tumor growth and increased the apoptosis rate in vivo in H1299 NSCLC xenografts. Evidence suggests that HDAC inhibitors increased the half-life of rIGFBP-3 protein by blocking protein kinase C (PKC)-mediated phosphorylation and degradation of rIGFBP-3. In addition, combined treatment of IGFBP-3 with an HDAC inhibitor facilitates apoptosis through up-regulation of rIGFBP-3 stability and Akt signaling inhibition. The ability of HDAC inhibitors to decrease PKC activation may enhance apoptotic activities of rIGFBP-3 in NSCLC cells in vitro and in vivo. These results indicated that combined treatment with HDAC inhibitor and rIGFBP-3 could be an effective treatment strategy for NSCLC and HNSCC with highly activated PKC. PMID:22362554

  13. Insulin-like growth factors require phosphatidylinositol 3-kinase to signal myogenesis: dominant negative p85 expression blocks differentiation of L6E9 muscle cells.

    PubMed

    Kaliman, P; Canicio, J; Shepherd, P R; Beeton, C A; Testar, X; Palacín, M; Zorzano, A

    1998-01-01

    Phosphatidylinositol 3 (PI 3)-kinases are potently inhibited by two structurally unrelated membrane-permeant reagents: wortmannin and LY294002. By using these two inhibitors we first suggested the involvement of a PI 3-kinase activity in muscle cell differentiation. However, several reports have described that these compounds are not as selective for PI 3-kinase activity as assumed. Here we show that LY294002 blocks the myogenic pathway elicited by insulin-like growth factors (IGFs), and we confirm the specific involvement of PI 3-kinase in IGF-induced myogenesis by overexpressing in L6E9 myoblasts a dominant negative p85 PI 3-kinase-regulatory subunit (L6E9-delta p85). IGF-I, des(1-3)IGF-I, or IGF-II induced L6E9 skeletal muscle cell differentiation as measured by myotube formation, myogenin gene expression, and GLUT4 glucose carrier induction. The addition of LY294002 to the differentiation medium totally inhibited these IGF-induced myogenic events without altering the expression of a non-muscle-specific protein, beta1-integrin. Independent clones of L6E9 myoblasts expressing a dominant negative mutant of the p85-regulatory subunit (delta p85) showed markedly impaired glucose transport activity and formation of p85/p110 complexes in response to insulin, consistent with the inhibition of PI 3-kinase activity. IGF-induced myogenic parameters in L6E9-delta p85 cells, ie. cell fusion and myogenin gene and GLUT4 expression, were severely impaired compared with parental cells or L6E9 cells expressing wild-type p85. In all, data presented here indicate that PI 3-kinase is essential for IGF-induced muscle differentiation and that the specific PI 3-kinase subclass involved in myogenesis is the heterodimeric p85-p110 enzyme. PMID:9440811

  14. Steps to translate preconditioning from basic research to the clinic

    PubMed Central

    Bahjat, Frances R; Gesuete, Raffaella; Stenzel-Poore, Mary P

    2012-01-01

    Efforts to treat cardiovascular and cerebrovascular diseases often focus on the mitigation of ischemia-reperfusion (I/R) injury. Many treatments or “preconditioners” are known to provide substantial protection against the I/R injury when administered prior to the event. Brief periods of ischemia itself have been validated as a means to achieve neuroprotection in many experimental disease settings, in multiple organ systems, and in multiple species suggesting a common pathway leading to tolerance. In addition, pharmacological agents that act as potent preconditioners have been described. Experimental induction of neuroprotection using these various preconditioning paradigms has provided a unique window into the brain’s endogenous protective mechanisms. Moreover, preconditioning agents themselves hold significant promise as clinical-stage therapies for prevention of I/R injury. The aim of this article is to explore several key steps involved in the preclinical validation of preconditioning agents prior to the conduct of clinical studies in humans. Drug development is difficult, expensive and relies on multi-factorial analysis of data from diverse disciplines. Importantly, there is no single path for the preclinical development of a novel therapeutic and no proven strategy to ensure success in clinical translation. Rather, the conduct of a diverse array of robust preclinical studies reduces the risk of clinical failure by varying degrees depending upon the relevance of preclinical models and drug pharmacology to humans. A strong sense of urgency and high tolerance of failure are often required to achieve success in the development of novel treatment paradigms for complex human conditions. PMID:23504609

  15. Calcium preconditioning triggers neuroprotection in retinal ganglion cells

    PubMed Central

    Brandt, Sean K.; Weatherly, Monique E.; Ware, Lillian; Linn, David M.; Linn, Cindy L.

    2010-01-01

    In the mammalian retina, excitotoxicity has been shown to be involved in apoptotic retinal ganglion cell (RGC) death and is associated with certain retinal disease states including glaucoma, diabetic retinopathy and retinal ischemia. Previous studies from this lab (Wehrwein et al., 2004) have demonstrated that acetylcholine (ACh) and nicotine protects against glutamate-induced excitotoxicity in isolated adult pig RGCs through nicotinic acetylcholine receptors (nAChRs). Activation of nAChRs in these RGCs triggers cell survival signaling pathways and inhibits apoptotic enzymes (Asomugha et al., 2010). However, the link between binding of nAChRs and activation of neuroprotective pathways is unknown. In this study, we examine the hypothesis that calcium permeation through nAChR channels is required for ACh-induced neuroprotection against glutamate-induced excitotoxicity in isolated pig RGCs. RGCs were isolated from other retinal tissue using a two step panning technique and cultured for 3 days under different conditions. In some studies, calcium imaging experiments were performed using the fluorescent calcium indicator, fluo-4, and demonstrated that calcium permeates the nAChR channels located on pig RGCs. In other studies, the extracellular calcium concentration was altered to determine the effect on nicotine-induced neuroprotection. Results support the hypothesis that calcium is required for nicotine-induced neuroprotection in isolated pig RGCs. Lastly, studies were performed to analyze the effects of preconditioning on glutamate-induced excitotoxicity and neuroprotection. In these studies, a preconditioning dose of calcium was introduced to cells using a variety of mechanisms before a large glutamate insult was applied to cells. Results from these studies support the hypothesis that preconditioning cells with a relatively low level of calcium before an excitotoxic insult leads to neuroprotection. In the future, these results could provide important information

  16. Preconditioning a product of matrices arising in trust region subproblems

    SciTech Connect

    Hribar, M.E.; Plantenga, T.D.

    1996-03-01

    In solving large scale optimization problems, we find it advantageous to use iterative methods to solve the sparse linear systems that arise. In the ETR software for solving equality constrained optimization problems, we use a conjugate gradient method to approximately solve the trust region subproblems. To speed up the convergence of the conjugate gradient routine, we need to precondition matrices of the form Z{sup T} W Z, which are not explicitly stored. Four preconditioners were implemented and the results for each are given.

  17. Ischemic preconditioning enhances integrity of coronary endothelial tight junctions

    SciTech Connect

    Li, Zhao; Jin, Zhu-Qiu

    2012-08-31

    Highlights: Black-Right-Pointing-Pointer Cardiac tight junctions are present between coronary endothelial cells. Black-Right-Pointing-Pointer Ischemic preconditioning preserves the structural and functional integrity of tight junctions. Black-Right-Pointing-Pointer Myocardial edema is prevented in hearts subjected to ischemic preconditioning. Black-Right-Pointing-Pointer Ischemic preconditioning enhances translocation of ZO-2 from cytosol to cytoskeleton. -- Abstract: Ischemic preconditioning (IPC) is one of the most effective procedures known to protect hearts against ischemia/reperfusion (IR) injury. Tight junction (TJ) barriers occur between coronary endothelial cells. TJs provide barrier function to maintain the homeostasis of the inner environment of tissues. However, the effect of IPC on the structure and function of cardiac TJs remains unknown. We tested the hypothesis that myocardial IR injury ruptures the structure of TJs and impairs endothelial permeability whereas IPC preserves the structural and functional integrity of TJs in the blood-heart barrier. Langendorff hearts from C57BL/6J mice were prepared and perfused with Krebs-Henseleit buffer. Cardiac function, creatine kinase release, and myocardial edema were measured. Cardiac TJ function was evaluated by measuring Evans blue-conjugated albumin (EBA) content in the extravascular compartment of hearts. Expression and translocation of zonula occludens (ZO)-2 in IR and IPC hearts were detected with Western blot. A subset of hearts was processed for the observation of ultra-structure of cardiac TJs with transmission electron microscopy. There were clear TJs between coronary endothelial cells of mouse hearts. IR caused the collapse of TJs whereas IPC sustained the structure of TJs. IR increased extravascular EBA content in the heart and myocardial edema but decreased the expression of ZO-2 in the cytoskeleton. IPC maintained the structure of TJs. Cardiac EBA content and edema were reduced in IPC hearts. IPC

  18. Preconditioning methods for ideal and multiphase fluid flows

    NASA Astrophysics Data System (ADS)

    Gupta, Ashish

    The objective of this study is to develop a preconditioning method for ideal and multiphase multispecies compressible fluid flow solver using homogeneous equilibrium mixture model. The mathematical model for fluid flow going through phase change uses density and temperature in the formulation, where the density represents the multiphase mixture density. The change of phase of the fluid is then explicitly determined using the equation of state of the fluid, which only requires temperature and mixture density. The method developed is based on a finite-volume framework in which the numerical fluxes are computed using Roe's approximate Riemann solver and the modified Harten, Lax and Van-leer scheme (HLLC). All speed Roe and HLLC flux based schemes have been developed either by using preconditioning or by directly modifying dissipation to reduce the effect of acoustic speed in its numerical dissipation when Mach number decreases. Preconditioning proposed by Briley, Taylor and Whitfield, Eriksson and Turkel are studied in this research, where as low dissipation schemes proposed by Rieper and Thornber, Mosedale, Drikakis, Youngs and Williams are also considered. Various preconditioners are evaluated in terms of development, performance, accuracy and limitations in simulations at various Mach numbers. A generalized preconditioner is derived which possesses well conditioned eigensystem for multiphase multispecies flow simulations. Validation and verification of the solution procedure are carried out on several small model problems with comparison to experimental, theoretical, and other numerical results. Preconditioning methods are evaluated using three basic geometries; 1) bump in a channel 2) flow over a NACA0012 airfoil and 3) flow over a cylinder, which are then compared with theoretical and numerical results. Multiphase capabilities of the solver are evaluated in cryogenic and non-cryogenic conditions. For cryogenic conditions the solver is evaluated by predicting

  19. Interface preconditionings for domain-decomposed convection-diffusion operators

    NASA Technical Reports Server (NTRS)

    Chan, Tony F.; Keyes, David E.

    1990-01-01

    The performance of five different interface preconditionings for domain-decomposed convection-diffusion problems, including a novel one known as the spectral probe is tested in a three-dimensional parameter space consisting of mesh parameters, Reynolds number, and domain aspect ratio. The preconditioners are representative of the range of practically computable possibilities that have appeared in the literature for the treatment of nonoverlapping subdomains. Numerical examples show that no single preconditioner can be considered uniformly superior or uniformly inferior to the rest, but that knowledge of the particulars of the shape and strength of the convection is important in selecting among them in a given problem.

  20. Preconditioning at a distance: Involvement of endothelial vasoactive substances in cardioprotection against ischemia-reperfusion injury.

    PubMed

    Aggarwal, Sapna; Randhawa, Puneet Kaur; Singh, Nirmal; Jaggi, Amteshwar Singh

    2016-04-15

    There is growing preclinical as well as clinical evidence supporting remote ischemic preconditioning (RIPC), in which short cycles of non-fatal ischemia followed by reperfusion to an organ or tissue distant from the heart elicits cardioprotection. It is the most practical, non-invasive, cost-free, and clinically compatible, secure procedure for reducing ischemia-reperfusion induced injury. The use of a conventional blood pressure cuff on the upper or lower limb in eliciting cardioprotection has expedited its clinical applicability. Endothelium has been documented to respond very quickly to blood flow and hypoxia by releasing different humoral factors such as endothelium derived releasing factor, endothelium derived contracting factor, endothelium derived hyperpolarizing factor. In recent years, there have been studies suggesting the key role of endothelial derived factors in RIPC induced cardioprotection. The signaling cascade involves nitric oxide, gap junctions, epoxyeicosatrienoic (EETs) acids, Ca-activated K(+) channels, angiotensin II, thromboxane A2, superoxide anions and prostacyclin. The present review describes the role of these endothelial derived factors in RIPC induced cardioprotection with possible mechanisms. PMID:26979771

  1. Augmentation of aerobic respiration and mitochondrial biogenesis in skeletal muscle by hypoxia preconditioning with cobalt chloride

    SciTech Connect

    Saxena, Saurabh; Shukla, Dhananjay; Bansal, Anju

    2012-11-01

    High altitude/hypoxia training is known to improve physical performance in athletes. Hypoxia induces hypoxia inducible factor-1 (HIF-1) and its downstream genes that facilitate hypoxia adaptation in muscle to increase physical performance. Cobalt chloride (CoCl{sub 2}), a hypoxia mimetic, stabilizes HIF-1, which otherwise is degraded in normoxic conditions. We studied the effects of hypoxia preconditioning by CoCl{sub 2} supplementation on physical performance, glucose metabolism, and mitochondrial biogenesis using rodent model. The results showed significant increase in physical performance in cobalt supplemented rats without (two times) or with training (3.3 times) as compared to control animals. CoCl{sub 2} supplementation in rats augmented the biological activities of enzymes of TCA cycle, glycolysis and cytochrome c oxidase (COX); and increased the expression of glucose transporter-1 (Glut-1) in muscle showing increased glucose metabolism by aerobic respiration. There was also an increase in mitochondrial biogenesis in skeletal muscle observed by increased mRNA expressions of mitochondrial biogenesis markers which was further confirmed by electron microscopy. Moreover, nitric oxide production increased in skeletal muscle in cobalt supplemented rats, which seems to be the major reason for peroxisome proliferator activated receptor-gamma coactivator-1α (PGC-1α) induction and mitochondrial biogenesis. Thus, in conclusion, we state that hypoxia preconditioning by CoCl{sub 2} supplementation in rats increases mitochondrial biogenesis, glucose uptake and metabolism by aerobic respiration in skeletal muscle, which leads to increased physical performance. The significance of this study lies in understanding the molecular mechanism of hypoxia adaptation and improvement of work performance in normal as well as extreme conditions like hypoxia via hypoxia preconditioning. -- Highlights: ► We supplemented rats with CoCl{sub 2} for 15 days along with training. ► Co

  2. MIC(0) preconditioning of 3D FEM problems on unstructured grids: Conforming and non-conforming elements

    NASA Astrophysics Data System (ADS)

    Margenov, Svetozar; Kosturski, Nikola

    2009-04-01

    In this study, the topics of grid generation and FEM applications are studied together following their natural synergy. We consider the following three tetrahedral grid generators: NETGEN, TetGen, and Gmsh. After that, the performance of the MIC(0) preconditioned conjugate gradient (PCG) solver is analyzed for both conforming and non-conforming linear FEM problems. If positive off-diagonal entries appear in the corresponding matrix, a diagonal compensation is applied to get an auxiliary M-matrix allowing a stable MIC(0) factorization. The presented numerical experiments for elliptic and parabolic problems well illustrate the similar PCG convergence rate of the MIC(0) preconditioner for both, structured and unstructured grids.

  3. Atrioventricular block after ASD closure

    PubMed Central

    Asakai, Hiroko; Weskamp, Sofia; Eastaugh, Lucas; d'Udekem, Yves; Pflaumer, Andreas

    2016-01-01

    Objective Secundum atrial septal defect (ASD) is a common congenital heart defect. There is limited data on both early and late atrioventricular (AV) block post ASD closure. The aim of this study was to determine the incidence and risk factors of AV block associated with ASD closure. Methods A retrospective analysis of all patients who underwent ASD closure either with a device or surgical method at the Royal Children's Hospital Melbourne between 1996 and 2010 was performed. Baseline demographics, procedural details and follow-up data were collected from medical records. Results A total of 378 patients were identified; 242 in the device group and 136 in the surgical group. Fourteen patients (3.7%) had AV block (1 with second degree and 13 with first degree) at a median follow-up of 28 months; 11/242 (4.5%) in the device group and 3/135 (2.2%) in the surgical group (p=0.39). Six patients had new-onset AV block after ASD closure. In the device subgroup, patients with AV block at follow-up had a larger indexed device size compared with those without (22 (15–31) vs 18(7–38), p=0.02). Multivariate analysis revealed the presence of AV block either pre procedure or post procedure to be the only variables associated with late AV block. Conclusions Late AV block in patients with repaired ASD is rare and most likely independent of the technique used. In the device subgroup, the only risk factor identified to be associated with late AV block was the presence of either preprocedural or postprocedural AV block, so long-term follow-up for these patients should be provided. PMID:27540418

  4. Effects of Ischemic Preconditioning of Different Intraoperative Ischemic Times of Vascularized Bone Graft Rabbit Models

    PubMed Central

    Wan Ahmad Kamal, Wan Syazli Rodzaia; Noor, Norizal Mohd; Abdullah, Shafie

    2013-01-01

    Background Ischemic preconditioning has been shown to improve the outcomes of hypoxic tolerance of the heart, brain, lung, liver, jejunum, skin, and muscle tissues. However, to date, no report of ischemic preconditioning on vascularized bone grafts has been published. Methods Sixteen rabbits were divided into four groups with ischemic times of 2, 6, 14, and 18 hours. Half of the rabbits in each group underwent ischemic preconditioning. The osteomyocutaneous flaps consisted of the tibia bone, from which the overlying muscle and skin were raised. The technique of ischemic preconditioning involved applying a vascular clamp to the pedicle for 3 cycles of 10 minutes each. The rabbits then underwent serial plain radiography and computed tomography imaging on the first, second, fourth, and sixth postoperative weeks. Following this, all of the rabbits were sacrificed and histological examinations were performed. Results The results showed that for clinical analysis of the skin flaps and bone grafts, the preconditioned groups showed better survivability. In the plain radiographs, except for two non-preconditioned rabbits with intraoperative ischemic times of 6 hours, all began to show early callus formation at the fourth week. The computed tomography findings showed more callus formation in the preconditioned groups for all of the ischemic times except for the 18-hour group. The histological findings correlated with the radiological findings. There was no statistical significance in the difference between the two groups. Conclusions In conclusion, ischemic preconditioning improved the survivability of skin flaps and increased callus formation during the healing process of vascularized bone grafts. PMID:24286040

  5. Sensory Preconditioning in Newborn Rabbits: From Common to Distinct Odor Memories

    ERIC Educational Resources Information Center

    Coureaud, Gerard; Tourat, Audrey; Ferreira, Guillaume

    2013-01-01

    This study evaluated whether olfactory preconditioning is functional in newborn rabbits and based on joined or independent memory of odorants. First, after exposure to odorants A+B, the conditioning of A led to high responsiveness to odorant B. Second, responsiveness to B persisted after amnesia of A. Third, preconditioning was also functional…

  6. 40 CFR 85.2220 - Preconditioned two speed idle test-EPA 91.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 19 2013-07-01 2013-07-01 false Preconditioned two speed idle test-EPA... Warranty Short Tests § 85.2220 Preconditioned two speed idle test—EPA 91. (a) General requirements—(1...-speed mode followed immediately by a first-chance idle mode. (ii) The second-chance test as...

  7. 40 CFR 85.2220 - Preconditioned two speed idle test-EPA 91.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 19 2012-07-01 2012-07-01 false Preconditioned two speed idle test-EPA... Warranty Short Tests § 85.2220 Preconditioned two speed idle test—EPA 91. (a) General requirements—(1...-speed mode followed immediately by a first-chance idle mode. (ii) The second-chance test as...

  8. 40 CFR 85.2220 - Preconditioned two speed idle test-EPA 91.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 18 2010-07-01 2010-07-01 false Preconditioned two speed idle test-EPA... Warranty Short Tests § 85.2220 Preconditioned two speed idle test—EPA 91. (a) General requirements—(1... between 2200 and 2800 rpm. If the engine speed falls below 2200 rpm or exceeds 2800 rpm for more than...

  9. Preconditioning ischemia time determines the degree of glycogen depletion and infarct size reduction in rat hearts.

    PubMed

    Barbosa, V; Sievers, R E; Zaugg, C E; Wolfe, C L

    1996-02-01

    The cardioprotective effect of preconditioning is associated with glycogen depletion and attenuation of intracellular acidosis during subsequent prolonged ischemia. This study determined the effects of increasing preconditioning ischemia time on myocardial glycogen depletion and on infarct size reduction. In addition, this study determined whether infarct size reduction by preconditioning correlates with glycogen depletion before prolonged ischemia. Anesthetized rats underwent a single episode of preconditioning lasting 1.25, 2.5, 5, or 10 minutes or multiple episodes cumulating in 10 (2 x 5 min) or 20 minutes (4 x 5 or 2 x 10 min) of preconditioning ischemia time, each followed by 5 minutes of reperfusion. Then both preconditioned and control rats underwent 45 minutes of ischemia induced by left coronary artery (LCA) occlusion and 120 minutes of reperfusion. After prolonged ischemia, infarct size was determined by dual staining with triphenyltetrazolium chloride and phthalocyanine blue dye. Glycogen levels were determined by an enzymatic assay in selected rats from each group before prolonged ischemia. We found that increasing preconditioning ischemia time resulted in glycogen depletion and infarct size reduction that could both be described by exponential functions. Furthermore, infarct size reduction correlated with glycogen depletion before prolonged ischemia (r = 0.98; p < 0.01). These findings suggest a role for glycogen depletion in reducing ischemic injury in the preconditioned heart. PMID:8579012

  10. 40 CFR 85.2220 - Preconditioned two speed idle test-EPA 91.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 18 2011-07-01 2011-07-01 false Preconditioned two speed idle test-EPA... Warranty Short Tests § 85.2220 Preconditioned two speed idle test—EPA 91. (a) General requirements—(1...-speed mode followed immediately by a first-chance idle mode. (ii) The second-chance test as...

  11. Stress Preconditioning of Spreading Depression in the Locust CNS

    PubMed Central

    Rodgers, Corinne I.; Armstrong, Gary A. B.; Shoemaker, Kelly L.; LaBrie, John D.; Moyes, Christopher D.; Robertson, R. Meldrum

    2007-01-01

    Cortical spreading depression (CSD) is closely associated with important pathologies including stroke, seizures and migraine. The mechanisms underlying SD in its various forms are still incompletely understood. Here we describe SD-like events in an invertebrate model, the ventilatory central pattern generator (CPG) of locusts. Using K+ -sensitive microelectrodes, we measured extracellular K+ concentration ([K+]o) in the metathoracic neuropile of the CPG while monitoring CPG output electromyographically from muscle 161 in the second abdominal segment to investigate the role K+ in failure of neural circuit operation induced by various stressors. Failure of ventilation in response to different stressors (hyperthermia, anoxia, ATP depletion, Na+/K+ ATPase impairment, K+ injection) was associated with a disturbance of CNS ion homeostasis that shares the characteristics of CSD and SD-like events in vertebrates. Hyperthermic failure was preconditioned by prior heat shock (3 h, 45°C) and induced-thermotolerance was associated with an increase in the rate of clearance of extracellular K+ that was not linked to changes in ATP levels or total Na+/K+ ATPase activity. Our findings suggest that SD-like events in locusts are adaptive to terminate neural network operation and conserve energy during stress and that they can be preconditioned by experience. We propose that they share mechanisms with CSD in mammals suggesting a common evolutionary origin. PMID:18159249

  12. Parallelizable approximate solvers for recursions arising in preconditioning

    SciTech Connect

    Shapira, Y.

    1996-12-31

    For the recursions used in the Modified Incomplete LU (MILU) preconditioner, namely, the incomplete decomposition, forward elimination and back substitution processes, a parallelizable approximate solver is presented. The present analysis shows that the solutions of the recursions depend only weakly on their initial conditions and may be interpreted to indicate that the inexact solution is close, in some sense, to the exact one. The method is based on a domain decomposition approach, suitable for parallel implementations with message passing architectures. It requires a fixed number of communication steps per preconditioned iteration, independently of the number of subdomains or the size of the problem. The overlapping subdomains are either cubes (suitable for mesh-connected arrays of processors) or constructed by the data-flow rule of the recursions (suitable for line-connected arrays with possibly SIMD or vector processors). Numerical examples show that, in both cases, the overhead in the number of iterations required for convergence of the preconditioned iteration is small relatively to the speed-up gained.

  13. Ischemic preconditioning stimulates sodium and proton transport in isolated rat hearts.

    PubMed Central

    Ramasamy, R; Liu, H; Anderson, S; Lundmark, J; Schaefer, S

    1995-01-01

    One or more brief periods of ischemia, termed preconditioning, dramatically limits infarct size and reduces intracellular acidosis during subsequent ischemia, potentially via enhanced sarcolemmal proton efflux mechanisms. To test the hypothesis that preconditioning increases the functional activity of sodium-dependent proton efflux pathways, isolated rat hearts were subjected to 30 min of global ischemia with or without preconditioning. Intracellular sodium (Nai) was assessed using 23Na magnetic resonance spectroscopy, and the activity of the Na-H exchanger and Na-K-2Cl cotransporter was measured by transiently exposing the hearts to an acid load (NH4Cl washout). Creatine kinase release was reduced by greater than 60% in the preconditioned hearts (P < 0.05) and was associated with improved functional recovery on reperfusion. Preconditioning increased Nai by 6.24 +/- 2.04 U, resulting in a significantly higher level of Nai before ischemia than in the control hearts. Nai increased significantly at the onset of ischemia (8.48 +/- 1.21 vs. 2.57 +/- 0.81 U, preconditioned vs. control hearts; P < 0.01). Preconditioning did not reduce Nai accumulation during ischemia, but the decline in Nai during the first 5 min of reperfusion was significantly greater in the preconditioned than in the control hearts (13.48 +/- 1.73 vs. 2.54 +/- 0.41 U; P < 0.001). Exposure of preconditioned hearts to ethylisopropylamiloride or bumetanide in the last reperfusion period limited in the increase in Nai during ischemia and reduced the beneficial effects of preconditioning. After the NH4Cl prepulse, preconditioned hearts acidified significantly more than control hearts and had significantly more rapid recovery of pH (preconditioned, delta pH = 0.35 +/- 0.04 U over 5 min; control, delta pH = 0.15 +/- 0.02 U over 5 min). This rapid pH recovery was not affected by inhibition of the Na-K-2Cl cotransporter but was abolished by inhibition of the Na-H exchanger. These results demonstrate that

  14. Preconditioning techniques for constrained vector potential integral equations, with application to 3-D magnetoquasistatic analysis of electronic packages

    SciTech Connect

    Kamon, M.; Phillips, J.R.

    1994-12-31

    In this paper techniques are presented for preconditioning equations generated by discretizing constrained vector integral equations associated with magnetoquasistatic analysis. Standard preconditioning approaches often fail on these problems. The authors present a specialized preconditioning technique and prove convergence bounds independent of the constraint equations and electromagnetic excitation frequency. Computational results from analyzing several electronic packaging examples are given to demonstrate that the new preconditioning approach can sometimes reduce the number of GMRES iterations by more than an order of magnitude.

  15. Local and remote ischemic preconditioning protect against intestinal ischemic/reperfusion injury after supraceliac aortic clamping

    PubMed Central

    Erling, Nilon; de Souza Montero, Edna Frasson; Sannomiya, Paulina; Poli-de-Figueiredo (in memoriam), Luiz Francisco

    2013-01-01

    OBJECTIVES: This study tests the hypothesis that local or remote ischemic preconditioning may protect the intestinal mucosa against ischemia and reperfusion injuries resulting from temporary supraceliac aortic clamping. METHODS: Twenty-eight Wistar rats were divided into four groups: the sham surgery group, the supraceliac aortic occlusion group, the local ischemic preconditioning prior to supraceliac aortic occlusion group, and the remote ischemic preconditioning prior to supraceliac aortic occlusion group. Tissue samples from the small bowel were used for quantitative morphometric analysis of mucosal injury, and blood samples were collected for laboratory analyses. RESULTS: Supraceliac aortic occlusion decreased intestinal mucosal length by reducing villous height and elevated serum lactic dehydrogenase and lactate levels. Both local and remote ischemic preconditioning mitigated these histopathological and laboratory changes. CONCLUSIONS: Both local and remote ischemic preconditioning protect intestinal mucosa against ischemia and reperfusion injury following supraceliac aortic clamping. PMID:24473514

  16. Contribution of the maritime continent convection during the preconditioning stage of the Madden-Julian Oscillation

    NASA Astrophysics Data System (ADS)

    Kubota, H.; Yoneyama, K.; Nasuno, T.; Hamada, J.

    2013-12-01

    During the international field experiment 'Cooperative Indian Ocean experiment on intraseasonal variability in the Year 2011 (CINDY2011)', the preconditioning process of the MJO was observed. In this study, the contribution of the maritime continent convection was focused on the preconditioning process of the third MJO. During the preconditioning stage of the MJO, westward propagating disturbances were observed from Sumatera Island to the central Indian Ocean and moistened the atmosphere. Convections over the Sumatera Island were activated around December 15th when the moist air mass reached from South China Sea. The origin of the moist air mass was tropical cyclone which was formed in South China Sea in December 10th. The high moisture associated with tropical cyclone activated the convection over Sumatera Island, promoted westward propagating disturbances, and acted a favorable environment for the preconditioning of the MJO. This preconditioning stage of the MJO is simulated by Nonhydrostatic ICosahedral Atmospheric Model (NICAM) and investigated the moistening process.

  17. Novel role of Engrailed 1 as a prosurvival transcription factor in basal-like breast cancer and engineering of interference peptides block its oncogenic function

    PubMed Central

    Beltran, A S; Graves, L M; Blancafort, P

    2014-01-01

    Basal-like breast tumors are aggressive cancers associated with high proliferation and metastasis. Chemotherapy is currently the only treatment option; however, resistance often occurs resulting in recurrence and patient death. Some extremely aggressive cancers are also associated with hypoxia, inflammation and high leukocyte infiltration. Herein, we discovered that the neural-specific transcription factor, Engrailed 1 (EN1), is exclusively overexpressed in these tumors. Short hairpin RNA (shRNA)-mediated knockdown of EN1 triggered potent and selective cell death. In contrast, ectopic overexpression of EN1 in normal cells activated survival pathways and conferred resistance to chemotherapeutic agents. Exogenous expression of EN1 cDNA reprogrammed the breast epithelial cells toward a long-lived, neural-like phenotype displaying dopaminergic markers. Gene expression microarrays demonstrated that the EN1 cDNA altered transcription of a high number of inflammatory molecules, notably chemokines and chemokine receptors, which could mediate prosurvival pathways. To block EN1 function, we engineered synthetic interference peptides (iPeps) comprising the EN1-specific sequences that mediate essential protein-protein interactions necessary for EN1 function and an N-terminal cell-penetrating peptide/nuclear localization sequence. These EN1-iPeps rapidly mediated a strong apoptotic response in tumor cells overexpressing EN1, with no toxicity to normal or non EN1-expressing cells. Delivery of EN1-iPeps into basal-like cancer cells significantly decreased the fifty percent inhibitory concentrations (IC50) of chemotherapeutic drugs routinely used to treat breast cancer. Lastly, matrix-assisted laser desorption/ionization-time of flight mass spectrometry and immunoprecipitation assays demonstrated that EN1-iPeps captured targets involved in transcriptional and post-transcriptional regulation. Importantly, the EN1-iPeps bound the glutamyl-prolyl tRNA synthetase (EPRS) target, which

  18. Hypoxic preconditioning with cobalt attenuates hypobaric hypoxia-induced oxidative damage in rat lungs.

    PubMed

    Shukla, Dhananjay; Saxena, Saurabh; Jayamurthy, Purushotman; Sairam, Mustoori; Singh, Mrinalini; Jain, Swatantra Kumar; Bansal, Anju; Ilavazaghan, Govindaswamy

    2009-01-01

    Shukla, Dhananjay, Saurabh Saxena, Purushotman Jayamurthy, Mustoori Sairam, Mrinalini, Singh, Swatantra Kumar Jain, Anju Bansal, and Govindaswamy Ilavazaghan. High Alt. Med. Biol. 10:57-69, 2009.-Hypoxic preco759nditioning (HPC) provides robust protection against injury from subsequent prolonged hypobaric hypoxia, which is a characteristic of high altitude and is known to induce oxidative injury in lung by increasing the generation of reactive oxygen species (ROS) and decreasing the effectiveness of the antioxidant defense system. We hypothesize that HPC with cobalt might protect the lung from subsequent hypobaric hypoxia-induced lung injury. HPC with cobalt can be achieved by oral feeding of CoCl(2) (12.5 mg kg(-1)) in rats for 7 days. Nonpreconditioned rats responded to hypobaric hypoxia (7619 m) by increased reactive oxygen species (ROS) generation and a decreased GSH/GSSG ratio. They also showed a marked increase in lipid peroxidation, heat-shock proteins (HSP32, HSP70), metallothionins (MT), levels of inflammatory cytokines (TNF-alpha, IFN-gamma, MCP-1), and SOD, GPx, and GST enzyme activity. In contrast, rats preconditioned with cobalt were far less impaired by severe hypobaric hypoxia, as observed by decreased ROS generation, lipid peroxidation, and inflammatory cytokine release and an inceased GSH/GSSG ratio. Increased expression of antioxidative proeins Nrf-1, HSP-32, and MT was also observed in cobalt- preconditioned animals. A marked increase in the protein expression and DNA binding activity of hypoxia-inducible transcriptional factor (HIF-1alpha) and its regulated genes, such as erythropoietin (EPO) and glucose transporter-1 (glut-1), was observed after HPC with cobalt. We conclude that HPC with cobalt enhances antioxidant status in the lung and protects from subsequent hypobaric hypoxia-induced oxidative stress. PMID:19278353

  19. Elasmobranch qPCR reference genes: a case study of hypoxia preconditioned epaulette sharks

    PubMed Central

    2010-01-01

    Background Elasmobranch fishes are an ancient group of vertebrates which have high potential as model species for research into evolutionary physiology and genomics. However, no comparative studies have established suitable reference genes for quantitative PCR (qPCR) in elasmobranchs for any physiological conditions. Oxygen availability has been a major force shaping the physiological evolution of vertebrates, especially fishes. Here we examined the suitability of 9 reference candidates from various functional categories after a single hypoxic insult or after hypoxia preconditioning in epaulette shark (Hemiscyllium ocellatum). Results Epaulette sharks were caught and exposed to hypoxia. Tissues were collected from 10 controls, 10 individuals with single hypoxic insult and 10 individuals with hypoxia preconditioning (8 hypoxic insults, 12 hours apart). We produced sequence information for reference gene candidates and monitored mRNA expression levels in four tissues: cerebellum, heart, gill and eye. The stability of the genes was examined with analysis of variance, geNorm and NormFinder. The best ranking genes in our study were eukaryotic translation elongation factor 1 beta (eef1b), ubiquitin (ubq) and polymerase (RNA) II (DNA directed) polypeptide F (polr2f). The performance of the ribosomal protein L6 (rpl6) was tissue-dependent. Notably, in one tissue the analysis of variance indicated statistically significant differences between treatments for genes that were ranked as the most stable candidates by reference gene software. Conclusions Our results indicate that eef1b and ubq are generally the most suitable reference genes for the conditions and tissues in the present epaulette shark studies. These genes could also be potential reference gene candidates for other physiological studies examining stress in elasmobranchs. The results emphasise the importance of inter-group variation in reference gene evaluation. PMID:20416043

  20. Causal role of oxidative stress in liver preconditioning by thyroid hormone in rats.

    PubMed

    Fernández, Virginia; Tapia, Gladys; Varela, Patricia; Gaete, Leonardo; Vera, Gemma; Mora, Catalina; Vial, María T; Videla, Luis A

    2008-05-01

    Hepatic ischemia-reperfusion (IR) injury, a major clinical drawback during surgery, is abolished by L-3,3',5-triiodothyronine (T(3)) administration. Considering that the triggering mechanisms are unknown, the aim of this study is to assess the role of oxidative stress in T(3) preconditioning using N-acetylcysteine (NAC) before T(3) administration. Male Sprague-Dawley rats given a single dose of 0.1 mg of T(3)/kg were subjected to 1 h ischemia followed by 20 h reperfusion, in groups of animals pretreated with 0.5 g of NAC/kg 0.5 h before T(3) or with the respective control vehicles. At the end of the reperfusion period, blood and liver samples were taken for analysis of serum aspartate aminotransferase (AST) and hepatic histology, glutathione (GSH) and protein carbonyl contents, and nuclear factor-kappaB (NF-kappaB) and activating protein 1 (AP-1) DNA binding. The IR protocol used led to a 4.5-fold increase in serum AST levels and drastic changes in liver histology, with significant GSH depletion and enhancement of protein carbonyl levels and of the protein carbonyl/GSH content ratio, whereas NF-kappaB and AP-1 DNA binding was decreased and enhanced, respectively. In a time window of 48 h, T(3) exerted protection against hepatic IR injury, with 88% reduction in the protein carbonyl/GSH ratio and normalization of NF-kappaB and AP-1 DNA binding, changes that were suppressed by NAC administration before T(3). Data presented suggest that a transient increase in the oxidative stress status of the liver is an important trigger for T(3) preconditioning, evidenced in a warm IR injury model through antioxidant intervention. PMID:18291118

  1. THE FIRST GRADE CLINIC--A MEDIUM FOR EARLY IDENTIFICATION OF PHYSICAL, SOCIAL, EMOTIONAL, AND MENTAL DEVELOPMENT FACTOR THAT MAY TEND TO BLOCK OR IMPEDE SCHOOL PROGRESS.

    ERIC Educational Resources Information Center

    MCGAHAN, F.E.

    DURING A 5-YEAR PERIOD, A FIRST GRADE CLINIC IDENTIFIED, AT THE START OF EACH SCHOOL YEAR, CHILDREN WITH DEVIATIONS IN BEHAVIOR, SOCIAL AND EMOTIONAL ADJUSTMENT, AND MENTAL MATURATION THAT MIGHT BLOCK OR RETARD SUCCESS IN SCHOOL. THESE CHILDREN WERE REFERRED FOR FURTHER DIAGNOSTIC EVALUATIONS. THE PROGRAM WAS FIRST TRIED IN ONE CLASSROOM. A 3-YEAR…

  2. Fatigue characteristics of carbon nanotube blocks under compression

    NASA Astrophysics Data System (ADS)

    Suhr, J.; Ci, L.; Victor, P.; Ajayan, P. M.

    2008-03-01

    In this paper we investigate the mechanical response from repeated high compressive strains on freestanding, long, vertically aligned multiwalled carbon nanotube membranes and show that the arrays of nanotubes under compression behave very similar to soft tissue and exhibit viscoelastic behavior. Under compressive cyclic loading, the mechanical response of nanotube blocks shows initial preconditioning and hysteresis characteristic of viscoeleastic materials. Furthermore, no fatigue failure is observed even at high strain amplitudes up to half million cycles. The outstanding fatigue life and extraordinary soft tissue-like mechanical behavior suggest that properly engineered carbon nanotube structures could mimic artificial muscles.

  3. Types of Heart Block

    MedlinePlus

    ... Block Explore Heart Block What Is... Electrical System & EKG Results Types Causes Who Is at Risk Signs & ... the P and the R waves on the EKG (electrocardiogram). First-degree heart block may not cause ...

  4. Calcium preconditioning triggers neuroprotection in retinal ganglion cells.

    PubMed

    Brandt, S K; Weatherly, M E; Ware, L; Linn, D M; Linn, C L

    2011-01-13

    In the mammalian retina, excitotoxicity has been shown to be involved in apoptotic retinal ganglion cell (RGC) death and is associated with certain retinal disease states including glaucoma, diabetic retinopathy and retinal ischemia. Previous studies from this lab [Wehrwein E, Thompson SA, Coulibaly SF, Linn DM, Linn CL (2004) Invest Ophthalmol Vis Sci 45:1531-1543] have demonstrated that acetylcholine (ACh) and nicotine protects against glutamate-induced excitotoxicity in isolated adult pig RGCs through nicotinic acetylcholine receptors (nAChRs). Activation of nAChRs in these RGCs triggers cell survival signaling pathways and inhibits apoptotic enzymes [Asomugha CO, Linn DM, Linn CL (2010) J Neurochem 112:214-226]. However, the link between binding of nAChRs and activation of neuroprotective pathways is unknown. In this study, we examine the hypothesis that calcium permeation through nAChR channels is required for ACh-induced neuroprotection against glutamate-induced excitotoxicity in isolated pig RGCs. RGCs were isolated from other retinal tissue using a two step panning technique and cultured for 3 days under different conditions. In some studies, calcium imaging experiments were performed using the fluorescent calcium indicator, fluo-4, and demonstrated that calcium permeates the nAChR channels located on pig RGCs. In other studies, the extracellular calcium concentration was altered to determine the effect on nicotine-induced neuroprotection. Results support the hypothesis that calcium is required for nicotine-induced neuroprotection in isolated pig RGCs. Lastly, studies were performed to analyze the effects of preconditioning on glutamate-induced excitotoxicity and neuroprotection. In these studies, a preconditioning dose of calcium was introduced to cells using a variety of mechanisms before a large glutamate insult was applied to cells. Results from these studies support the hypothesis that preconditioning cells with a relatively low level of calcium before

  5. Ischemic Preconditioning and Placebo Intervention Improves Resistance Exercise Performance.

    PubMed

    Marocolo, Moacir; Willardson, Jeffrey M; Marocolo, Isabela C; Ribeiro da Mota, Gustavo; Simão, Roberto; Maior, Alex S

    2016-05-01

    Marocolo, M, Willardson, JM, Marocolo, IC, da Mota, GR, Simão, R, and Maior, AS. Ischemic preconditioning and PLACEBO intervention improves resistance exercise performance. J Strength Cond Res 30(5): 1462-1469, 2016-This study evaluated the effect of ischemic preconditioning (IPC) on resistance exercise performance in the lower limbs. Thirteen men participated in a randomized crossover design that involved 3 separate sessions (IPC, PLACEBO, and control). A 12-repetition maximum (12RM) load for the leg extension exercise was assessed through test and retest sessions before the first experimental session. The IPC session consisted of 4 cycles of 5 minutes of occlusion at 220 mm Hg of pressure alternated with 5 minutes of reperfusion at 0 mm Hg for a total of 40 minutes. The PLACEBO session consisted of 4 cycles of 5 minutes of cuff administration at 20 mm Hg of pressure alternated with 5 minutes of pseudo-reperfusion at 0 mm Hg for a total of 40 minutes. The occlusion and reperfusion phases were conducted alternately between the thighs, with subjects remaining seated. No ischemic pressure was applied during the control (CON) session and subjects sat passively for 40 minutes. Eight minutes after IPC, PLACEBO, or CON, subjects performed 3 repetition maximum sets of the leg extension (2-minute rest between sets) with the predetermined 12RM load. Four minutes after the third set for each condition, blood lactate was assessed. The results showed that for the first set, the number of repetitions significantly increased for both the IPC (13.08 ± 2.11; p = 0.0036) and PLACEBO (13.15 ± 0.88; p = 0.0016) conditions, but not for the CON (11.88 ± 1.07; p > 0.99) condition. In addition, the IPC and PLACEBO conditions resulted insignificantly greater repetitions vs. the CON condition on the first set (p = 0.015; p = 0.007) and second set (p = 0.011; p = 0.019), but not on the third set (p = 0.68; p > 0.99). No difference (p = 0.465) was found in the fatigue index and lactate

  6. Diazoxide preconditioning of endothelial progenitor cells from streptozotocin-induced type 1 diabetic rats improves their ability to repair diabetic cardiomyopathy.

    PubMed

    Ali, Muhammad; Mehmood, Azra; Anjum, Muhammad Sohail; Tarrar, Moazzam Nazir; Khan, Shaheen N; Riazuddin, Sheikh

    2015-12-01

    Type 1 diabetes mellitus (DM) is a strong risk factor for the development of diabetic cardiomyopathy (DCM) which is the leading cause of morbidity and mortality in the type 1 diabetic patients. Stem cells may act as a therapeutic agent for the repair of DCM. However, deteriorated functional abilities and survival of stem cells derived from type 1 diabetic subjects need to be overcome for obtaining potential outcome of the stem cell therapy. Diazoxide (DZ) a highly selective mitochondrial ATP-sensitive K(+) channel opener has been previously shown to improve the ability of mesenchymal stem cells for the repair of heart failure. In the present study, we evaluated the effects of DZ preconditioning in improving the ability of streptozotocin-induced type 1 diabetes affected bone marrow-derived endothelial progenitor cells (DM-EPCs) for the repair of DCM in the type 1 diabetic rats. DM-EPCs were characterized by immunocytochemistry, flow cytometry, and reverse transcriptase PCR for endothelial cell-specific markers like vWF, VE cadherin, VEGFR2, PECAM, CD34, and eNOS. In vitro studies included preconditioning of DM-EPCs with 200 μM DZ for 30 min followed by exposure to either 200 μM H2O2 for 2 h (for oxidative stress induction) or 30 mM glucose media (for induction of hyperglycemic stress) for 48 h. Non-preconditioned EPCs with and without exposure to H2O2 and 30 mM high glucose served as controls. These cells were then evaluated for survival (by MTT and XTT cell viability assays), senescence, paracrine potential (by ELISA for VEGF), and alteration in gene expression [VEGF, stromal derived factor-1α (SDF-1α), HGF, bFGF, Bcl2, and Caspase-3]. DZ preconditioned DM-EPCs demonstrated significantly increased survival and VEGF release while reduced cell injury and senescence. Furthermore, DZ preconditioned DM-EPCs exhibited up-regulated expression of prosurvival genes (VEGF, SDF-1α, HGF, bFGF, and Bcl2) on exposure to H2O2, and VEGF and Bcl2 on exposure to hyperglycemia

  7. A frequency dependent preconditioned wavelet method for atmospheric tomography

    NASA Astrophysics Data System (ADS)

    Yudytskiy, Mykhaylo; Helin, Tapio; Ramlau, Ronny

    2013-12-01

    Atmospheric tomography, i.e. the reconstruction of the turbulence in the atmosphere, is a main task for the adaptive optics systems of the next generation telescopes. For extremely large telescopes, such as the European Extremely Large Telescope, this problem becomes overly complex and an efficient algorithm is needed to reduce numerical costs. Recently, a conjugate gradient method based on wavelet parametrization of turbulence layers was introduced [5]. An iterative algorithm can only be numerically efficient when the number of iterations required for a sufficient reconstruction is low. A way to achieve this is to design an efficient preconditioner. In this paper we propose a new frequency-dependent preconditioner for the wavelet method. In the context of a multi conjugate adaptive optics (MCAO) system simulated on the official end-to-end simulation tool OCTOPUS of the European Southern Observatory we demonstrate robustness and speed of the preconditioned algorithm. We show that three iterations are sufficient for a good reconstruction.

  8. A Large-Scale Investigation of Hypoxia-Preconditioned Allogeneic Mesenchymal Stem Cells for Myocardial Repair in Nonhuman Primates

    PubMed Central

    Hu, Xinyang; Xu, Yinchuan; Zhong, Zhiwei; Wu, Yan; Zhao, Jing; Wang, Yingchao; Cheng, Haifeng; Kong, Minjian; Zhang, Fengjiang; Chen, Qi; Sun, Jianzhong; Li, Qian; Jin, Jing; Li, Qingju; Chen, Lihong; Wang, Chen; Zhan, Hongwei; Fan, Youqi; Yang, Qian; Yu, Lei; Wu, Rongrong; Liang, Jie; Zhu, Jinyun; Wang, Ya; Jin, Yiping; Lin, Yifan; Yang, Fan; Jia, Liangliang; Zhu, Wei; Chen, Jinghai; Yu, Hong

    2016-01-01

    Rationale: The effectiveness of transplanted bone marrow mesenchymal stem cells (MSCs) for cardiac repair has been limited; thus, strategies for optimizing stem-cell–based myocardial therapy are needed. Objective: The present study was designed to test our central hypothesis that hypoxia-preconditioned MSCs (HP-MSCs) are more effective than MSCs cultured under ambient oxygen levels for the treatment of myocardial injury in a large-scale (N=49), long-term (9 months), nonhuman primate (Cynomolgous monkeys) investigation. Methods and Results: MSCs were engineered to express green fluorescent protein, cultured under ambient oxygen or 0.5% oxygen (HP-MSCs) for 24 hours and then tested in the infarcted hearts of Cynomolgus monkeys (1×107 cells per heart). Hypoxia preconditioning increased the expression of several prosurvival/proangiogenic factors in cultured MSCs, and measurements of infarct size and left-ventricular function at day 90 after myocardial infarction were significantly more improved in monkeys treated with HP-MSCs than in monkeys treated with the control vehicle; functional improvements in normal cultured bone marrow mesenchymal stem cells–treated monkeys were not significant. HP-MSCs transplantation was also associated with increases in cardiomyocyte proliferation, vascular density, myocardial glucose uptake, and engraftment of the transplanted cells and with declines in endogenous cell apoptosis, but did not increase the occurrence of arrhythmogenic complications. Conclusions: Hypoxia preconditioning improved the effectiveness of MSCs transplantation for the treatment of myocardial infarction in nonhuman primates without increasing the occurrence of arrhythmogenic complications, which suggests that future clinical trials of HP-MSCs transplantation are warranted. PMID:26838793

  9. AdVEGF-All6A+ Preconditioning of Murine Ischemic Skin Flaps Is Comparable to Surgical Delay

    PubMed Central

    Gersch, Robert P.; Fourman, Mitchell S.; Phillips, Brett T.; Nasser, Ahmed; McClain, Steve A.; Khan, Sami U.; Dagum, Alexander B.

    2015-01-01

    Background: Surgical flap delay is commonly used in preconditioning reconstructive flaps to prevent necrosis. However, staged procedures are not ideal. Pharmacologic up-regulation of angiogenic and arteriogenic factors before flap elevation poses a nonsurgical approach to improve flap survival. Methods: Male Sprague Dawley rats were divided into control (n = 16), surgical delay (Delay), AdNull, AdEgr-1, and AdVEGF (n ≥ 9/group) groups. Delay rats had a 9 cm × 3 cm cranial based pedicle skin flap incised 10 days prior to elevation. Adenoviral groups received 28 intradermal injections (109 pu/animal total) throughout the distal two thirds of the flap 1 week prior to elevation. At postoperative day (POD) 0 flaps were elevated and silicone sheeting was placed between flap and wound bed. Perfusion analysis in arbitrary perfusion units of the ischemic middle third of the flap using laser Doppler imaging was conducted preoperatively and on POD 0, 3, and 7. Clinical and histopathologic assessments of the skin flaps were performed on POD 7. Results: AdVEGF (50.8 ± 10.9 APU) and AdEgr-1 (39.3 ± 10.6 APU) perfusion levels were significantly higher than controls (16.5 ± 4.2 APU) on POD 7. Delay models were equivalent to controls (25.9 ± 6.8 APU). AdVEGF and Delay animals showed significantly more viable surface area on POD 7 (14.4 ± 1.3 cm2, P < 0.01 and 12.4 ± 1.2 cm2, P < 0.05, respectively) compared with Controls (8.7 ± 0.7 cm2). Conclusions: AdVEGF preconditioning resulted in flap survival comparable to surgical delay. Adenoviral preconditioning maintained perfusion levels postoperatively while surgical delay did not. PMID:26495207

  10. Rural water-supply and sanitation planning: The use of socioeconomic preconditions in project identification

    NASA Astrophysics Data System (ADS)

    Warner, Dennis B.

    1984-02-01

    Recognition of the socioeconomic preconditions for successful rural water-supply and sanitation projects in developing countries is the key to identifying a new project. Preconditions are the social, economic and technical characteristics defining the project environment. There are two basic types of preconditions: those existing at the time of the initial investigation and those induced by subsequent project activities. Successful project identification is dependent upon an accurate recognition of existing constraints and a carefully tailored package of complementary investments intended to overcome the constraints. This paper discusses the socioeconomic aspects of preconditions in the context of a five-step procedure for project identification. The procedure includes: (1) problem identification; (2) determination of socioeconomic status; (3) technology selection; (4) utilization of support conditions; and (5) benefit estimation. Although the establishment of specific preconditions should be based upon the types of projects likely to be implemented, the paper outlines a number of general relationships regarding favourable preconditions in water and sanitation planning. These relationships are used within the above five-step procedure to develop a set of general guidelines for the application of preconditions in the identification of rural water-supply and sanitation projects.

  11. The Effect of Hypoxic Preconditioning on Induced Schwann Cells under Hypoxic Conditions

    PubMed Central

    Chen, Ou; Wu, Miaomiao; Jiang, Liangfu

    2015-01-01

    Object Our objective was to explore the protective effects of hypoxic preconditioning on induced Schwann cells exposed to an environment with low concentrations of oxygen. It has been observed that hypoxic preconditioning of induced Schwann cells can promote axonal regeneration under low oxygen conditions. Method Rat bone marrow mesenchymal stem cells (MSCs) were differentiated into Schwann cells and divided into a normal oxygen control group, a hypoxia-preconditioning group and a hypoxia group. The ultrastructure of each of these groups of cells was observed by electron microscopy. In addition, flow cytometry was used to measure changes in mitochondrial membrane potential. Annexin V-FITC/PI staining was used to detect apoptosis, and Western blots were used to detect the expression of Bcl-2/Bax. Fluorescence microscopic observations of axonal growth in NG-108 cells under hypoxic conditions were also performed. Results The hypoxia-preconditioning group maintained mitochondrial cell membrane and crista integrity, and these cells exhibited less edema than the hypoxia group. In addition, the cells in the hypoxia-preconditioning group were found to be in early stages of apoptosis, whereas cells from the hypoxia group were in the later stages of apoptosis. The hypoxia-preconditioning group also had higher levels of Bcl-2/Bax expression and longer NG-108 cell axons than were observed in the hypoxia group. Conclusion Hypoxic preconditioning can improve the physiological state of Schwann cells in a severe hypoxia environment and improve the ability to promote neurite outgrowth. PMID:26509259

  12. Identifying hydrological pre-conditions and rainfall triggers of slope failures for 2014 storm events in the Ialomita Subcarpathians, Romania

    NASA Astrophysics Data System (ADS)

    Chitu, Zenaida; Bogaard, Thom; Busuioc, Aristita; Burcea, Sorin; Adler, Mary-Jeanne; Sandric, Ionut

    2015-04-01

    Like in many parts of the world, in Romania, landslides represent recurrent phenomena that produce numerous damages to infrastructure every few years. Various studies on landslide occurrence in the Curvature Subcarpathians reveal that rainfall represents the most important triggering factor for landslides. Depending on rainfall characteristics and environmental factors different types of landslides were recorded in the Ialomita Subcarpathians: slumps, earthflows and complex landslides. This area, located in the western part of Curvature Subcarpathians, is characterized by a very complex geology whose main features are represented by the nappes system, the post tectonic covers, the diapirism phenomena and vertical faults. This work aims to investigate hydrological pre-conditions and rainfall characteristics which triggered slope failures in 2014 in the Ialomita Subcarpathians, Romania. Hydrological pre-conditions were investigated by means of water balance analysis and low flow techniques, while spatial and temporal patterns of rainfalls were estimated using radar data and six rain gauges. Additionally, six soil moisture stations that are fitted with volumetric soil moisture sensors and temperature soil sensors were used to estimate the antecedent soil moisture conditions.

  13. Transcriptional signature of human adipose tissue-derived stem cells (hASCs) preconditioned for chondrogenesis in hypoxic conditions

    SciTech Connect

    Pilgaard, L.; Lund, P.; Duroux, M.; Lockstone, H.; Taylor, J.; Emmersen, J.; Fink, T.; Ragoussis, J.; Zachar, V.

    2009-07-01

    Hypoxia is an important factor involved in the control of stem cells. To obtain a better insight into the phenotypical changes brought about by hypoxic preconditioning prior to chondrogenic differentiation; we have investigated growth, colony-forming and chondrogenic capacity, and global transcriptional responses of six adipose tissue-derived stem cell lines expanded at oxygen concentrations ranging from ambient to 1%. The assessment of cell proliferation and colony-forming potential revealed that the hypoxic conditions corresponding to 1% oxygen played a major role. The chondrogenic inducibility, examined by high-density pellet model, however, did not improve on hypoxic preconditioning. While the microarray analysis revealed a distinctive inter-donor variability, the exposure to 1% hypoxia superseded the biological variability and produced a specific expression profile with 2581 significantly regulated genes and substantial functional enrichment in the pathways of cell proliferation and apoptosis. Additionally, exposure to 1% oxygen resulted in upregulation of factors related to angiogenesis and cell growth. In particular, leptin (LEP), the key regulator of body weight and food intake was found to be highly upregulated. In conclusion, the results of this investigation demonstrate the significance of donor demographics and the importance of further studies into the use of regulated oxygen tension as a tool for preparation of ASCs in order to exploit their full potential.

  14. Perfusion delay causes unintentional ischemic preconditioning in isolated heart preparation.

    PubMed

    Minhaz, U; Koide, S; Shohtsu, A; Fujishima, M; Nakazawa, H

    1995-01-01

    This study sought to show that unintentional preconditioning can be induced in the isolated perfused heart during the preparation procedure. The following four groups were compared: hearts were placed in ice cold saline and cooled for 15 s and then mounted to the Langendorff apparatus (n = 5; cool immediate group); hearts were cooled for 60 s and mounted (n = 5; cool delay group); hearts were mounted directly to the apparatus within 15 s after the isolation without cooling (n = 5; noncool immediate group); hearts were mounted without cooling, but the mounting was delayed for 60 s after the isolation (n = 5; noncool delay group). All hearts were paced at a fixed rate of 300 bpm, and an occlusion of left coronary (LCA) for 60 min was performed, which was followed by reperfusion for another 60 min. Coronary flow (CBF), left ventricular developed pressure (LVDP), and creatine phosphokinase (CPK) release did not change among the four groups during ischemia. At the end of reperfusion the LVDP values were 70 +/- 1%, 66 +/- 2%, 62 +/- 3%, and 73 +/- 2% of preischemic values in cool immediate, cool delay, noncool immediate, and noncool delay groups, respectively. CPK values were 116 +/- 4, 121 +/- 7, 138 +/- 6, and 29 +/- 1 x 10(3) U/g myocardium, and percentage necrosis/risk areas were 24 +/- 1.0%, 21 +/- 1.7%, 38 +/- 2.6%, and 13 +/- 0.5% in cool immediate, cool delay, noncool immediate, and noncool delay groups, respectively. The noncool delay group demonstrated high LVDP, least amount of CPK release, and smallest size of necrosis. These results indicate that an unintentional preconditioning effect can be induced when the cooling procedure is not applied and perfusion is delayed. PMID:8585864

  15. Preconditioning Provides Neuroprotection in Models of CNS Disease: Paradigms and Clinical Significance

    PubMed Central

    Stetler, R. Anne; Leak, Rehana K.; Gan, Yu; Li, Peiying; Hu, Xiaoming; Jing, Zheng; Chen, Jun; Zigmond, Michael J.; Gao, Yanqin

    2014-01-01

    Preconditioning is a phenomenon in which brief episodes of a sublethal insult induce robust protection against subsequent lethal injuries. Preconditioning has been observed in multiple organisms and can occur in the brain as well as other tissues. Extensive animal studies suggest that the brain can be preconditioned to resist acute injuries, such as ischemic stroke, neonatal hypoxia/ischemia, trauma, and agents that are used in models of neurodegenerative diseases, such as Parkinson’s disease and Alzheimer’s disease. Effective preconditioning stimuli are numerous and diverse, ranging from transient ischemia, hypoxia, hyperbaric oxygen, hypothermia and hyperthermia, to exposure to neurotoxins and pharmacological agents. The phenomenon of “cross-tolerance,” in which a sublethal stress protects against a different type of injury, suggests that different preconditioning stimuli may confer protection against a wide range of injuries. Research conducted over the past few decades indicates that brain preconditioning is complex, involving multiple effectors such as metabolic inhibition, activation of extra- and intracellular defense mechanisms, a shift in the neuronal excitatory/inhibitory balance, and reduction in inflammatory sequelae. An improved understanding of brain preconditioning should help us identify innovative therapeutic strategies that prevent or at least reduce neuronal damage in susceptible patients. In this review, we focus on the experimental evidence of preconditioning in the brain and systematically survey the models used to develop paradigms for neuroprotection, and then discuss the clinical potential of brain preconditioning. In a subsequent components of this two-part series, we will discuss the cellular and molecular events that are likely to underlie these phenomena. PMID:24389580

  16. Political and Organizational Preconditions for Application of the Standards for Educational Evaluation: The "Standards for Educational Evaluation" Seen in a Wider Perspective in Relation to Policy Making and Organization.

    ERIC Educational Resources Information Center

    Scheerens, Jaap; Van Seventer, Chris W.

    1984-01-01

    The "Standards for Evaluation of Educational Programs, Projects and Materials" focuses on contextual influences at the individual research project level. Macro-level political and organizational factors can be preconditions for applying the standards at project level. A study of Dutch educational evaluation research is used to illustrate this…

  17. 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

  18. Eigenmode Analysis of Boundary Conditions for One-Dimensional Preconditioned Euler Equations

    NASA Technical Reports Server (NTRS)

    Darmofal, David L.

    1998-01-01

    An analysis of the effect of local preconditioning on boundary conditions for the subsonic, one-dimensional Euler equations is presented. Decay rates for the eigenmodes of the initial boundary value problem are determined for different boundary conditions. Riemann invariant boundary conditions based on the unpreconditioned Euler equations are shown to be reflective with preconditioning, and, at low Mach numbers, disturbances do not decay. Other boundary conditions are investigated which are non-reflective with preconditioning and numerical results are presented confirming the analysis.

  19. Characterization of bone marrow-derived mesenchymal stem cells from dimethyloxallyl glycine-preconditioned mice: Evaluation of the feasibility of dimethyloxallyl glycine as a mobilization agent

    PubMed Central

    GE, TINGTING; YU, QIN; LIU, WEI; CONG, LI; LIU, LIZHEN; WANG, YAN; ZHOU, LIPING; LIN, DEJU

    2016-01-01

    The prolyl hydroxylase inhibitor dimethyloxallyl glycine (DMOG) has been increasingly studied with regards to stem cell therapy. Previous studies have demonstrated that endogenous mesenchymal stem cells (MSCs) may be mobilized into peripheral circulation by pharmaceutical preconditioning. In addition, our previous study confirmed that DMOG, as a novel mobilization agent, could induce mouse/rat MSC migration into peripheral blood circulation. Therefore, the present study conducted studies to characterize bone marrow-derived MSCs (BM-MSCs) collected from mice following DMOG intraperitoneal injection. The surface antigen immune phenotype, differentiation capability, proliferative ability, migratory capacity and paracrine capacity of the BM-MSCs collected from DMOG-preconditioned mice (DBM-MSCs) or normal saline-treated mice (NBM-MSCs) were evaluated by means of flow cytometry, differentiation induction, Cell Counting kit-8, Transwell assay and enzyme-linked immunosorbent assay, respectively. Compared with NBM-MSCs, DBM-MSCs displayed a similar immune phenotype and multilineage differentiation capability, reduced proliferative ability and migratory capacity, and similar transforming growth factor and platelet-derived growth factor secretion capacity. These results provide a novel insight into the biological properties of BM-MSCs from mice preconditioned with DMOG. DBM-MSCs exhibited slightly distinct characteristics to NBM-MSCs; however, they may have therapeutic potential for future stem cell therapy. In addition, the present study suggested that DMOG may be used as a novel mobilization agent in future clinical trials as no adverse effects were observed. PMID:26935134

  20. Skin delivery by block copolymer nanoparticles (block copolymer micelles).

    PubMed

    Laredj-Bourezg, Faiza; Bolzinger, Marie-Alexandrine; Pelletier, Jocelyne; Valour, Jean-Pierre; Rovère, Marie-Rose; Smatti, Batoule; Chevalier, Yves

    2015-12-30

    Block copolymer nanoparticles often referred to as "block copolymer micelles" have been assessed as carriers for skin delivery of hydrophobic drugs. Such carriers are based on organic biocompatible and biodegradable materials loaded with hydrophobic drugs: poly(lactide)-block-poly(ethylene glycol) copolymer (PLA-b-PEG) nanoparticles that have a solid hydrophobic core made of glassy poly(d,l-lactide), and poly(caprolactone)-block-poly(ethylene glycol) copolymer (PCL-b-PEG) nanoparticles having a liquid core of polycaprolactone. In vitro skin absorption of all-trans retinol showed a large accumulation of retinol in stratum corneum from both block copolymer nanoparticles, higher by a factor 20 than Polysorbate 80 surfactant micelles and by a factor 80 than oil solution. Additionally, skin absorption from PLA-b-PEG nanoparticles was higher by one order of magnitude than PCL-b-PEG, although their sizes (65nm) and external surface (water-swollen PEG layer) were identical as revealed by detailed structural characterizations. Fluorescence microscopy of histological skin sections provided a non-destructive picture of the storage of Nile Red inside stratum corneum, epidermis and dermis. Though particle cores had a different physical states (solid or liquid as measured by (1)H NMR), the ability of nanoparticles for solubilization of the drug assessed from their Hildebrand solubility parameters appeared the parameter of best relevance regarding skin absorption. PMID:26602293

  1. Testing block subdivision algorithms on block designs

    NASA Astrophysics Data System (ADS)

    Wiseman, Natalie; Patterson, Zachary

    2016-01-01

    Integrated land use-transportation models predict future transportation demand taking into account how households and firms arrange themselves partly as a function of the transportation system. Recent integrated models require parcels as inputs and produce household and employment predictions at the parcel scale. Block subdivision algorithms automatically generate parcel patterns within blocks. Evaluating block subdivision algorithms is done by way of generating parcels and comparing them to those in a parcel database. Three block subdivision algorithms are evaluated on how closely they reproduce parcels of different block types found in a parcel database from Montreal, Canada. While the authors who developed each of the algorithms have evaluated them, they have used their own metrics and block types to evaluate their own algorithms. This makes it difficult to compare their strengths and weaknesses. The contribution of this paper is in resolving this difficulty with the aim of finding a better algorithm suited to subdividing each block type. The proposed hypothesis is that given the different approaches that block subdivision algorithms take, it's likely that different algorithms are better adapted to subdividing different block types. To test this, a standardized block type classification is used that consists of mutually exclusive and comprehensive categories. A statistical method is used for finding a better algorithm and the probability it will perform well for a given block type. Results suggest the oriented bounding box algorithm performs better for warped non-uniform sites, as well as gridiron and fragmented uniform sites. It also produces more similar parcel areas and widths. The Generalized Parcel Divider 1 algorithm performs better for gridiron non-uniform sites. The Straight Skeleton algorithm performs better for loop and lollipop networks as well as fragmented non-uniform and warped uniform sites. It also produces more similar parcel shapes and patterns.

  2. Aromatase Inhibition Attenuates Desflurane-Induced Preconditioning against Acute Myocardial Infarction in Male Mouse Heart In Vivo

    PubMed Central

    Jazbutyte, Virginija; Stumpner, Jan; Redel, Andreas; Lorenzen, Johan M.; Roewer, Norbert

    2012-01-01

    The volatile anesthetic desflurane (DES) effectively reduces cardiac infarct size following experimental ischemia/reperfusion injury in the mouse heart. We hypothesized that endogenous estrogens play a role as mediators of desflurane-induced preconditioning against myocardial infarction. In this study, we tested the hypothesis that desflurane effects local estrogen synthesis by modulating enzyme aromatase expression and activity in the mouse heart. Aromatase metabolizes testosterone to 17β- estradiol (E2) and thereby significantly contributes to local estrogen synthesis. We tested aromatase effects in acute myocardial infarction model in male mice. The animals were randomized and subjected to four groups which were pre-treated with the selective aromatase inhibitor anastrozole (A group) and DES alone (DES group) or in combination (A+DES group) for 15 minutes prior to surgical intervention whereas the control group received 0.9% NaCl (CON group). All animals were subjected to 45 minutes ischemia following 180 minutes reperfusion. Anastrozole blocked DES induced preconditioning and increased infarct size compared to DES alone (37.94±15.5% vs. 17.1±3.62%) without affecting area at risk and systemic hemodynamic parameters following ischemia/reperfusion. Protein localization studies revealed that aromatase was abundant in the murine cardiovascular system with the highest expression levels in endothelial and smooth muscle cells. Desflurane application at pharmacological concentrations efficiently upregulated aromatase expression in vivo and in vitro. We conclude that desflurane efficiently regulates aromatase expression and activity which might lead to increased local estrogen synthesis and thus preserve cellular integrity and reduce cardiac damage in an acute myocardial infarction model. PMID:22876297

  3. AMPK-Regulated and Akt-Dependent Enhancement of Glucose Uptake Is Essential in Ischemic Preconditioning-Alleviated Reperfusion Injury

    PubMed Central

    Liu, Wenchong; Huang, Qichao; Yang, Weidong; Fu, Feng; Ma, Heng; Su, Hui; Wang, Haichang; Wang, Jing; Zhang, Haifeng; Gao, Feng

    2013-01-01

    Aims Ischemic preconditioning (IPC) is a potent form of endogenous protection. However, IPC-induced cardioprotective effect is significantly blunted in insulin resistance-related diseases and the underlying mechanism is unclear. This study aimed to determine the role of glucose metabolism in IPC-reduced reperfusion injury. Methods Normal or streptozotocin (STZ)-treated diabetic rats subjected to 2 cycles of 5 min ischemia/5 min reperfusion prior to myocardial ischemia (30 min)/reperfusion (3 h). Myocardial glucose uptake was determined by 18F-fluorodeoxyglucose-positron emission tomography (PET) scan and gamma-counter biodistribution assay. Results IPC exerted significant cardioprotection and markedly improved myocardial glucose uptake 1 h after reperfusion (P<0.01) as evidenced by PET images and gamma-counter biodistribution assay in ischemia/reperfused rats. Meanwhile, myocardial translocation of glucose transporter 4 (GLUT4) to plasma membrane together with myocardial Akt and AMPK phosphorylation were significantly enhanced in preconditioned hearts. Intramyocardial injection of GLUT4 siRNA markedly decreased GLUT4 expression and blocked the cardioprotection of IPC as evidence by increased myocardial infarct size. Moreover, the PI3K inhibitor wortmannin significantly inhibited activation of Akt and AMPK, reduced GLUT4 translocation, glucose uptake and ultimately, depressed IPC-induced cardioprotection. Furthermore, IPC-afforded antiapoptotic effect was markedly blunted in STZ-treated diabetic rats. Exogenous insulin supplementation significantly improved glucose uptake via co-activation of myocardial AMPK and Akt and alleviated ischemia/reperfusion injury as evidenced by reduced myocardial apoptosis and infarction size in STZ-treated rats (P<0.05). Conclusions The present study firstly examined the role of myocardial glucose metabolism during reperfusion in IPC using direct genetic modulation in vivo. Augmented glucose uptake via co-activation of myocardial AMPK

  4. Preconditioning for Numerical Simulation of Low Mach Number Three-Dimensional Viscous Turbomachinery Flows

    NASA Technical Reports Server (NTRS)

    Tweedt, Daniel L.; Chima, Rodrick V.; Turkel, Eli

    1997-01-01

    A preconditioning scheme has been implemented into a three-dimensional viscous computational fluid dynamics code for turbomachine blade rows. The preconditioning allows the code, originally developed for simulating compressible flow fields, to be applied to nearly-incompressible, low Mach number flows. A brief description is given of the compressible Navier-Stokes equations for a rotating coordinate system, along with the preconditioning method employed. Details about the conservative formulation of artificial dissipation are provided, and different artificial dissipation schemes are discussed and compared. The preconditioned code was applied to a well-documented case involving the NASA large low-speed centrifugal compressor for which detailed experimental data are available for comparison. Performance and flow field data are compared for the near-design operating point of the compressor, with generally good agreement between computation and experiment. Further, significant differences between computational results for the different numerical implementations, revealing different levels of solution accuracy, are discussed.

  5. Analysis of a Lipid/Polymer Membrane for Bitterness Sensing with a Preconditioning Process.

    PubMed

    Yatabe, Rui; Noda, Junpei; Tahara, Yusuke; Naito, Yoshinobu; Ikezaki, Hidekazu; Toko, Kiyoshi

    2015-01-01

    It is possible to evaluate the taste of foods or medicines using a taste sensor. The taste sensor converts information on taste into an electrical signal using several lipid/polymer membranes. A lipid/polymer membrane for bitterness sensing can evaluate aftertaste after immersion in monosodium glutamate (MSG), which is called "preconditioning". However, we have not yet analyzed the change in the surface structure of the membrane as a result of preconditioning. Thus, we analyzed the change in the surface by performing contact angle and surface zeta potential measurements, Fourier transform infrared spectroscopy (FTIR), X-ray photon spectroscopy (XPS) and gas cluster ion beam time-of-flight secondary ion mass spectrometry (GCIB-TOF-SIMS). After preconditioning, the concentrations of MSG and tetradodecylammonium bromide (TDAB), contained in the lipid membrane were found to be higher in the surface region than in the bulk region. The effect of preconditioning was revealed by the above analysis methods. PMID:26404301

  6. Some Dilemmas of Institutional Evaluation and Their Relationship to Preconditions and Procedures.

    ERIC Educational Resources Information Center

    Adelman, Clem

    1980-01-01

    Using "A Study of Student Choice in Context of Institutional Change (SCIC)" is an example of an evaluation using social anthropological methods. The problems of confidentiality, rapport, evaluator autonomy, and unclear preconditions are discussed and illustrated. (BW)

  7. Blocking and the detection of odor components in blends.

    PubMed

    Hosler, J S; Smith, B H

    2000-09-01

    Recent studies of olfactory blocking have revealed that binary odorant mixtures are not always processed as though they give rise to mixture-unique configural properties. When animals are conditioned to one odorant (A) and then conditioned to a mixture of that odorant with a second (X), the ability to learn or express the association of X with reinforcement appears to be reduced relative to animals that were not preconditioned to A. A recent model of odor-based response patterns in the insect antennal lobe predicts that the strength of the blocking effect will be related to the perceptual similarity between the two odorants, i.e. greater similarity should increase the blocking effect. Here, we test that model in the honeybee Apis mellifera by first establishing a generalization matrix for three odorants and then testing for blocking between all possible combinations of them. We confirm earlier findings demonstrating the occurrence of the blocking effect in olfactory learning of compound stimuli. We show that the occurrence and the strength of the blocking effect depend on the odorants used in the experiment. In addition, we find very good agreement between our results and the model, and less agreement between our results and an alternative model recently proposed to explain the effect. PMID:10952879

  8. Hypoxia Precondition Promotes Adipose-Derived Mesenchymal Stem Cells Based Repair of Diabetic Erectile Dysfunction via Augmenting Angiogenesis and Neuroprotection

    PubMed Central

    Li, ShaoDan; Xu, Yong; Chen, Ping; Liu, Yi; Ding, Qiang; Wahafu, Wasilijiang; Hong, BaoFa; Yang, MingHui

    2015-01-01

    The aim of the present study was to examine whether hypoxia preconditioning could improve therapeutic effects of adipose derived mesenchymal stem cells (AMSCs) for diabetes induced erectile dysfunction (DED). AMSCs were pretreated with normoxia (20% O2, N-AMSCs) or sub-lethal hypoxia (1% O2, H-AMSCs). The hypoxia exposure up-regulated the expression of several angiogenesis and neuroprotection related cytokines in AMSCs, including vascular endothelial growth factor (VEGF) and its receptor FIK-1, angiotensin (Ang-1), basic fibroblast growth factor (bFGF), brain-derived neurotrophic factor (BDNF), glial cell-derived neurotrophic factor (GDNF), stromal derived factor-1 (SDF-1) and its CXC chemokine receptor 4 (CXCR4). DED rats were induced via intraperitoneal injection of streptozotocin (60 mg/kg) and were randomly divided into three groups—Saline group: intracavernous injection with phosphate buffer saline; N-AMSCs group: N-AMSCs injection; H-AMSCs group: H-AMSCs injection. Ten rats without any treatment were used as normal control. Four weeks after injection, the mean arterial pressure (MAP) and intracavernosal pressure (ICP) were measured. The contents of endothelial, smooth muscle, dorsal nerve in cavernoursal tissue were assessed. Compared with N-AMSCs and saline, intracavernosum injection of H-AMSCs significantly raised ICP and ICP/MAP (p<0.05). Immunofluorescent staining analysis demonstrated that improved erectile function by MSCs was significantly associated with increased expression of endothelial markers (CD31 and vWF) (p<0.01) and smooth muscle markers (α-SMA) (p<0.01). Meanwhile, the expression of nNOS was also significantly higher in rats receiving H-AMSCs injection than those receiving N-AMSCs or saline injection. The results suggested that hypoxic preconditioning of MSCs was an effective approach to enhance their therapeutic effect for DED, which may be due to their augmented angiogenesis and neuroprotection. PMID:25790284

  9. Angiopoietin-1 preconditioning enhances survival and functional recovery of mesenchymal stem cell transplantation*

    PubMed Central

    Liu, Xian-bao; Chen, Han; Chen, Hui-qiang; Zhu, Mei-fei; Hu, Xin-yang; Wang, Ya-ping; Jiang, Zhi; Xu, Yin-chuan; Xiang, Mei-xiang; Wang, Jian-an

    2012-01-01

    Objective: Mesenchymal stem cell (MSC) transplantation is a promising therapy for ischemic heart diseases. However, poor cell survival after transplantation greatly limits the therapeutic efficacy of MSCs. The purpose of this study was to investigate the protective effect of angiopoietin-1 (Ang1) preconditioning on MSC survival and subsequent heart function improvement after transplantation. Methods: MSCs were cultured with or without 50 ng/ml Ang1 in complete medium for 24 h prior to experiments on cell survival and transplantation. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and Hoechst staining were applied to evaluate MSC survival after serum deprivation in vitro, while cell survival in vivo was detected by terminal deoxynucleotidyl transferase biotin-dUPT nick end labeling (TUNEL) assay 24 and 72 h after transplantation. Heart function and infarct size were measured four weeks later by small animal echocardiography and Masson’s trichrome staining, respectively. Results: Ang1 preconditioning induced Akt phosphorylation and increased expression of Bcl-2 and the ratio of Bcl-2/Bax. In comparison with non-preconditioned MSCs, Ang1-preconditioned cell survival was significantly increased while the apoptotic rate decreased in vitro. However, the PI3K/Akt pathway inhibitor, LY294002, abrogated the protective effect of Ang1 preconditioning. After transplantation, the Ang1-preconditioned-MSC group showed a lower death rate, smaller infarct size, and better heart functional recovery compared to the non-preconditioned-MSC group. Conclusions: Ang1 preconditioning enhances MSC survival, contributing to further improvement of heart function. PMID:22843181

  10. Preconditioned domain decomposition scheme for three-dimensional aerodynamic sensitivity analysis

    NASA Technical Reports Server (NTRS)

    Eleshaky, Mohammed E.; Baysal, Oktay

    1993-01-01

    A preconditioned domain decomposition scheme is introduced for the solution of the 3D aerodynamic sensitivity equation. This scheme uses the iterative GMRES procedure to solve the effective sensitivity equation of the boundary-interface cells in the sensitivity analysis domain-decomposition scheme. Excluding the dense matrices and the effect of cross terms between boundary-interfaces is found to produce an efficient preconditioning matrix.

  11. Monophasic action potentials and Ca2+ transients in ischaemically preconditioned rabbit ventricular muscle

    PubMed Central

    Dekker, L.R.C.; van Bavel, E.; Opthof, T.; Coronel, R.; Janse, M.J.

    2003-01-01

    Background ATP-sensitive K+ (KATP) channels play an important role in the protective mechanism underlying ischaemic preconditioning. Ample evidence indicates, however, that action potential shortening is not a prerequisite for the cardioprotective effect of preconditioning. Methods Monophasic action potential duration (MAPD), tissue resistance, intracellular Ca2+ (Indo-1) and mechanical activity were simultaneously assessed in arterially perfused rabbit papillary muscles. We studied four experimental protocols preceding sustained ischaemia: 1. control perfusion (n=6), 2. ischaemic preconditioning (PC; n=4), 3. pretreatment with a KATP channel blocker, glibenclamide (15 μmol/1), prior to ischaemic preconditioning (PC+glib; n=3), 4. glibenclamide pretreatment only (Glib; n=2). Results In the PC group an increase in the diastolic Ca2+ level and a prolongation of the Ca2+ transient just prior to the induction of sustained ischaemia correlate to the postponement of the onset of irreversible ischaemic damage, as established by a rise in [Ca2+]i, electrical uncoupling and contracture. Glibenclamide antagonised these changes in the Ca2+ transient and the cardioprotection induced by preconditioning. MAPD was equal in all experimental groups. Conclusions Prolongation of the Ca2+ transient and increase of diastolic [Ca2+]i just prior to the induction of sustained ischaemia and not action potential shortening are involved in the cardioprotective effect of ischaemic preconditioning. Therefore, a glibenclamide-sensitive mechanism, other than the sarcolemmal KATP channels, is involved in the protective effect of ischaemic preconditioning. Changes in Ca2+ metabolism may play a crucial role in ischaemic preconditioning. ImagesFigure 1 PMID:25696182

  12. Ischemic preconditioning affects long-term cell fate through DNA damage-related molecular signaling and altered proliferation.

    PubMed

    Kapoor, Sorabh; Berishvili, Ekaterine; Bandi, Sriram; Gupta, Sanjeev

    2014-10-01

    Despite the potential of ischemic preconditioning for organ protection, long-term effects in terms of molecular processes and cell fates are ill defined. We determined consequences of hepatic ischemic preconditioning in rats, including cell transplantation assays. Ischemic preconditioning induced persistent alterations; for example, after 5 days liver histology was normal, but γ-glutamyl transpeptidase expression was observed, with altered antioxidant enzyme content, lipid peroxidation, and oxidative DNA adducts. Nonetheless, ischemic preconditioning partially protected from toxic liver injury. Similarly, primary hepatocytes from donor livers preconditioned with ischemia exhibited undesirably altered antioxidant enzyme content and lipid peroxidation, but better withstood insults. However, donor hepatocytes from livers preconditioned with ischemia did not engraft better than hepatocytes from control livers. Moreover, proliferation of hepatocytes from donor livers preconditioned with ischemia decreased under liver repopulation conditions. Hepatocytes from donor livers preconditioned with ischemia showed oxidative DNA damage with expression of genes involved in MAPK signaling that impose G1/S and G2/M checkpoint restrictions, including p38 MAPK-regulated or ERK-1/2-regulated cell-cycle genes such as FOS, MAPK8, MYC, various cyclins, CDKN2A, CDKN2B, TP53, and RB1. Thus, although ischemic preconditioning allowed hepatocytes to better withstand secondary insults, accompanying DNA damage and molecular events simultaneously impaired their proliferation capacity over the long term. Mitigation of ischemic preconditioning-induced DNA damage and deleterious molecular perturbations holds promise for advancing clinical applications. PMID:25128377

  13. Opioid-induced preconditioning: recent advances and future perspectives.

    PubMed

    Peart, Jason N; Gross, Eric R; Gross, Garrett J

    2005-01-01

    Opioids, named by Acheson for compounds with morphine-like actions despite chemically distinct structures, have received much research interest, particularly for their central nervous system (CNS) actions involved in pain management, resulting in thousands of scientific papers focusing on their effects on the CNS and other organ systems. A more recent area which may have great clinical importance concerns the role of opioids, either endogenous or exogenous compounds, in limiting the pathogenesis of ischemia-reperfusion injury in heart and brain. The role of endogenous opioids in hibernation provides tantalizing evidence for the protective potential of opioids against ischemia or hypoxia. Mammalian hibernation, a distinct energy-conserving state, is associated with depletion of energy stores, intracellular acidosis and hypoxia, similar to those which occur during ischemia. However, despite the potentially detrimental cellular state induced with hibernation, the myocardium remains resilient for many months. What accounts for the hypoxia-tolerant state is of great interest. During hibernation, circulating levels of opioid peptides are increased dramatically, and indeed, are considered a "trigger" of hibernation. Furthermore, administration of opioid antagonists can effectively reverse hibernation in mammals. Therefore, it is not surprising that activation of opioid receptors has been demonstrated to preserve cellular status following a hypoxic insult, such as ischemia-reperfusion in many model systems including the intestine [Zhang, Y., Wu, Y.X., Hao, Y.B., Dun, Y. Yang, S.P., 2001. Role of endogenous opioid peptides in protection of ischemic preconditioning in rat small intestine. Life Sci. 68, 1013-1019], skeletal muscle [Addison, P.D., Neligan, P.C., Ashrafpour, H., Khan, A., Zhong, A., Moses, M., Forrest, C.R., Pang, C.Y., 2003. Noninvasive remote ischemic preconditioning for global protection of skeletal muscle against infarction. Am. J. Physiol. Heart Circ

  14. Hyperbaric oxygen preconditioning induces tolerance against spinal cord ischemia by upregulation of antioxidant enzymes in rabbits.

    PubMed

    Nie, Huang; Xiong, Lize; Lao, Ning; Chen, Shaoyang; Xu, Ning; Zhu, Zhenghua

    2006-05-01

    The present study examined the hypothesis that spinal cord ischemic tolerance induced by hyperbaric oxygen (HBO) preconditioning is triggered by an initial oxidative stress and is associated with an increase of antioxidant enzyme activities as one effector of the neuroprotection. New Zealand White rabbits were subjected to HBO preconditioning, hyperbaric air (HBA) preconditioning, or sham pretreatment once daily for five consecutive days before spinal cord ischemia. Activities of catalase (CAT) and superoxide dismutase were increased in spinal cord tissue in the HBO group 24 h after the last pretreatment and reached a higher level after spinal cord ischemia for 20 mins followed by reperfusion for 24 or 48 h, in comparison with those in control and HBA groups. The spinal cord ischemic tolerance induced by HBO preconditioning was attenuated when a CAT inhibitor, 3-amino-1,2,4-triazole,1 g/kg, was administered intraperitoneally 1 h before ischemia. In addition, administration of a free radical scavenger, dimethylthiourea, 500 mg/kg, intravenous, 1 h before each day's preconditioning, reversed the increase of the activities of both enzymes in spinal cord tissue. The results indicate that an initial oxidative stress, as a trigger to upregulate the antioxidant enzyme activities, plays an important role in the formation of the tolerance against spinal cord ischemia by HBO preconditioning. PMID:16136055

  15. Mesenchymal stem cells preconditioned with trimetazidine promote neovascularization of hearts under hypoxia/reoxygenation injury

    PubMed Central

    Hu, Xiaowu; Yang, Junjie; Wang, Ying; Zhang, You; Ii, Masaaki; Shen, Zhenya; Hui, Jie

    2015-01-01

    Background: Cell-based angiogenesis is a promising treatment for ischemic diseases; however, survival of implanted cells is impaired by the ischemic microenvironment. In this study, mesenchymal stem cells (MSCs) for cell transplantation were preconditioned with trimetazidine (TMZ). We hypothesized that TMZ enhances the survival rate of MSCs under hypoxic stimuli through up-regulation of HIF1-α. Methods and results: Bone marrow-derived rat mesenchymal stem cells were preconditioned with 10 μM TMZ for 6 h. TMZ preconditioning of MSCs remarkably increased cell viability and the expression of HIF1-α and Bcl-2, when cells were under hypoxia/reoxygenation (H/R) stimuli. But the protective effects of TMZ were abolished after knocking down of HIF-1α. Three days after implantation of the cells into the peri-ischemic zone of rat myocardial ischemia-reperfusion (I/R) injury model, survival of the TMZ-preconditioned MSCs was high. Furthermore, capillary density and cardiac function were significantly better in the rats implanted with TMZ-preconditioned MSCs 28 days after cell injection. Conclusions: TMZ preconditioning increased the survival rate of MSCs, through up-regulation of HIF1-α, thus contributing to neovascularization and improved cardiac function of rats subjected to myocardial I/R injury. PMID:26629255

  16. Preconditioning of Cardiosphere-Derived Cells With Hypoxia or Prolyl-4-Hydroxylase Inhibitors Increases Stemness and Decreases Reliance on Oxidative Metabolism.

    PubMed

    Tan, Suat Cheng; Gomes, Renata S M; Yeoh, Kar Kheng; Perbellini, Filippo; Malandraki-Miller, Sophia; Ambrose, Lucy; Heather, Lisa C; Faggian, Giuseppe; Schofield, Christopher J; Davies, Kay E; Clarke, Kieran; Carr, Carolyn A

    2016-01-01

    Cardiosphere-derived cells (CDCs), which can be isolated from heart explants, are a promising candidate cell source for infarcted myocardium regeneration. However, current protocols used to expand CDCs require at least 1 month in vitro to obtain sufficient cells for transplantation. We report that CDC culture can be optimized by preconditioning the cells under hypoxia (2% oxygen), which may reflect the physiological oxygen level of the stem cell niche. Under hypoxia, the CDC proliferation rate increased by 1.4-fold, generating 6 × 10(6) CDCs with higher expression of cardiac stem cell and pluripotency gene markers compared to normoxia. Furthermore, telomerase (TERT), cytokines/ligands involved in stem cell trafficking (SDF/CXCR-4), erythropoiesis (EPO), and angiogenesis (VEGF) were increased under hypoxia. Hypoxic preconditioning was mimicked by treatment with two types of hypoxia-inducible factor (HIF) prolyl-4-hydroxylase inhibitors (PHDIs): dimethyloxaloylglycine (DMOG) and 2-(1-chloro-4-hydroxyisoquinoline-3-carboxamido) acetic acid (BIC). Despite the difference in specificity, both PHDIs significantly increased c-Kit expression and activated HIF, EPO, and CXCR-4. Furthermore, treatment with PHDIs for 24 h increased cell proliferation. Notably, all hypoxic and PHDI-preconditioned CDCs had decreased oxygen consumption and increased glycolytic metabolism. In conclusion, cells cultured under hypoxia could have potentially enhanced therapeutic potential, which can be mimicked, in part, by PHDIs. PMID:25751158

  17. Hypoxia preconditioning increases survival and decreases expression of Toll-like receptor 4 in pulmonary artery endothelial cells exposed to lipopolysaccharide.

    PubMed

    Ali, Irshad; Nanchal, Rahul; Husnain, Fouad; Audi, Said; Konduri, G Ganesh; Densmore, John C; Medhora, Meetha; Jacobs, Elizabeth R

    2013-09-01

    Abstract Pulmonary or systemic infections and hypoxemic respiratory failure are among the leading causes of admission to intensive care units, and these conditions frequently exist in sequence or in tandem. Inflammatory responses to infections are reproduced by lipopolysaccharide (LPS) engaging Toll-like receptor 4 (TLR4). Apoptosis is a hallmark of lung injury in sepsis. This study was conducted to determine whether preexposure to LPS or hypoxia modulated the survival of pulmonary artery endothelial cells (PAECs). We also investigated the role TLR4 receptor expression plays in apoptosis due to these conditions. Bovine PAECs were cultured in hypoxic or normoxic environments and treated with LPS. TLR4 antagonist TAK-242 was used to probe the role played by TLR4 receptors in cell survival. Cell apoptosis and survival were measured by caspase 3 activity and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) incorporation. TLR4 expression and tumor necrosis factor α (TNF-α) production were also determined. LPS increased caspase 3 activity in a TAK-242-sensitive manner and decreased MTT incorporation. Apoptosis was decreased in PAECs preconditioned with hypoxia prior to LPS exposure. LPS increased TNF-α production, and hypoxic preconditioning blunted it. Hypoxic preconditioning reduced LPS-induced TLR4 messenger RNA and TLR4 protein. TAK-242 decreased to baseline the LPS-stimulated expression of TLR4 messenger RNA regardless of environmental conditions. In contrast, LPS followed by hypoxia substantially increased apoptosis and cell death. In conclusion, protection from LPS-stimulated PAEC apoptosis by hypoxic preconditioning is attributable in part to reduction in TLR4 expression. If these signaling pathways apply to septic patients, they may account for differing sensitivities of individuals to acute lung injury depending on oxygen tensions in PAECs in vivo. PMID:24618542

  18. Hypoxia preconditioning increases survival and decreases expression of Toll-like receptor 4 in pulmonary artery endothelial cells exposed to lipopolysaccharide

    PubMed Central

    Nanchal, Rahul; Audi, Said; Konduri, G. Ganesh; Medhora, Meetha

    2013-01-01

    Abstract Pulmonary or systemic infections and hypoxemic respiratory failure are among the leading causes of admission to intensive care units, and these conditions frequently exist in sequence or in tandem. Inflammatory responses to infections are reproduced by lipopolysaccharide (LPS) engaging Toll-like receptor 4 (TLR4). Apoptosis is a hallmark of lung injury in sepsis. This study was conducted to determine whether preexposure to LPS or hypoxia modulated the survival of pulmonary artery endothelial cells (PAECs). We also investigated the role TLR4 receptor expression plays in apoptosis due to these conditions. Bovine PAECs were cultured in hypoxic or normoxic environments and treated with LPS. TLR4 antagonist TAK-242 was used to probe the role played by TLR4 receptors in cell survival. Cell apoptosis and survival were measured by caspase 3 activity and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) incorporation. TLR4 expression and tumor necrosis factor α (TNF-α) production were also determined. LPS increased caspase 3 activity in a TAK-242-sensitive manner and decreased MTT incorporation. Apoptosis was decreased in PAECs preconditioned with hypoxia prior to LPS exposure. LPS increased TNF-α production, and hypoxic preconditioning blunted it. Hypoxic preconditioning reduced LPS-induced TLR4 messenger RNA and TLR4 protein. TAK-242 decreased to baseline the LPS-stimulated expression of TLR4 messenger RNA regardless of environmental conditions. In contrast, LPS followed by hypoxia substantially increased apoptosis and cell death. In conclusion, protection from LPS-stimulated PAEC apoptosis by hypoxic preconditioning is attributable in part to reduction in TLR4 expression. If these signaling pathways apply to septic patients, they may account for differing sensitivities of individuals to acute lung injury depending on oxygen tensions in PAECs in vivo. PMID:24618542

  19. Preconditioning donor with a combination of tacrolimus and rapamacyn to decrease ischaemia–reperfusion injury in a rat syngenic kidney transplantation model

    PubMed Central

    Cicora, F; Roberti, J; Vasquez, D; Guerrieri, D; Lausada, N; Cicora, P; Palti, G; Chuluyan, E; Gonzalez, P; Stringa, P; Raimondi, C

    2012-01-01

    Reperfusion injury remains one of the major problems in transplantation. Repair from ischaemic acute renal failure (ARF) involves stimulation of tubular epithelial cell proliferation. The aim of this exploratory study was to evaluate the effects of preconditioning donor animals with rapamycin and tacrolimus to prevent ischaemia–reperfusion (I/R) injury. Twelve hours before nephrectomy, the donor animals received immunosuppressive drugs. The animals were divided into four groups, as follows: group 1 control: no treatment; group 2: rapamycin (2 mg/kg); group 3 FK506 (0, 3 mg/kg); and group 4: FK506 (0, 3 mg/kg) plus rapamycin (2 mg/kg). The left kidney was removed and after 3 h of cold ischaemia, the graft was transplanted. Twenty-four hours after transplant, the kidney was recovered for histological analysis and cytokine expression. Preconditioning treatment with rapamycin or tacrolimus significantly reduced blood urea nitrogen and creatinine compared with control [blood urea nitrogen (BUN): P < 0·001 versus control and creatinine: P < 0·001 versus control]. A further decrease was observed when rapamycin was combined with tacrolimus. Acute tubular necrosis was decreased significantly in donors treated with immunosuppressants compared with the control group (P < 0·001 versus control). Moreover, the number of apoptotic nuclei in the control group was higher compared with the treated groups (P < 0·001 versus control). Surprisingly, only rapamycin preconditioning treatment increased anti-apoptotic Bcl2 levels (P < 0·001). Finally, inflammatory cytokines, such as tumour necrosis factor (TNF)-α and interleukin (IL)-6, showed lower levels in the graft of those animals that had been pretreated with rapamycin or tacrolimus. This exploratory study demonstrates that preconditioning donor animals with rapamycin or tacrolimus improves clinical outcomes and reduce necrosis and apoptosis in kidney I/R injury. PMID:22132896

  20. Intestinal ischemic preconditioning reduces liver ischemia reperfusion injury in rats

    PubMed Central

    XUE, TONG-MIN; TAO, LI-DE; ZHANG, JIE; ZHANG, PEI-JIAN; LIU, XIA; CHEN, GUO-FENG; ZHU, YI-JIA

    2016-01-01

    The aim of the current study was to investigate whether intestinal ischemic preconditioning (IP) reduces damage to the liver during hepatic ischemia reperfusion (IR). Sprague Dawley rats were used to model liver IR injury, and were divided into the sham operation group (SO), IR group and IP group. The results indicated that IR significantly increased Bax, caspase 3 and NF-κBp65 expression levels, with reduced expression of Bcl-2 compared with the IP group. Compared with the IR group, the levels of AST, ALT, MPO, MDA, TNF-α and IL-1 were significantly reduced in the IP group. Immunohistochemistry for Bcl-2 and Bax indicated that Bcl-2 expression in the IP group was significantly increased compared with the IR group. In addition, IP reduced Bax expression compared with the IR group. The average liver injury was worsened in the IR group and improved in the IP group, as indicated by the morphological evaluation of liver tissues. The present study suggested that IP may alleviates apoptosis, reduce the release of pro-inflammatory cytokines, ameloriate reductions in liver function and reduce liver tissue injury. To conclude, IP provided protection against hepatic IR injury. PMID:26821057

  1. Protective effects of remote ischemic preconditioning in isolated rat hearts

    PubMed Central

    Teng, Xiao; Yuan, Xin; Tang, Yue; Shi, Jingqian

    2015-01-01

    To use Langendorff model to investigate whether remote ischemic preconditioning (RIPC) attenuates post-ischemic mechanical dysfunction on isolated rat heart and to explore possible mechanisms. SD rats were randomly divided into RIPC group, RIPC + norepinephrine (NE) depletion group, RIPC + pertussis toxin (PTX) pretreatment group, ischemia/reperfusion group without treatment (ischemia group) and time control (TC) group. RIPC was achieved through interrupted occlusion of anterior mesenteric artery. Then, Langendorff model was established using routine methods. Heart function was tested; immunohistochemistry and ELISA methods were used to detect various indices related to myocardial injury. Compared with ischemia group in which the hemodynamic parameters deteriorated significantly, heart function recovered to a certain degree among the RIPC, RIPC + NE depletion, and RIPC + PTX groups (P<0.05). More apoptotic nuclei were observed in ischemia group than in the other three groups (P<0.05); more apoptotic nuclei were detected in NE depletion and PTX groups than in RIPC group (P<0.05). While, there was no significant difference between NE depletion and PTX groups. In conclusion, RIPC protection on I/R myocardium extends to the period after hearts are isolated. NE and PTX-sensitive inhibitory G protein might have a role in the protection process. PMID:26550168

  2. [Phytoadaptogens-induced phenomenon similar to ischemic preconditioning].

    PubMed

    Arbuzov, A G; Maslov, L N; Burkova, V N; Krylatov, A V; Konkovskaia, Iu N; Safronov, S M

    2009-04-01

    The course administration (16 mg/kg per os for 5 days) of extracts of Panax ginseng or Rhodiola rosea induced a decrease in the infarction size/the area at risk (IS AAR) ratio during a 45-min local ischemia and a 2-hr reperfusion in artificially ventilated chloralose-anaesthetized rats. Single administration of ginseng or Rhodiola 24 h before ischemia did not affect the IS/AAR ratio. Chronic administration of Extracts of Eleutherococcus senticosus, Leuzea carthamoides and Aralia mandshurica had no effect on the IS/AAR ratio. Pretreatment with extract ofAralia mandshurica prevented appearance of ventricular arrhythmias during first 10 min coronary artery occlusion. Pretreatment with extract of Rhodiola rosea decreased the incidence of ventricular fibrillation during ischemia. Single administration of extracts of Panax ginseng or Rhodiola rosea in a dose of 16 mg/kg had no effect on the IS/AAR ratio. The authors conclude that extracts of ginseng or Rhodiola exhibit a powerful cardioprotective effect. Extract of Aralia exhibit a strong antiarrhythmic effect. Extracts of ginseng and Rhodiola do not mimic phenomena of ischemia preconditioning. PMID:19505042

  3. Remote Limb Ischemic Preconditioning: A Neuroprotective Technique in Rodents.

    PubMed

    Brandli, Alice

    2015-01-01

    Sublethal ischemia protects tissues against subsequent, more severe ischemia through the upregulation of endogenous mechanisms in the affected tissue. Sublethal ischemia has also been shown to upregulate protective mechanisms in remote tissues. A brief period of ischemia (5-10 min) in the hind limb of mammals induces self-protective responses in the brain, lung, heart and retina. The effect is known as remote ischemic preconditioning (RIP). It is a therapeutically promising way of protecting vital organs, and is already under clinical trials for heart and brain injuries. This publication demonstrates a controlled, minimally invasive method of making a limb - specifically the hind limb of a rat - ischemic. A blood pressure cuff developed for use in human neonates is connected to a manual sphygmomanometer and used to apply 160 mmHg pressure around the upper part of the hind limb. A probe designed to detect skin temperature is used to verify the ischemia, by recording the drop in skin temperature caused by pressure-induced occlusion of the leg arteries, and the rise in temperature which follows release of the cuff. This method of RIP affords protection to the rat retina against bright light-induced damage and degeneration. PMID:26065365

  4. Effects of hypoxic preconditioning on synaptic ultrastructure in mice.

    PubMed

    Liu, Yi; Sun, Zhishan; Sun, Shufeng; Duan, Yunxia; Shi, Jingfei; Qi, Zhifeng; Meng, Ran; Sun, Yongxin; Zeng, Xianwei; Chui, Dehua; Ji, Xunming

    2015-01-01

    Hypoxic preconditioning (HPC) elicits resistance to more drastic subsequent insults, which potentially provide neuroprotective therapeutic strategy, but the underlying mechanisms remain to be fully elucidated. Here, we examined the effects of HPC on synaptic ultrastructure in olfactory bulb of mice. Mice underwent up to five cycles of repeated HPC treatments, and hypoxic tolerance was assessed with a standard gasp reflex assay. As expected, HPC induced an increase in tolerance time. To assess synaptic responses, Western blots were used to quantify protein levels of representative markers for glia, neuron, and synapse, and transmission electron microscopy was used to examine synaptic ultrastructure and mitochondrial density. HPC did not significantly alter the protein levels of astroglial marker (GFAP), neuron-specific markers (GAP43, Tuj-1, and OMP), synaptic number markers (synaptophysin and SNAP25) or the percentage of excitatory synapses versus inhibitory synapses. However, HPC significantly affected synaptic curvature and the percentage of synapses with presynaptic mitochondria, which showed concomitant change pattern. These findings demonstrate that HPC is associated with changes in synaptic ultrastructure. PMID:25155519

  5. Cerenkov luminescence tomography based on preconditioning orthogonal matching pursuit

    NASA Astrophysics Data System (ADS)

    Liu, Haixiao; Hu, Zhenhua; Wang, Kun; Tian, Jie; Yang, Xin

    2015-03-01

    Cerenkov luminescence imaging (CLI) is a novel optical imaging method and has been proved to be a potential substitute of the traditional radionuclide imaging such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT). This imaging method inherits the high sensitivity of nuclear medicine and low cost of optical molecular imaging. To obtain the depth information of the radioactive isotope, Cerenkov luminescence tomography (CLT) is established and the 3D distribution of the isotope is reconstructed. However, because of the strong absorption and scatter, the reconstruction of the CLT sources is always converted to an ill-posed linear system which is hard to be solved. In this work, the sparse nature of the light source was taken into account and the preconditioning orthogonal matching pursuit (POMP) method was established to effectively reduce the ill-posedness and obtain better reconstruction accuracy. To prove the accuracy and speed of this algorithm, a heterogeneous numerical phantom experiment and an in vivo mouse experiment were conducted. Both the simulation result and the mouse experiment showed that our reconstruction method can provide more accurate reconstruction result compared with the traditional Tikhonov regularization method and the ordinary orthogonal matching pursuit (OMP) method. Our reconstruction method will provide technical support for the biological application for Cerenkov luminescence.

  6. Remote Ischemic Preconditioning (RIPC) Modifies Plasma Proteome in Humans

    PubMed Central

    Hepponstall, Michele; Ignjatovic, Vera; Binos, Steve; Monagle, Paul; Jones, Bryn; Cheung, Michael H. H.; d’Udekem, Yves; Konstantinov, Igor E.

    2012-01-01

    Remote Ischemic Preconditioning (RIPC) induced by brief episodes of ischemia of the limb protects against multi-organ damage by ischemia-reperfusion (IR). Although it has been demonstrated that RIPC affects gene expression, the proteomic response to RIPC has not been determined. This study aimed to examine RIPC induced changes in the plasma proteome. Five healthy adult volunteers had 4 cycles of 5 min ischemia alternating with 5 min reperfusion of the forearm. Blood samples were taken from the ipsilateral arm prior to first ischaemia, immediately after each episode of ischemia as well as, at 15 min and 24 h after the last episode of ischemia. Plasma samples from five individuals were analysed using two complementary techniques. Individual samples were analysed using 2Dimensional Difference in gel electrophoresis (2D DIGE) and mass spectrometry (MS). Pooled samples for each of the time-points underwent trypsin digestion and peptides generated were analysed in triplicate using Liquid Chromatography and MS (LC-MS). Six proteins changed in response to RIPC using 2D DIGE analysis, while 48 proteins were found to be differentially regulated using LC-MS. The proteins of interest were involved in acute phase response signalling, and physiological molecular and cellular functions. The RIPC stimulus modifies the plasma protein content in blood taken from the ischemic arm in a cumulative fashion and evokes a proteomic response in peripheral blood. PMID:23139772

  7. Arnoldi preconditioning for solving large linear biomedical systems.

    PubMed

    Deo, Makarand; Vigmond, Edward

    2005-01-01

    Simulations of biomedical systems often involve solving large, sparse, linear systems of the form Ax = b. In initial value problems, this system is solved at every time step, so a quick solution is essential for tractability. Iterative solvers, especially preconditioned conjugate gradient, are attractive since memory demands are minimized compared to direct methods, albeit at a cost of solution speed. A proper preconditioner can drastically reduce computation and remains an area of active research. In this paper, we propose a novel preconditioner based on system order reduction using the Arnoldi method. Systems of orders up to a million, generated from a finite element method formulation of the elliptic portion of the bidomain equations, are solved with the new preconditioner and performance is compared with that of other preconditioners. Results indicate that the new method converges considerably faster, often within a single iteration. It also uses less memory than an incomplete LU decomposition (ILU). For solving a system repeatedly, the Arnoldi transformation must be continually recomputed, unlike ILU, but this can be done quickly. In conclusion, for solving a system once, the Arnoldi preconditioner offers a greatly reduced solution time, and for repeated solves, will still be faster than an ILU preconditioner. PMID:17282853

  8. Simple preconditioning for time-dependent density functional perturbation theory.

    PubMed

    Lehtovaara, Lauri; Marques, Miguel A L

    2011-07-01

    By far, the most common use of time-dependent density functional theory is in the linear-reponse regime, where it provides information about electronic excitations. Ideally, the linear-response equations should be solved by a method that avoids the use of the unoccupied Kohn-Sham states--such as the Sternheimer method--as this reduces the complexity and increases the precision of the calculation. However, the Sternheimer equation becomes ill-conditioned near and indefinite above the first resonant frequency, seriously hindering the use of efficient iterative solution methods. To overcome this serious limitation, and to improve the general convergence properties of the iterative techniques, we propose a simple preconditioning strategy. In our method, the Sternheimer equation is solved directly as a linear equation using an iterative Krylov subspace method, i.e., no self-consistent cycle is required. Furthermore, the preconditioner uses the information of just a few unoccupied states and requires simple and minimal modifications to existing implementations. In this way, convergence can be reached faster and in a considerably wider frequency range than the traditional approach. PMID:21744884

  9. Accelerating large cardiac bidomain simulations by arnoldi preconditioning.

    PubMed

    Deo, Makarand; Bauer, Steffen; Plank, Gernot; Vigmond, Edward

    2006-01-01

    Bidomain simulations of cardiac systems often in volve solving large, sparse, linear systems of the form Ax=b. These simulations are computationally very expensive in terms of run time and memory requirements. Therefore, efficient solvers are essential to keep simulations tractable. In this paper, an efficient preconditioner for the conjugate gradient (CG) method based on system order reduction using the Arnoldi method (A-PCG) is explained. Large order systems generated during cardiac bidomain simulations using a finite element method formulation, are solved using the A-PCG method. Its performance is compared with incomplete LU (ILU) preconditioning. Results indicate that the A-PCG estimates an approximate solution considerably faster than the ILU, often within a single iteration. To reduce the computational demands in terms of memory and run time, the use of a cascaded preconditioner is suggested. The A-PCG can be applied to quickly obtain an approximate solution, subsequently a cheap iterative method such as successive overrelaxation (SOR) is applied to further refine the solution to arrive at a desired accuracy. The memory requirements are less than direct LU but more than ILU method. The proposed scheme is shown to yield significant speedups when solving time evolving systems. PMID:17946209

  10. Strains and tilts on crustal blocks

    NASA Technical Reports Server (NTRS)

    Bilham, R. G.; Beavan, R. J.

    1979-01-01

    Geodetic work done over the past century is examined to investigate block motion in areas of intense tectonic deformation, with special attention to geodetic releveling data obtained for Japan. Problems in interpreting strainmeter and tiltmeter to study the behavior of crustal blocks and block boundaries are discussed. Block dimensions of 5 to 50 km seem to occur frequently in regions of intense tectonic activity. Block boundaries are often considerably weaker than contiguous crustal blocks, resulting in a concentration of strains at boundaries and decrease of strains within blocks. Block to block variations in tilt phase and magnitude are observed. There is some evidence that block boundaries may exhibit strain-dependent elastic properties or respond viscoelastically, possibly accounting for the slow transmission of tectonic deformation reported in Japan. If nonlinear behavior is characteristic of regions fragmented by crustal blocks, it will generally not be possible to apply a site correction factor based on the observed distortion of tidal or seismic strains in interpreting secular strains.

  11. Global gene expression profiles of ischemic preconditioning in deceased donor liver transplantation.

    PubMed

    Raza, Ali; Dikdan, George; Desai, Kunj K; Shareef, Asif; Fernandes, Helen; Aris, Virginie; de la Torre, Andrew N; Wilson, Dorian; Fisher, Adrian; Soteropoulos, Patricia; Koneru, Baburao

    2010-05-01

    The benefits of ischemic preconditioning (IPC) in reducing ischemia/reperfusion injury (IRI) remain indistinct in human liver transplantation (LT). To further understand mechanistic aspects of IPC, we performed microarray analyses as a nested substudy in a randomized trial of 10-minute IPC in 101 deceased donor LTs. Liver biopsies were performed after cold storage and at 90 minutes postreperfusion in 40 of 101 subjects. Global gene expression profiles in 6 biopsy pairs in IPC and work standard organ recovery groups at both time points were compared using the Affymetrix GeneChip Human Gene 1.0 ST array. Transcripts with >1.5-fold change and P < 0.05 were considered significant. IPC altered expression of 82 transcripts in antioxidant, immunological, lipid biosynthesis, cell development and growth, and other groups. Real-time polymerase chain reaction and immunoblotting validated our microarray data. IPC-induced overexpression of glutathione S-transferase mu transcripts (GSTM1, GSTM3, GSTM4, and GSTM5) was accompanied by increased protein expression and may contribute to a decrease in oxidative stress. However, the increased expression of fatty acid synthase may increase oxidative stress, and tumor necrosis factor ligand superfamily member 10 may promote apoptosis. These changes, in combination with decreased expression of heparin-binding epidermal growth factor-like growth factor and insulin-like growth factor binding protein-1, both of which inhibit apoptosis, may increase IRI. In our study of deceased donor LT, IPC induces changes in gene expression, some of which are potentially beneficial but some which are potentially injurious. Thus, our findings of changes in gene expression mirror the outcomes in our clinical trial. PMID:20440768

  12. Block That Pain!

    MedlinePlus

    ... combination produces a unique effect, blocking pain-sensing neurons without impairing signals from other cells. In contrast, ... surgical procedures block activity in all types of neurons. This can cause numbness, paralysis, and other nervous ...

  13. The involvement of cytokines in the second window of ischaemic preconditioning.

    PubMed

    Yamashita, N; Hoshida, S; Otsu, K; Taniguchi, N; Kuzuya, T; Hori, M

    2000-10-01

    We utilized a rat model of myocardial infarction to investigate whether manganese superoxide dismutase (Mn-SOD), an intrinsic radical scavenger, and tumour necrosis factor- alpha (TNF-alpha) and/or interleukin-1beta (IL-1beta) are involved in the late phase of ischaemic preconditioning (IP). IP was induced in anaesthetized rats by four 3-min left coronary artery (LCA) occlusions, each separated by 10 min of reperfusion. Twenty-four hours after the repetitive brief ischaemia, the LCA was occluded for 20 min followed by reperfusion for 48 h. IP reduced the infarct size by approximately 46% as determined after 48 h of reperfusion. Antisense oligodeoxynucleotides to Mn-SOD inhibited the increases in Mn-SOD content and activity, and abolished the expected decrease in myocardial infarct size. Sense or scrambled oligodeoxynucleotides did not abolish either Mn-SOD induction or tolerance to ischaemia/reperfusion. The simultaneous administration of the antibodies to TNF-alpha (0.5 ml) and IL-1beta (0.5 mg) prior to IP abolished the cardioprotection and the increase in Mn-SOD activity induced by IP. We conclude that the induction and activation of Mn-SOD, mediated by TNF-alpha and IL-1beta after IP, plays an important role in the acquisition of late-phase cardioprotection against ischaemia/reperfusion injury in rats. PMID:11015290

  14. Remote ischemic preconditioning as treatment for non-ischemic gastrointestinal disorders: beyond ischemia-reperfusion injury.

    PubMed

    Camara-Lemarroy, Carlos Rodrigo

    2014-04-01

    Common gastrointestinal diseases such as radiation enteritis (RE), acute pancreatitis, inflammatory bowel diseases (IBD) and drug-induced hepatotoxicity share pathophysiological mechanisms at the molecular level, mostly involving the activation of many pathways of the immune response, ultimately leading to tissue injury. Increased oxidative stress, inflammatory cytokine release, inflammatory cell infiltration and activation and the up-regulation of inflammatory transcription factors participate in the pathophysiology of these complex entities. Treatment varies in each specific disease, but at least in the cases of RE and IBD immunosuppressors are effective. However, full therapeutic responses are not always achieved. The pathophysiology of ischemia-reperfusion (IR) injury shares many of these mechanisms. Brief and repetitive periods of ischemia in an organ or limb have been shown to protect against subsequent major IR injury in distant organs, a phenomenon called remote ischemic preconditioning (RIP). This procedure has been shown to protect the gut, pancreas and liver by modulating many of the same inflammatory mechanisms. Since RIP is safe and tolerable, and has shown to be effective in some recent clinical trials, I suggest that RIP could be used as a physiologically relevant adjunct treatment for non-ischemic gastrointestinal inflammatory conditions. PMID:24707140

  15. Effect of Preconditioning and Soldering on Failures of Chip Tantalum Capacitors

    NASA Technical Reports Server (NTRS)

    Teverovsky, Alexander A.

    2014-01-01

    Soldering of molded case tantalum capacitors can result in damage to Ta205 dielectric and first turn-on failures due to thermo-mechanical stresses caused by CTE mismatch between materials used in the capacitors. It is also known that presence of moisture might cause damage to plastic cases due to the pop-corning effect. However, there are only scarce literature data on the effect of moisture content on the probability of post-soldering electrical failures. In this work, that is based on a case history, different groups of similar types of CWR tantalum capacitors from two lots were prepared for soldering by bake, moisture saturation, and longterm storage at room conditions. Results of the testing showed that both factors: initial quality of the lot, and preconditioning affect the probability of failures. Baking before soldering was shown to be effective to prevent failures even in lots susceptible to pop-corning damage. Mechanism of failures is discussed and recommendations for pre-soldering bake are suggested based on analysis of moisture characteristics of materials used in the capacitors' design.

  16. New preconditioning strategy for Jacobian-free solvers for variably saturated flows with Richards' equation

    NASA Astrophysics Data System (ADS)

    Lipnikov, Konstantin; Moulton, David; Svyatskiy, Daniil

    2016-08-01

    We develop a new approach for solving the nonlinear Richards' equation arising in variably saturated flow modeling. The growing complexity of geometric models for simulation of subsurface flows leads to the necessity of using unstructured meshes and advanced discretization methods. Typically, a numerical solution is obtained by first discretizing PDEs and then solving the resulting system of nonlinear discrete equations with a Newton-Raphson-type method. Efficiency and robustness of the existing solvers rely on many factors, including an empiric quality control of intermediate iterates, complexity of the employed discretization method and a customized preconditioner. We propose and analyze a new preconditioning strategy that is based on a stable discretization of the continuum Jacobian. We will show with numerical experiments for challenging problems in subsurface hydrology that this new preconditioner improves convergence of the existing Jacobian-free solvers 3-20 times. We also show that the Picard method with this preconditioner becomes a more efficient nonlinear solver than a few widely used Jacobian-free solvers.

  17. The Block Scheduling Handbook.

    ERIC Educational Resources Information Center

    Queen, J. Allen

    Block scheduling encourages increased comprehensive immersion into subject matter, improved teacher-student relationships, and decreased disciplinary problems. While block scheduling may offer many advantages, moving to a block schedule from conventional scheduling can be a major adjustment for both students and teachers. This guide is intended to…

  18. Block Scheduling. Research Brief

    ERIC Educational Resources Information Center

    Muir, Mike

    2003-01-01

    What are the effects of block scheduling? Results of transitioning from traditional to block scheduling are mixed. Some studies indicate no change in achievement results, nor change in teachers' opinions about instructional strategies. Other studies show that block scheduling doesn't work well for Advanced Placement or Music courses, that "hard to…

  19. Forced Exercise Preconditioning Attenuates Experimental Autoimmune Neuritis by Altering Th1 Lymphocyte Composition and Egress.

    PubMed

    Calik, Michael W; Shankarappa, Sahadev A; Langert, Kelly A; Stubbs, Evan B

    2015-01-01

    A short-term exposure to moderately intense physical exercise affords a novel measure of protection against autoimmune-mediated peripheral nerve injury. Here, we investigated the mechanism by which forced exercise attenuates the development and progression of experimental autoimmune neuritis (EAN), an established animal model of Guillain-Barré syndrome. Adult male Lewis rats remained sedentary (control) or were preconditioned with forced exercise (1.2 km/day × 3 weeks) prior to P2-antigen induction of EAN. Sedentary rats developed a monophasic course of EAN beginning on postimmunization day 12.3 ± 0.2 and reaching peak severity on day 17.0 ± 0.3 (N = 12). By comparison, forced-exercise preconditioned rats exhibited a similar monophasic course but with significant (p < .05) reduction of disease severity. Analysis of popliteal lymph nodes revealed a protective effect of exercise preconditioning on leukocyte composition and egress. Compared with sedentary controls, forced exercise preconditioning promoted a sustained twofold retention of P2-antigen responsive leukocytes. The percentage distribution of pro-inflammatory (Th1) lymphocytes retained in the nodes from sedentary EAN rats (5.1 ± 0.9%) was significantly greater than that present in nodes from forced-exercise preconditioned EAN rats (2.9 ± 0.6%) or from adjuvant controls (2.0 ± 0.3%). In contrast, the percentage of anti-inflammatory (Th2) lymphocytes (7-10%) and that of cytotoxic T lymphocytes (∼20%) remained unaltered by forced exercise preconditioning. These data do not support an exercise-inducible shift in Th1:Th2 cell bias. Rather, preconditioning with forced exercise elicits a sustained attenuation of EAN severity, in part, by altering the composition and egress of autoreactive proinflammatory (Th1) lymphocytes from draining lymph nodes. PMID:26186926

  20. Exploring the Human Plasma Proteome for Humoral Mediators of Remote Ischemic Preconditioning - A Word of Caution

    PubMed Central

    Helgeland, Erik; Breivik, Lars Ertesvåg; Vaudel, Marc; Svendsen, Øyvind Sverre; Garberg, Hilde; Nordrehaug, Jan Erik; Berven, Frode Steingrimsen; Jonassen, Anne Kristine

    2014-01-01

    Despite major advances in early revascularization techniques, cardiovascular diseases are still the leading cause of death worldwide, and myocardial infarctions contribute heavily to this. Over the past decades, it has become apparent that reperfusion of blood to a previously ischemic area of the heart causes damage in and of itself, and that this ischemia reperfusion induced injury can be reduced by up to 50% by mechanical manipulation of the blood flow to the heart. The recent discovery of remote ischemic preconditioning (RIPC) provides a non-invasive approach of inducing this cardioprotection at a distance. Finding its endogenous mediators and their operative mode is an important step toward increasing the ischemic tolerance. The release of humoral factor(s) upon RIPC was recently demonstrated and several candidate proteins were published as possible mediators of the cardioprotection. Before clinical applicability, these potential biomarkers and their efficiency must be validated, a task made challenging by the large heterogeneity in reported data and results. Here, in an attempt to reproduce and provide more experimental data on these mediators, we conducted an unbiased in-depth analysis of the human plasma proteome before and after RIPC. From the 68 protein markers reported in the literature, only 28 could be mapped to manually reviewed (Swiss-Prot) protein sequences. 23 of them were monitored in our untargeted experiment. However, their significant regulation could not be reproducibly estimated. In fact, among the 394 plasma proteins we accurately quantified, no significant regulation could be confidently and reproducibly assessed. This indicates that it is difficult to both monitor and reproduce published data from experiments exploring for RIPC induced plasma proteomic regulations, and suggests that further work should be directed towards small humoral factors. To simplify this task, we made our proteomic dataset available via ProteomeXchange, where

  1. Blocking Delaunay triangulations

    PubMed Central

    Aichholzer, Oswin; Fabila-Monroy, Ruy; Hackl, Thomas; van Kreveld, Marc; Pilz, Alexander; Ramos, Pedro; Vogtenhuber, Birgit

    2013-01-01

    Given a set B of n black points in general position, we say that a set of white points W blocks B if in the Delaunay triangulation of B∪W there is no edge connecting two black points. We give the following bounds for the size of the smallest set W blocking B: (i) 3n/2 white points are always sufficient to block a set of n black points, (ii) if B is in convex position, 5n/4 white points are always sufficient to block it, and (iii) at least n−1 white points are always necessary to block a set of n black points. PMID:23483043

  2. Blocking Delaunay triangulations.

    PubMed

    Aichholzer, Oswin; Fabila-Monroy, Ruy; Hackl, Thomas; van Kreveld, Marc; Pilz, Alexander; Ramos, Pedro; Vogtenhuber, Birgit

    2013-02-01

    Given a set B of n black points in general position, we say that a set of white points W blocks B if in the Delaunay triangulation of [Formula: see text] there is no edge connecting two black points. We give the following bounds for the size of the smallest set W blocking B: (i) [Formula: see text] white points are always sufficient to block a set of n black points, (ii) if B is in convex position, [Formula: see text] white points are always sufficient to block it, and (iii) at least [Formula: see text] white points are always necessary to block a set of n black points. PMID:23483043

  3. Multivariate Regression with Block-structured Predictors

    NASA Astrophysics Data System (ADS)

    Ye, Saier

    We study the problem of predicting multiple responses with a common set of predicting variables. Applying generalized Ordinary Least Squares (OLS) criterion on the responses altogether is practically equivalent to OLS estimation on the responses separately. Possible correlations between the response variables are overlooked. In order to take advantage of these interrelationships, Reduced-Rank Regression (RRR) imposes rank constraint on the coefficient matrix. RRR constructs latent factors from the original predicting variables, and the latent factors are the effective predictors. RRR reduces number of parameters to be estimated, and improves estimation efficiency. In the present work, we explore a novel regression model to incorporate "block-structured" predicting variables, where the predictors can be naturally partitioned into several groups or blocks. Variables in the same block share similar characteristics. It is reasonable to assume that in addition to an overall impact, predictors also have block-specific effects on the responses. Furthermore, we impose rank constraints on the coefficient matrices. In our framework, we construct two types of latent factors that drive the variation in the responses. We have joint factors, which are formed by all predictors across all blocks; and individual factors, which are formed by variables within individual blocks. The proposed method exceeds RRR in terms of prediction accuracy and ease of interpretation in the presence of block structure in the predicting variables.

  4. Effects of ischemic preconditioning on short-duration cycling performance.

    PubMed

    Cruz, Rogério Santos de Oliveira; de Aguiar, Rafael Alves; Turnes, Tiago; Salvador, Amadeo Félix; Caputo, Fabrizio

    2016-08-01

    It has been demonstrated that ischemic preconditioning (IPC) improves endurance performance. However, the potential benefits during anaerobic events and the mechanism(s) underlying these benefits remain unclear. Fifteen recreational cyclists were assessed to evaluate the effects of IPC of the upper thighs on anaerobic performance, skeletal muscle activation, and metabolic responses during a 60-s sprint performance. After an incremental test and a familiarization visit, subjects were randomly submitted in visits 3 and 4 to a performance protocol preceded by intermittent bilateral cuff inflation (4 × (5 min of blood flow restriction + 5 min reperfusion)) at either 220 mm Hg (IPC) or 20 mm Hg (control). To increase data reliability, each intervention was replicated, which was also in a random manner. In addition to the mean power output, the pulmonary oxygen uptake, blood lactate kinetics, and quadriceps electromyograms (EMGs) were analyzed during performance and throughout 45 min of passive recovery. After IPC, performance was improved by 2.1% compared with control (95% confidence intervals of 0.8% to 3.3%, P = 0.001), followed by increases in (i) the accumulated oxygen deficit, (ii) the amplitude of blood lactate kinetics, (iii) the total amount of oxygen consumed during recovery, and (iv) the overall EMG amplitude (P < 0.05). In addition, the ratio between EMG and power output was higher during the final third of performance after IPC (P < 0.05). These results suggest an increased skeletal muscle activation and a higher anaerobic contribution as the ultimate responses of IPC on short-term exercise performance. PMID:27404398

  5. Exercise preconditioning attenuates pressure overload-induced pathological cardiac hypertrophy

    PubMed Central

    Xu, Tongyi; Tang, Hao; Zhang, Ben; Cai, Chengliang; Liu, Xiaohong; Han, Qingqi; Zou, Liangjian

    2015-01-01

    Pathological cardiac hypertrophy, a common response of the heart to a variety of cardiovascular diseases, is typically associated with myocytes remodeling and fibrotic replacement, cardiac dysfunction. Exercise preconditioning (EP) increases the myocardial mechanical load and enhances tolerance of cardiac ischemia-reperfusion injury (IRI), however, is less reported in pathological cardiac hypertrophy. To determine the effect of EP in pathological cardiac hypertrophy, Male 10-wk-old Sprague-Dawley rats (n=30) were subjected to 4 weeks of EP followed by 4-8 weeks of pressure overload (transverse aortic constriction, TAC) to induce pathological remodeling. TAC in untrained controls (n=30) led to pathological cardiac hypertrophy, depressed systolic function. We observed that left ventricular wall thickness in end diastole, heart size, heart weight-to-body weight ratio, heart weight-to-tibia length ratio, cross-sectional area of cardiomyocytes and the reactivation of fetal genes (atrial natriuretic peptide and brain natriuretic peptide) were markedly increased, meanwhile left ventricular internal dimension at end-diastole, systolic function were significantly decreased by TAC at 4 wks after operation (P < 0.01), all of which were effectively inhibited by EP treatment (P < 0.05), but the differences of these parameters were decreased at 8 wks after operation. Furthermore, EP treatment inhibited degradation of IκBα, and decreased NF-κB p65 subunit levels in the nuclear fraction, and then reduced IL2 levels in the myocardium of rats subject to TAC. EP can effectively attenuate pathological cardiac hypertrophic responses induced by TAC possibly through inhibition of degradation of IκB and blockade of the NF-κB signaling pathway in the early stage of pathological cardiac hypertrophy. PMID:25755743

  6. Ischemic preconditioning reduces hemodynamic response during metaboreflex activation.

    PubMed

    Mulliri, Gabriele; Sainas, Gianmarco; Magnani, Sara; Palazzolo, Girolamo; Milia, Nicola; Orrù, Andrea; Roberto, Silvana; Marongiu, Elisabetta; Milia, Raffaele; Crisafulli, Antonio

    2016-05-01

    Ischemic preconditioning (IP) has been shown to improve exercise performance and to delay fatigue. However, the precise mechanisms through which IP operates remain elusive. It has been hypothesized that IP lowers the sensation of fatigue by reducing the discharge of group III and IV nerve endings, which also regulate hemodynamics during the metaboreflex. We hypothesized that IP reduces the blood pressure response during the metaboreflex. Fourteen healthy males (age between 25 and 48 yr) participated in this study. They underwent the following randomly assigned protocol: postexercise muscle ischemia (PEMI) test, during which the metaboreflex was elicited after dynamic handgrip; control exercise recovery session (CER) test; and PEMI after IP (IP-PEMI) test. IP was obtained by occluding forearm circulation for three cycles of 5 min spaced by 5 min of reperfusion. Hemodynamics were evaluated by echocardiography and impedance cardiography. The main results were that after IP the mean arterial pressure response was reduced compared with the PEMI test (means ± SD +3.37 ± 6.41 vs. +9.16 ± 7.09 mmHg, respectively). This was the consequence of an impaired venous return that impaired the stroke volume during the IP-PEMI more than during the PEMI test (-1.43 ± 15.35 vs. +10.28 ± 10.479 ml, respectively). It was concluded that during the metaboreflex, IP affects hemodynamics mainly because it impairs the capacity to augment venous return and to recruit the cardiac preload reserve. It was hypothesized that this is the consequence of an increased nitric oxide production, which reduces the possibility to constrict venous capacity vessels. PMID:26936782

  7. Glaciations in response to climate variations preconditioned by evolving topography.

    PubMed

    Pedersen, Vivi Kathrine; Egholm, David Lundbek

    2013-01-10

    Landscapes modified by glacial erosion show a distinct distribution of surface area with elevation (hypsometry). In particular, the height of these regions is influenced by climatic gradients controlling the altitude where glacial and periglacial processes are the most active, and as a result, surface area is focused just below the snowline altitude. Yet the effect of this distinct glacial hypsometric signature on glacial extent and therefore on continued glacial erosion has not previously been examined. Here we show how this topographic configuration influences the climatic sensitivity of Alpine glaciers, and how the development of a glacial hypsometric distribution influences the intensity of glaciations on timescales of more than a few glacial cycles. We find that the relationship between variations in climate and the resulting variation in areal extent of glaciation changes drastically with the degree of glacial modification in the landscape. First, in landscapes with novel glaciations, a nearly linear relationship between climate and glacial area exists. Second, in previously glaciated landscapes with extensive area at a similar elevation, highly nonlinear and rapid glacial expansions occur with minimal climate forcing, once the snowline reaches the hypsometric maximum. Our results also show that erosion associated with glaciations before the mid-Pleistocene transition at around 950,000 years ago probably preconditioned the landscape--producing glacial landforms and hypsometric maxima--such that ongoing cooling led to a significant change in glacial extent and erosion, resulting in more extensive glaciations and valley deepening in the late Pleistocene epoch. We thus provide a mechanism that explains previous observations from exposure dating and low-temperature thermochronology in the European Alps, and suggest that there is a strong topographic control on the most recent Quaternary period glaciations. PMID:23302860

  8. Meclizine Preconditioning Protects the Kidney Against Ischemia-Reperfusion Injury.

    PubMed

    Kishi, Seiji; Campanholle, Gabriela; Gohil, Vishal M; Perocchi, Fabiana; Brooks, Craig R; Morizane, Ryuji; Sabbisetti, Venkata; Ichimura, Takaharu; Mootha, Vamsi K; Bonventre, Joseph V

    2015-09-01

    Global or local ischemia contributes to the pathogenesis of acute kidney injury (AKI). Currently there are no specific therapies to prevent AKI. Potentiation of glycolytic metabolism and attenuation of mitochondrial respiration may decrease cell injury and reduce reactive oxygen species generation from the mitochondria. Meclizine, an over-the-counter anti-nausea and -dizziness drug, was identified in a 'nutrient-sensitized' chemical screen. Pretreatment with 100 mg/kg of meclizine, 17 h prior to ischemia protected mice from IRI. Serum creatinine levels at 24 h after IRI were 0.13 ± 0.06 mg/dl (sham, n = 3), 1.59 ± 0.10 mg/dl (vehicle, n = 8) and 0.89 ± 0.11 mg/dl (meclizine, n = 8). Kidney injury was significantly decreased in meclizine treated mice compared with vehicle group (p < 0.001). Protection was also seen when meclizine was administered 24 h prior to ischemia. Meclizine reduced inflammation, mitochondrial oxygen consumption, oxidative stress, mitochondrial fragmentation, and tubular injury. Meclizine preconditioned kidney tubular epithelial cells, exposed to blockade of glycolytic and oxidative metabolism with 2-deoxyglucose and NaCN, had reduced LDH and cytochrome c release. Meclizine upregulated glycolysis in glucose-containing media and reduced cellular ATP levels in galactose-containing media. Meclizine inhibited the Kennedy pathway and caused rapid accumulation of phosphoethanolamine. Phosphoethanolamine recapitulated meclizine-induced protection both in vitro and in vivo. PMID:26501107

  9. Meclizine Preconditioning Protects the Kidney Against Ischemia–Reperfusion Injury

    PubMed Central

    Kishi, Seiji; Campanholle, Gabriela; Gohil, Vishal M.; Perocchi, Fabiana; Brooks, Craig R.; Morizane, Ryuji; Sabbisetti, Venkata; Ichimura, Takaharu; Mootha, Vamsi K.; Bonventre, Joseph V.

    2015-01-01

    Global or local ischemia contributes to the pathogenesis of acute kidney injury (AKI). Currently there are no specific therapies to prevent AKI. Potentiation of glycolytic metabolism and attenuation of mitochondrial respiration may decrease cell injury and reduce reactive oxygen species generation from the mitochondria. Meclizine, an over-the-counter anti-nausea and -dizziness drug, was identified in a ‘nutrient-sensitized’ chemical screen. Pretreatment with 100 mg/kg of meclizine, 17 h prior to ischemia protected mice from IRI. Serum creatinine levels at 24 h after IRI were 0.13 ± 0.06 mg/dl (sham, n = 3), 1.59 ± 0.10 mg/dl (vehicle, n = 8) and 0.89 ± 0.11 mg/dl (meclizine, n = 8). Kidney injury was significantly decreased in meclizine treated mice compared with vehicle group (p < 0.001). Protection was also seen when meclizine was administered 24 h prior to ischemia. Meclizine reduced inflammation, mitochondrial oxygen consumption, oxidative stress, mitochondrial fragmentation, and tubular injury. Meclizine preconditioned kidney tubular epithelial cells, exposed to blockade of glycolytic and oxidative metabolism with 2-deoxyglucose and NaCN, had reduced LDH and cytochrome c release. Meclizine upregulated glycolysis in glucose-containing media and reduced cellular ATP levels in galactose-containing media. Meclizine inhibited the Kennedy pathway and caused rapid accumulation of phosphoethanolamine. Phosphoethanolamine recapitulated meclizine-induced protection both in vitro and in vivo. PMID:26501107

  10. Dynamic preconditioning of the September sea-ice extent minimum

    NASA Astrophysics Data System (ADS)

    Williams, James; Tremblay, Bruno; Newton, Robert; Allard, Richard

    2016-04-01

    There has been an increased interest in seasonal forecasting of the sea-ice extent in recent years, in particular the minimum sea-ice extent. We propose a dynamical mechanism, based on winter preconditioning through first year ice formation, that explains a significant fraction of the variance in the anomaly of the September sea-ice extent from the long-term linear trend. To this end, we use a Lagrangian trajectory model to backtrack the September sea-ice edge to any time during the previous winter and quantify the amount of sea-ice divergence along the Eurasian and Alaskan coastlines as well as the Fram Strait sea-ice export. We find that coastal divergence that occurs later in the winter (March, April and May) is highly correlated with the following September sea-ice extent minimum (r = ‑0.73). This is because the newly formed first year ice will melt earlier allowing for other feedbacks (e.g. ice albedo feedback) to start amplifying the signal early in the melt season when the solar input is large. We find that the winter mean Fram Strait sea-ice export anomaly is also correlated with the minimum sea-ice extent the following summer. Next we backtrack a synthetic ice edge initialized at the beginning of the melt season (June 1st) in order to develop hindcast models of the September sea-ice extent that do not rely on a-priori knowledge of the minimum sea-ice extent. We find that using a multi-variate regression model of the September sea-ice extent anomaly based on coastal divergence and Fram Strait ice export as predictors reduces the error by 41%. A hindcast model based on the mean DJFMA Arctic Oscillation index alone reduces the error by 24%.

  11. Analysis and modeling of neural processes underlying sensory preconditioning.

    PubMed

    Matsumoto, Yukihisa; Hirashima, Daisuke; Mizunami, Makoto

    2013-03-01

    Sensory preconditioning (SPC) is a procedure to demonstrate learning to associate between relatively neutral sensory stimuli in the absence of an external reinforcing stimulus, the underlying neural mechanisms of which have remained obscure. We address basic questions about neural processes underlying SPC, including whether neurons that mediate reward or punishment signals in reinforcement learning participate in association between neutral sensory stimuli. In crickets, we have suggested that octopaminergic (OA-ergic) or dopaminergic (DA-ergic) neurons participate in memory acquisition and retrieval in appetitive or aversive conditioning, respectively. Crickets that had been trained to associate an odor (CS2) with a visual pattern (CS1) (phase 1) and then to associate CS1 with water reward or quinine punishment (phase 2) exhibited a significantly increased or decreased preference for CS2 that had never been paired with the US, demonstrating successful SPC. Injection of an OA or DA receptor antagonist at different phases of the SPC training and testing showed that OA-ergic or DA-ergic neurons do not participate in learning of CS2-CS1 association in phase 1, but that OA-ergic neurons participate in learning in phase 2 and memory retrieval after appetitive SPC training. We also obtained evidence suggesting that association between CS2 and US, which should underlie conditioned response of crickets to CS2, is formed in phase 2, contrary to the standard theory of SPC assuming that it occurs in the final test. We propose models of SPC to account for these findings, by extending our model of classical conditioning. PMID:23380289

  12. A taxonomy and comparison of parallel block multi-level preconditioners for the incompressible Navier-Stokes equations.

    SciTech Connect

    Shadid, John Nicolas; Elman, Howard; Shuttleworth, Robert R.; Howle, Victoria E.; Tuminaro, Raymond Stephen

    2007-04-01

    In recent years, considerable effort has been placed on developing efficient and robust solution algorithms for the incompressible Navier-Stokes equations based on preconditioned Krylov methods. These include physics-based methods, such as SIMPLE, and purely algebraic preconditioners based on the approximation of the Schur complement. All these techniques can be represented as approximate block factorization (ABF) type preconditioners. The goal is to decompose the application of the preconditioner into simplified sub-systems in which scalable multi-level type solvers can be applied. In this paper we develop a taxonomy of these ideas based on an adaptation of a generalized approximate factorization of the Navier-Stokes system first presented in [25]. This taxonomy illuminates the similarities and differences among these preconditioners and the central role played by efficient approximation of certain Schur complement operators. We then present a parallel computational study that examines the performance of these methods and compares them to an additive Schwarz domain decomposition (DD) algorithm. Results are presented for two and three-dimensional steady state problems for enclosed domains and inflow/outflow systems on both structured and unstructured meshes. The numerical experiments are performed using MPSalsa, a stabilized finite element code.

  13. The inhibition of angiogenesis and tumor growth by denbinobin is associated with the blocking of insulin-like growth factor-1 receptor signaling.

    PubMed

    Tsai, An-Chi; Pan, Shiow-Lin; Lai, Chin-Yu; Wang, Chih-Ya; Chen, Chien-Chih; Shen, Chien-Chang; Teng, Che-Ming

    2011-07-01

    Denbinobin, which is a phenanthraquinone derivative present in the stems of Ephemerantha lonchophylla, has been demonstrated to display antitumor activity. Recent reports suggest that the enhanced activity of insulin-like growth factor-1 receptor (IGF-1R) is closely associated with tumor angiogenesis and growth. This study aims at investigating the roles of denbinobin in suppressing these effects and at further elucidating the underlying molecular mechanisms. In the present study, we used an in vivo xenograft model antitumor and the Matrigel implant assays to show that denbinobin suppresses lung adenocarcinoma A549 growth and microvessel formation. Additionally, crystal violet and capillary-like tube formation assays indicated that denbinobin selectively inhibits insulin-like growth factor-1 (IGF-1)-induced proliferation (GI50=1.3×10⁻⁸ M) and tube formation of human umbilical vascular endothelial cells (HUVECs) without influencing the effect of epidermal growth factor; vascular endothelial growth factor and basic fibroblast growth factor. Furthermore, denbinobin inhibited the IGF-1-induced migration of HUVECs in a concentration-dependent fashion. Western blotting and immunoprecipitation demonstrated that denbinobin causes more efficient inhibition of IGF-1-induced activation of IGF-1R and its downstream signaling targets, including , extracellular signal-regulated kinase, Akt, mTOR, p70S6K, 4EBP and cyclin D1. All of our results provide evidences that denbinobin suppresses the activation of IGF-1R and its downstream signaling pathway, which leads to the inhibition of angiogenesis. Our findings suggest that denbinobin may be a novel IGF-1R kinase inhibitor and has potential therapeutic abilities for angiogenesis-related diseases such as cancer. PMID:20951021

  14. Ethyl-p-methoxycinnamate isolated from kaempferia galanga inhibits inflammation by suppressing interleukin-1, tumor necrosis factor-α, and angiogenesis by blocking endothelial functions

    PubMed Central

    Umar, Muhammad Ihtisham; Asmawi, Mohd Zaini; Sadikun, Amirin; Majid, Amin Malik Shah Abdul; Al-Suede, Fouad Saleih R.; Hassan, Loiy Elsir Ahmed; Altaf, Rabia; Ahamed, Mohamed B. Khadeer

    2014-01-01

    OBJECTIVE: The present study aimed to investigate the mechanisms underlying the anti-inflammatory and anti-angiogenic effects of ethyl-p-methoxycinnamate isolated from Kaempferia galanga. METHODS: The anti-inflammatory effects of ethyl-p-methoxycinnamate were assessed using the cotton pellet granuloma assay in rats, whereby the levels of interleukin-1 and tumor necrosis factor-α were measured in the animals' blood. In addition, the levels of interleukin, tumor necrosis factor, and nitric oxide were measured in vitro using the human macrophage cell line (U937). The analgesic effects of ethyl-p-methoxycinnamate were assessed by the tail flick assay in rats. The anti-angiogenic effects were evaluated first by the rat aortic ring assay and, subsequently, by assessing the inhibitory effects of ethyl-p-methoxycinnamate on vascular endothelial growth factor, proliferation, migration, and tube formation in human umbilical vein endothelial cells. RESULTS: Ethyl-p-methoxycinnamate strongly inhibited granuloma tissue formation in rats. It prolonged the tail flick time in rats by more than two-fold compared with the control animals. The inhibition of interleukin and tumor necrosis factor by ethyl-p-methoxycinnamate was significant in both in vivo and in vitro models; however, only a moderate inhibition of nitric oxide was observed in macrophages. Furthermore, ethyl-p-methoxycinnamate considerably inhibited microvessel sprouting from the rat aorta. These mechanistic studies showed that ethyl-p-methoxycinnamate strongly inhibited the differentiation and migration of endothelial cells, which was further confirmed by the reduced level of vascular endothelial growth factor. CONCLUSION: Ethyl-p-methoxycinnamate exhibits significant anti-inflammatory potential by inhibiting pro-inflammatory cytokines and angiogenesis, thus inhibiting the main functions of endothelial cells. Thus, ethyl-p-methoxycinnamate could be a promising therapeutic agent for the treatment of inflammatory and

  15. Essential role of adenosine, adenosine A1 receptors, and ATP-sensitive K+ channels in cerebral ischemic preconditioning.

    PubMed Central

    Heurteaux, C; Lauritzen, I; Widmann, C; Lazdunski, M

    1995-01-01

    Preconditioning with sublethal ischemia protects against neuronal damage after subsequent lethal ischemic insults in hippocampal neurons. A pharmacological approach using agonists and antagonists at the adenosine A1 receptor as well as openers and blockers of ATP-sensitive K+ channels has been combined with an analysis of neuronal death and gene expression of subunits of glutamate and gamma-aminobutyric acid receptors, HSP70, c-fos, c-jun, and growth factors. It indicates that the mechanism of ischemic tolerance involves a cascade of events including liberation of adenosine, stimulation of adenosine A1 receptors, and, via these receptors, opening of sulfonylurea-sensitive ATP-sensitive K+ channels. Images Fig. 2 Fig. 3 PMID:7753861

  16. Super-low Dose Endotoxin Pre-conditioning Exacerbates Sepsis Mortality

    PubMed Central

    Chen, Keqiang; Geng, Shuo; Yuan, Ruoxi; Diao, Na; Upchurch, Zachary; Li, Liwu

    2015-01-01

    Sepsis mortality varies dramatically in individuals of variable immune conditions, with poorly defined mechanisms. This phenomenon complements the hypothesis that innate immunity may adopt rudimentary memory, as demonstrated in vitro with endotoxin priming and tolerance in cultured monocytes. However, previous in vivo studies only examined the protective effect of endotoxin tolerance in the context of sepsis. In sharp contrast, we report herein that pre-conditioning with super-low or low dose endotoxin lipopolysaccharide (LPS) cause strikingly opposite survival outcomes. Mice pre-conditioned with super-low dose LPS experienced severe tissue damage, inflammation, increased bacterial load in circulation, and elevated mortality when they were subjected to cecal-ligation and puncture (CLP). This is in contrast to the well-reported protective phenomenon with CLP mice pre-conditioned with low dose LPS. Mechanistically, we demonstrated that super-low and low dose LPS differentially modulate the formation of neutrophil extracellular trap (NET) in neutrophils. Instead of increased ERK activation and NET formation in neutrophils pre-conditioned with low dose LPS, we observed significantly reduced ERK activation and compromised NET generation in neutrophils pre-conditioned with super-low dose LPS. Collectively, our findings reveal a mechanism potentially responsible for the dynamic programming of innate immunity in vivo as it relates to sepsis risks. PMID:26029736

  17. Blocked randomization with randomly selected block sizes.

    PubMed

    Efird, Jimmy

    2011-01-01

    When planning a randomized clinical trial, careful consideration must be given to how participants are selected for various arms of a study. Selection and accidental bias may occur when participants are not assigned to study groups with equal probability. A simple random allocation scheme is a process by which each participant has equal likelihood of being assigned to treatment versus referent groups. However, by chance an unequal number of individuals may be assigned to each arm of the study and thus decrease the power to detect statistically significant differences between groups. Block randomization is a commonly used technique in clinical trial design to reduce bias and achieve balance in the allocation of participants to treatment arms, especially when the sample size is small. This method increases the probability that each arm will contain an equal number of individuals by sequencing participant assignments by block. Yet still, the allocation process may be predictable, for example, when the investigator is not blind and the block size is fixed. This paper provides an overview of blocked randomization and illustrates how to avoid selection bias by using random block sizes. PMID:21318011

  18. Research on the Changes to the Lipid/Polymer Membrane Used in the Acidic Bitterness Sensor Caused by Preconditioning.

    PubMed

    Harada, Yuhei; Noda, Junpei; Yatabe, Rui; Ikezaki, Hidekazu; Toko, Kiyoshi

    2016-01-01

    A taste sensor that uses lipid/polymer membranes can evaluate aftertastes felt by humans using Change in membrane Potential caused by Adsorption (CPA) measurements. The sensor membrane for evaluating bitterness, which is caused by acidic bitter substances such as iso-alpha acid contained in beer, needs an immersion process in monosodium glutamate (MSG) solution, called "MSG preconditioning". However, what happens to the lipid/polymer membrane during MSG preconditioning is not clear. Therefore, we carried out three experiments to investigate the changes in the lipid/polymer membrane caused by the MSG preconditioning, i.e., measurements of the taste sensor, measurements of the amount of the bitterness substance adsorbed onto the membrane and measurements of the contact angle of the membrane surface. The CPA values increased as the preconditioning process progressed, and became stable after 3 d of preconditioning. The response potentials to the reference solution showed the same tendency of the CPA value change during the preconditioning period. The contact angle of the lipid/polymer membrane surface decreased after 7 d of MSG preconditioning; in short, the surface of the lipid/polymer membrane became hydrophilic during MSG preconditioning. The amount of adsorbed iso-alpha acid was increased until 5 d preconditioning, and then it decreased. In this study, we revealed that the CPA values increased with the progress of MSG preconditioning in spite of the decrease of the amount of iso-alpha acid adsorbed onto the lipid/polymer membrane, and it was indicated that the CPA values increase because the sensor sensitivity was improved by the MSG preconditioning. PMID:26891299

  19. Inhibition of multiple vascular endothelial growth factor receptors (VEGFR) blocks lymph node metastases but inhibition of VEGFR-2 is sufficient to sensitize tumor cells to platinum-based chemotherapeutics.

    PubMed

    Sini, Patrizia; Samarzija, Ivana; Baffert, Fabienne; Littlewood-Evans, Amanda; Schnell, Christian; Theuer, Andreas; Christian, Sven; Boos, Anja; Hess-Stumpp, Holger; Foekens, John A; Setyono-Han, Buddy; Wood, Jeanette; Hynes, Nancy E

    2008-03-01

    Vascular endothelial growth factor receptors (VEGFR) have important roles in cancer, affecting blood and lymphatic vessel functionality as well as tumor cells themselves. We compared the efficacy of a VEGFR tyrosine kinase inhibitor, PTK787/ZK222584 (PTK/ZK), which targets the three VEGFRs, with blocking antibodies directed against VEGFR-2 (DC101) or VEGF-A (Pab85618) in a metastatic melanoma model. Although all inhibitors exerted comparable effects on primary tumor growth, only PTK/ZK significantly reduced lymph node metastasis formation. A comparable decrease in lymphatic vessel density following blockade of VEGFR-2 (DC101) or the three VEGFRs (PTK/ZK) was observed in the metastases. However, the functionality of lymphatics surrounding the primary tumor was more significantly disrupted by PTK/ZK, indicating the importance of multiple VEGFRs in the metastatic process. The antimetastatic properties of PTK/ZK were confirmed in a breast carcinoma model. B16/BL6 tumor cells express VEGF ligands and their receptors. Blockade of a VEGFR-1 autocrine loop with PTK/ZK inhibited tumor cell migration. Furthermore, the tumor cells also showed enhanced sensitivity to platinum-based chemotherapy in combination with PTK/ZK, indicating that autocrine VEGFRs are promoting tumor cell migration and survival. In summary, our results suggest that, in addition to blocking angiogenesis, combined inhibition of the three VEGFRs may more efficiently target other aspects of tumor pathophysiology, including lymphatic vessel functionality, tumor cell dissemination, survival pathways, and response to chemotherapeutic compounds. PMID:18316624

  20. Block ground interaction of rockfalls

    NASA Astrophysics Data System (ADS)

    Volkwein, Axel; Gerber, Werner; Kummer, Peter

    2016-04-01

    During a rockfall the interaction of the falling block with the ground is one of the most important factors that define the evolution of a rockfall trajectory. It steers the rebound, the rotational movement, possibly brake effects, friction losses and damping effects. Therefore, if most reliable rockfall /trajectory simulation software is sought a good understanding of the block ground interaction is necessary. Today's rockfall codes enable the simulation of a fully 3D modelled block within a full 3D surface . However, the details during the contact, i.e. the contact duration, the penetration depth or the dimension of the marks in the ground are usually not part of the simulation. Recent field tests with rocks between 20 and 80 kg have been conducted on a grassy slope in 2014 [1]. A special rockfall sensor [2] within the blocks measured the rotational velocity and the acting accelerations during the tests. External video records and a so-called LocalPositioningSystem deliver information on the travel velocity. With these data not only the flight phases of the trajectories but also the contacts with the ground can be analysed. During the single jumps of a block the flight time, jump length, the velocity, and the rotation are known. During the single impacts their duration and the acting accelerations are visible. Further, the changes of rotational and translational velocity influence the next jump of the block. The change of the rotational velocity over the whole trajectory nicely visualizes the different phases of a rockfall regarding general acceleration and deceleration in respect to the inclination and the topography of the field. References: [1] Volkwein A, Krummenacher B, Gerber W, Lardon J, Gees F, Brügger L, Ott T (2015) Repeated controlled rockfall trajectory testing. [Abstract] Geophys. Res. Abstr. 17: EGU2015-9779. [2] Volkwein A, Klette J (2014) Semi-Automatic Determination of Rockfall Trajectories. Sensors 14: 18187-18210.

  1. Efficient Multi-Stage Time Marching for Viscous Flows via Local Preconditioning

    NASA Technical Reports Server (NTRS)

    Kleb, William L.; Wood, William A.; vanLeer, Bram

    1999-01-01

    A new method has been developed to accelerate the convergence of explicit time-marching, laminar, Navier-Stokes codes through the combination of local preconditioning and multi-stage time marching optimization. Local preconditioning is a technique to modify the time-dependent equations so that all information moves or decays at nearly the same rate, thus relieving the stiffness for a system of equations. Multi-stage time marching can be optimized by modifying its coefficients to account for the presence of viscous terms, allowing larger time steps. We show it is possible to optimize the time marching scheme for a wide range of cell Reynolds numbers for the scalar advection-diffusion equation, and local preconditioning allows this optimization to be applied to the Navier-Stokes equations. Convergence acceleration of the new method is demonstrated through numerical experiments with circular advection and laminar boundary-layer flow over a flat plate.

  2. Preconditioned conjugate gradient technique for the analysis of symmetric anisotropic structures

    NASA Technical Reports Server (NTRS)

    Noor, Ahmed K.; Peters, Jeanne M.

    1987-01-01

    An efficient preconditioned conjugate gradient (PCG) technique and a computational procedure are presented for the analysis of symmetric anisotropic structures. The technique is based on selecting the preconditioning matrix as the orthotropic part of the global stiffness matrix of the structure, with all the nonorthotropic terms set equal to zero. This particular choice of the preconditioning matrix results in reducing the size of the analysis model of the anisotropic structure to that of the corresponding orthotropic structure. The similarities between the proposed PCG technique and a reduction technique previously presented by the authors are identified and exploited to generate from the PCG technique direct measures for the sensitivity of the different response quantities to the nonorthotropic (anisotropic) material coefficients of the structure. The effectiveness of the PCG technique is demonstrated by means of a numerical example of an anisotropic cylindrical panel.

  3. Does nitric oxide generation contribute to the mechanism of remote ischemic preconditioning?

    PubMed

    Petrishchev, N N.; Vlasov, T D.; Sipovsky, V G.; Kurapeev, D I.; Galagudza, M M.

    2001-03-01

    The protective effect of local or remote ischemic preconditioning (IPC) on subsequent 40-min ischemic and 120-min reperfusion myocardial damage was investigated. Preconditioned rats underwent one cycle of myocardial ischemia/reperfusion consisting of 5-min ischemia produced as a left coronary artery (LCA) occlusion and 5 min of reperfusion. Remote IPC was produced as 15 min of small intestinal ischemia with 15 min of reperfusion as well as 30 min of limb ischemia with 15 min of reperfusion. A marked protective action was afforded by both IPC protocols with a more significant effect of local (classic) ischemic preconditioning. Since the protective effect of remote IPC was not abolished by nitric oxide (NO) synthase inhibition with Nomega-nitro-L-arginine (L-NNA) it is concluded that NO generation may not be involved in the mechanism of remote IPC. PMID:11228397

  4. Preconditioning for the Navier-Stokes equations with finite-rate chemistry

    NASA Technical Reports Server (NTRS)

    Godfrey, Andrew G.; Walters, Robert W.; Van Leer, Bram

    1993-01-01

    The preconditioning procedure for generalized finite-rate chemistry and the proper preconditioning for the one-dimensional Navier-Stokes equations are presented. Eigenvalue stiffness is resolved and convergence-rate acceleration is demonstrated over the entire Mach-number range from the incompressible to the hypersonic. Specific benefits are realized at low and transonic flow speeds. The extended preconditioning matrix accounts for thermal and chemical non-equilibrium and its implementation is explained for both explicit and implicit time marching. The effect of higher-order spatial accuracy and various flux splittings is investigated. Numerical analysis reveals the possible theoretical improvements from using proconditioning at all Mach numbers. Numerical results confirm the expectations from the numerical analysis. Representative test cases include flows with previously troublesome embedded high-condition-number regions.

  5. Novel Genes Critical for Hypoxic Preconditioning in Zebrafish Are Regulators of Insulin and Glucose Metabolism

    PubMed Central

    Manchenkov, Tania; Pasillas, Martina P.; Haddad, Gabriel G.; Imam, Farhad B.

    2015-01-01

    Severe hypoxia is a common cause of major brain, heart, and kidney injury in adults, children, and newborns. However, mild hypoxia can be protective against later, more severe hypoxia exposure via “hypoxic preconditioning,” a phenomenon that is not yet fully understood. Accordingly, we have established and optimized an embryonic zebrafish model to study hypoxic preconditioning. Using a functional genomic approach, we used this zebrafish model to identify and validate five novel hypoxia-protective genes, including irs2, crtc3, and camk2g2, which have been previously implicated in metabolic regulation. These results extend our understanding of the mechanisms of hypoxic preconditioning and affirm the discovery potential of this novel vertebrate hypoxic stress model. PMID:25840431

  6. [Hypoxic preconditioning is a phenomenon increasing tolerance of cardiomyocytes to hypoxia-reoxygenation].

    PubMed

    Maslov, L N; Lishmanov, Iu B; Kolar, F; Portnichenko, A G; Podoksenov, Iu K; Khaliulin, I G; Wang, H; Pei, J M

    2010-12-01

    The work covers the problem of hypoxic preconditioning (HP) carried out in isolated cardiomyocytes. Papers on delayed HP in vivo are comparatively few, and only some single works are devoted to early preconditioning in vivo. It has been established that the HP limits necrosis and apoptosis of cardiomyocytes and improves contractility of the isolated heart after ischemia (hypoxia) and reperfusion (reoxygenation). It was found that adenosine was a trigger of iP in vitro. It was proved that NO* was a trigger of HP both in vitro and in vivo. It was shown that reactive oxygen species also were triggers of hypoxic preconditioning. It was shown that ERK1/2 and p38 kinase played important role in delayed HP in vitro. PMID:21473105

  7. Wide-field fluorescence molecular tomography with compressive sensing based preconditioning

    PubMed Central

    Yao, Ruoyang; Pian, Qi; Intes, Xavier

    2015-01-01

    Wide-field optical tomography based on structured light illumination and detection strategies enables efficient tomographic imaging of large tissues at very fast acquisition speeds. However, the optical inverse problem based on such instrumental approach is still ill-conditioned. Herein, we investigate the benefit of employing compressive sensing-based preconditioning to wide-field structured illumination and detection approaches. We assess the performances of Fluorescence Molecular Tomography (FMT) when using such preconditioning methods both in silico and with experimental data. Additionally, we demonstrate that such methodology could be used to select the subset of patterns that provides optimal reconstruction performances. Lastly, we compare preconditioning data collected using a normal base that offers good experimental SNR against that directly acquired with optimal designed base. An experimental phantom study is provided to validate the proposed technique. PMID:26713202

  8. The nuclear localization of the Arabidopsis transcription factor TIP is blocked by its interaction with the coat protein of Turnip crinkle virus

    SciTech Connect

    Ren Tao; Qu Feng; Morris, T. Jack . E-mail: jmorris@unlnotes.unl.edu

    2005-01-20

    We have previously reported that TIP, an Arabidopsis protein, interacts with the coat protein (CP) of Turnip crinkle virus (TCV) in yeast cells and that this interaction correlated with the resistance response in the TCV-resistant Arabidopsis ecotype Dijon-17. TIP was also able to activate transcription of reporter genes in yeast cells, suggesting that it is likely a transcription factor. We have now verified the physical interaction between TIP and TCV CP in vitro and showed that CP mutants unable to interact with TIP in yeast cells bind TIP with much lower affinity in vitro. Secondly, we have performed gel shift experiments demonstrating that TIP does not bind to DNA in a sequence-specific manner. The subcellular localization of TIP was also investigated by transiently expressing green fluorescence protein (GFP)-tagged TIP in Nicotiana benthamiana plant cells, which showed that GFP-tagged TIP localizes primarily to nuclei. Significantly, co-expression of TCVCP and GFP-TIP prevented the nuclear localization of TIP. Together, these results suggest that TIP might be a transcription factor involved in regulating the defense response of Arabidopsis to TCV and that its normal role is compromised by interaction with the invading viral CP.

  9. Anasazi Block Eigensolvers Package

    Energy Science and Technology Software Center (ESTSC)

    2004-03-01

    ANASAZI is an extensible and interoperable framework for large-scale eigenvalue algorithms. The motivation for this framework is to provide a generic interface to a collection of algorithms for solving large-scale eigenvalue problems. ANASAZI is interoperable because both the matrix and vectors (defining the eigenspace) are considered to be opaque objects---only knowledge of the matrix and vectors via elementary operations is necessary. An implementation of Anasazi is accomplished via the use of interfaces. One of themore » goals of ANASAZI is to allow the user the flexibility to specify the data representation for the matrix and vectors and so leverage any existing software investment. The algorithms that will be included in package are Krylov-based and preconditioned eigensolvers.« less

  10. Protein based Block Copolymers

    PubMed Central

    Rabotyagova, Olena S.; Cebe, Peggy; Kaplan, David L.

    2011-01-01

    Advances in genetic engineering have led to the synthesis of protein-based block copolymers with control of chemistry and molecular weight, resulting in unique physical and biological properties. The benefits from incorporating peptide blocks into copolymer designs arise from the fundamental properties of proteins to adopt ordered conformations and to undergo self-assembly, providing control over structure formation at various length scales when compared to conventional block copolymers. This review covers the synthesis, structure, assembly, properties, and applications of protein-based block copolymers. PMID:21235251

  11. Failure and rescue of preconditioning-induced neuroprotection in severe stroke-like insults.

    PubMed

    Tauskela, Joseph S; Aylsworth, Amy; Hewitt, Melissa; Brunette, Eric; Blondeau, Nicolas

    2016-06-01

    Preconditioning is a well established neuroprotective modality. However, the mechanism and relative efficacy of neuroprotection between diverse preconditioners is poorly defined. Cultured neurons were preconditioned by 4-aminopyridine and bicuculline (4-AP/bic), rendering neurons tolerant to normally lethal (sufficient to kill most neurons) oxygen-glucose deprivation (OGD) or a chemical OGD-mimic, ouabain/TBOA, by suppression of extracellular glutamate (glutamateex) elevations. However, subjecting preconditioned neurons to longer-duration supra-lethal insults caused neurotoxic glutamateex elevations, thereby identifying a 'ceiling' to neuroprotection. Neuroprotective 'rescue' of neurons could be obtained by administration of an NMDA receptor antagonist, MK-801, just before glutamateex rose during these supra-lethal insults. Next, we evaluated if these concepts of glutamateex suppression during lethal OGD, and a neuroprotective ceiling requiring MK-801 rescue under supra-lethal OGD, extended to the preconditioning field. In screening a panel of 42 diverse putative preconditioners, neuroprotection against normally lethal OGD was observed in 12 cases, which correlated with glutamateex suppression, both of which could be reversed, either by the inclusion of a glutamate uptake inhibitor (TBOA, to increase glutamateex levels) during OGD or by exposure to supra-lethal OGD. Administrating MK-801 during the latter stages of supra-lethal OGD again rescued neurons, although to varying degrees dependent on the preconditioning agent. Thus, 'stress-testing' against the harshest ischemic-like insults yet tested identifies the most efficacious preconditioners, which dictates how early MK-801 needs to be administered during the insult in order to maintain neuroprotection. Preconditioning delays a neurotoxic rise in glutamateex levels, thereby 'buying time' for acute anti-excitotoxic pharmacologic rescue. PMID:26867506

  12. How preconditioning affects the measurement of poro-viscoelastic mechanical properties in biological tissues.

    PubMed

    Hosseini, Sayyed Mohsen; Wilson, Wouter; Ito, Keita; van Donkelaar, Corrinus C

    2014-06-01

    It is known that initial loading curves of soft biological tissues are substantially different from subsequent loadings. The later loading curves are generally used for assessing the mechanical properties of a tissue, and the first loading cycles, referred to as preconditioning, are omitted. However, slow viscoelastic phenomena related to fluid flow or collagen viscoelasticity are initiated during these first preconditioning loading cycles and may persist during the actual data collection. When these data are subsequently used for fitting of material properties, the viscoelastic phenomena that occurred during the initial cycles are not accounted for. The aim of the present study is to explore whether the above phenomena are significant for articular cartilage, by evaluating the effect of such time-dependent phenomena by means of computational modeling. Results show that under indentation, collagen viscoelasticity dominates the time-dependent behavior. Under UC, fluid-dependent effects are more important. Interestingly, viscoelastic and poroelastic effects may act in opposite directions and may cancel each other out in a stress-strain curve. Therefore, equilibrium may be apparent in a stress-strain relationship, even though internally the tissue is not in equilibrium. Also, the time-dependent effects of viscoelasticity and poroelasticity may reinforce each other, resulting in a sustained effect that lasts longer than suggested by their individual effects. Finally, the results illustrate that data collected from a mechanical test may depend on the preconditioning protocol. In conclusion, preconditioning influences the mechanical response of articular cartilage significantly and therefore cannot be neglected when determining the mechanical properties. To determine the full viscoelastic and poroelastic properties of articular cartilage requires fitting to both preconditioning and post-preconditioned loading cycles. PMID:23864393

  13. Combustion of coal/water mixtures with thermal preconditioning. Final report

    SciTech Connect

    Novack, M.; Roffe, G.; Miller, G.

    1985-12-01

    Thermal preconditioning is a process in which coal/water mixtures are vaporized to produce coal/steam suspensions, and then superheated to allow the coal to devolatilize producing suspensions of char particles in hydrocarbon gases and steam. This final product of the process can be injected without atomization, and burned directly in a gas turbine combustor. This paper reports on the results of an experimental program in which thermally preconditioned coal/water mixture was successfully burned with a stable flame in a gas turbine combustor test rig. Tests were performed at a mixture flowrate of 300 lb/hr and combustor pressure of 8 atmospheres. The coal/water mixture was thermally preconditioned and injected into the combustor over a temperature range from 350 to 600/sup 0/F, and combustion air was supplied at between 600 to 725/sup 0/F. Test durations generally varied between 10 to 20 minutes. Major results of the combustion testing were that: a stable flame was maintained over a wide equivalence ratio range, between phi = 2.4 (rich) to 0.2 (lean); and, combustion efficiency of over 99% was achieved when the mixture was preconditioned to 600/sup 0/F and the combustion air preheated to 725/sup 0/F. Measurements of ash particulates captured in the exhaust sampling probe located 20 inches from the injector face, show typical sizes collected to be about 1 micron, with agglomerates of these particulates to be not more than 8 microns. The original mean coal particle size for these tests, prior to preconditioning was 25 microns. System studies indicate that preconditioning can be incorporated into either stationary or mobile power plant designs without system derating. On the basis of these results, thermal pretreatment offers a practical alternative to fuel atomization in gas turbine applications. 20 figs., 4 tabs.

  14. A preconditioned semi-staggered dilation-free finite volume method for the incompressible Navier-Stokes equations on all-hexahedral elements

    NASA Astrophysics Data System (ADS)

    Sahin, Mehmet

    2005-11-01

    A new semi-staggered finite volume method is presented for the solution of the incompressible Navier-Stokes equations on all-quadrilateral (2D)/hexahedral (3D) meshes. The velocity components are defined at element node points while the pressure term is defined at element centroids. The continuity equation is satisfied exactly within each elements. The checkerboard pressure oscillations are prevented using a special filtering matrix as a preconditioner for the saddle-point problem resulting from second-order discretization of the incompressible Navier-Stokes equations. The preconditioned saddle-point problem is solved using block preconditioners with GMRES solver. In order to achieve higher performance FORTRAN source code is based on highly efficient PETSc and HYPRE libraries. As test cases the 2D/3D lid-driven cavity flow problem and the 3D flow past array of circular cylinders are solved in order to verify the accuracy of the proposed method.

  15. Hypoxia-induced preconditioning in adult stimulated cardiomyocytes is mediated by the opening and trafficking of sarcolemmal KATP channels

    PubMed Central

    Budas, Grant R.; Jovanovic, Sofija; Crawford, Russell M.; Jovanovic, Aleksandar

    2007-01-01

    The opening of sarcolemmal and mitochondrial ATP-sensitive K+ (KATP) channels in the heart is believed to mediate ischemic preconditioning, a phenomenon whereby brief periods of ischemia/reperfusion protect the heart against myocardial infarction. Here, we have applied digital epifluorescent microscopy, immunoprecipitation and Western blotting, perforated patch clamp electrophysiology, and immunofluorescence/laser confocal microscopy to examine the involvement of KATP channels in cardioprotection afforded by preconditioning. We have shown that adult, stimulated-to-beat, guinea-pig cardiomyocytes survived in sustained hypoxia for ∼17 min. An episode of 5-min-long hypoxia/5-min-long reoxygenation before sustained hypoxia dramatically increased the duration of cellular survival. Experiments with different antagonists of KATP channels, applied at different times during the experimental protocol, suggested that the opening of sarcolemmal KATP channels at the beginning of sustained hypoxia mediate preconditioning. This conclusion was supported by perforated patch clamp experiments that revealed activation of sarcolemmal KATP channels by preconditioning. Immunoprecipitation and Western blotting as well as immunofluorescence and laser confocal microscopy showed that the preconditioning is associated with the increase in KATP channel proteins in sarcolemma. Inhibition of trafficking of KATP channel subunits prevented preconditioning without affecting sensitivity of cardiomyocytes to hypoxia in the absence of preconditioning. We conclude that the preconditioning is mediated by the activation and trafficking of sarcolemmal KATP channels. PMID:15084521

  16. Solving nonlinear heat conduction problems with multigrid preconditioned Newton-Krylov methods

    SciTech Connect

    Rider, W.J.; Knoll, D.A.

    1997-09-01

    Our objective is to investigate the utility of employing multigrid preconditioned Newton-Krylov methods for solving initial value problems. Multigrid based method promise better performance from the linear scaling associated with them. Our model problem is nonlinear heat conduction which can model idealized Marshak waves. Here we will investigate the efficiency of using a linear multigrid method to precondition a Krylov subspace method. In effect we will show that a fixed point nonlinear iterative method provides an effective preconditioner for the nonlinear problem.

  17. Propulsion-related flowfields using the preconditioned Navier-Stokes equations

    NASA Technical Reports Server (NTRS)

    Venkateswaran, S.; Weiss, J. M.; Merkle, C. L.; Choi, Y.-H.

    1992-01-01

    A previous time-derivative preconditioning procedure for solving the Navier-Stokes is extended to the chemical species equations. The scheme is implemented using both the implicit ADI and the explicit Runge-Kutta algorithms. A new definition for time-step is proposed to enable grid-independent convergence. Several examples of both reacting and non-reacting propulsion-related flowfields are considered. In all cases, convergence that is superior to conventional methods is demonstrated. Accuracy is verified using the example of a backward facing step. These results demonstrate that preconditioning can enhance the capability of density-based methods over a wide range of Mach and Reynolds numbers.

  18. Preconditioning electromyographic data for an upper extremity model using neural networks

    NASA Technical Reports Server (NTRS)

    Roberson, D. J.; Fernjallah, M.; Barr, R. E.; Gonzalez, R. V.

    1994-01-01

    A back propagation neural network has been employed to precondition the electromyographic signal (EMG) that drives a computational model of the human upper extremity. This model is used to determine the complex relationship between EMG and muscle activation, and generates an optimal muscle activation scheme that simulates the actual activation. While the experimental and model predicted results of the ballistic muscle movement are very similar, the activation function between the start and the finish is not. This neural network preconditions the signal in an attempt to more closely model the actual activation function over the entire course of the muscle movement.

  19. Preconditioning for the Navier-Stokes equations with finite-rate chemistry

    NASA Technical Reports Server (NTRS)

    Godfrey, Andrew G.

    1993-01-01

    The extension of Van Leer's preconditioning procedure to generalized finite-rate chemistry is discussed. Application to viscous flow is begun with the proper preconditioning matrix for the one-dimensional Navier-Stokes equations. Eigenvalue stiffness is resolved and convergence-rate acceleration is demonstrated over the entire Mach-number range from nearly stagnant flow to hypersonic. Specific benefits are realized at the low and transonic flow speeds typical of complete propulsion-system simulations. The extended preconditioning matrix necessarily accounts for both thermal and chemical nonequilibrium. Numerical analysis reveals the possible theoretical improvements from using a preconditioner for all Mach number regimes. Numerical results confirm the expectations from the numerical analysis. Representative test cases include flows with previously troublesome embedded high-condition-number areas. Van Leer, Lee, and Roe recently developed an optimal, analytic preconditioning technique to reduce eigenvalue stiffness over the full Mach-number range. By multiplying the flux-balance residual with the preconditioning matrix, the acoustic wave speeds are scaled so that all waves propagate at the same rate, an essential property to eliminate inherent eigenvalue stiffness. This session discusses a synthesis of the thermochemical nonequilibrium flux-splitting developed by Grossman and Cinnella and the characteristic wave preconditioning of Van Leer into a powerful tool for implicitly solving two and three-dimensional flows with generalized finite-rate chemistry. For finite-rate chemistry, the state vector of unknowns is variable in length. Therefore, the preconditioning matrix extended to generalized finite-rate chemistry must accommodate a flexible system of moving waves. Fortunately, no new kind of wave appears in the system. The only existing waves are entropy and vorticity waves, which move with the fluid, and acoustic waves, which propagate in Mach number dependent

  20. Platelet Rich Plasma Clot Releasate Preconditioning Induced PI3K/AKT/NFκB Signaling Enhances Survival and Regenerative Function of Rat Bone Marrow Mesenchymal Stem Cells in Hostile Microenvironments

    PubMed Central

    Peng, Yan; Huang, Sha; Wu, Yan; Nie, Xiaohu; Liu, Hongwei; Ma, Kui; Zhou, Jiping; Gao, Dongyun; Feng, Changjiang; Yang, Siming

    2013-01-01

    Mesenchymal stem cells (MSCs) have been optimal targets in the development of cell based therapies, but their limited availability and high death rate after transplantation remains a concern in clinical applications. This study describes novel effects of platelet rich clot releasate (PRCR) on rat bone marrow-derived MSCs (BM-MSCs), with the former driving a gene program, which can reduce apoptosis and promote the regenerative function of the latter in hostile microenvironments through enhancement of paracrine/autocrine factors. By using reverse transcription–polymerase chain reaction, immunofluorescence and western blot analyses, we showed that PRCR preconditioning could alleviate the apoptosis of BM-MSCs under stress conditions induced by hydrogen peroxide (H2O2) and serum deprivation by enhancing expression of vascular endothelial growth factor and platelet-derived growth factor (PDGF) via stimulation of the platelet-derived growth factor receptor (PDGFR)/PI3K/AKT/NF-κB signaling pathways. Furthermore, the effects of PRCR preconditioned GFP-BM-MSCs subcutaneously transplanted into rats 6 h after wound surgery were examined by histological and other tests from days 0–22 after transplantation. Engraftment of the PRCR preconditioned BM-MSCs not only significantly attenuated apoptosis and wound size but also improved epithelization and blood vessel regeneration of skin via regulation of the wound microenvironment. Thus, preconditioning with PRCR, which reprograms BM-MSCs to tolerate hostile microenvironments and enhance regenerative function by increasing levels of paracrine factors through PDGFR-α/PI3K/AKT/NF-κB signaling pathways would be a safe method for boosting the effectiveness of transplantation therapy in the clinic. PMID:23885779

  1. The noble gas xenon induces pharmacological preconditioning in the rat heart in vivo via induction of PKC-ɛ and p38 MAPK

    PubMed Central

    Weber, Nina C; Toma, Octavian; Wolter, Jessica I; Obal, Detlef; Müllenheim, Jost; Preckel, Benedikt; Schlack, Wolfgang

    2004-01-01

    Xenon is an anesthetic with minimal hemodynamic side effects, making it an ideal agent for cardiocompromised patients. We investigated if xenon induces pharmacological preconditioning (PC) of the rat heart and elucidated the underlying molecular mechanisms. For infarct size measurements, anesthetized rats were subjected to 25 min of coronary artery occlusion followed by 120 min of reperfusion. Rats received either the anesthetic gas xenon, the volatile anesthetic isoflurane or as positive control ischemic preconditioning (IPC) during three 5-min periods before 25-min ischemia. Control animals remained untreated for 45 min. To investigate the involvement of protein kinase C (PKC) and p38 mitogen-activated protein kinase (MAPK), rats were pretreated with the PKC inhibitor calphostin C (0.1 mg kg−1) or the p38 MAPK inhibitor SB203580 (1 mg kg−1). Additional hearts were excised for Western blot and immunohistochemistry. Infarct size was reduced from 50.9±16.7% in controls to 28.1±10.3% in xenon, 28.6±9.9% in isoflurane and to 28.5±5.4% in IPC hearts. Both, calphostin C and SB203580, abolished the observed cardioprotection after xenon and isoflurane administration but not after IPC. Immunofluorescence staining and Western blot assay revealed an increased phosphorylation and translocation of PKC-ɛ in xenon treated hearts. This effect could be blocked by calphostin C but not by SB203580. Moreover, the phosphorylation of p38 MAPK was induced by xenon and this effect was blocked by calphostin C. In summary, we demonstrate that xenon induces cardioprotection by PC and that activation of PKC-ɛ and its downstream target p38 MAPK are central molecular mechanisms involved. Thus, the results of the present study may contribute to elucidate the beneficial cardioprotective effects of this anesthetic gas. PMID:15644876

  2. Isoflurane Preconditioning Elicits Competent Endogenous Mechanisms of Protection from Oxidative Stress in Cardiomyocytes Derived from Human Embryonic Stem Cells

    PubMed Central

    Sepac, Ana; Sedlic, Filip; Si-Tayeb, Karim; Lough, John; Duncan, Stephen A.; Bienengraeber, Martin; Park, Frank; Kim, Jinhee; Bosnjak, Zeljko J.

    2010-01-01

    Background Human embryonic stem cell (hESC)-derived cardiomyocytes potentially represent a powerful experimental model complementary to myocardium obtained from patients, relatively inaccessible for research purposes. We tested whether anesthetic-induced preconditioning (APC) with isoflurane elicits competent protective mechanisms in hESC-derived cardiomyocytes against oxidative stress to be used as a model of human cardiomyocytes for studying preconditioning. Methods H1 hESC cell line was differentiated into cardiomyocytes using growth factors activin A and bone morphogenetic protein-4. Living ventricular hESC-derived cardiomyocytes were identified using lentiviral vector expressing a reporter gene (enhanced green fluorescent protein) driven by a cardiac-specific human myosin light chain 2v promoter. Mitochondrial membrane potential, reactive oxygen species production, opening of mitochondrial permeability transition pore, and survival of hESC-derived cardiomyocytes were assessed using confocal microscopy. Oxygen consumption was measured in contracting cell clusters. Results Differentiation yielded a high percentage (∼85%) of cardiomyocytes in beating clusters that were positive for cardiac-specific markers and exhibited action potentials resembling mature cardiomyocytes. Isoflurane depolarized mitochondria, attenuated oxygen consumption, and stimulated generation of reactive oxygen species. APC protected these cells from oxidative stress-induced death and delayed mitochondrial permeability transition pore opening. Conclusions APC elicits competent protective mechanisms against oxidative stress in hESC-derived cardiomyocytes, suggesting the feasibility to use these cells as a model of human cardiomyocytes for studying APC and potentially other treatments/diseases. Our differentiation protocol is very efficient and yields a high percentage of cardiomyocytes. These results also suggest a promising ability of APC to protect and improve engraftment of h

  3. Asiatic acid inhibits cardiac hypertrophy by blocking interleukin-1β-activated nuclear factor-κB signaling in vitro and in vivo

    PubMed Central

    Xu, Xiaohan; Si, Linjie; Xu, Jing; Yi, Chenlong; Wang, Fang; Gu, Weijuan

    2015-01-01

    Background Activated interleukin (IL)-1β signaling pathway is closely associated with pathological cardiac hypertrophy. This study investigated whether asiatic acid (AA) could inhibit IL-1β-related hypertrophic signaling, and thus suppressing the development of cardiac hypertrophy. Methods Transverse aortic constriction (TAC) induced cardiac hypertrophy in C57BL/6 mice and cultured neonatal cardiac myocytes stimulated with IL-1β were used to evaluate the role of AA in cardiac hypertrophy. The expression of atrial natriuretic peptide (ANP) was evaluated by quantitative polymerase chain reaction (qPCR) and the nuclear factor (NF)-κB binding activity was measured by electrophoretic mobility shift assays (EMSA). Results AA pretreatment significantly attenuated the IL-1β-induced hypertrophic response of cardiomyocytes as reflected by reduction in the cardiomyocyte surface area and the inhibition of ANP mRNA expression. The protective effect of AA on IL-1β-stimulated cardiomyocytes was associated with the reduction of NF-κB binding activity. In addition, AA prevented TAC-induced cardiac hypertrophy in vivo. It was found that AA markedly reduced the excessive expression of IL-1β and ANP, and inhibited the activation of NF-κB in the hypertrophic myocardium. Conclusions Our data suggest that AA may be a novel therapeutic agent for cardiac hypertrophy. The inhibition of IL-1β-activated NF-κB signaling may be the mechanism through which AA prevents cardiac hypertrophy. PMID:26623102

  4. The Hepatocyte Growth Factor/c-Met Antagonist, Divalinal-Angiotensin IV, Blocks the Acquisition of Methamphetamine Dependent Conditioned Place Preference in Rats

    PubMed Central

    Wright, John W.; Wilson, Wendy L.; Wakeling, Vanessa; Boydstun, Alan S.; Jensen, Audrey; Kawas, Leen; Harding, Joseph W.

    2012-01-01

    The use of methamphetamine (MA) is increasing in the U.S. and elsewhere around the world. MA’s capacity to cause addiction significantly exceeds other psychostimulant drugs, and its use negatively impacts learning and memory. Recently, attempts have been made to interfere with the presumed mechanism(s) underlying the establishment of drug-induced memory consolidation. The majority of these studies have employed matrix metalloproteinase (MMP) inhibitors to disrupt MMP-induced extracellular matrix molecule dependent synaptic reconfiguration, or GABA receptor agonists. The present investigation utilized an angiotensin IV (AngIV) analogue, Divalinal-AngIV (divalinal), to disrupt acquisition of MA-induced dependence in rats as measured using the conditioned place preference paradigm. Results indicate that both acute and chronic intracerebroventricular infusion of divalinal prior to each daily subcutaneous injection of MA prevented acquisition. However, divalinal was unable to prevent MA-induced reinstatement after prior acquisition followed by extinction trials. These results indicate that prevention of MA dependence can be accomplished by blockade of the brain AT4 receptor subtype. On the other hand, once MA-induced memory consolidation is in place divalinal appears to be ineffective. Mechanistic studies indicated that divalinal is a potent inhibitor of the hepatocyte growth factor (HGF)/c-Met receptor system, and thus it appears that a functional HGF/c-Met system is required for the acquisition of MA-mediated conditioned place preference. PMID:24961196

  5. Vaccination with a mutated variant of human Vascular Endothelial Growth Factor (VEGF) blocks VEGF-induced retinal neovascularization in a rabbit experimental model.

    PubMed

    Morera, Yanelys; González, Rafael; Lamdan, Humberto; Pérez, Lincidio; González, Yorlandis; Agüero, Judith; Castro, Jorge; Romero, Juan C; Etchegoyen, Ana Yansy; Ayala, Marta; Gavilondo, Jorge V

    2014-05-01

    Vascular Endothelial Growth Factor (VEGF) is a key driver of the neovascularization and vascular permeability that leads to the loss of visual acuity of eye diseases like wet age-related macular degeneration, diabetic macular edema, and retinopathy of premature. Among the several anti-VEGF therapies under investigation for the treatment of neovascular eye diseases, our group has developed the vaccine candidate CIGB-247-V that uses a mutated form of human VEGF as antigen. In this work we evaluated if the vaccine could prevent or attenuate VEGF-induced retinal neovascularization in the course of a rabbit eye neovascularization model, based on direct intravitreal injection of human VEGF. Our experimental findings have shown that anti-VEGF IgG antibodies induced by the vaccine were available in the retina blood circulation, and could neutralize in situ the neovascularization effect of VEGF. CIGB-247-V vaccination proved to effectively reduce retinal neovascularization caused by intravitreal VEGF injection. Altogether, these results open the way for human studies of the vaccine in neovascular eye syndromes, and inform on the potential mechanisms involved in its effect. PMID:24675387

  6. WARP3D-Release 10.8: Dynamic Nonlinear Analysis of Solids using a Preconditioned Conjugate Gradient Software Architecture

    NASA Technical Reports Server (NTRS)

    Koppenhoefer, Kyle C.; Gullerud, Arne S.; Ruggieri, Claudio; Dodds, Robert H., Jr.; Healy, Brian E.

    1998-01-01

    This report describes theoretical background material and commands necessary to use the WARP3D finite element code. WARP3D is under continuing development as a research code for the solution of very large-scale, 3-D solid models subjected to static and dynamic loads. Specific features in the code oriented toward the investigation of ductile fracture in metals include a robust finite strain formulation, a general J-integral computation facility (with inertia, face loading), an element extinction facility to model crack growth, nonlinear material models including viscoplastic effects, and the Gurson-Tver-gaard dilatant plasticity model for void growth. The nonlinear, dynamic equilibrium equations are solved using an incremental-iterative, implicit formulation with full Newton iterations to eliminate residual nodal forces. The history integration of the nonlinear equations of motion is accomplished with Newmarks Beta method. A central feature of WARP3D involves the use of a linear-preconditioned conjugate gradient (LPCG) solver implemented in an element-by-element format to replace a conventional direct linear equation solver. This software architecture dramatically reduces both the memory requirements and CPU time for very large, nonlinear solid models since formation of the assembled (dynamic) stiffness matrix is avoided. Analyses thus exhibit the numerical stability for large time (load) steps provided by the implicit formulation coupled with the low memory requirements characteristic of an explicit code. In addition to the much lower memory requirements of the LPCG solver, the CPU time required for solution of the linear equations during each Newton iteration is generally one-half or less of the CPU time required for a traditional direct solver. All other computational aspects of the code (element stiffnesses, element strains, stress updating, element internal forces) are implemented in the element-by- element, blocked architecture. This greatly improves

  7. Remote ischemic preconditioning confers late protection against myocardial ischemia-reperfusion injury in mice by upregulating interleukin-10

    PubMed Central

    Parajuli, Nirmal; Zheng, Xiaoxu; Becker, Lewis

    2013-01-01

    Remote ischemic preconditioning (RIPC) induces a prolonged late phase of multi-organ protection against ischemia-reperfusion (IR) injury. In the present study, we tested the hypothesis that RIPC confers late protection against myocardial IR injury by upregulating expression of interleukin (IL)-10. Mice were exposed to lower limb RIPC or sham ischemia. After 24 h, mice with RIPC demonstrated decreased myocardial infarct size and improved cardiac contractility following 30-min ischemia and 120-min reperfusion (I-30/R-120). These effects of RIPC were completely blocked by anti-IL-10 receptor antibodies. In IL-10 knockout mice, RIPC cardioprotection was lost, but it was mimicked by exogenous IL-10. Administration of IL-10 to isolated perfused hearts increased phosphory-lation of the protein kinase Akt and limited infarct size after I-30/R-120. In wild-type mice, RIPC increased plasma and cardiac IL-10 protein levels and caused activation of Akt and endothelial nitric oxide synthase in the heart at 24 h, which was also blocked by anti-IL-10 receptor antibodies. In the gastrocnemius muscle, RIPC resulted in immediate inactivation of the phosphatase PTEN and activation of Stat3, with increased IL-10 expression 24 h later. Myocyte-specific PTEN inactivation led to increased Stat3 phosphorylation and IL-10 protein expression in the gastrocnemius muscle. Taken together, these results suggest that RIPC induces late protection against myocardial IR injury by increasing expression of IL-10 in the remote muscle, followed by release of IL-10 into the circulation, and activation of protective signaling pathways in the heart. This study provides a scientific basis for the use of RIPC to confer systemic protection against IR injury. PMID:22752341

  8. High Relief Block Printing.

    ERIC Educational Resources Information Center

    Foster, Michael

    1989-01-01

    Explains a method of block printing using styrofoam shapes to make high relief. Describes the creation of the block design as well as the actual printing process. Uses a range of paper types for printing so children can see the results of using different media. (LS)

  9. Surviving Block Scheduling.

    ERIC Educational Resources Information Center

    Haley, Marjorie

    A discussion of block scheduling for second language instruction looks at the advantages and disadvantages and offers some suggestions for classroom management and course organization. It is argued that block scheduling may offer a potential solution to large classes, insufficient time for labs, too little individualized instruction; few…

  10. Block Scheduling Revisited.

    ERIC Educational Resources Information Center

    Queen, J. Allen

    2000-01-01

    Successful block scheduling depends on provision of initial and ongoing instructional training. Teaching strategies should vary and include cooperative learning, the case method, the socratic seminar, synectics, concept attainment, the inquiry method, and simulations. Recommendations for maximizing block scheduling are outlined. (Contains 52…

  11. Thermally actuated wedge block

    DOEpatents

    Queen, Jr., Charles C.

    1980-01-01

    This invention relates to an automatically-operating wedge block for maintaining intimate structural contact over wide temperature ranges, including cryogenic use. The wedging action depends on the relative thermal expansion of two materials having very different coefficients of thermal expansion. The wedge block expands in thickness when cooled to cryogenic temperatures and contracts in thickness when returned to room temperature.

  12. Research on the Changes to the Lipid/Polymer Membrane Used in the Acidic Bitterness Sensor Caused by Preconditioning

    PubMed Central

    Harada, Yuhei; Noda, Junpei; Yatabe, Rui; Ikezaki, Hidekazu; Toko, Kiyoshi

    2016-01-01

    A taste sensor that uses lipid/polymer membranes can evaluate aftertastes felt by humans using Change in membrane Potential caused by Adsorption (CPA) measurements. The sensor membrane for evaluating bitterness, which is caused by acidic bitter substances such as iso-alpha acid contained in beer, needs an immersion process in monosodium glutamate (MSG) solution, called “MSG preconditioning”. However, what happens to the lipid/polymer membrane during MSG preconditioning is not clear. Therefore, we carried out three experiments to investigate the changes in the lipid/polymer membrane caused by the MSG preconditioning, i.e., measurements of the taste sensor, measurements of the amount of the bitterness substance adsorbed onto the membrane and measurements of the contact angle of the membrane surface. The CPA values increased as the preconditioning process progressed, and became stable after 3 d of preconditioning. The response potentials to the reference solution showed the same tendency of the CPA value change during the preconditioning period. The contact angle of the lipid/polymer membrane surface decreased after 7 d of MSG preconditioning; in short, the surface of the lipid/polymer membrane became hydrophilic during MSG preconditioning. The amount of adsorbed iso-alpha acid was increased until 5 d preconditioning, and then it decreased. In this study, we revealed that the CPA values increased with the progress of MSG preconditioning in spite of the decrease of the amount of iso-alpha acid adsorbed onto the lipid/polymer membrane, and it was indicated that the CPA values increase because the sensor sensitivity was improved by the MSG preconditioning. PMID:26891299

  13. Remote ischaemic preconditioning does not alter perioperative cytokine production in high-risk cardiac surgery

    PubMed Central

    Williams, Jenni M; Young, Paul; Pilcher, Janine; Weatherall, Mark; Miller, John Holmes; Beasley, Richard; La Flamme, Anne Camille

    2012-01-01

    Rationale Remote ischaemic preconditioning (RIPC) is a novel cardioprotective strategy that uses brief intermittent limb ischaemia to protect the myocardium and other organs from perioperative ischaemic damage. The precise mechanism through which this protective effect occurs is unknown, but potentially could be related to changes in blood-borne mediators such as cytokines. Objective To determine whether RIPC alters inflammatory cytokine expression in a double-blind, randomised, controlled trial of patients undergoing high-risk cardiac surgery. Methods and results Serum interleukin (IL)-6, IL-8, and IL-10 levels from 95 patients randomised to RIPC (n=47) or control treatment (n=48) were measured preoperatively, and 1, 2, 3, 6 and 12 h after cross-clamp removal. Systemic concentrations of all cytokines were increased from baseline following surgery, and, compared with simple procedures, complex surgeries were associated with significantly higher release of IL-6 (ratio of mean area under the curves 1.54 (95% CI 1.02 to 2.34), p=0.04) and IL-10 (1.97 (1.16 to 3.35), p=0.012). No significant difference in mean cytokine levels between the RIPC and control groups was detected at any time point, irrespective of the type of surgery undergone. Conclusions High levels of IL-6, IL-8 and IL-10 are produced during high-risk cardiac surgery, and RIPC does not alter these elevated perioperative cytokine concentrations. Identification of factors that influence the ability to induce RIPC-mediated cardioprotection should be the priority of future research. Trial registration is in the Australian New Zealand Clinical Trials Registry (http://www.anzctr.org.au; ACTRN12609000965202)

  14. EFFECTS OF HELIUM PRECONDITIONING ON INTESTINAL ISCHEMIA AND REPERFUSION INJURY IN RATS.

    PubMed

    Du, Lei; Zhang, Rongjia; Luo, Tianhang; Nie, Mingming; Bi, Jianwei

    2015-10-01

    Intestinal ischemia-reperfusion (I/R) injury can occur in clinical settings such as organ transplantation, cardiopulmonary bypass and trauma. The noble gas helium attenuates I/R injury in a number of animal organs and thus may offer a strategy for reducing I/R-induced intestinal injury in clinical settings. In the present study, we used four different helium preconditioning (HPC) profiles to investigate the potential beneficial effect of HPC on I/R-induced intestinal injury. Male Sprague-Dawley rats were pretreated with three cycles of air breathing for 5 min combined with three cycles of breathing a 70% helium:30% oxygen mixture for either 2, 5, 10, or 15 min, after which they were subjected to 60-min intestinal ischemia and 60-min reperfusion. Sixty minutes after reperfusion, the intestinal tissues of the variously treated rats were analyzed using histology, immunohistochemistry, terminal dUTP nick-end labeling staining, myeloperoxidase activity assay, Western blotting, and enzyme-linked immunosorbent assay for tumor necrosis factor α and macrophage inflammatory protein 1α. Intestinal permeability was assayed by measuring fluorescein isothiocyanate-dextran release in blood samples. The results showed that the HPC profile consisting of three cycles of 10 or 15 min of helium breathing and three cycles of 5 min of air breathing reduced I/R-induced intestinal injury, cell apoptosis, and the inflammatory response. However, the 2- or 5-min helium breathing did not confer any protective effects. It seems that longer helium episodes should be used in HPC profiles designed to attenuate intestinal I/R injury. PMID:26052960

  15. Solar Ultraviolet Irradiation Reduces Collagen in Photoaged Human Skin by Blocking Transforming Growth Factor-β Type II Receptor/Smad Signaling

    PubMed Central

    Quan, Taihao; He, Tianyuan; Kang, Sewon; Voorhees, John J.; Fisher, Gary J.

    2004-01-01

    Ultraviolet (UV) irradiation from the sun reduces production of type I procollagen (COLI), the major structural protein in human skin. This reduction is a key feature of the pathophysiology of premature skin aging (photoaging). Photoaging is the most common form of skin damage and is associated with skin carcinoma. TGF-β/Smad pathway is the major regulator of type I procollagen synthesis in human skin. We have previously reported that UV irradiation impairs transforming growth factor-β (TGF-β)/Smad signaling in mink lung epithelial cells. We have investigated the mechanism of UV irradiation impairment of the TGF-β/Smad pathway and the impact of this impairment on type I procollagen production in human skin fibroblasts, the major collagen-producing cells in skin. We report here that UV irradiation impairs TGF-β/Smad pathway in human skin by down-regulation of TGF-β type II receptor (TβRII). This loss of TβRII occurs within 8 hours after UV irradiation and precedes down-regulation of type I procollagen expression in human skin in vivo. In human skin fibroblasts, UV-induced TβRII down-regulation is mediated by transcriptional repression and results in 90% reduction of specific, cell-surface binding of TGF-β. This loss of TβRII prevents downstream activation of Smad2/3 by TGF-β, thereby reducing expression of type I procollagen. Preventing loss of TβRII by overexpression protects against UV inhibition of type I procollagen gene expression in human skin fibroblasts. UV-induced down-regulation of TβRII, with attendant reduction of type I procollagen production, is a critical molecular mechanism in the pathophysiology of photoaging. PMID:15331399

  16. Approximate inverse preconditioning of iterative methods for nonsymmetric linear systems

    SciTech Connect

    Benzi, M.; Tuma, M.

    1996-12-31

    A method for computing an incomplete factorization of the inverse of a nonsymmetric matrix A is presented. The resulting factorized sparse approximate inverse is used as a preconditioner in the iterative solution of Ax = b by Krylov subspace methods.

  17. Gauge Blocks - A Zombie Technology.

    PubMed

    Doiron, Ted

    2008-01-01

    Gauge blocks have been the primary method for disseminating length traceability for over 100 years. Their longevity was based on two things: the relatively low cost of delivering very high accuracy to users, and the technical limitation that the range of high precision gauging systems was very small. While the first reason is still true, the second factor is being displaced by changes in measurement technology since the 1980s. New long range sensors do not require master gauges that are nearly the same length as the part being inspected, and thus one of the primary attributes of gauge blocks, wringing stacks to match the part, is no longer needed. Relaxing the requirement that gauges wring presents an opportunity to develop new types of end standards that would increase the accuracy and usefulness of gauging systems. PMID:27096119

  18. An anisotropic preconditioning for the Wilson fermion matrix on the lattice

    SciTech Connect

    Balint Joo, Robert G. Edwards, Michael J. Peardon

    2010-01-01

    A preconditioning for the Wilson fermion matrix on the lattice is defined which is particularly suited to the case when the temporal lattice spacing is much smaller than the spatial one. Details on the implementation of the scheme are given. The method is tested in numerical studies of QCD on anisotropic lattices.

  19. Cognitive Preconditions of Early Reading and Spelling: A Latent-Variable Approach with Longitudinal Data

    ERIC Educational Resources Information Center

    Preßler, Anna-Lena; Könen, Tanja; Hasselhorn, Marcus; Krajewski, Kristin

    2014-01-01

    The aim of the present study was to empirically disentangle the interdependencies of the impact of nonverbal intelligence, working memory capacities, and phonological processing skills on early reading decoding and spelling within a latent variable approach. In a sample of 127 children, these cognitive preconditions were assessed before the onset…

  20. 40 CFR 92.125 - Pre-test procedures and preconditioning.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... preconditioning. 92.125 Section 92.125 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) CONTROL OF AIR POLLUTION FROM LOCOMOTIVES AND LOCOMOTIVE ENGINES Test Procedures § 92... the temperature of intake air entering the engine after compression and cooling in the charge...

  1. An M-step preconditioned conjugate gradient method for parallel computation

    NASA Technical Reports Server (NTRS)

    Adams, L.

    1983-01-01

    This paper describes a preconditioned conjugate gradient method that can be effectively implemented on both vector machines and parallel arrays to solve sparse symmetric and positive definite systems of linear equations. The implementation on the CYBER 203/205 and on the Finite Element Machine is discussed and results obtained using the method on these machines are given.

  2. Preconditioning of heart by repeated stunning. Adaptive modification of antioxidative defense system.

    PubMed

    Das, D K; Prasad, M R; Lu, D; Jones, R M

    1992-11-01

    Previous studies demonstrated that preconditioning of a heart by repeated stunning can reduce the cellular injury to the heart from subsequent acute ischemic insult. To examine the possible biochemical mechanism for such myocardial preservation afforded by preconditioning, swine heart was subjected to four episodes of 5 min. stunning by occluding the left anterior descending coronary artery (LAD), followed by 10 min. of reperfusion after each stunning. Heart was then made regionally ischemic for 60 min. by LAD occlusion, followed by 6 hrs. reperfusion. Control heart was perfused for 60 min., followed by 60 min. ischemia and 6 hrs. reperfusion. The results of our studies indicated the stimulation of a number of antioxidative enzymes, including Mn-superoxide dismutase (Mn-SOD), catalase, glutathione peroxidase, and glutathione reductase, after repeated stunning and reperfusion. In addition, a number of new proteins were expressed after preconditioning the heart, including some oxidative-stress related proteins and 72 kDa heat-shock protein. These results suggest that preconditioning of a heart by repeated stunning may lead to strengthening of the oxidative defense system of the heart, which is likely to play a role in myocardial preservation during subsequent ischemic and reperfusion injury. PMID:1472901

  3. An indirect method to assess wrist ligament forces with particular regard to the effect of preconditioning.

    PubMed

    Savelberg, H H; Kooloos, J G; Huiskes, R; Kauer, J M

    1993-11-01

    A method has been developed to calculate the forces that are developed in the ligaments of a joint specimen during motions. This indirect method is needed since direct measurements fail in the case of small ligaments. As an example the small ligaments of the carpal joint are considered. The rationale of the method is that the force generated in a ligament depends on the amount of strain to which it is subjected and on its material characteristics. In the method presented the lengths of the ligaments are determined in vitro at several joint positions by means of röntgenstereophotogrammetry. The zero-force length and the force-elongation relationship are determined on the same ligaments isolated in a materials testing machine. Over a considerable part of the strain range the measurement errors are relatively small compared to the forces determined, less than 10%. The method is applicable to joints in situations where other measuring methods cannot be used. The present analysis shows, however, that the force values determined are susceptible to preconditioning of the ligaments. In preconditioned ligaments the forces could be up to 50% lower than in the non-preconditioned situation. This suggests that ligament forces may vary considerably in vivo, depending on the extent of preconditioning provoked by a particular function. PMID:8262996

  4. 40 CFR 85.2218 - Preconditioned idle test-EPA 91.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 18 2010-07-01 2010-07-01 false Preconditioned idle test-EPA 91. 85.2218 Section 85.2218 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) CONTROL OF AIR POLLUTION FROM MOBILE SOURCES Emission Control System Performance Warranty...

  5. 40 CFR 85.2219 - Idle test with loaded preconditioning-EPA 91.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 18 2010-07-01 2010-07-01 false Idle test with loaded preconditioning-EPA 91. 85.2219 Section 85.2219 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) CONTROL OF AIR POLLUTION FROM MOBILE SOURCES Emission Control...

  6. Analysis of Off-Board Powered Thermal Preconditioning in Electric Drive Vehicles: Preprint

    SciTech Connect

    Barnitt, R. A.; Brooker, A. D.; Ramroth, L.; Rugh , J.; Smith, K. A.

    2010-12-01

    Following a hot or cold thermal soak, vehicle climate control systems (air conditioning or heat) are required to quickly attain a cabin temperature comfortable to the vehicle occupants. In a plug-in hybrid electric or electric vehicle (PEV) equipped with electric climate control systems, the traction battery is the sole on-board power source. Depleting the battery for immediate climate control results in reduced charge-depleting (CD) range and additional battery wear. PEV cabin and battery thermal preconditioning using off-board power supplied by the grid or a building can mitigate the impacts of climate control. This analysis shows that climate control loads can reduce CD range up to 35%. However, cabin thermal preconditioning can increase CD range up to 19% when compared to no thermal preconditioning. In addition, this analysis shows that while battery capacity loss over time is driven by ambient temperature rather than climate control loads, concurrent battery thermal preconditioning can reduce capacity loss up to 7% by reducing pack temperature in a high ambient temperature scenario.

  7. On preconditioning techniques for dense linear systems arising from singular boundary integral equations

    SciTech Connect

    Chen, Ke

    1996-12-31

    We study various preconditioning techniques for the iterative solution of boundary integral equations, and aim to provide a theory for a class of sparse preconditioners. Two related ideas are explored here: singularity separation and inverse approximation. Our preliminary conclusion is that singularity separation based preconditioners perform better than approximate inverse based while it is desirable to have both features.

  8. Noise suppression using preconditioned least-squares prestack time migration: application to the Mississippian limestone

    NASA Astrophysics Data System (ADS)

    Guo, Shiguang; Zhang, Bo; Wang, Qing; Cabrales-Vargas, Alejandro; Marfurt, Kurt J.

    2016-08-01

    Conventional Kirchhoff migration often suffers from artifacts such as aliasing and acquisition footprint, which come from sub-optimal seismic acquisition. The footprint can mask faults and fractures, while aliased noise can focus into false coherent events which affect interpretation and contaminate amplitude variation with offset, amplitude variation with azimuth and elastic inversion. Preconditioned least-squares migration minimizes these artifacts. We implement least-squares migration by minimizing the difference between the original data and the modeled demigrated data using an iterative conjugate gradient scheme. Unpreconditioned least-squares migration better estimates the subsurface amplitude, but does not suppress aliasing. In this work, we precondition the results by applying a 3D prestack structure-oriented LUM (lower–upper–middle) filter to each common offset and common azimuth gather at each iteration. The preconditioning algorithm not only suppresses aliasing of both signal and noise, but also improves the convergence rate. We apply the new preconditioned least-squares migration to the Marmousi model and demonstrate how it can improve the seismic image compared with conventional migration, and then apply it to one survey acquired over a new resource play in the Mid-Continent, USA. The acquisition footprint from the targets is attenuated and the signal to noise ratio is enhanced. To demonstrate the impact on interpretation, we generate a suite of seismic attributes to image the Mississippian limestone, and show that the karst-enhanced fractures in the Mississippian limestone can be better illuminated.

  9. Ischemic preconditioning and inflammatory response syndrome after reperfusion injury: an experimental model in diabetic rats.

    PubMed

    Grigorescu, Bianca Liana; Georgescu, Anca Meda; Cioc, Adrian-Dan; Fodor, Raluca-Ştefania; Cotoi, Ovidiu Simion; Fodor, Pal; Copotoiu, Sanda Maria; Azamfirei, Leonard

    2015-01-01

    Quantification of local ischemia and inflammatory response syndrome correlated with histological changes associated with ischemia-reperfusion injury (IRI) after revascularization techniques. We included 12 adult male Wistar rats, aged eight weeks that were randomly divided into two groups. The first group acted as the control and at the second group, we induced diabetes by intraperitoneal streptozotocin administration (60 mg/kg). After eight weeks, the rats were subject to ischemic preconditioning for 10 minutes at three regular intervals. Twenty-four hours post-preconditioning, both groups were subject to ischemia for 20 minutes, followed by 30 minutes of reperfusion. Oxygen extraction was higher in Group 1, the arterio-venous CO2 gradient was higher in the control group, but not significant. The lactate production was higher in Group 1. The second group had a higher Na+ and also a significant difference in K+ values. Receptor for Advanced Glycation End (RAGE) values were higher in the second group but with no significant difference (RAGE1=0.32 ng/mL versus RAGE2=0.40 ng/mL). The muscle samples from the control group displayed significant rhabdomyolysis, damage to the nucleus, while the preconditioned group showed almost normal morphological characteristics. The lungs and kidneys were most damaged in the control group, with damage expressed as thickened alveolar septa, neutrophil infiltrates, eosinophilic precipitates in the proximal convolute tubule. Ischemic preconditioning significantly attenuates the ischemic reperfusion injury. PMID:26743274

  10. Progress Toward a Stabilization and Preconditioning Protocol for Polycrystalline Thin-Film Photovoltaic Modules

    SciTech Connect

    del Cueto, J. A.; Deline, C. A.; Rummel, S. R.; Anderberg, A.

    2010-08-01

    Cadmium telluride (CdTe) and copper indium gallium diselenide (CIGS) thin-film photovoltaic (PV) modules can exhibit substantial variation in measured performance depending on prior exposure history. This study examines the metastable performance changes in these PV modules with the goal of establishing standard preconditioning or stabilization exposure procedures to mitigate measured variations prior to current-voltage (IV) measurements.

  11. 40 CFR 86.153-98 - Vehicle and canister preconditioning; refueling test.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 18 2010-07-01 2010-07-01 false Vehicle and canister preconditioning; refueling test. 86.153-98 Section 86.153-98 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) CONTROL OF EMISSIONS FROM NEW AND IN-USE HIGHWAY VEHICLES AND ENGINES Emission Regulations for 1977 and...

  12. Professors' and Trainees' Perceptions of Educational Quality as Related to Preconditions of Deep Learning in "Musikdidaktik"

    ERIC Educational Resources Information Center

    Ferm, Cecilia; Johansen, Geir

    2008-01-01

    Interview-based case studies, involving two institutions, four professors and 11 music teacher trainees were conducted in order to investigate the preconditions for deep learning in the subject of higher music education called "musikdidaktik". Analysis was based on the "didaktiktriangle" which is a theoretical model that…

  13. Preconditioned iterative methods for nonselfadjoint or indefinite elliptic boundary value problems

    SciTech Connect

    Bramble, J.H.; Pasciak, J.E.

    1984-01-01

    We consider a Galerkin-Finite Element approximation to a general linear elliptic boundary value problem which may be nonselfadjoint or indefinite. We show how to precondition the equations so that the resulting systems of linear algebraic equations lead to iteration procedures whose iterative convergence rates are independent of the number of unknowns in the solution.

  14. The osteoregenerative effects of platelet-derived growth factor BB cotransplanted with mesenchymal stem cells, loaded on freeze-dried mineral bone block: a pilot study in dog mandible.

    PubMed

    Khojasteh, Arash; Dashti, Seyedeh Ghazaleh; Dehghan, Mohammad Mehdi; Behnia, Hossein; Abbasnia, Pegah; Morad, Golnaz

    2014-11-01

    Due to shortcomings associated with autogenous bone graft, the gold standard of craniofacial grafting, investigators seek alternatives that are accessible, efficient, and affordable. Accordingly, in the present pilot study, bone regeneration was induced using bone marrow-derived mesenchymal stem cells (BMSCs) loaded onto freeze-dried mineral bone block (FDMBB) in the presence or absence of recombinant platelet-derived growth factor-BB (rh PDGF-BB). Eight weeks after the bilateral extraction of premolars of four mongrel dogs, 25 × 10 mm defects were created at both sides of the mandible. The right mandible received autogenous-BMSC loaded on FDMBB (MSC group), whereas the left mandible received cellular blocks impregnated with rhPDGF-BB (MSC + PDGF Group). Animals were euthanized 8 weeks after grafting. Micro-computed tomography (micro-CT) and histomorphometric analysis demonstrated higher levels of bone formation for the test group (10.34% ± 0.20 and 26.63% ± 3.14, respectively) when compared to the control group (8.20% ± 0.20 and 21.38% ± 5.11). The differences were not statistically significant (P > 0.05). According to the performed micro-CT and histomorphometric analysis, adding 0.5 mg rhPDGF-BB (0.3 mg/mL) to the combination of BMSC/FDMBB did not significantly increase bone formation in supracrestal defect in dog mandible. PMID:24706585

  15. Light extraction block with curved surface

    DOEpatents

    Levermore, Peter; Krall, Emory; Silvernail, Jeffrey; Rajan, Kamala; Brown, Julia J.

    2016-03-22

    Light extraction blocks, and OLED lighting panels using light extraction blocks, are described, in which the light extraction blocks include various curved shapes that provide improved light extraction properties compared to parallel emissive surface, and a thinner form factor and better light extraction than a hemisphere. Lighting systems described herein may include a light source with an OLED panel. A light extraction block with a three-dimensional light emitting surface may be optically coupled to the light source. The three-dimensional light emitting surface of the block may includes a substantially curved surface, with further characteristics related to the curvature of the surface at given points. A first radius of curvature corresponding to a maximum principal curvature k.sub.1 at a point p on the substantially curved surface may be greater than a maximum height of the light extraction block. A maximum height of the light extraction block may be less than 50% of a maximum width of the light extraction block. Surfaces with cross sections made up of line segments and inflection points may also be fit to approximated curves for calculating the radius of curvature.

  16. Effects of ischemic preconditioning in a pig model of large-for-size liver transplantation

    PubMed Central

    Leal, Antonio José Gonçalves; Tannuri, Ana Cristina Aoun; Belon, Alessandro Rodrigo; Guimarães, Raimundo Renato Nunes; Coelho, Maria Cecília Mendonça; de Oliveira Gonçalves, Josiane; Serafini, Suellen; de Melo, Evandro Sobroza; Tannuri, Uenis

    2015-01-01

    OBJECTIVE: In most cases of pediatric liver transplantation, the clinical scenario of large-for-size transplants can lead to hepatic dysfunction and a decreased blood supply to the liver graft. The objective of the present experimental investigation was to evaluate the effects of ischemic preconditioning on this clinical entity. METHODS: Eighteen pigs were divided into three groups and underwent liver transplantation: a control group, in which the weights of the donors were similar to those of the recipients, a large-for-size group, and a large-for-size + ischemic preconditioning group. Blood samples were collected from the recipients to evaluate the pH and the sodium, potassium, aspartate aminotransferase and alanine aminotransferase levels. In addition, hepatic tissue was sampled from the recipients for histological evaluation, immunohistochemical analyses to detect hepatocyte apoptosis and proliferation and molecular analyses to evaluate the gene expression of Bax (pro-apoptotic), Bcl-XL (anti-apoptotic), c-Fos and c-Jun (immediate-early genes), ischemia-reperfusion-related inflammatory cytokines (IL-1, TNF-alpha and IL-6, which is also a stimulator of hepatocyte regeneration), intracellular adhesion molecule, endothelial nitric oxide synthase (a mediator of the protective effect of ischemic preconditioning) and TGF-beta (a pro-fibrogenic cytokine). RESULTS: All animals developed acidosis. At 1 hour and 3 hours after reperfusion, the animals in the large-for-size and large-for-size + ischemic preconditioning groups had decreased serum levels of Na and increased serum levels of K and aspartate aminotransferase compared with the control group. The molecular analysis revealed higher expression of the Bax, TNF-alpha, I-CAM and TGF-beta genes in the large-for-size group compared with the control and large-for-size + ischemic preconditioning groups. Ischemic preconditioning was responsible for an increase in c-Fos, IL-1, IL-6 and e-NOS gene expression. CONCLUSION

  17. Block data distribution for parallel nested dissection

    SciTech Connect

    Charrier, P.; Facq, L.; Roman, J.

    1995-12-01

    In this paper, we consider the problem of data partitioning for block sparse Cholesky factorization on distributed memory MIMD computers. We propose a preprocessing algorithm which computes and distributes a column block partition based on an initial partition induced by a nested dissection ordering. This preprocessing algorithm works by optimizing load balancing under precedence constraints and communication traffic. It can be performed in linear time and space complexities.

  18. Ischemic preconditioning attenuates functional, metabolic, and morphologic injury from ischemic acute renal failure in the rat.

    PubMed

    Cochrane, J; Williams, B T; Banerjee, A; Harken, A H; Burke, T J; Cairns, C B; Shapiro, J I

    1999-03-01

    Ischemic preconditioning has been shown to ameliorate injury due to subsequent ischemia in several organs. However, relatively little is known about preconditioning and the kidney. To address this, rats were randomized to control (C, N = 14), 2 min of ischemic preconditioning (P2 N = 10), 3 periods of 2 min of ischemia separated by 5 min periods of reflow (P2,3 N = 7), or three 5 min periods of ischemia separated by 5 min of reflow (P5,3 N = 6) prior to 45 min of bilateral renal ischemia followed by 24 hours of reperfusion. We observed a lower serum creatinine after 24 hours of reflow in P2, P2, 3 but not P5, 3 rats compared with C. Histology was examined in the C and P2, 3 groups and demonstrated less severe injury in the P2, 3 group. To gain insight into the mechanism by which preconditioning ameliorated ischemic injury, we performed near IR spectroscopy and 31P NMR spectroscopy. Based on near IR spectroscopy, the P2, 3 group had closer coupling of cytochrome aa3 redox state with that of hemoglobin during reflow. In the 31P NMR studies, the changes in ATP and pHi were similar during ischemia, but the P2, 3 group recovered ATP and pHi faster than C. These data suggest that ischemic preconditioning may ameliorate ischemic renal injury as assessed by functional, metabolic and morphological methods. The mechanism(s) by which this occurs requires additional study. PMID:10088174

  19. Effects of Bordetella pertussis toxin pretreatment on the antiarrhythmic action of ischaemic preconditioning in anaesthetized rats.

    PubMed Central

    Piacentini, L; Wainwright, C L; Parratt, J R

    1995-01-01

    1. Bordetella pertussis toxin, which catalyses the ADP-ribosylation of certain guanine nucleotide binding proteins (G proteins), thus functionally uncoupling them from associated receptors, was examined to determine whether it modified the antiarrhythmic effect of ischaemic preconditioning in anaesthetized rats. 2. Pertussis toxin (25 micrograms kg-1, i.p., 48 h prior to heart isolation) attenuated the negative chronotropic effect of acetylcholine (ACh) in rat isolated Langendorff perfused hearts. ACh (10 microM) reduced heart rate by 4% in hearts taken from pertussis toxin-treated animals, compared to a reduction of 57% in hearts taken from animals treated only with vehicle. 3. In anaesthetized rats, ischaemic preconditioning (a single 3 min occlusion of the left main coronary artery followed by 10 min reperfusion) had a pronounced antiarrhythmic effect during a subsequent 30 min period of regional myocardial ischaemia. Compared to hearts receiving only a 30 min period of left coronary occlusion, there was a reduced mortality (67% and 0% for control and preconditioned groups, respectively; P < 0.01) and decreased incidences of ventricular tachycardia (VT) and ventricular fibrillation (VF). Pretreatment with pertussis toxin (25 micrograms kg-1, i.p., 48 h previously) did not modify the arrhythmias associated with a 30 min period of regional myocardial ischaemia, neither did it modify the reduction in mortality (from 56% to 0%; P < 0.05) associated with preconditioning. Furthermore, the decrease in total ventricular premature beat count induced by preconditioning seen in controls (from 427 +/- 130 to 95 +/- 45) was also seen in pertussis toxin-treated rats (from 252 +/- 190 to 57 +/- 25).(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7773535

  20. Cell block eleven (left) and cell block fifteen, looking from ...

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

    Cell block eleven (left) and cell block fifteen, looking from cell block two into the "Death Row" exercise yard - Eastern State Penitentiary, 2125 Fairmount Avenue, Philadelphia, Philadelphia County, PA

  1. View of cell block eight (left), cell block seven, and ...

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

    View of cell block eight (left), cell block seven, and southwest guard tower, looking from cell block eight roof - Eastern State Penitentiary, 2125 Fairmount Avenue, Philadelphia, Philadelphia County, PA

  2. Blocked tear duct

    MedlinePlus

    ... your baby may have an eye infection called conjunctivitis . ... increase the chance of other infections, such as conjunctivitis. ... be prevented. Proper treatment of nasal infections and conjunctivitis may reduce the risk of having a blocked ...

  3. RX for Writer's Block.

    ERIC Educational Resources Information Center

    Tompkins, Gail E.; Camp, Donna J.

    1988-01-01

    Describes four prewriting techniques that elementary and middle grade students can use to gather and organize ideas for writing, and by so doing, cure writer's block. Techniques discussed are: (1) brainstorming; (2) clustering; (3) freewriting; and (4) cubing.

  4. Superalloy Lattice Block Structures

    NASA Technical Reports Server (NTRS)

    Nathal, M. V.; Whittenberger, J. D.; Hebsur, M. G.; Kantzos, P. T.; Krause, D. L.

    2004-01-01

    Initial investigations of investment cast superalloy lattice block suggest that this technology will yield a low cost approach to utilize the high temperature strength and environmental resistance of superalloys in lightweight, damage tolerant structural configurations. Work to date has demonstrated that relatively large superalloy lattice block panels can be successfully investment cast from both IN-718 and Mar-M247. These castings exhibited mechanical properties consistent with the strength of the same superalloys measured from more conventional castings. The lattice block structure also accommodates significant deformation without failure, and is defect tolerant in fatigue. The potential of lattice block structures opens new opportunities for the use of superalloys in future generations of aircraft applications that demand strength and environmental resistance at elevated temperatures along with low weight.

  5. Block copolymer battery separator

    DOEpatents

    Wong, David; Balsara, Nitash Pervez

    2016-04-26

    The invention herein described is the use of a block copolymer/homopolymer blend for creating nanoporous materials for transport applications. Specifically, this is demonstrated by using the block copolymer poly(styrene-block-ethylene-block-styrene) (SES) and blending it with homopolymer polystyrene (PS). After blending the polymers, a film is cast, and the film is submerged in tetrahydrofuran, which removes the PS. This creates a nanoporous polymer film, whereby the holes are lined with PS. Control of morphology of the system is achieved by manipulating the amount of PS added and the relative size of the PS added. The porous nature of these films was demonstrated by measuring the ionic conductivity in a traditional battery electrolyte, 1M LiPF.sub.6 in EC/DEC (1:1 v/v) using AC impedance spectroscopy and comparing these results to commercially available battery separators.

  6. Use of the preconditioned conjugate gradient algorithm as a generic solver for mixed-model equations in animal breeding applications.

    PubMed

    Tsuruta, S; Misztal, I; Strandén, I

    2001-05-01

    Utility of the preconditioned conjugate gradient algorithm with a diagonal preconditioner for solving mixed-model equations in animal breeding applications was evaluated with 16 test problems. The problems included single- and multiple-trait analyses, with data on beef, dairy, and swine ranging from small examples to national data sets. Multiple-trait models considered low and high genetic correlations. Convergence was based on relative differences between left- and right-hand sides. The ordering of equations was fixed effects followed by random effects, with no special ordering within random effects. The preconditioned conjugate gradient program implemented with double precision converged for all models. However, when implemented in single precision, the preconditioned conjugate gradient algorithm did not converge for seven large models. The preconditioned conjugate gradient and successive overrelaxation algorithms were subsequently compared for 13 of the test problems. The preconditioned conjugate gradient algorithm was easy to implement with the iteration on data for general models. However, successive overrelaxation requires specific programming for each set of models. On average, the preconditioned conjugate gradient algorithm converged in three times fewer rounds of iteration than successive overrelaxation. With straightforward implementations, programs using the preconditioned conjugate gradient algorithm may be two or more times faster than those using successive overrelaxation. However, programs using the preconditioned conjugate gradient algorithm would use more memory than would comparable implementations using successive overrelaxation. Extensive optimization of either algorithm can influence rankings. The preconditioned conjugate gradient implemented with iteration on data, a diagonal preconditioner, and in double precision may be the algorithm of choice for solving mixed-model equations when sufficient memory is available and ease of implementation is

  7. Nrf2 activation in astrocytes contributes to spinal cord ischemic tolerance induced by hyperbaric oxygen preconditioning.

    PubMed

    Xu, Jiajun; Huang, Guoyang; Zhang, Kun; Sun, Jinchuan; Xu, Tao; Li, Runping; Tao, Hengyi; Xu, Weigang

    2014-08-01

    In this study, we investigated whether nuclear factor erythroid 2-related factor 2 (Nrf2) activation in astrocytes contributes to the neuroprotection induced by a single hyperbaric oxygen preconditioning (HBO-PC) against spinal cord ischemia/reperfusion (SCIR) injury. In vivo: At 24 h after a single HBO-PC at 2.5 atmospheres absolute for 90 min, the male ICR mice underwent SCIR injury by aortic cross-clamping surgery and observed for 48 h. HBO-PC significantly improved hindlimb motor function, reduced secondary spinal cord edema, ameliorated the reactivity of spinal motor-evoked potentials, and slowed down the process of apoptosis to exert neuroprotective effects against SCIR injury. At 12 h or 24 h after HBO-PC without aortic cross-clamping surgery, Western blot, enzyme-linked immunosorbent assay, realtime-polymerase chain reaction and double-immunofluorescence staining were used to detect the Nrf2 activity of spinal cord tissue, such as mRNA level, protein content, DNA binding activity, and the expression of downstream gene, such as glutamate-cysteine ligase, γ-glutamyltransferase, multidrug resistance protein 1, which are key proteins for intracellular glutathione synthesis and transit. The Nrf2 activity and downstream genes expression were all enhanced in normal spinal cord with HBO-PC. Glutathione content of spinal cord tissue with HBO-PC significantly increased at all time points after SCIR injury. Moreover, Nrf2 overexpression mainly occurs in astrocytes. In vitro: At 24 h after HBO-PC, the primary spinal astrocyte-neuron co-cultures from ICR mouse pups were subjected to oxygen-glucose deprivation (OGD) for 90 min to simulate the ischemia-reperfusion injury. HBO-PC significantly increased the survival rate of neurons and the glutathione content in culture medium, which was mainly released from asctrocytes. Moreover, the Nrf2 activity and downstream genes expression induced by HBO-PC were mainly enhanced in astrocytes, but not in neurons. In

  8. The Treponema denticola FhbB Protein Is a Dominant Early Antigen That Elicits FhbB Variant-Specific Antibodies That Block Factor H Binding and Cleavage by Dentilisin.

    PubMed

    Miller, Daniel P; Oliver, Lee D; Tegels, Brittney K; Reed, Lucas A; O'Bier, Nathaniel S; Kurniyati, Kurni; Faust, Lindsay A; Lawson, Christine K; Allard, Anna M; Caimano, Melissa J; Marconi, Richard T

    2016-07-01

    The Treponema denticola FhbB protein contributes to immune evasion by binding factor H (FH). Cleavage of FH by the T. denticola protease, dentilisin, may contribute to the local immune dysregulation that is characteristic of periodontal disease (PD). Although three FhbB phyletic types have been defined (FhbB1, FhbB2, and FhbB3), the in vivo expression patterns and antigenic heterogeneity of FhbB have not been assessed. Here, we demonstrate that FhbB is a dominant early antigen that elicits FhbB type-specific antibody (Ab) responses. Using the murine skin abscess model, we demonstrate that the presence or absence of FhbB or dentilisin significantly influences Ab responses to infection and skin abscess formation. Competitive binding analyses revealed that α-FhbB Ab can compete with FH for binding to T. denticola and block dentilisin-mediated FH cleavage. Lastly, we demonstrate that dentilisin cleavage sites reside within critical functional domains of FH, including the complement regulatory domain formed by CCPs 1 to 4. Analysis of the FH cleavage products revealed that they lack cofactor activity. The data presented here provide insight into the in vivo significance of dentilisin, FhbB and its antigenic diversity, and the potential impact of FH cleavage on the regulation of complement activation. PMID:27113359

  9. The MADS-Domain Factors AGAMOUS-LIKE15 and AGAMOUS-LIKE18, along with SHORT VEGETATIVE PHASE and AGAMOUS-LIKE24, Are Necessary to Block Floral Gene Expression during the Vegetative Phase.

    PubMed

    Fernandez, Donna E; Wang, Chieh-Ting; Zheng, Yumei; Adamczyk, Benjamin J; Singhal, Rajneesh; Hall, Pamela K; Perry, Sharyn E

    2014-06-19

    Multiple factors, including the MADS-domain proteins AGAMOUS-LIKE15 (AGL15) and AGL18, contribute to the regulation of the transition from vegetative to reproductive growth. AGL15 and AGL18 were previously shown to act redundantly as floral repressors and upstream of FLOWERING LOCUS T (FT) in Arabidopsis (Arabidopsis thaliana). A series of genetic and molecular experiments, primarily focused on AGL15, was performed to more clearly define their role. agl15 agl18 mutations fail to suppress ft mutations but show additive interactions with short vegetative phase (svp) mutations in ft and suppressor of constans1 (soc1) backgrounds. Chromatin immunoprecipitation analyses with AGL15-specific antibodies indicate that AGL15 binds directly to the FT locus at sites that partially overlap those bound by SVP and FLOWERING LOCUS C. In addition, expression of AGL15 in the phloem effectively restores wild-type flowering times in agl15 agl18 mutants. When agl15 agl18 mutations are combined with agl24 svp mutations, the plants show upward curling of rosette and cauline leaves, in addition to early flowering. The change in leaf morphology is associated with elevated levels of FT and ectopic expression of SEPALLATA3 (SEP3), leading to ectopic expression of floral genes. Leaf curling is suppressed by sep3 and ft mutations and enhanced by soc1 mutations. Thus, AGL15 and AGL18, along with SVP and AGL24, are necessary to block initiation of floral programs in vegetative organs. PMID:24948837

  10. Impression block with orientator

    NASA Astrophysics Data System (ADS)

    Brilin, V. I.; Ulyanova, O. S.

    2015-02-01

    Tool review, namely the impression block, applied to check the shape and size of the top of fish as well as to determine the appropriate tool for fishing operation was realized. For multiple application and obtaining of the impress depth of 3 cm and more, the standard volumetric impression blocks with fix rods are used. However, the registered impress of fish is not oriented in space and the rods during fishing are in the extended position. This leads to rods deformation and sinking due to accidental impacts of impression block over the borehole irregularity and finally results in faulty detection of the top end of fishing object in hole. The impression blocks with copy rods and fixed magnetic needle allow estimating the object configuration and fix the position of magnetic needle determining the position of the top end of object in hole. However, the magnetic needle fixation is realized in staged and the rods are in extended position during fishing operations as well as it is in standard design. The most efficient tool is the impression block with copy rods which directs the examined object in the borehole during readings of magnetic needles data from azimuth plate and averaging of readings. This significantly increases the accuracy of fishing toll direction. The rods during fishing are located in the body and extended only when they reach the top of fishing object.

  11. Displacement decomposition ACO based preconditioning of FEM elasticity systems

    NASA Astrophysics Data System (ADS)

    Sviercoski, R. F.; Margenov, S.

    2013-10-01

    Computational simulations of multiscale deformable porous media are routinely encountered as a part of research and development activities in a number of engineering, environmental and biomedical fields. The efficiency of multilevel iterative solution of such problems is a challenging topic on numerical methods for large-scale scientific computing, this is because predicting the mechanical behavior of such systems with hierarchical structures with multiple scales is very computationally demanding. Our main interest application concerns medium that has complex hierarchical morphology in the sense that features ranges from nanometer to millimeter scales. The goal of this work is to propose a computationally efficient numerical tool that can be used to perform everyday predictive simulations as an integral part of osteoporosis treatment, for example. To achieve that, highly heterogeneous media are considered that resembles trabecular bone tissues. The related fine-scale linear elasticity problem is of high contrast and high frequency. The finite element method (FEM) is applied for discretization of the related linear elasticity problem, using separable displacement decomposition. The new feature in this work is that at coarser levels, a block diagonal preconditioner is applied that incorporates an analytical effective tensor into the simulation, avoiding costly numerical solutions of local problems that are inherent in methods for multiscale problems. The robustness of the new proposed algorithm is measured by comparing the number of V-cycles necessary to resolve the considered multiscale problems with other well known techniques.

  12. Role of nitric oxide in the mechanism of preclamping and remote ischemic preconditioning of adipocutaneous flaps in a rat model.

    PubMed

    Küntscher, Markus V; Juran, Sebastian; Altmann, Jens; Menke, Henrik; Gebhard, Martha Maria; Germann, Günter

    2003-01-01

    IP since the administration of an NO-donor previous to ischemia simulates the effect of IP, while the unspecific blocking of NO synthesis by L-NAME eliminates the protective effect of flap preconditioning by preclamping as well as by remote IP. Exogenous NO application is insufficient to provide protection once the endogenous NO synthesis is blocked. PMID:12582969

  13. S{sub 2}SA preconditioning for the S{sub n} equations with strictly non negative spatial discretization

    SciTech Connect

    Bruss, D. E.; Morel, J. E.; Ragusa, J. C.

    2013-07-01

    Preconditioners based upon sweeps and diffusion-synthetic acceleration have been constructed and applied to the zeroth and first spatial moments of the 1-D S{sub n} transport equation using a strictly non negative nonlinear spatial closure. Linear and nonlinear preconditioners have been analyzed. The effectiveness of various combinations of these preconditioners are compared. In one dimension, nonlinear sweep preconditioning is shown to be superior to linear sweep preconditioning, and DSA preconditioning using nonlinear sweeps in conjunction with a linear diffusion equation is found to be essentially equivalent to nonlinear sweeps in conjunction with a nonlinear diffusion equation. The ability to use a linear diffusion equation has important implications for preconditioning the S{sub n} equations with a strictly non negative spatial discretization in multiple dimensions. (authors)

  14. PRECONDITIONED CONJUGATE-GRADIENT 2 (PCG2), a computer program for solving ground-water flow equations

    USGS Publications Warehouse

    Hill, Mary C.

    1990-01-01

    This report documents PCG2 : a numerical code to be used with the U.S. Geological Survey modular three-dimensional, finite-difference, ground-water flow model . PCG2 uses the preconditioned conjugate-gradient method to solve the equations produced by the model for hydraulic head. Linear or nonlinear flow conditions may be simulated. PCG2 includes two reconditioning options : modified incomplete Cholesky preconditioning, which is efficient on scalar computers; and polynomial preconditioning, which requires less computer storage and, with modifications that depend on the computer used, is most efficient on vector computers . Convergence of the solver is determined using both head-change and residual criteria. Nonlinear problems are solved using Picard iterations. This documentation provides a description of the preconditioned conjugate gradient method and the two preconditioners, detailed instructions for linking PCG2 to the modular model, sample data inputs, a brief description of PCG2, and a FORTRAN listing.

  15. The effect of transient proanthocyanidins preconditioning on the cross-linking and mechanical properties of demineralized dentin.

    PubMed

    Liu, Ruirui; Fang, Ming; Xiao, Yuhong; Li, Fang; Yu, Lan; Zhao, Sanjun; Shen, Lijuan; Chen, Jihua

    2011-11-01

    Proanthocyanidin-based preconditioners were prepared by adding powdered proanthocyanidins-rich grape seed extract to various solvents at different concentrations. Demineralized dentin specimens were preconditioned for 20, 30, 60 or 120 s, followed by the evaluation of their cross-linking degree, mechanical properties and micromorphology. The cross-linking degree of the demineralized dentin collagen exhibited concentration- and time- dependent increase after preconditioning treatment, irrespective of the preconditioner and the solvent. When treated for the same exposure time, specimens after 15% proanthocyanidins preconditioning resulted in the highest mean ultimate tensile strength compared with all the other groups tested. Five percent glutaraldehyde control group produced the highest cross-linking degree, but the ultimate tensile strength was lower than that of 15% proanthocyanidins group. The field emission scanning electron microscopy confirmed that the demineralized dentin collagen was in a homogeneous and regular arrangement after preconditioning and maintained expanding, regardless of the surface moisture conditions. PMID:21979164

  16. Submarine landslides offshore Vancouver Island along the northern Cascadia margin, British Columbia: why preconditioning is likely required to trigger slope failure

    NASA Astrophysics Data System (ADS)

    Scholz, Nastasja A.; Riedel, Michael; Urlaub, Morelia; Spence, George D.; Hyndman, Roy D.

    2016-05-01

    Bathymetric data reveal abundant submarine landslides along the deformation front of the northern Cascadia margin that might have significant tsunami potential. Radiocarbon age dating showed that slope failures are early to mid-Holocene. The aim of this study is the analysis of slope stability to investigate possible trigger mechanisms using the factor of safety analysis technique on two prominent frontal ridges. First-order values for the earthquake shaking required to generate instability are derived. These are compared to estimated ground accelerations for large (M=5 to 8) crustal earthquakes to giant (M=8 to 9) megathrust events. The results suggest that estimated earthquake accelerations are insufficient to destabilize the slopes, unless the normal sediment frictional resistance is significantly reduced by, for example, excess pore pressure. Elevated pore pressure (overpressure ratio of 0.4) should significantly lower the threshold for earthquake shaking, so that a medium-sized M=5 earthquake at 10 km distance may trigger submarine landslides. Preconditioning of the slopes must be limited primarily to the mid- to early Holocene as slope failures are constrained to this period. The most likely causes for excess pore pressures include rapid sedimentation at the time of glacial retreat, sediment tectonic deformation, and gas hydrate dissociation as result of ocean warming and sea level rise. No slope failures comparable in size and volume have occurred since that time. Megathrust earthquakes have occurred frequently since the most recent failures in the mid-Holocene, which emphasizes the importance of preconditioning for submarine slope stability.

  17. Preconditioning chemotherapy with paclitaxel and cisplatin enhances the antitumor activity of cytokine induced-killer cells in a murine lung carcinoma model.

    PubMed

    Huang, Xiang; Huang, Guichun; Song, Haizhu; Chen, Longbang

    2011-08-01

    Adoptive cell therapy involving the use of ex vivo generated cytokine-induced killer cells (CIKs) provides a promising approach to immunotherapy. However, the therapeutic activity of CIKs is limited by the immunosuppressive factors active in the host. It has become increasingly apparent that manipulation of the recipient immune system with the preconditioning regimen is essential to guarantee the antitumor effect of subsequent adoptive cell therapy. In our study, paclitaxel (PTX) and cisplatin (DDP) were used as preconditioning drugs combined with CIKs to illustrate the potential mechanisms underlying the synergic antitumor effect against Lewis lung cancer cells in vitro and in vivo. We found that 3LL cells displayed an increased sensitization to CIKs-induced lysis after treatment with PTX or DDP in vitro. Significant inhibition of tumor growth was observed in mice treated with combinatorial chemo-immunotherapy with respect to untreated or single regimen treated ones. Prior chemotherapy markedly enhanced the intratumoral accumulation of CD3(+) T lymphocytes and the homing of CIKs to the spleen and tumor. Moreover, the frequencies of intratumoral and splenic regulatory T cells (Tregs) were significantly decreased after chemotherapy pretreatment. Our findings provide a new rationale for combining immunotherapy and chemotherapy to induce a synergistic antitumor response in patients with lung cancer. PMID:20878978

  18. Bactericidal block copolymer micelles.

    PubMed

    Vyhnalkova, Renata; Eisenberg, Adi; van de Ven, Theo

    2011-05-12

    Block copolymer micelles with bactericidal properties were designed to deactivate pathogens such as E. coli bacteria. The micelles of PS-b-PAA and PS-b-P4VP block copolymers were loaded with biocides TCMTB or TCN up to 20 or 30 wt.-%, depending on the type of antibacterial agent. Bacteria were exposed to loaded micelles and bacterial deactivation was evaluated. The micelles loaded with TCN are bactericidal; bacteria are killed in less than two minutes of exposure. The most likely interpretation of the data is that the biocide is transferred to the bacteria by repeated micelle/bacteria contacts, and not via the solution. PMID:21275041

  19. The effects of adding different whole-body vibration frequencies to preconditioning exercise on subsequent sprint performance.

    PubMed

    Rønnestad, Bent R; Ellefsen, Stian

    2011-12-01

    Rønnestad, BR and Ellefsen, S. The effects of adding different whole-body vibration frequencies to preconditioning exercise on subsequent sprint performance. J Strength Cond Res 25(12): 3306-3310, 2011-The phenomenon postactivation potentiation can possibly be used to acutely improve sprint performance. The purpose of this study was to investigate the effect of adding whole-body vibration (WBV) to body-loaded half-squats, performed as preconditioning activity to the 40-m sprint test. Nine male amateur soccer players performed 1 familiarization session and 6 separate test sessions. Each session included a standardized warm-up followed by 1 of the after preconditioning exercises: 30-seconds of half-squats with WBV at either 50 or 30 Hz or half-squats without WBV. The 40-m sprint was performed 1 minute after the preconditioning exercise. For each subject, each of the 3 protocols was repeated twice on separate days in a randomized order. Mean values were used in the statistical analysis. Performing the preconditioning exercise with WBV at a frequency of 50 Hz resulted in a superior 40-m sprint performance compared to preconditioning exercise without WBV (5.48 ± 0.19 vs. 5.52 ± 0.21 seconds, respectively, p < 0.05). There was no difference between preconditioning exercise with WBV at a frequency of 30 Hz and the no-WBV condition. In conclusion, preconditioning exercise performed with WBV at 50 Hz seems to enhance 40-m sprint performance in recreationally trained soccer players. The present findings suggest that coaches can incorporate such exercise into the warm-up to improve sprint performance or the quality of the sprint training. PMID:22076085

  20. Gadolinium and ruthenium red attenuate remote hind limb preconditioning-induced cardioprotection: possible role of TRP and especially TRPV channels.

    PubMed

    Randhawa, Puneet Kaur; Jaggi, Amteshwar Singh

    2016-08-01

    Remote ischemic preconditioning is a well reported therapeutic strategy that induces cardioprotective effects but the underlying intracellular mechanisms have not been widely explored. The current study was designed to investigate the involvement of TRP and especially TRPV channels in remote hind limb preconditioning-induced cardioprotection. Remote hind limb preconditioning stimulus (4 alternate cycles of inflation and deflation of 5 min each) was delivered using a blood pressure cuff tied on the hind limb of the anesthetized rat. Using Langendorff's system, the heart was perfused and subjected to 30-min ischemia and 120-min reperfusion. The myocardial injury was assessed by measuring infarct size, lactate dehydrogenase (LDH), creatine kinase (CK), LVDP, +dp/dtmax, -dp/dtmin, heart rate, and coronary flow rate. Gadolinium, TRP blocker, and ruthenium red, TRPV channel blocker, were employed as pharmacological tools. Remote hind limb preconditioning significantly reduced the infarct size, LDH release, CK release and improved coronary flow rate, hemodynamic parameters including LVDP, +dp/dtmax, -dp/dtmin, and heart rate. However, gadolinium (7.5 and 15 mg kg(-1)) and ruthenium red (4 and 8 mg kg(-1)) significantly attenuated the cardioprotective effects suggesting the involvement of TRP especially TRPV channels in mediating remote hind limb preconditioning-induced cardioprotection. Remote hind limb preconditioning stimulus possibly activates TRPV channels on the heart or sensory nerve fibers innervating the heart to induce cardioprotective effects. Alternatively, remote hind limb preconditioning stimulus may also activate the mechanosensitive TRP and especially TRPV channels on the sensory nerve fibers innervating the skeletal muscles to trigger cardioprotective neurogenic signaling cascade. The cardioprotective effects of remote hind limb preconditioning may be mediated via activation of mechanosensitive TRP and especially TRPV channels. PMID:27118661