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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. Activation of IL-11/STAT3 pathway in preconditioned human skeletal myoblasts blocks apoptotic cascade under oxidant stress.

    PubMed

    Idris, Niagara Muhammad; Ashraf, Muhammad; Ahmed, Rafeeq P H; Shujia, Jiang; Haider, Khawaja H

    2012-01-01

    To determine whether our novel approach of diazoxide-induced stem cell preconditioning might be extrapolated to human skeletal myoblasts to support their survival under lethal oxidant stress. Using an in vitro model of H(2)O(2) treatment of human skeletal myoblasts, we report the ability of diazoxide-preconditioned human skeletal myoblasts to express cytokines and growth factors, which act in an autocrine and paracrine fashion to promote their own survival. Preconditioning of skeletal myoblasts was cytoprotective and significantly reduced their apoptotic index (p < 0.05). IL-11 gene and protein expression was significantly increased in preconditioned skeletal myoblasts. Transfection of skeletal myoblasts with IL-11-specific siRNA incurred their death under oxidant stress. The cytoprotective effect of diazoxide preconditioning was blocked by Erk1/2 inhibitor PD98059 (20-100 µM), which abrogated STAT-3 phosphorylation, thus confirming a possible involvement of Erk1/2/STAT3 signaling downstream of IL-11 in cell survival. We also investigated the time course of subcellular changes and signaling pathway of skeletal myoblasts apoptosis under oxidant stress before and after preconditioning. Apoptosis was induced in skeletal myoblasts with 100-500 µM H(2)O(2) for time points ranging from 1 to 24 h. Release of lactate dehydrogenase, disruption of the mitochondrial membrane potential and cytochrome-c translocation into cytoplasm were the earliest signs of apoptosis. Total Akt protein remained unchanged whereas marked reduction in pAkt was observed in the native skeletal myoblasts. Terminal dUTP nick end-labeling and annexin-V positivity were significantly increased after 4 h. Ultra-structure studies showed condensed chromatin, shriveled nuclei and swollen mitochondria. These data suggest that skeletal myoblasts undergo apoptosis under oxidant stress in a time-dependent manner and preconditioning of skeletal myoblasts significantly prevented their apoptosis via IL-11/STAT3

  4. Teko: A block preconditioning capability with concrete example applications in Navier--Stokes and MHD

    SciTech Connect

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

    2016-10-27

    This study describes the design of Teko, an object-oriented C++ library for implementing advanced block preconditioners. Mathematical design criteria that elucidate the needs of block preconditioning libraries and techniques are explained and shown to motivate the structure of Teko. For instance, a principal design choice was for Teko to strongly reflect the mathematical statement of the preconditioners to reduce development burden and permit focus on the numerics. Additional mechanisms are explained that provide a pathway to developing an optimized production capable block preconditioning capability with Teko. Finally, Teko is demonstrated on fluid flow and magnetohydrodynamics applications. In addition to highlighting the features of the Teko library, these new results illustrate the effectiveness of recent preconditioning developments applied to advanced discretization approaches.

  5. Teko: A block preconditioning capability with concrete example applications in Navier--Stokes and MHD

    DOE PAGES

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

    2016-10-27

    This study describes the design of Teko, an object-oriented C++ library for implementing advanced block preconditioners. Mathematical design criteria that elucidate the needs of block preconditioning libraries and techniques are explained and shown to motivate the structure of Teko. For instance, a principal design choice was for Teko to strongly reflect the mathematical statement of the preconditioners to reduce development burden and permit focus on the numerics. Additional mechanisms are explained that provide a pathway to developing an optimized production capable block preconditioning capability with Teko. Finally, Teko is demonstrated on fluid flow and magnetohydrodynamics applications. In addition to highlightingmore » the features of the Teko library, these new results illustrate the effectiveness of recent preconditioning developments applied to advanced discretization approaches.« less

  6. Efficient block preconditioned eigensolvers for linear response time-dependent density functional theory

    DOE PAGES

    Vecharynski, Eugene; Brabec, Jiri; Shao, Meiyue; ...

    2017-08-24

    Within this paper, we present two efficient iterative algorithms for solving the linear response eigenvalue problem arising from the time dependent density functional theory. Although the matrix to be diagonalized is nonsymmetric, it has a special structure that can be exploited to save both memory and floating point operations. In particular, the nonsymmetric eigenvalue problem can be transformed into an eigenvalue problem that involves the product of two matrices M and K. We show that, because MK is self-adjoint with respect to the inner product induced by the matrix K, this product eigenvalue problem can be solved efficiently by amore » modified Davidson algorithm and a modified locally optimal block preconditioned conjugate gradient (LOBPCG) algorithm that make use of the K-inner product. Additionally, the solution of the product eigenvalue problem yields one component of the eigenvector associated with the original eigenvalue problem. We show that the other component of the eigenvector can be easily recovered in an inexpensive postprocessing procedure. As a result, the algorithms we present here become more efficient than existing methods that try to approximate both components of the eigenvectors simultaneously. In particular, our numerical experiments demonstrate that the new algorithms presented here consistently outperform the existing state-of-the-art Davidson type solvers by a factor of two in both solution time and storage.« less

  7. Hypoxia-inducible factor 1 is required for remote ischemic preconditioning of the heart.

    PubMed

    Cai, Zheqing; Luo, Weibo; Zhan, Huiwang; Semenza, Gregg L

    2013-10-22

    Both preclinical and clinical studies suggest that brief cycles of ischemia and reperfusion in the arm or leg may protect the heart against injury following prolonged coronary artery occlusion and reperfusion, a phenomenon known as remote ischemic preconditioning. Recent studies in mice indicate that increased plasma interleukin-10 (IL-10) levels play an important role in remote ischemic preconditioning induced by clamping the femoral artery for 5 min followed by 5 min of reperfusion for a total of three cycles. In this study, we demonstrate that remote ischemic preconditioning increases plasma IL-10 levels and decreases myocardial infarct size in wild-type mice but not in littermates that are heterozygous for a knockout allele at the locus encoding hypoxia-inducible factor (HIF) 1α. Injection of a recombinant adenovirus encoding a constitutively active form of HIF-1α into mouse hind limb muscle was sufficient to increase plasma IL-10 levels and decrease myocardial infarct size. Exposure of C2C12 mouse myocytes to cyclic hypoxia and reoxygenation rapidly increased levels of IL-10 mRNA, which was blocked by administration of the HIF-1 inhibitor acriflavine or by expression of short hairpin RNA targeting HIF-1α or HIF-1β. Chromatin immunoprecipitation assays demonstrated that binding of HIF-1 to the Il10 gene was induced when myocytes were subjected to cyclic hypoxia and reoxygenation. Taken together, these data indicate that HIF-1 activates Il10 gene transcription and is required for remote ischemic preconditioning.

  8. Block-preconditioned conjugate-gradient-like methods for numerical reservoir simulation

    SciTech Connect

    Eisenstat, S.C.; Elman, H.C.; Schultz, M.H.

    1985-02-01

    The authors describe a collection of block-preconditioners for use in solving large sparse linear systems of equations by iterative methods, and they compare their performance with several point-preconditioners in solving some systems arising in numerical reservoir simulation. They consider block-preconditioners that handle either lines or planes in an implicit manner, and pointwise incomplete LU factorizations combined with partial elimination preprocessors. Their conclusions are that the best of the pointwise methods are both more robust and faster, but that the best of the block methods are competitive for certain orderings of unknowns and require less storage.

  9. Hypoxic preconditioning decreases nuclear factor κB activity via Disrupted in Schizophrenia-1.

    PubMed

    Liu, Jia-Ren; Liu, Qian; Khoury, Joseph; Li, Yue-Jin; Han, Xiao-Hui; Li, Jing; Ibla, Juan C

    2016-01-01

    Nuclear factor κB is a key mediator of inflammation during conditions of hypoxia. Here, we used models of hypoxic pre-conditioning as mechanism to decrease nuclear factor κB activity induced by hypoxia. Our initial studies suggested that Disrupted in Schizophrenia-1 may be induced by hypoxic pre-conditioning and possibly involved in the regulation of nuclear factor κB. In this study we used Disrupted in Schizophrenia-1 exogenous over-expression and knock-down to determine its effect on ataxia telangiectasia mutated--nuclear factor κB activation cascade. Our results demonstrated that hypoxic pre-conditioning significantly increased the expression of Disrupted in Schizophrenia-1 at mRNA and protein levels both in vitro and in vivo. Over-expression of Disrupted in Schizophrenia-1 significantly attenuated the hypoxia-mediated ataxia telangiectasia mutated phosphorylation and prevented its cytoplasm translocation where it functions to activate nuclear factor κB. We further determined that Disrupted in Schizophrenia-1 activated the protein phosphatase 2A, preventing the phosphorylation of ataxia telangiectasia mutated serine-1981, the main regulatory site of ataxia telangiectasia mutated activity. Cellular levels of Disrupted in Schizophrenia-1 protein significantly decreased nuclear factor κB activation profiles and pro-inflammatory gene expression. Taken together, these results demonstrate that hypoxic pre-conditioning decreases the activation of nuclear factor κB through the transcriptional induction of Disrupted in Schizophrenia-1.

  10. Hypoxic preconditioning protects photoreceptors against light damage independently of hypoxia inducible transcription factors in rods.

    PubMed

    Kast, Brigitte; Schori, Christian; Grimm, Christian

    2016-05-01

    Hypoxic preconditioning protects photoreceptors against light-induced degeneration preserving retinal morphology and function. Although hypoxia inducible transcription factors 1 and 2 (HIF1, HIF2) are the main regulators of the hypoxic response, photoreceptor protection does not depend on HIF1 in rods. Here we used rod-specific Hif2a single and Hif1a;Hif2a double knockout mice to investigate the potential involvement of HIF2 in rods for protection after hypoxic preconditioning. To identify potential HIF2 target genes in rods we determined the retinal transcriptome of hypoxic control and rod-specific Hif2a knockouts by RNA sequencing. We show that rods do not need HIF2 for hypoxia-induced increased survival after light exposure. The transcriptomic analysis revealed a number of genes that are potentially regulated by HIF2 in rods; among those were Htra1, Timp3 and Hmox1, candidates that are interesting due to their connection to human degenerative diseases of the retina. We conclude that neither HIF1 nor HIF2 are required in photoreceptors for protection by hypoxic preconditioning. We hypothesize that HIF transcription factors may be needed in other cells to produce protective factors acting in a paracrine fashion on photoreceptor cells. Alternatively, hypoxic preconditioning induces a rod-intrinsic response that is independent of HIF transcription factors.

  11. 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.

  12. Using Chebyshev polynomials and approximate inverse triangular factorizations for preconditioning the conjugate gradient method

    NASA Astrophysics Data System (ADS)

    Kaporin, I. E.

    2012-02-01

    In order to precondition a sparse symmetric positive definite matrix, its approximate inverse is examined, which is represented as the product of two sparse mutually adjoint triangular matrices. In this way, the solution of the corresponding system of linear algebraic equations (SLAE) by applying the preconditioned conjugate gradient method (CGM) is reduced to performing only elementary vector operations and calculating sparse matrix-vector products. A method for constructing the above preconditioner is described and analyzed. The triangular factor has a fixed sparsity pattern and is optimal in the sense that the preconditioned matrix has a minimum K-condition number. The use of polynomial preconditioning based on Chebyshev polynomials makes it possible to considerably reduce the amount of scalar product operations (at the cost of an insignificant increase in the total number of arithmetic operations). The possibility of an efficient massively parallel implementation of the resulting method for solving SLAEs is discussed. For a sequential version of this method, the results obtained by solving 56 test problems from the Florida sparse matrix collection (which are large-scale and ill-conditioned) are presented. These results show that the method is highly reliable and has low computational costs.

  13. Multiple preconditioning paradigms converge on interferon regulatory factor-dependent signaling to promote tolerance to ischemic brain injury.

    PubMed

    Stevens, Susan L; Leung, Philberta Y; Vartanian, Keri B; Gopalan, Banu; Yang, Tao; Simon, Roger P; Stenzel-Poore, Mary P

    2011-06-08

    Ischemic tolerance can be induced by numerous preconditioning stimuli, including various Toll-like receptor (TLR) ligands. We have shown previously that systemic administration of the TLR4 ligand LPS or the TLR9 ligand unmethylated CpG oligodeoxynucleotide before transient brain ischemia in mice confers substantial protection against ischemic damage. To elucidate the molecular mechanisms of preconditioning, we compared brain genomic profiles in response to preconditioning with these TLR ligands and with preconditioning via exposure to brief ischemia. We found that exposure to the TLR ligands and brief ischemia induced genomic changes in the brain characteristic of a TLR pathway-mediated response. Interestingly, all three preconditioning stimuli resulted in a reprogrammed response to stroke injury that converged on a shared subset of 13 genes not evident in the genomic profile from brains that were subjected to stroke without prior preconditioning. Analysis of the promoter region of these shared genes showed sequences required for interferon regulatory factor (IRF)-mediated transcription. The importance of this IRF gene network was tested using mice deficient in IRF3 or IRF7. Our data show that both transcription factors are required for TLR-mediated preconditioning and neuroprotection. These studies are the first to discover a convergent mechanism of neuroprotection induced by preconditioning--one that potentially results in reprogramming of the TLR-mediated response to stroke and requires the presence of IRF3 and IRF7.

  14. Targeting the pathway of GSK-3β/nerve growth factor to attenuate post-infarction arrhythmias by preconditioned adipose-derived stem cells.

    PubMed

    Lee, Tsung-Ming; Harn, Horng-Jyh; Chiou, Tzyy-Wen; Chuang, Ming-Hsi; Chen, Chun-Hung; Lin, Po-Cheng; Lin, Shinn-Zong

    2017-03-01

    Adipose-derived stem cell (ADSC) transplantation is a promising new therapy to improve cardiac function after myocardial infarction. However, its low efficacy of transdifferentiation hampers its usefulness. Glycogen synthase kinase-3β (GSK-3β) signal has been shown to play a role in preconditioning-induced cardioprotection. We assessed whether n-butylidenephthalide (BP) primed ADSCs can attenuate arrhythmias by a GSK-3β-dependent pathway after myocardial infarction. Male Wistar rats after coronary ligation was randomly allocated to receive intramyocardial injection of vehicle, ADSCs, BP-preconditioned ADSCs, (BP+lithium)-preconditioned ADSCs, (BP+SB216763)-preconditioned ADSCs, and (BP+LY294002)-preconditioned ADSCs. ADSCs were primed for 16h before implantation. After 4weeks of implantation, ADSCs were retained in myocardium, reduced fibrosis and improved cardiac function. Sympathetic hyperinnervation was blunted after administering ADSCs, assessed by immunofluorescent analysis, and Western blotting and real-time quantitative RT-PCR of nerve growth factor. Arrhythmic scores during programmed stimulation in the ADSC-treated infarcted rats were significantly lower than vehicle. BP-preconditioned ADSCs had superior cardioprotection, greater ADSC engraftment and transdifferentiation, and antiarrhythmic effects compared with ADSCs alone. Simultaneously, BP increased the levels of phospho-Akt and down-regulated GSK-3β activity. The effects of BP against sympathetic hyperinnervation were blocked by LY294002, a PI3K inhibitor. Addition of either lithium or SB216763 did not have additional effects compared with BP alone. Compared with ADSC alone, BP-primed ADSC implantation improved stem cell engraftment and attenuated sympathetic hyperinnervation and arrhythmias through a PI3K/Akt/GSK-3β-dependent pathway, suggesting that a synergic action was achieved between BP pretreatment and ADSCs.

  15. Aldehyde dehydrogenase-2 inhibition blocks remote preconditioning in experimental and human models.

    PubMed

    Contractor, Hussain; Støttrup, Nicolaj B; Cunnington, Colin; Manlhiot, Cedric; Diesch, Jonathan; Ormerod, Julian O M; Jensen, Rebekka; Bøtker, Hans Erik; Redington, Andrew; Schmidt, Michael R; Ashrafian, Houman; Kharbanda, Rajesh K

    2013-05-01

    Mitochondrial aldehyde dehydrogenase-2 (ALDH-2) is involved in preconditioning pathways, but its role in remote ischaemic preconditioning (rIPC) is unknown. We investigated its role in animal and human models of rIPC. (i) In a rabbit model of myocardial infarction, rIPC alone reduced infarct size [69 ± 5.8 % (n = 11) to 40 ± 6.5 % (n = 12), P = 0.019]. However, rIPC protection was lost after pre-treatment with the ALDH-2 inhibitor cyanamide (62 ± 7.6 % controls, n = 10, versus 61 ± 6.9 % rIPC after cyanamide, n = 10, P > 0.05). (ii) In a forearm plethysmography model of endothelial ischaemia-reperfusion injury, 24 individuals of Asian ethnic origin underwent combined rIPC and ischaemia-reperfusion (IR). 11 had wild-type (WT) enzyme and 13 carried the Glu504Lys (ALDH2*2) polymorphism (rendering ALDH-2 functionally inactive). In WT individuals, rIPC protected against impairment of response to acetylcholine (P = 0.9), but rIPC failed to protect carriers of Glu504Lys polymorphism (P = 0.004). (iii) In a second model of endothelial IR injury, 12 individuals participated in a double-blind placebo-controlled crossover study, receiving the ALDH-2 inhibitor disulfiram 600 mg od or placebo for 48 h prior to assessment of flow-mediated dilation (FMD) before and after combined rIPC and IR. With placebo, rIPC was effective with no difference in FMD before and after IR (6.18 ± 1.03 % and 4.76 ± 0.93 % P = 0.1), but disulfiram inhibited rIPC with a reduction in FMD after IR (7.87 ± 1.27 % and 3.05 ± 0.53 %, P = 0.001). This study demonstrates that ALDH-2 is involved in the rIPC pathway in three distinct rabbit and human models. This has potential implications for future clinical studies of remote conditioning.

  16. The Chronic Protective Effects of Limb Remote Preconditioning and the Underlying Mechanisms Involved in Inflammatory Factors in Rat Stroke

    PubMed Central

    Chen, Xiaoyuan; Zhao, Heng

    2012-01-01

    We recently demonstrated that limb remote preconditioning (LRP) protects against focal ischemia measured 2 days post-stroke. Here, we studied whether LRP provides long-term protection and improves neurological function. We also investigated whether LRP transmits its protective signaling via the afferent nerve pathways from the preconditioned limb to the ischemic brain and whether inflammatory factors are involved in LRP, including the novel galectin-9/Tim-3 inflammatory cell signaling pathway, which induces cell death in lymphocytes. LRP in the left hind femoral artery was performed immediately before stroke. LRP reduced brain injury size both at 2 days and 60 days post-stroke and improved behavioral outcomes for up to 2 months. The sensory nerve inhibitors capsaicin and hexamethonium, a ganglion blocker, abolished the protective effects of LRP. In addition, LRP inhibited edema formation and blood-brain barrier (BBB) permeability measured 2 days post-stroke. Western blot and immunostaining analysis showed that LRP inhibited protein expression of both galectin-9 and T-cell immunoglobulin domain and mucin domain 3 (Tim-3), which were increased after stroke. In addition, LRP decreased iNOS and nitrotyrosine protein expression after stroke. In conclusion, LRP executes long-term protective effects against stroke and may block brain injury by inhibiting activities of the galectin-9/Tim-3 pathway, iNOS, and nitrotyrosine. PMID:22347410

  17. 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.

  18. Time course of neuroprotection induced by in vivo normobaric hyperoxia preconditioning and angiogenesis factors

    PubMed Central

    Shahhoseini, Meisam; Bigdeli, Mohammad Reza

    2017-01-01

    Objective(s): Every year, a large number of people lose their lives due to stroke. Stroke is the second leading cause of death worldwide. Surprisingly, recent studies have shown that preconditioning with hyperoxia (HO) increases tissue tolerance to ischemia, ultimately reducing damages caused by stroke. Addressed in this study are beneficial contributions from HO preconditioning into reduced harm to be incurred by the attack, as well as its effect on the expression levels of vascular endothelial growth factor (VEGF) and endostatin. Materials and Methods: A set of experiments was conducted where a number of rats were divided into three groups. The animals in the first group received 90% oxygen for 4 hr a day, for 6 days. The second group was housed in room air and the third group was a sham (surgical stress). After 60 min of ischemia, 24 hr blood flow, neurological deficit score (NDS) and infarct volume (IV) in the group MCAO (Middle Cerebral Artery Occlusion) were investigated. Immediately following a 48 hr HO pre-treatment, sampling was performed to measure the expression levels of VEGF and endostatin. Results: Preconditioning with alternating HO led to reduced infarct volume and NDS. Moreover, pre-treatment with HO resulted in increased VEGF expression while decreasing endostatin. Conclusion: Although further studies are deemed necessary to clarify the mechanisms of ischemic tolerance, apparently, somewhat intermittent hyperoxia can be associated with positive impacts by increasing VEGF and decreasing expression of endostatin. PMID:28133527

  19. 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.

  20. Translational downregulation of the noncatalytic growth factor receptor TrkB.T1 by ischemic preconditioning of primary neurons.

    PubMed

    Steinbeck, Julius A; Methner, Axel

    2005-01-01

    Short episodes of ischemia can protect neuronal cells and tissue against a subsequent lethal ischemia by a phenomenon called ischemic preconditioning. The development of this tolerance depends on protein synthesis and takes at least 1 day. It therefore seems reasonable that preconditioning leads to upregulation and translation of protective genes or posttranslational modification of pro- or antiapoptotic proteins. We recently used suppression subtractive hybridization to identify transcripts upregulated in rat primary neuronal cultures preconditioned by oxygen glucose deprivation. In this contribution, we describe the previously unknown 7-kb full-length sequence of an upregulated expressed sequence tag and show that it constitutes the 3' end of the large untranslated region of the noncatalytic "truncated" growth factor receptor TrkB.T1. TrkB.T1 is expressed most prominently in the adult brain and its mRNA was found to be 2.1-fold upregulated by ischemic preconditioning. At the protein level, however, TrkB.T1 was clearly downregulated, possibly by increased degradation in preconditioned cultures. TrKB.T1 can act as a dominant-negative inhibitor of its catalytic counterpart TrkB, which is the receptor for brain-derived neurotrophic factor (BDNF), a factor induced by ischemia that can protect from ischemia-induced neuron loss. We hypothesize that the downregulation of TrkB.T1 at the protein level can prolong BDNF-mediated protective signaling via the catalytic receptor and thus participates in the development of ischemic preconditioning.

  1. 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

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

    PubMed

    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.

  3. Essential role for nuclear factor kappaB in ischemic preconditioning for cold ischemia-reperfusion injury of intestinal transplantation.

    PubMed

    Wei, Z; Fan, L; Xiangming, C

    2009-12-01

    The present study was designed to examine whether ischemic preconditioning could play a protective role on cold ischemia and reperfusion injury associated with intestinal transplantation in rats. The 48 male Sprague Dawley (SD) rats were randomly assigned to 2 groups. Ischemic preconditioning was performed in experimental but not control rats by preserving the self donor small bowel in Ringer lactate solution at 4 degrees C for 3 hours (n = 6), 6 hours (n = 6), 12 hours (n = 6), or 18 hours (n = 6). One hour reperfusion was performed for every rat after orthotopic transplantation of donor small bowel. Small bowel samples were obtained for histological examination and immunohistochemistry analysis of nuclear factor kappaB (NF-kappaB) expression. The small intestinal villus was arranged more regularly in experimental compared with control rats. Ischemia preconditioning also decreased edema in the muscule layer and increased Chiu score in experimental rats. Immunohistochemistry analysis revealed that ischemic preconditioning down-regulated the expression of NF-kappaB in the epithelia of experimental rats. Ischemic preconditioning improved intestinal transplantation in rats from cold ischemia and reperfusion injury by down-regulating the expression of NF-kappaB.

  4. Cardiomyocyte mitochondria as targets of humoral factors released by remote ischemic preconditioning

    PubMed Central

    Gedik, Nilguen; Maciel, Leonardo; Schulte, Christiane; Skyschally, Andreas; Heusch, Gerd

    2016-01-01

    Introduction Remote ischemic preconditioning (RIPC) reduces myocardial infarct size, and protection can be transferred with plasma to other individuals, even across species. Mitochondria are the end-effectors of cardioprotection by local ischemic conditioning maneuvers. We have now analyzed mitochondrial function in response to RIPC. Material and methods Plasma from pigs undergoing placebo or RIPC (infarct size reduction by 67% in RIPC pigs compared to placebo) was transferred to isolated perfused rat hearts subjected to 30 min global ischemia followed by 120 min reperfusion for infarct size measurement. Additional experiments were terminated at 10 min reperfusion to isolate mitochondria for functional measurements. Effects of RIPC pig plasma were compared to local ischemic preconditioning (IPC) or to infusion of tumor necrosis factor α (TNF-α). Results Ischemia/reperfusion (I/R) induced an infarct of 41 ±2% of total ventricular mass. Placebo pig plasma did not affect infarct size (38 ±1, p = 0.13). The RIPC pig plasma reduced infarct size (27 ±2, p < 0.001), as did IPC (20 ±1, p < 0.001) and TNF-α (28 ±2, p < 0.001). Associated with cardioprotection, reductions of mitochondrial adenosine diphosphate (ADP)-stimulated respiration, adenosine triphosphate (ATP) production and calcium retention capacity (CRC) by I/R and placebo pig plasma were prevented by RIPC pig plasma, as they were by IPC and TNF-α. Mitochondrial reactive oxygen species production (nmol H2O2/100 µg protein) induced by I/R (272 ±34) was comparable in response to placebo pig plasma (234 ±28, p = 0.37) and was reduced by RIPC pig plasma (83 ±15, p < 0.001) as well as by IPC (78 ±21, p < 0.001) and TNF-α (125 ±42, p = 0.002). Conclusions In rat myocardium, mitochondria are an intracellular target of protection induced by humoral factors retrieved from pigs undergoing RIPC. PMID:28261301

  5. Influence of ischemic preconditioning on levels of nerve growth factor, brain-derived neurotrophic factor and their high-affinity receptors in hippocampus following forebrain ischemia.

    PubMed

    Lee, Tsong-Hai; Yang, Jen-Tsung; Ko, Yu-Shien; Kato, Hiroyuki; Itoyama, Yasuto; Kogure, Kyuya

    2008-01-02

    NGF and BDNF and their corresponding receptors in the vulnerable CA1 neurons after the second lethal ischemia, suggesting that growth factors might play a role in the protective mechanism of ischemic preconditioning.

  6. 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.

  7. Berberine Preconditioning Protects Neurons Against Ischemia via Sphingosine-1-Phosphate and Hypoxia-Inducible Factor-1[Formula: see text].

    PubMed

    Zhang, Qichun; Bian, Huimin; Guo, Liwei; Zhu, Huaxu

    2016-01-01

    Berberine exerts neuroprotective and modulates hypoxia inducible factor-1-alpha (HIF-1[Formula: see text]. Based on the role of HIF-1[Formula: see text] in hypoxia preconditioning and association between HIF-1[Formula: see text] and sphingosine-1-phosphate (S1P), we hypothesized that berberine preconditioning (BP) would ameliorate the cerebral injury induced by ischemia through activating the system of HIF-1[Formula: see text] and S1P. Adult male rats with middle cerebral artery occlusion (MCAO) and rat primary cortical neurons treated with oxygen and glucose deprivation (OGD) with BP at 24[Formula: see text]h (40[Formula: see text]mg/kg) and 2[Formula: see text]h (10[Formula: see text][Formula: see text]mol/L), respectively, were used to determine the neuroprotective effects. The HIF-1[Formula: see text] accumulation, and S1P metabolism were assayed in the berberine-preconditioned neurons, and the HIF-1[Formula: see text]-mediated transcriptional modulation of sphingosine kinases (Sphk) 1 and 2 was analyzed using chromatin immunoprecipitation and real-time polymerase chain reaction. BP significantly prevented cerebral ischemic injury in the MCAO rats at 24[Formula: see text]h and 72[Formula: see text]h following ischemia/reperfusion. In OGD-treated neurons, BP enhanced HIF-1[Formula: see text] accumulation with activation of PI3K/Akt, and induced S1P production by activating Sphk2 via the promotion of HIF-1[Formula: see text]-mediated Sphk2 transcription. In conclusion, BP activated endogenous neuroprotective mechanisms associated with the S1P/HIF-1 pathway and helped protect neuronal cells against hypoxia/ischemia.

  8. 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.

  9. 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.

  10. Computing eigenvectors of block tridiagonal matrices based on twisted block factorizations

    PubMed Central

    König, Gerhard; Moldaschl, Michael; Gansterer, Wilfried N.

    2012-01-01

    New methods for computing eigenvectors of symmetric block tridiagonal matrices based on twisted block factorizations are explored. The relation of the block where two twisted factorizations meet to an eigenvector of the block tridiagonal matrix is reviewed. Based on this, several new algorithmic strategies for computing the eigenvector efficiently are motivated and designed. The underlying idea is to determine a good starting vector for an inverse iteration process from the twisted block factorizations such that a good eigenvector approximation can be computed with a single step of inverse iteration. An implementation of the new algorithms is presented and experimental data for runtime behaviour and numerical accuracy based on a wide range of test cases are summarized. Compared with competing state-of-the-art tridiagonalization-based methods, the algorithms proposed here show strong reductions in runtime, especially for very large matrices and/or small bandwidths. The residuals of the computed eigenvectors are in general comparable with state-of-the-art methods. In some cases, especially for strongly clustered eigenvalues, a loss in orthogonality of some eigenvectors is observed. This is not surprising, and future work will focus on investigating ways for improving these cases. PMID:23471102

  11. Preconditioning and stem cell survival.

    PubMed

    Haider, Husnain Kh; Ashraf, Muhammad

    2010-04-01

    The harsh ischemic and cytokine-rich microenvironment in the infarcted myocardium, infiltrated by the inflammatory and immune cells, offers a significant challenge to the transplanted donor stem cells. Massive cell death occurs during transplantation as well as following engraftment which significantly lowers the effectiveness of the heart cell therapy. Various approaches have been adopted to overcome this problem nevertheless with multiple limitations with each of these current approaches. Cellular preconditioning and reprogramming by physical, chemical, genetic, and pharmacological manipulation of the cells has shown promise and "prime" the cells to the "state of readiness" to withstand the rigors of lethal ischemia in vitro as well as posttransplantation. This review summarizes the past and present novel approaches of ischemic preconditioning, pharmacological and genetic manipulation using preconditioning mimetics, recombinant growth factor protein treatment, and reprogramming of stem cells to overexpress survival signaling molecules, microRNAs, and trophic factors for intracrine, autocrine, and paracrine effects on cytoprotection.

  12. 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.

  13. Cardioprotective Effects of Transfusion of Late-Phase Preconditioned Plasma May Be Induced by Activating the Reperfusion Injury Salvage Kinase Pathway but Not the Survivor Activating Factor Enhancement Pathway in Rats

    PubMed Central

    Zheng, Zhi-nan; Pi, Yan-na; Liang, Xue

    2017-01-01

    A previous study in our laboratory demonstrated that transfusion of plasma collected at the late phase of remote ischemic preconditioning (RIPC) could reduce myocardial infarct size. Here, we tested whether the reperfusion injury salvage kinase (RISK) and survivor activating factor enhancement (SAFE) pathways are involved in transferring protection. In a two-part study, donor rats (n = 3) donated plasma 48 hours after RIPC (preconditioned plasma) or control (nonpreconditioned plasma). Normal (part 1) or ischemic (part 2) myocardia were collected from recipients (n = 6) 24 hours after receiving normal saline, nonpreconditioned plasma, and preconditioned plasma or after further suffering ischemia reperfusion. Western blot was performed to analyze STAT3, Akt, and Erk1/2 phosphorylation in normal and ischemic myocardium (central area and border area). In normal myocardia, preconditioned plasma increased Akt and Erk1/2 phosphorylation significantly compared to nonpreconditioned plasma and normal saline; no STAT3 phosphorylation was detected. In ischemic myocardia, preconditioned plasma increased Akt and Erk1/2 phosphorylation significantly in both central and border areas compared to other fluids; no significant difference in STAT3 phosphorylation occurred among groups. Transfusion of preconditioned plasma collected at the late phase of RIPC could activate the RISK but not SAFE pathway, suggesting that RISK pathway may be involved in transferring protection. PMID:28828146

  14. Geometrical factors in propagation block and spiral wave initiation

    NASA Astrophysics Data System (ADS)

    Zykov, Vladimir; Krekhov, Alexei; Bodenschatz, Eberhard

    2017-09-01

    Many theoretical and experimental studies indicate that a propagation block represents an important factor in spiral wave initiation in excitable media. The analytical and numerical results we obtained for a generic two-component reaction-diffusion system demonstrate quantitative conditions for the propagation block in a one-dimensional and a two-dimensional medium due to a sharp spatial increase of the medium's excitability or the coupling strength above a certain critical value. Here, we prove that this critical value strongly depends on the medium parameters and the geometry of the inhomogeneity. For an exemplary two-dimensional medium, we show how the propagation block can be used to initiate spiral waves by a specific choice of the size and shape of the medium's inhomogeneity.

  15. Role of hypoxia-inducible factor-1α in preconditioning-induced protection of retinal ganglion cells in glaucoma.

    PubMed

    Zhu, Yanli; Zhang, Lihong; Gidday, Jeffrey M

    2013-01-01

    We recently demonstrated in a mouse model of glaucoma that endogenous epigenetic mechanisms can be activated by a repetitive hypoxic preconditioning (RHP) stimulus to provide robust retinal ganglion cell (RGC) protection. Although we also provided evidence that RHP prevents or delays the apoptotic demise of the RGC soma, the mechanisms responsible for signaling this epigenetic response, as well as the effectors of the glaucoma-tolerant phenotype at the somatic and axonal levels, remain unidentified. In the present study, we used conditional mutant mice lacking hypoxia-inducible factor-1α (HIF-1α) in RGCs (HIF-1α RGC-knockout [KO] mice) to test the hypothesis that RHP-mediated activation of this transcription factor in these cells protects them from glaucomatous injury. Adult HIF-1α RGC-KO mice, generated by mating floxed HIF-1α mice with math5-Cre mice, were used. Experimental glaucoma was induced unilaterally in the HIF-1α RGC-KO mice and matched wild-types by elevating the intraocular pressure to 16-20 mmHg for 3 consecutive weeks, secondary to episcleral vein ligation. Mice of each genotype were randomized to either an RHP protocol (six total exposures to systemic hypoxia [11% oxygen], interspersed over a 2-week period, completed 3 days before ligation surgery) or to an untreated group. RGC soma and axon injury was quantified with Neuronal Nuclei (NeuN) immunohistochemistry in retinal flat mounts and SMI32 immunohistochemistry in cross sections of the post-laminar optic nerve, respectively. HIF-1α RGC-KO mice exhibited normal retinal function and morphology, and crosses of math5-Cre mice with floxed ROSA26 reporter mice confirmed Cre recombinase activity was confined to the RGC axons and soma. Untreated wild-type mice exhibited a 30±2% loss of RGC soma and a 31±3% loss of RGC axons after 3 weeks of intraocular hypertension (both p<0.05 versus fellow eye). The 90% and 81% improvement in soma and axon survival, respectively, observed in the wild

  16. 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.

  17. 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.

  18. 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.

  19. Islet preconditioning via multimodal microfluidic modulation of intermittent hypoxia.

    PubMed

    Lo, Joe F; Wang, Yong; Blake, Alexander; Yu, Gene; Harvat, Tricia A; Jeon, Hyojin; Oberholzer, Jose; Eddington, David T

    2012-02-21

    Simultaneous stimulation of ex vivo pancreatic islets with dynamic oxygen and glucose is a critical technique for studying how hypoxia alters glucose-stimulated response, especially in transplant environments. Standard techniques using a hypoxic chamber cannot provide both oxygen and glucose modulations, while monitoring stimulus-secretion coupling factors in real-time. Using novel microfluidic device with integrated glucose and oxygen modulations, we quantified hypoxic impairment of islet response by calcium influx, mitochondrial potentials, and insulin secretion. Glucose-induced calcium response magnitude and phase were suppressed by hypoxia, while mitochondrial hyperpolarization and insulin secretion decreased in coordination. More importantly, hypoxic response was improved by preconditioning islets to intermittent hypoxia (IH, 1 min/1 min 5-21% cycling for 1 h), translating to improved insulin secretion. Moreover, blocking mitochondrial K(ATP) channels removed preconditioning benefits of IH, similar to mechanisms in preconditioned cardiomyocytes. Additionally, the multimodal device can be applied to a variety of dynamic oxygen-metabolic studies in other ex vivo tissues.

  20. 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.

  1. Preconditioning of adipose tissue-derived mesenchymal stem cells with deferoxamine increases the production of pro-angiogenic, neuroprotective and anti-inflammatory factors: Potential application in the treatment of diabetic neuropathy

    PubMed Central

    Oses, Carolina; Olivares, Belén; Ezquer, Marcelo; Acosta, Cristian; Bosch, Paul; Donoso, Macarena; Léniz, Patricio

    2017-01-01

    Diabetic neuropathy (DN) is one of the most frequent and troublesome complications of diabetes mellitus. Evidence from diabetic animal models and diabetic patients suggests that reduced availability of neuroprotective and pro-angiogenic factors in the nerves in combination with a chronic pro-inflammatory microenvironment and high level of oxidative stress, contribute to the pathogenesis of DN. Mesenchymal stem cells (MSCs) are of great interest as therapeutic agents for regenerative purposes, since they can secrete a broad range of cytoprotective and anti-inflammatory factors. Therefore, the use of the MSC secretome may represent a promising approach for DN treatment. Recent data indicate that the paracrine potential of MSCs could be boosted by preconditioning these cells with an environmental or pharmacological stimulus, enhancing their therapeutic efficacy. In the present study, we observed that the preconditioning of human adipose tissue-derived MSCs (AD-MSCs) with 150μM or 400μM of the iron chelator deferoxamine (DFX) for 48 hours, increased the abundance of the hypoxia inducible factor 1 alpha (HIF-1α) in a concentration dependent manner, without affecting MSC morphology and survival. Activation of HIF-1α led to the up-regulation of the mRNA levels of pro-angiogenic factors like vascular endothelial growth factor alpha and angiopoietin 1. Furthermore this preconditioning increased the expression of potent neuroprotective factors, including nerve growth factor, glial cell-derived neurotrophic factor and neurotrophin-3, and cytokines with anti-inflammatory activity like IL4 and IL5. Additionally, we observed that these molecules, which could also be used as therapeutics, were also increased in the secretome of MSCs preconditioned with DFX compared to the secretome obtained from non-preconditioned cells. Moreover, DFX preconditioning significantly increased the total antioxidant capacity of the MSC secretome and they showed neuroprotective effects when

  2. Preconditioning of adipose tissue-derived mesenchymal stem cells with deferoxamine increases the production of pro-angiogenic, neuroprotective and anti-inflammatory factors: Potential application in the treatment of diabetic neuropathy.

    PubMed

    Oses, Carolina; Olivares, Belén; Ezquer, Marcelo; Acosta, Cristian; Bosch, Paul; Donoso, Macarena; Léniz, Patricio; Ezquer, Fernando

    2017-01-01

    Diabetic neuropathy (DN) is one of the most frequent and troublesome complications of diabetes mellitus. Evidence from diabetic animal models and diabetic patients suggests that reduced availability of neuroprotective and pro-angiogenic factors in the nerves in combination with a chronic pro-inflammatory microenvironment and high level of oxidative stress, contribute to the pathogenesis of DN. Mesenchymal stem cells (MSCs) are of great interest as therapeutic agents for regenerative purposes, since they can secrete a broad range of cytoprotective and anti-inflammatory factors. Therefore, the use of the MSC secretome may represent a promising approach for DN treatment. Recent data indicate that the paracrine potential of MSCs could be boosted by preconditioning these cells with an environmental or pharmacological stimulus, enhancing their therapeutic efficacy. In the present study, we observed that the preconditioning of human adipose tissue-derived MSCs (AD-MSCs) with 150μM or 400μM of the iron chelator deferoxamine (DFX) for 48 hours, increased the abundance of the hypoxia inducible factor 1 alpha (HIF-1α) in a concentration dependent manner, without affecting MSC morphology and survival. Activation of HIF-1α led to the up-regulation of the mRNA levels of pro-angiogenic factors like vascular endothelial growth factor alpha and angiopoietin 1. Furthermore this preconditioning increased the expression of potent neuroprotective factors, including nerve growth factor, glial cell-derived neurotrophic factor and neurotrophin-3, and cytokines with anti-inflammatory activity like IL4 and IL5. Additionally, we observed that these molecules, which could also be used as therapeutics, were also increased in the secretome of MSCs preconditioned with DFX compared to the secretome obtained from non-preconditioned cells. Moreover, DFX preconditioning significantly increased the total antioxidant capacity of the MSC secretome and they showed neuroprotective effects when

  3. 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. Copyright © 2015 Elsevier Inc. All rights reserved.

  4. 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.

  5. Two classes of preconditioners computed using block matrix factorization techniques

    SciTech Connect

    Baca, L.S.; Salane, D.E.

    1987-07-01

    Two methods for computing preconditioners for nonsymmetric block tridiagonal systems of linear equations are investigated. Adaptable general purpose implementations are given for both methods. 11 refs.

  6. FACTORS MODIFYING THE ACTION OF NEUROMUSCULAR BLOCKING AGENTS.

    DTIC Science & Technology

    neuromuscular blocking properties of another intravenous anaesthetic the eugenol derivative G.34075 and a recently synthesised relaxant diallyl-nortoxiferine were also investigated with this preparation. (Author)

  7. 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.

  8. Helium induces preconditioning in human endothelium in vivo.

    PubMed

    Smit, Kirsten F; Oei, Gezina T M L; Brevoord, Daniel; Stroes, Erik S; Nieuwland, Rienk; Schlack, Wolfgang S; Hollmann, Markus W; Weber, Nina C; Preckel, Benedikt

    2013-01-01

    Helium protects myocardium by inducing preconditioning in animals. We investigated whether human endothelium is preconditioned by helium inhalation in vivo. Forearm ischemia-reperfusion (I/R) in healthy volunteers (each group n = 10) was performed by inflating a blood pressure cuff for 20 min. Endothelium-dependent and endothelium-independent responses were measured after cumulative dose-response infusion of acetylcholine and sodium nitroprusside, respectively, at baseline and after 15 min of reperfusion using strain-gauge, venous occlusion plethysmography. Helium preconditioning was applied by inhalation of helium (79% helium, 21% oxygen) either 15 min (helium early preconditioning [He-EPC]) or 24 h before I/R (helium late preconditioning). Additional measurements of He-EPC were done after blockade of endothelial nitric oxide synthase. Plasma levels of cytokines, adhesion molecules, and cell-derived microparticles were determined. Forearm I/R attenuated endothelium-dependent vasodilation (acetylcholine) with unaltered endothelium-independent response (sodium nitroprusside). Both He-EPC and helium late preconditioning attenuated I/R-induced endothelial dysfunction (max increase in forearm blood flow in response to acetylcholine after I/R was 180 ± 24% [mean ± SEM] without preconditioning, 573 ± 140% after He-EPC, and 290 ± 32% after helium late preconditioning). Protection of helium was comparable to ischemic preconditioning (max forearm blood flow 436 ± 38%) and was not abolished after endothelial nitric oxide synthase blockade. He-EPC did not affect plasma levels of cytokines, adhesion molecules, or microparticles. Helium is a nonanesthetic, nontoxic gas without hemodynamic side effects, which induces early and late preconditioning of human endothelium in vivo. Further studies have to investigate whether helium may be an instrument to induce endothelial preconditioning in patients with cardiovascular risk factors.

  9. 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.

  10. 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.

  11. Dexmedetomidine preconditioning for myocardial protection in ischaemia-reperfusion injury in rats by downregulation of the high mobility group box 1-toll-like receptor 4-nuclear factor κB signalling pathway.

    PubMed

    Yang, Yu-Fan; Peng, Ke; Liu, Hong; Meng, Xiao-Wen; Zhang, Jing-Jing; Ji, Fu-Hai

    2017-03-01

    Pharmacological preconditioning reduces myocardial infarct size in ischaemia-reperfusion (I-R) injury. Dexmedetomidine, a selective α2 -adrenoceptor agonist, has a proven cardioprotective effect when administered prior to I-R, although the underlying mechanisms for this effect are not fully understood. We evaluated whether dexmedetomidine preconditioning could induce a myocardio-protective effect against I-R injury by inhibiting associated inflammatory processes through downregulation of the high mobility group box 1 (HMGB1)-toll-like receptor 4 (TLR4)-nuclear factor κB (NF-κB) signalling pathway. Seventy rats were randomly assigned to seven groups: a control and six test groups, involving I-R for 30 and 120 minutes, respectively, in isolated rat hearts and different pretreatment protocols with dexmedetomidine (10 nmol/L) as well as yohimbine (1 μmol/L) and recombinant HMGB1 peptide (rHMGB1; 20 μg/L), alone or in combination with dexmedetomidine. Cardiac function was recorded; myocardial HMGB1, TLR4, and NF-κB activities and levels of tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were measured as were lactate dehydrogenase (LDH) and creatine kinase (CK) in coronary outflow. Dexmedetomidine preconditioning significantly improved cardiac function (P<.05), downregulated the expression of HMGB1-TLR4-NF-κB, reduced levels of TNF-α and IL-6 in isolated ventricles during I-R injury, and significantly reduced CK and LDH levels in coronary outflow (P<.05). All of these effects were partially reversed by yohimbine (P<.05) or rHMGB1 (P<.05). Dexmedetomidine preconditioning alleviated myocardial I-R injury in rats through inhibition of inflammatory processes associated with downregulation of the HMGB1-TLR4-NF-κB signalling pathway via activation at α2 -adrenergic receptors. © 2016 John Wiley & Sons Australia, Ltd.

  12. Leukemia inhibitory factor blocks expression of Crx and Nrl transcription factors to inhibit photoreceptor differentiation.

    PubMed

    Graham, Dianca R; Overbeek, Paul A; Ash, John D

    2005-07-01

    Activating ligands of gp130, including leukemia inhibitory factor (LIF), can block differentiation and function of retinal neurons. This study focused on determining whether LIF inhibits differentiation of photoreceptors by altering cell fate or by blocking the expression of essential transcription factors in vivo. Transgenic mice were generated that had lens-specific expression of the secreted human LIF protein. Retinal differentiation was assessed by histology and by gene expression analysis, with in situ hybridization, immunohistochemistry, and real-time qRT-PCR. Electroretinograms were used to assess retinal function. LIF did not prevent or alter the timing of outer and inner nuclear layer separation, but it inhibited phototransduction gene expression in both rods and cones, thereby blocking functional maturation of photoreceptors. LIF also reduced the expression of Crx, Nrl, and Nr2e3, and upregulated the expression of transcription inhibitors Baf and Fiz1. LIF expression did not appear to alter photoreceptor cell fate specification, but it inhibited subsequent differentiation. These results suggest that gp130 ligands can inhibit photoreceptor functional differentiation by reducing Crx- and Nrl-dependent transcription.

  13. Across-Species Transfer of Protection by Remote Ischemic Preconditioning With Species-Specific Myocardial Signal Transduction by Reperfusion Injury Salvage Kinase and Survival Activating Factor Enhancement Pathways.

    PubMed

    Skyschally, Andreas; Gent, Sabine; Amanakis, Georgios; Schulte, Christiane; Kleinbongard, Petra; Heusch, Gerd

    2015-07-17

    Reduction of myocardial infarct size by remote ischemic preconditioning (RIPC), that is, cycles of ischemia/reperfusion in an organ remote from the heart before sustained myocardial ischemia/reperfusion, was confirmed in all species so far, including humans. To identify myocardial signal transduction of cardioprotection by RIPC. Anesthetized pigs were subjected to RIPC (4×5/5 minutes hindlimb ischemia/reperfusion) or placebo (PLA) before 60/180 minutes coronary occlusion/reperfusion. Phosphorylation of protein kinase B, extracellular signal-regulated kinase 1/2 (reperfusion injury salvage kinase [RISK] pathway), and signal transducer and activator of transcription 3 (survival activating factor enhancement [SAFE] pathway) in the area at risk was determined by Western blot. Wortmannin/U0126 or AG490 was used for pharmacological RISK or SAFE blockade, respectively. Plasma sampled after RIPC or PLA, respectively, was transferred to isolated bioassay rat hearts subjected to 30/120 minutes global ischemia/reperfusion. RIPC reduced infarct size in pigs to 16±11% versus 43±11% in PLA (% area at risk; mean±SD; P<0.05). RIPC increased the phosphorylation of signal transducer and activator of transcription 3 at early reperfusion, and AG490 abolished the protection, whereas RISK blockade did not. Signal transducer and activator of transcription 5 phosphorylation was decreased at early reperfusion in both RIPC and PLA. In isolated rat hearts, pig plasma taken after RIPC reduced infarct size (25±5% of ventricular mass versus 38±5% in PLA; P<0.05) and activated both RISK and SAFE. RISK or SAFE blockade abrogated this protection. Cardioprotection by RIPC in pigs causally involves activation of signal transducer and activator of transcription 3 but not of RISK. Protection can be transferred with plasma from pigs to isolated rat hearts where activation of both RISK and SAFE is causally involved. The myocardial signal transduction of RIPC is the same as that of ischemic

  14. 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.

  15. The Influence of Diabetes Mellitus in Myocardial Ischemic Preconditioning.

    PubMed

    Rezende, Paulo Cury; Rahmi, Rosa Maria; Hueb, Whady

    Ischemic preconditioning (IP) is a powerful mechanism of protection discovered in the heart in which ischemia paradoxically protects the myocardium against other ischemic insults. Many factors such as diseases and medications may influence IP expression. Although diabetes poses higher cardiovascular risk, the physiopathology underlying this condition is uncertain. Moreover, although diabetes is believed to alter intracellular pathways related to myocardial protective mechanisms, it is still controversial whether diabetes may interfere with ischemic preconditioning and whether this might influence clinical outcomes. This review article looks at published reports with animal models and humans that tried to evaluate the possible influence of diabetes in myocardial ischemic preconditioning.

  16. Preconditioning of bone marrow-derived mesenchymal stromal cells by tetramethylpyrazine enhances cell migration and improves functional recovery after focal cerebral ischemia in rats.

    PubMed

    Li, Lin; Chu, Lisheng; Fang, Yan; Yang, Yan; Qu, Tiebing; Zhang, Jianping; Yin, Yuanjun; Gu, Jingjing

    2017-05-12

    Transplantation of bone marrow-derived mesenchymal stem cells (BMSCs) is one of the new therapeutic strategies for treating ischemic stroke. However, the relatively poor migratory capacity of BMSCs toward infarcted regions limited the therapeutic potential of this approach. Pharmacological preconditioning can increase the expression of CXC chemokine receptor 4 (CXCR4) in BMSCs and enhance cell migration toward the injury site. In the present study, we investigated whether tetramethylpyrazine (TMP) preconditioning could enhance BMSCs migration to the ischemic brain and improve functional recovery through upregulating CXCR4 expression. BMSCs were identified by flow cytometry analysis. BMSCs migration was evaluated in vitro by transwell migration assay, and CXCR4 expression was measured by quantitative reverse transcription-polymerase chain reaction and western blot analysis. In rats with focal cerebral ischemia, the neurological function was evaluated by the modified neurological severity score, the adhesive removal test and the corner test. The homing BMSCs and angiogenesis were detected by immunofluorescence, and expression of stromal cell-derived factor-1 (SDF-1) and CXCR4 was measured by western blot analysis. Flow cytometry analysis demonstrated that BMSCs expressed CD29 and CD90, but not CD34 and CD45. TMP pretreatment dose-dependently induced BMSCs migration and CXCR4 expression in vitro, which was significantly inhibited by AMD3100, a CXCR4 antagonist. In rat stroke models, we found more TMP-preconditioned BMSCs homing toward the infarcted regions than nonpreconditioned cells, leading to improved neurological performance and enhanced angiogenesis. Moreover, TMP-preconditioned BMSCs significantly upregulated the protein expression of SDF-1 and CXCR4 in the ischemic boundary regions. These beneficial effects of TMP preconditioning were blocked by AMD3100. TMP preconditioning enhances the migration and homing ability of BMSCs, increases CXCR4 expression

  17. Hyperbaric oxygen preconditioning attenuates postoperative cognitive impairment in aged rats.

    PubMed

    Sun, Li; Xie, Keliang; Zhang, Changsheng; Song, Rui; Zhang, Hong

    2014-06-18

    Cognitive decline after surgery in the elderly population is a major clinical problem with high morbidity. Hyperbaric oxygen (HBO) preconditioning can induce significant neuroprotection against acute neurological injury. We hypothesized that HBO preconditioning would prevent the development of postoperative cognitive impairment. Elderly male rats (20 months old) underwent stabilized tibial fracture operation under general anesthesia after HBO preconditioning (once a day for 5 days). Separate cohorts of animals were tested for cognitive function with fear conditioning and Y-maze tests, or euthanized at different times to assess the blood-brain barrier integrity, systemic and hippocampal proinflammatory cytokines, and caspase-3 activity. Animals exhibited significant cognitive impairment evidenced by a decreased percentage of freezing time and an increased number of learning trials on days 1, 3, and 7 after surgery, which were significantly prevented by HBO preconditioning. Furthermore, HBO preconditioning significantly ameliorated the increase in serum and hippocampal proinflammatory cytokines tumor necrosis factor-α, interleukin-1 β (IL-1β), IL-6, and high-mobility group protein 1 in surgery-challenged animals. Moreover, HBO preconditioning markedly improved blood-brain barrier integrity and caspase-3 activity in the hippocampus of surgery-challenged animals. These findings suggest that HBO preconditioning could significantly mitigate surgery-induced cognitive impairment, which is strongly associated with the reduction of systemic and hippocampal proinflammatory cytokines and caspase-3 activity.

  18. Preconditioned cues have no value.

    PubMed

    Sharpe, Melissa J; Batchelor, Hannah M; Schoenbaum, Geoffrey

    2017-09-19

    Sensory preconditioning has been used to implicate midbrain dopamine in model-based learning, contradicting the view that dopamine transients reflect model-free value. However, it has been suggested that model-free value might accrue directly to the preconditioned cue through mediated learning. Here, building on previous work (Sadacca et al., 2016), we address this question by testing whether a preconditioned cue will support conditioned reinforcement in rats. We found that while both directly conditioned and second-order conditioned cues supported robust conditioned reinforcement, a preconditioned cue did not. These data show that the preconditioned cue in our procedure does not directly accrue model-free value and further suggest that the cue may not necessarily access value even indirectly in a model-based manner. If so, then phasic response of dopamine neurons to cues in this setting cannot be described as signaling errors in predicting value.

  19. Electrical preconditioning of stem cells with a conductive polymer scaffold enhances stroke recovery.

    PubMed

    George, Paul M; Bliss, Tonya M; Hua, Thuy; Lee, Alex; Oh, Byeongtaek; Levinson, Alexa; Mehta, Swapnil; Sun, Guohua; Steinberg, Gary K

    2017-10-01

    Exogenous human neural progenitor cells (hNPCs) are promising stroke therapeutics, but optimal delivery conditions and exact recovery mechanisms remain elusive. To further elucidate repair processes and improve stroke outcomes, we developed an electrically conductive, polymer scaffold for hNPC delivery. Electrical stimulation of hNPCs alters their transcriptome including changes to the VEGF-A pathway and genes involved in cell survival, inflammatory response, and synaptic remodeling. In our experiments, exogenous hNPCs were electrically stimulated (electrically preconditioned) via the scaffold 1 day prior to implantation. After in vitro stimulation, hNPCs on the scaffold are transplanted intracranially in a distal middle cerebral artery occlusion rat model. Electrically preconditioned hNPCs improved functional outcomes compared to unstimulated hNPCs or hNPCs where VEGF-A was blocked during in vitro electrical preconditioning. The ability to manipulate hNPCs via a conductive scaffold creates a new approach to optimize stem cell-based therapy and determine which factors (such as VEGF-A) are essential for stroke recovery. Copyright © 2017 Elsevier Ltd. All rights reserved.

  20. Popliteal blocks for foot and ankle surgery: success rate and contributing factors.

    PubMed

    Hegewald, Kenneth; McCann, Kevin; Elizaga, Andrew; Hutchinson, Byron L

    2014-01-01

    The purpose of the present study was to evaluate the factors contributing to the success of popliteal nerve blocks performed by podiatric surgical residents in various stages of training. A retrospective review was conducted of 143 consecutively performed blocks during a 2-year period. A total of 29 blocks using a lateral approach and 114 blocks using a modified posterior approach were performed. The intrinsic and extrinsic variables contributing to block outcome were analyzed. A total of 109 successful blocks were performed, for an overall success rate of 76.2%. Significant differences (p < .002) were found between the success and failure groups with respect to the patients body mass index and age. No differences were observed between the success and failure groups with respect to the block approach or months of resident training. In conclusion, podiatric surgical residents in all stages of training can safely and effectively perform popliteal nerve blocks for peri- and postoperative analgesia. Surgeons should be aware of the potential influence of patients body mass index and age on the overall block success rates.

  1. 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

  2. 40 CFR 80.52 - Vehicle preconditioning.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 17 2014-07-01 2014-07-01 false Vehicle preconditioning. 80.52 Section...) REGULATION OF FUELS AND FUEL ADDITIVES Reformulated Gasoline § 80.52 Vehicle preconditioning. (a) Initial vehicle preconditioning and preconditioning between tests with different fuels shall be performed...

  3. 40 CFR 80.52 - Vehicle preconditioning.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 17 2012-07-01 2012-07-01 false Vehicle preconditioning. 80.52 Section...) REGULATION OF FUELS AND FUEL ADDITIVES Reformulated Gasoline § 80.52 Vehicle preconditioning. (a) Initial vehicle preconditioning and preconditioning between tests with different fuels shall be performed...

  4. 40 CFR 80.52 - Vehicle preconditioning.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 17 2013-07-01 2013-07-01 false Vehicle preconditioning. 80.52 Section...) REGULATION OF FUELS AND FUEL ADDITIVES Reformulated Gasoline § 80.52 Vehicle preconditioning. (a) Initial vehicle preconditioning and preconditioning between tests with different fuels shall be performed...

  5. 40 CFR 80.52 - Vehicle preconditioning.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 16 2011-07-01 2011-07-01 false Vehicle preconditioning. 80.52 Section...) REGULATION OF FUELS AND FUEL ADDITIVES Reformulated Gasoline § 80.52 Vehicle preconditioning. (a) Initial vehicle preconditioning and preconditioning between tests with different fuels shall be performed...

  6. 40 CFR 80.52 - Vehicle preconditioning.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 16 2010-07-01 2010-07-01 false Vehicle preconditioning. 80.52 Section...) REGULATION OF FUELS AND FUEL ADDITIVES Reformulated Gasoline § 80.52 Vehicle preconditioning. (a) Initial vehicle preconditioning and preconditioning between tests with different fuels shall be performed...

  7. Hypoxic preconditioning facilitates acclimatization to hypobaric hypoxia in rat heart.

    PubMed

    Singh, Mrinalini; Shukla, Dhananjay; Thomas, Pauline; Saxena, Saurabh; Bansal, Anju

    2010-12-01

    Acute systemic hypoxia induces delayed cardioprotection against ischaemia-reperfusion injury in the heart. As cobalt chloride (CoCl₂) is known to elicit hypoxia-like responses, it was hypothesized that this chemical would mimic the preconditioning effect and facilitate acclimatization to hypobaric hypoxia in rat heart. Male Sprague-Dawley rats treated with distilled water or cobalt chloride (12.5 mg Co/kg for 7 days) were exposed to simulated altitude at 7622 m for different time periods (1, 2, 3 and 5 days). Hypoxic preconditioning with cobalt appreciably attenuated hypobaric hypoxia-induced oxidative damage as observed by a decrease in free radical (reactive oxygen species) generation, oxidation of lipids and proteins. Interestingly, the observed effect was due to increased expression of the antioxidant proteins hemeoxygenase and metallothionein, as no significant change was observed in antioxidant enzyme activity. Hypoxic preconditioning with cobalt increased hypoxia-inducible factor 1α (HIF-1α) expression as well as HIF-1 DNA binding activity, which further resulted in increased expression of HIF-1 regulated genes such as erythropoietin, vascular endothelial growth factor and glucose transporter. A significant decrease was observed in lactate dehydrogenase activity and lactate levels in the heart of preconditioned animals compared with non-preconditioned animals exposed to hypoxia. The results showed that hypoxic preconditioning with cobalt induces acclimatization by up-regulation of hemeoxygenase 1 and metallothionein 1 via HIF-1 stabilization. © 2010 The Authors. JPP © 2010 Royal Pharmaceutical Society of Great Britain.

  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. 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.

  10. 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.

  11. 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.

  12. Delayed remote ischemic preconditioning produces an additive cardioprotection to sevoflurane postconditioning through an enhanced heme oxygenase 1 level partly via nuclear factor erythroid 2-related factor 2 nuclear translocation.

    PubMed

    Zhou, Chenghui; Li, Huatong; Yao, Yuntai; Li, Lihuan

    2014-11-01

    Although both sevoflurane postconditioning (SPoC) and delayed remote ischemic preconditioning (DRIPC) have been proved effective in various animal and human studies, the combined effect of these 2 strategies remains unclear. Therefore, this study was designed to investigate this effect and elucidate the related signal mechanisms in a Langendorff perfused rat heart model. After 30-minute balanced perfusion, isolated hearts were subjected to 30-minute ischemia followed by 60-minute reperfusion except 90-minute perfusion for control. A synergic cardioprotective effect of SPoC (3% v/v) and DRIPC (4 cycles 5-minute occlusion/5-minute reflow at the unilateral hindlimb once per day for 3 days before heart isolation) was observed with facilitated cardiac functional recovery and decreased cardiac enzyme release. The infarct size-limiting effect was more pronounced in the combined group (6.76% ± 2.18%) than in the SPoC group (16.50% ± 4.55%, P < .001) or in the DRIPC group (10.22% ± 2.57%, P = .047). Subsequent analysis revealed that an enhanced heme oxygenase 1 (HO-1) expression, but not protein kinase B/AKt or extracellular signal-regulated kinase 1 and 2 activation, was involved in the synergic cardioprotective effect, which was further confirmed in the messenger RNA level of HO-1. Such trend was also observed in the nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear translocation, an upstream regulation of HO-1. In addition, correlation analysis showed a significantly positive relationship between HO-1 expression and Nrf2 translocation (r = 0.729, P < .001). Hence, we conclude that DRIPC may produce an additive cardioprotection to SPoC through an enhanced HO-1 expression partly via Nrf2 translocation.

  13. Preconditioning-induced CXCL12 upregulation minimizes leukocyte infiltration after stroke in ischemia-tolerant mice.

    PubMed

    Selvaraj, Uma Maheswari; Ortega, Sterling B; Hu, Ruilong; Gilchrist, Robert; Kong, Xiangmei; Partin, Alexander; Plautz, Erik J; Klein, Robyn S; Gidday, Jeffrey M; Stowe, Ann M

    2017-03-01

    Repetitive hypoxic preconditioning creates long-lasting, endogenous protection in a mouse model of stroke, characterized by reductions in leukocyte-endothelial adherence, inflammation, and infarct volumes. The constitutively expressed chemokine CXCL12 can be upregulated by hypoxia and limits leukocyte entry into brain parenchyma during central nervous system inflammatory autoimmune disease. We therefore hypothesized that the sustained tolerance to stroke induced by repetitive hypoxic preconditioning is mediated, in part, by long-term CXCL12 upregulation at the blood-brain barrier (BBB). In male Swiss Webster mice, repetitive hypoxic preconditioning elevated cortical CXCL12 protein levels, and the number of cortical CXCL12+ microvessels, for at least two weeks after the last hypoxic exposure. Repetitive hypoxic preconditioning-treated mice maintained more CXCL12-positive vessels than untreated controls following transient focal stroke, despite cortical decreases in CXCL12 mRNA and protein. Continuous administration of the CXCL12 receptor (CXCR4) antagonist AMD3100 for two weeks following repetitive hypoxic preconditioning countered the increase in CXCL12-positive microvessels, both prior to and following stroke. AMD3100 blocked the protective post-stroke reductions in leukocyte diapedesis, including macrophages and NK cells, and blocked the protective effect of repetitive hypoxic preconditioning on lesion volume, but had no effect on blood-brain barrier dysfunction. These data suggest that CXCL12 upregulation prior to stroke onset, and its actions following stroke, contribute to the endogenous, anti-inflammatory phenotype induced by repetitive hypoxic preconditioning.

  14. Exercise preconditioning of myocardial infarct size in dogs is triggered by calcium.

    PubMed

    Parra, Víctor M; Macho, Pilar; Sánchez, Gina; Donoso, Paulina; Domenech, Raúl J

    2015-03-01

    We showed that exercise induces early and late myocardial preconditioning in dogs and that these effects are mediated through nicotinamide adenine dinucleotide phosphate reduced form (NADPH) oxidase activation. As the intracoronary administration of calcium induces preconditioning and exercise enhances the calcium inflow to the cell, we studied if this effect of exercise triggers exercise preconditioning independently of its hemodynamic effects. We analyzed in 81 dogs the effect of blocking sarcolemmal L-type Ca channels with a low dose of verapamil on early and late preconditioning by exercise, and in other 50 dogs, we studied the effect of verapamil on NADPH oxidase activation in early exercise preconditioning. Exercise reduced myocardial infarct size by 76% and 52% (early and late windows respectively; P < 0.001 both), and these effects were abolished by a single low dose of verapamil given before exercise. This dose of verapamil did not modify the effect of exercise on metabolic and hemodynamic parameters. In addition, verapamil blocked the activation of NADPH oxidase during early preconditioning. The protective effect of exercise preconditioning on myocardial infarct size is triggered, at least in part, by calcium inflow increase to the cell during exercise and, during the early window, is mediated by NADPH oxidase activation.

  15. 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.

  16. Preconditioning for traumatic brain injury.

    PubMed

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

    2013-02-01

    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 preconditioning 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 future clinical situations, in which pre-TBI preconditioning could be considered.

  17. Regional block anesthesia in a patient with factor V Leiden mutation and axillary artery occlusion

    PubMed Central

    Erkalp, Kerem; Comlekci, Mevlut; Inan, Bekir; Basaranoglu, Gokcen; Ozdemir, Haluk; Saidoglu, Leyla

    2011-01-01

    Anesthetic management of patients with coagulation disorders presents safety and technical challenges. This case describes a 58-year-old woman with factor V Leiden mutation who required distal saphenous vein harvest and axillo-brachial bypass to treat axillary artery occlusion. The patient underwent surgery with satisfactory anesthesia using infraclavicular brachial plexus block, thoracic paravertebral block, and unilateral subarachnoid block. These three regional anesthetic interventions were performed in lieu of general anesthesia to minimize risks of thrombotic events, pain, and to decrease recovery time. Despite higher failure rates of regional anesthesia, longer time required for procedures, and added discomforts during surgery, the benefits may outweigh risks for selected high-risk patients, including those with factor V Leiden mutations. PMID:22915885

  18. Pharmacologic Preconditioning: Translating the Promise

    PubMed Central

    Gidday, Jeffrey M.

    2010-01-01

    A transient, ischemia-resistant phenotype known as “ischemic tolerance” can be established in brain in a rapid or delayed fashion by a preceding noninjurious “preconditioning” stimulus. Initial preclinical studies of this phenomenon relied primarily on brief periods of ischemia or hypoxia as preconditioning stimuli, but it was later realized that many other stressors, including pharmacologic ones, are also effective. This review highlights the surprisingly wide variety of drugs now known to promote ischemic tolerance, documented and to some extent mechanistically characterized in preclinical animal models of stroke. Although considerably more experimentation is needed to thoroughly validate the ability of any currently identified preconditioning agent to protect ischemic brain, the fact that some of these drugs are already clinically approved for other indications implies that the growing enthusiasm for translational success in the field of pharmacologic preconditioning may be well justified. PMID:21197121

  19. Hypoxic preconditioning enhances neural stem cell transplantation therapy after intracerebral hemorrhage in mice.

    PubMed

    Wakai, Takuma; Narasimhan, Purnima; Sakata, Hiroyuki; Wang, Eric; Yoshioka, Hideyuki; Kinouchi, Hiroyuki; Chan, Pak H

    2016-12-01

    Previous studies have shown that intraparenchymal transplantation of neural stem cells ameliorates neurological deficits in animals with intracerebral hemorrhage. However, hemoglobin in the host brain environment causes massive grafted cell death and reduces the effectiveness of this approach. Several studies have shown that preconditioning induced by sublethal hypoxia can markedly improve the tolerance of treated subjects to more severe insults. Therefore, we investigated whether hypoxic preconditioning enhances neural stem cell resilience to the hemorrhagic stroke environment and improves therapeutic effects in mice. To assess whether hypoxic preconditioning enhances neural stem cell survival when exposed to hemoglobin, neural stem cells were exposed to 5% hypoxia for 24 hours before exposure to hemoglobin. To study the effectiveness of hypoxic preconditioning on grafted-neural stem cell recovery, neural stem cells subjected to hypoxic preconditioning were grafted into the parenchyma 3 days after intracerebral hemorrhage. Hypoxic preconditioning significantly enhanced viability of the neural stem cells exposed to hemoglobin and increased grafted-cell survival in the intracerebral hemorrhage brain. Hypoxic preconditioning also increased neural stem cell secretion of vascular endothelial growth factor. Finally, transplanted neural stem cells with hypoxic preconditioning exhibited enhanced tissue-protective capability that accelerated behavioral recovery. Our results suggest that hypoxic preconditioning in neural stem cells improves efficacy of stem cell therapy for intracerebral hemorrhage.

  20. Comparison results for solving preconditioned linear systems

    NASA Astrophysics Data System (ADS)

    Li, Wen

    2005-04-01

    In this paper we present some comparison theorems between two different modified Gauss-Seidel (MGS) methods. The second preconditioning based on the first preconditioning is also discussed in this paper.

  1. 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.

  2. 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.

  3. Active iris mechanics and pupillary block: steady-state analysis and comparison with anatomical risk factors.

    PubMed

    Huang, Eric C; Barocas, Victor H

    2004-09-01

    Primary angle-closure glaucoma arises when the iris physically obstructs outflow of aqueous humor, increasing the intraocular pressure and damaging the optic nerve. Pupillary block, the predominant mechanism for angle closure, is believed to be driven by mechanical interaction between the aqueous humor and the iris. We performed steady-state simulations of this coupled fluid-solid system, including an active sphincter to control pupil constriction. Model results compared favorably against Mapstone's pupil-blocking force analysis. We also evaluated anatomical risk factors and quantified their contributions to pupillary block and angle closure. The results showed that greater lens curvature and shorter iris-zonule distance contribute significantly to pupillary block and the associated narrowing of the angle. Surprisingly, the model predicted that maximum pupillary block and angle closure occur at the minimum pupil dilation, contradicting the clinical observation that angle closure is most severe in dark conditions. This discrepancy suggests the involvement of one or more phenomena not captured by our current model.

  4. Resveratrol exerts pharmacological preconditioning by activating PGC-1alpha.

    PubMed

    Tan, Lan; Yu, Jin-Tai; Guan, Hua-Shi

    2008-11-01

    Resveratrol (RSV), a polyphenol phytoalexin abundantly found in grape skins and in wines, is currently the focus of intense research as a pharmacological preconditioning agent in kidney, heart, and brain from ischemic injury. However, the exact molecular mechanism of RSV preconditioning remains obscure. The data from current studies indicate that pharmacological preconditioning with RSV were attributed to its role as intracellular antioxidant, anti-inflammatory agent, its ability to induce nitric oxide synthase (NOS) expression, its ability to induce angiogenesis, and its ability to increases sirtuin 1 (SIRT1) activity. Peroxisome proliferators-activated receptor (PPAR) gamma co-activator-1alpha (PGC-1alpha) is a member of a family of transcription coactivators that owns mitochondrial biogenesis, antioxidation, growth factor signaling regulation, and angiogenesis activities. And, almost all the signaling pathways activated by RVS involve in PGC-1alpha activity. Moreover, it has been proofed that RVS could mediate an increase PGC-1alpha activity. These significant conditions support the hypothesis that RSV exerts pharmacological preconditioning by activating PGC-1alpha. Attempts to confirm this hypothesis will provide new directions in the study of pharmaceutical preconditioning and the development of new treatment approaches for reducing the extent of ischemia/reperfusion injury.

  5. The divergent roles of autophagy in ischemia and preconditioning

    PubMed Central

    Sheng, Rui; Qin, Zheng-hong

    2015-01-01

    Autophagy is an evolutionarily conserved and lysosome-dependent process for degrading and recycling cellular constituents. Autophagy is activated following an ischemic insult or preconditioning, but it may exert dual roles in cell death or survival during these two processes. Preconditioning or lethal ischemia may trigger autophagy via multiple signaling pathways involving endoplasmic reticulum (ER) stress, AMPK/TSC/mTOR, Beclin 1/BNIP3/SPK2, and FoxO/NF-κB transcription factors, etc. Autophagy then interacts with apoptotic and necrotic signaling pathways to regulate cell death. Autophagy may also maintain cell function by removing protein aggregates or damaged mitochondria. To date, the dual roles of autophagy in ischemia and preconditioning have not been fully clarified. The purpose of the present review is to summarize the recent progress in the mechanisms underlying autophagy activation during ischemia and preconditioning. A better understanding of the dual effects of autophagy in ischemia and preconditioning could help to develop new strategies for the preventive treatment of ischemia. PMID:25832421

  6. Xenon preconditioning reduces brain damage from neonatal asphyxia in rats.

    PubMed

    Ma, Daqing; Hossain, Mahmuda; Pettet, Garry K J; Luo, Yan; Lim, Ta; Akimov, Stanislav; Sanders, Robert D; Franks, Nicholas P; Maze, Mervyn

    2006-02-01

    Xenon attenuates on-going neuronal injury in both in vitro and in vivo models of hypoxic-ischaemic injury when administered during and after the insult. In the present study, we sought to investigate whether the neuroprotective efficacy of xenon can be observed when administered before an insult, referred to as 'preconditioning'. In a neuronal-glial cell coculture, preexposure to xenon for 2 h caused a concentration-dependent reduction of lactate dehydrogenase release from cells deprived of oxygen and glucose 24 h later; xenon's preconditioning effect was abolished by cycloheximide, a protein synthesis inhibitor. Preconditioning with xenon decreased propidium iodide staining in a hippocampal slice culture model subjected to oxygen and glucose deprivation. In an in vivo model of neonatal asphyxia involving hypoxic-ischaemic injury to 7-day-old rats, preconditioning with xenon reduced infarction size when assessed 7 days after injury. Furthermore, a sustained improvement in neurologic function was also evident 30 days after injury. Phosphorylated cAMP (cyclic adenosine 3',5'-monophosphate)-response element binding protein (pCREB) was increased by xenon exposure. Also, the prosurvival proteins Bcl-2 and brain-derived neurotrophic factor were upregulated by xenon treatment. These studies provide evidence for xenon's preconditioning effect, which might be caused by a pCREB-regulated synthesis of proteins that promote survival against neuronal injury.

  7. Peptide Nanofibers Preconditioned with Stem Cell Secretome Are Renoprotective

    PubMed Central

    Wang, Yin; Bakota, Erica; Chang, Benny H.J.; Entman, Mark; Hartgerink, Jeffrey D.

    2011-01-01

    Stem cells may contribute to renal recovery following acute kidney injury, and this may occur through their secretion of cytokines, chemokines, and growth factors. Here, we developed an acellular, nanofiber-based preparation of self-assembled peptides to deliver the secretome of embryonic stem cells (ESCs). Using an integrated in vitro and in vivo approach, we found that nanofibers preconditioned with ESCs could reverse cell hyperpermeability and apoptosis in vitro and protect against lipopolysaccharide-induced acute kidney injury in vivo. The renoprotective effect of preconditioned nanofibers associated with an attenuation of Rho kinase activation. We also observed that the combined presence of follistatin, adiponectin, and secretory leukoprotease during preconditioning was essential to the renoprotective properties of the nanofibers. In summary, we developed a designer-peptide nanofiber that can serve as a delivery platform for the beneficial effects of stem cells without the problems of teratoma formation or limited cell engraftment and viability. PMID:21415151

  8. Cortical spreading depression-induced preconditioning in the brain

    PubMed Central

    Shen, Ping-ping; Hou, Shuai; Ma, Di; Zhao, Ming-ming; Zhu, Ming-qin; Zhang, Jing-dian; Feng, Liang-shu; Cui, Li; Feng, Jia-chun

    2016-01-01

    Cortical spreading depression is a technique used to depolarize neurons. During focal or global ischemia, cortical spreading depression-induced preconditioning can enhance tolerance of further injury. However, the underlying mechanism for this phenomenon remains relatively unclear. To date, numerous issues exist regarding the experimental model used to precondition the brain with cortical spreading depression, such as the administration route, concentration of potassium chloride, induction time, duration of the protection provided by the treatment, the regional distribution of the protective effect, and the types of neurons responsible for the greater tolerance. In this review, we focus on the mechanisms underlying cortical spreading depression-induced tolerance in the brain, considering excitatory neurotransmission and metabolism, nitric oxide, genomic reprogramming, inflammation, neurotropic factors, and cellular stress response. Specifically, we clarify the procedures and detailed information regarding cortical spreading depression-induced preconditioning and build a foundation for more comprehensive investigations in the field of neural regeneration and clinical application in the future. PMID:28123433

  9. Preconditioned iterative methods for fractional diffusion equation

    NASA Astrophysics Data System (ADS)

    Lin, Fu-Rong; Yang, Shi-Wei; Jin, Xiao-Qing

    2014-01-01

    In this paper, we are concerned with numerical methods for the solution of initial-boundary value problems of anomalous diffusion equations of order α∈(1,2). The classical Crank-Nicholson method is used to discretize the fractional diffusion equation and then the spatial extrapolation is used to obtain temporally and spatially second-order accurate numerical estimates. Two preconditioned iterative methods, namely, the preconditioned generalized minimal residual (preconditioned GMRES) method and the preconditioned conjugate gradient for normal residual (preconditioned CGNR) method, are proposed to solve relevant linear systems. Numerical experiments are given to illustrate the efficiency of the methods.

  10. 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.

  11. Ischemic preconditioning. Experimental facts and clinical perspective.

    PubMed

    Post, H; Heusch, G

    2002-12-01

    Brief periods of non-lethal ischemia and reperfusion render the myocardium more resistant to subsequent ischemia. This adaption occurs in a biphasic pattern: the first being active immediately and lasting for 2-3 hrs (early preconditioning), the second starting at 24 hrs until 72 hrs after the initial ischemia (delayed preconditioning) and requiring genomic activation with de novo protein synthesis. Early preconditioning is more potent than delayed preconditioning in reducing infarct size; delayed preconditioning also attenuates myocardial stunning. Early preconditioning depends on the ischemia-induced release of adenosine and opioids and, to a lesser degree, also bradykinin and prostaglandins. These molecules activate G-protein coupled receptors, initiate the activation of KATP channels and generation of oxygen radicals, and stimulate a series of protein kinases with essential roles for protein kinase C, tyrosine kinases and members of the MAP kinase family. Delayed preconditioning is triggered by a similar sequence of events, but in addition essentially depends on eNOS-derived NO. Both early and pharmacological preconditioning can be pharmacologically mimicked by exogenous adenosine, opioids, NO and activators of protein kinase C. Newly synthetized proteins associated with delayed preconditioning comprise iNOS, COX-2, manganese superoxide dismutase and possibly heat shock proteins. The final mechanism of protection by preconditioning is yet unknown; energy metabolism, KATP channels, the sodium-proton exchanger, stabilisation of the cytoskeleton and volume regulation will be discussed. For ethical reasons, evidence for ischemic preconditioning in humans is hard to provide. Clinical findings that parallel experimental ischemic preconditioning are reduced ST-segment elevation and pain during repetitive PTCA or exercise tests, a better prognosis of patients in whom myocardial infarction was preceded by angina, and reduced serum markers of myocardial necrosis after

  12. A peptide derived from neutrophil inhibitory factor (NIF) blocks neutrophil adherence to endothelial cells.

    PubMed

    Madden, K; Janczak, J; McEnroe, G; Lim, D; Hartman, T; Liu, D; Stanton, L

    1997-06-01

    Peptides derived from neutrophil inhibitory factor (NIF), a known antagonist of Mac-1, were evaluated as inhibitors of neutrophil adherence. In vitro assays of adherence employed: 1) human polymorphonuclear cells (PMN), 2) human umbilical vein endothelial cells (HUVEC), and 3) CHO cells expressing ICAM-1 (CHO-ICAM cells). Cells, pretreated with NIF-derived peptides (0.1-100 microM) for 10 minutes, were permitted to adhere for 20 min in the continued presence of peptide. Cell-based assays: 1) PMN adherence to HUVEC, 2) PMN adhesion to immobilized human serum proteins, and 3) adherence of CHO-ICAM cells to immobilized Mac-1. A NIF-derived peptide of 29 amino acids blocked PMN adherence to HUVEC, but behaved somewhat differently than the parent NIF protein. NIF specifically antagonized Mac-1 dependent adherence, but the peptide blocked neutrophil adherence that was dependent upon both Mac-1 and LFA-1 integrins. CHO-ICAM adherence to Mac-1 was blocked by NIF, but not by the peptide. Binding studies with NIF and the peptide indicate that the molecules bind to different sites. A peptide derived from NIF blocks PMN adherence but, unlike NIF, the mechanism of action is not mediated by direct antagonism Mac-1.

  13. Cell signaling in NMDA preconditioning and neuroprotection in convulsions induced by quinolinic acid.

    PubMed

    Severino, Patricia Cardoso; Muller, Gabriele do Amaral Silva; Vandresen-Filho, Samuel; Tasca, Carla Inês

    2011-10-10

    The search for novel, less invasive therapeutic strategies to treat neurodegenerative diseases has stimulated scientists to investigate the mechanisms involved in preconditioning. Preconditioning has been report to occur in many organs and tissues. In the brain, the modulation of glutamatergic transmission is an important and promising target to the use of effective neuroprotective agents. The glutamatergic excitotoxicity is a factor common to neurodegenerative diseases and acute events such as cerebral ischemia, traumatic brain injury and epilepsy. In this review we focus on the neuroprotection and preconditioning by chemical agents. Specially, chemical preconditioning models using N-methyl-d-aspartate (NMDA) pre-treatment, which has demonstrated to lead to neuroprotection against seizures and damage to neuronal tissue induced by quinolinic acid (QA). Here we attempted to gather important results obtained in the study of cellular and molecular mechanisms involved in NMDA preconditioning and neuroprotection.

  14. 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

  15. A precondition prover for analogy.

    PubMed

    Bledsoe, W W

    1995-01-01

    We describe here a prover PC (precondition) that normally acts as an ordinary theorem prover, but which returns a 'precondition' when it is unable to prove the given formula. If F is the formula attempted to be proved and PC returns the precondition Q, then (Q-->F) is a theorem (that PC can prove). This prover, PC, uses a proof-plan. In its simplest mode, when there is no proof-plan, it acts like ordinary abduction. We show here how this method can be used to derive certain proofs by analogy. To do this, it uses a proof-plan from a given guiding proof to help construct the proof of a similar theorem, by 'debugging' (automatically) that proof-plan. We show here the analogy proofs of a few simple example theorems and one hard pair, Ex4 and Ex4L. The given proof-plan for Ex4 is used by the system to prove automatically Ex4; and that same proof-plan is then used to prove Ex4L, during which the proof-plan is 'debugged' (automatically). These two examples are similar to two other, more difficult, theorems from the theory of resolution, namely GCR (the ground completeness of resolution) and GCLR (the ground completeness of lock resolution). GCR and GCLR have also been handled, in essence, by this system but not completed in all their details.

  16. 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. © 2013.

  17. 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

    2016-07-19

    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.

  18. 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.

  19. Vitamin C blocks inflammatory platelet-activating factor mimetics created by cigarette smoking.

    PubMed Central

    Lehr, H A; Weyrich, A S; Saetzler, R K; Jurek, A; Arfors, K E; Zimmerman, G A; Prescott, S M; McIntyre, T M

    1997-01-01

    Cigarette smoking within minutes induces leukocyte adhesion to the vascular wall and formation of intravascular leukocyte-platelet aggregates. We find this is inhibited by platelet-activating factor (PAF) receptor antagonists, and correlates with the accumulation of PAF-like mediators in the blood of cigarette smoke-exposed hamsters. These mediators were PAF-like lipids, formed by nonenzymatic oxidative modification of existing phospholipids, that were distinct from biosynthetic PAF. These PAF-like lipids induced isolated human monocytes and platelets to aggregate, which greatly increased their secretion of IL-8 and macrophage inflammatory protein-1alpha. Both events were blocked by a PAF receptor antagonist. Similarly, blocking the PAF receptor in vivo blocked smoke-induced leukocyte aggregation and pavementing along the vascular wall. Dietary supplementation with the antioxidant vitamin C prevented the accumulation of PAF-like lipids, and it prevented cigarette smoke-induced leukocyte adhesion to the vascular wall and formation of leukocyte-platelet aggregates. This is the first in vivo demonstration of inflammatory phospholipid oxidation products and it suggests a molecular mechanism coupling cigarette smoke with rapid inflammatory changes. Inhibition of PAF-like lipid formation and their intravascular sequela by vitamin C suggests a simple dietary means to reduce smoking-related cardiovascular disease. PMID:9153277

  20. 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.

  1. 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.

  2. Protein disulfide isomerase inhibition blocks thrombin generation in humans by interfering with platelet factor V activation

    PubMed Central

    Stopa, Jack D.; Neuberg, Donna; Puligandla, Maneka; Furie, Bruce; Zwicker, Jeffrey I.

    2017-01-01

    BACKGROUND: Protein disulfide isomerase (PDI) is required for thrombus formation. We previously demonstrated that glycosylated quercetin flavonoids such as isoquercetin inhibit PDI activity and thrombus formation in animal models, but whether extracellular PDI represents a viable anticoagulant target in humans and how its inhibition affects blood coagulation remain unknown. METHODS: We evaluated effects of oral administration of isoquercetin on platelet-dependent thrombin generation in healthy subjects and patients with persistently elevated anti-phospholipid antibodies. RESULTS: Following oral administration of 1,000 mg isoquercetin to healthy adults, the measured peak plasma quercetin concentration (9.2 μM) exceeded its IC50 for inhibition of PDI by isoquercetin in vitro (2.5 ± 0.4 μM). Platelet-dependent thrombin generation decreased by 51% in the healthy volunteers compared with baseline (P = 0.0004) and by 64% in the anti-phospholipid antibody cohort (P = 0.015) following isoquercetin ingestion. To understand how PDI affects thrombin generation, we evaluated substrates of PDI identified using an unbiased mechanistic-based substrate trapping approach. These studies identified platelet factor V as a PDI substrate. Isoquercetin blocked both platelet factor Va and thrombin generation with an IC50 of ~5 μM. Inhibition of PDI by isoquercetin ingestion resulted in a 53% decrease in the generation of platelet factor Va (P = 0.001). Isoquercetin-mediated inhibition was reversed with addition of exogenous factor Va. CONCLUSION: These studies show that oral administration of isoquercetin inhibits PDI activity in plasma and diminishes platelet-dependent thrombin generation predominantly by blocking the generation of platelet factor Va. These pharmacodynamic and mechanistic observations represent an important step in the development of a novel class of antithrombotic agents targeting PDI. TRIAL REGISTRATION: Clinicaltrials.gov (NCT01722669) FUNDING: National Heart

  3. Cellular and Molecular Neurobiology of Brain Preconditioning

    PubMed Central

    Cadet, Jean Lud; Krasnova, Irina N.

    2009-01-01

    The tolerant brain which is a consequence of adaptation to repeated non-lethal insults is accompanied by the up-regulation of protective mechanisms and the down-regulation of pro-degenerative pathways. During the past 20 years, evidence has accumulated to suggest that protective mechanisms include increased production of chaperones, trophic factors, and other anti-apoptotic proteins. In contrast, preconditioning can cause substantial dampening of the organism’s metabolic state and decreased expression of pro-apoptotic proteins. Recent microarray analyses have also helped to document a role of several molecular pathways in the induction of the brain refractory state. The present review highlights some of these findings and suggests that a better understanding of these mechanisms will inform treatment of a number of neuropsychiatric disorders. PMID:19153843

  4. Cellular and molecular neurobiology of brain preconditioning.

    PubMed

    Cadet, Jean Lud; Krasnova, Irina N

    2009-02-01

    The tolerant brain which is a consequence of adaptation to repeated nonlethal insults is accompanied by the upregulation of protective mechanisms and the downregulation of prodegenerative pathways. During the past 20 years, evidence has accumulated to suggest that protective mechanisms include increased production of chaperones, trophic factors, and other antiapoptotic proteins. In contrast, preconditioning can cause substantial dampening of the organism's metabolic state and decreased expression of proapoptotic proteins. Recent microarray analyses have also helped to document a role of several molecular pathways in the induction of the brain refractory state. The present review highlights some of these findings and suggests that a better understanding of these mechanisms will inform treatment of a number of neuropsychiatric disorders.

  5. Factors Associated With Risk of Neurologic Complications After Peripheral Nerve Blocks: A Systematic Review.

    PubMed

    Sondekoppam, Rakesh V; Tsui, Ban C H

    2017-02-01

    The onset of neurologic complications after regional anesthesia is a complex process and may result from an interaction of host, agent, and environmental risk factors. The purpose of this systematic review was examine the qualitative evidence relating to various risk factors implicated in neurologic dysfunction after peripheral nerve block (PNB). The MEDLINE, OVID, and EMBASE databases were primary sources for literature. Cochrane, LILACS, DARE, IndMed, ERIC, NHS, and HTA via Centre for Reviews and Dissemination (CRD; York University) databases were searched for additional unique results. Randomized controlled studies, case-control studies, cohort studies, retrospective reviews, and case reports/case series reporting neurologic outcomes after PNB were included. Relevant, good-quality systematic reviews were also eligible. Human and animal studies evaluating factors important for neurologic outcomes were assessed separately. Information on study design, outcomes, and quality was extracted and reviewed independently by the 2 review authors. An overall rating of the quality of evidence was assigned using GRADE (Grading of Recommendations Assessment, Development and Evaluation) criteria. Relevant full-text articles were separated based on type (prospective, retrospective, and nonhuman studies). Strengths of association were defined as high, moderate, inconclusive, or inadequate based on study quality and direction of association. The evidence from 77 human studies was reviewed to assess various host, agent, and environmental factors that have been implicated as possible risks. Most of the available evidence regarding the injurious effects of the 3 cardinal agents of mechanical insult, pressure, and neurotoxicity was extracted from animal studies (42 studies). Among the risk factors investigated in humans, block type had a strong association with neurologic outcome. Intraneural injection, which seems to occur commonly with PNBs, showed an inconsistent direction of

  6. 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.

  7. Delayed ischemic preconditioning contributes to renal protection by upregulation of miR-21

    PubMed Central

    Xu, Xialian; Kriegel, Alison J.; Liu, Yong; Usa, Kristie; Mladinov, Domagoj; Liu, Hong; Fang, Yi; Ding, Xiaoqiang; Liang, Mingyu

    2013-01-01

    Delayed ischemic preconditioning effectively protects kidneys from ischemia-reperfusion injury but the mechanism underlying renal protection remains poorly understood. Here we examined the in vivo role of microRNA miR-21 in the renal protection conferred by delayed ischemic preconditioning in mice. A 15 minute renal ischemic preconditioning significantly increased the expression of miR-21 by 4 hours and substantially attenuated ischemia-reperfusion injury induced 4 days later. A locked nucleic acid-modified anti-miR-21 given at the time of ischemic preconditioning knocked down miR-21 and significantly exacerbated subsequent ischemia-reperfusion injury in the mouse kidney. Knockdown of miR-21 resulted in significant upregulation of programmed cell death protein 4, a pro-apoptotic target gene of miR-21, and substantially increased tubular cell apoptosis. Hypoxia inducible factor-1α in the kidney was activated after ischemic preconditioning and blockade of its activity with a decoy abolished the up-regulation of miR-21 in cultured human renal epithelial cells treated with the inducer cobalt chloride. In the absence of ischemic preconditioning, knockdown of miR-21 alone did not significantly affect ischemia-reperfusion injury in the mouse kidney. Thus, upregulation of miR-21 contributes to the protective effect of delayed ischemic preconditioning against subsequent renal ischemia-reperfusion injury. PMID:22785173

  8. Effect of ozone oxidative preconditioning in preventing early radiation-induced lung injury in rats.

    PubMed

    Bakkal, B H; Gultekin, F A; Guven, B; Turkcu, U O; Bektas, S; Can, M

    2013-09-01

    Ionizing radiation causes its biological effects mainly through oxidative damage induced by reactive oxygen species. Previous studies showed that ozone oxidative preconditioning attenuated pathophysiological events mediated by reactive oxygen species. As inhalation of ozone induces lung injury, the aim of this study was to examine whether ozone oxidative preconditioning potentiates or attenuates the effects of irradiation on the lung. Rats were subjected to total body irradiation, with or without treatment with ozone oxidative preconditioning (0.72 mg/kg). Serum proinflammatory cytokine levels, oxidative damage markers, and histopathological analysis were compared at 6 and 72 h after total body irradiation. Irradiation significantly increased lung malondialdehyde levels as an end-product of lipoperoxidation. Irradiation also significantly decreased lung superoxide dismutase activity, which is an indicator of the generation of oxidative stress and an early protective response to oxidative damage. Ozone oxidative preconditioning plus irradiation significantly decreased malondialdehyde levels and increased the activity of superoxide dismutase, which might indicate protection of the lung from radiation-induced lung injury. Serum tumor necrosis factor alpha and interleukin-1 beta levels, which increased significantly following total body irradiation, were decreased with ozone oxidative preconditioning. Moreover, ozone oxidative preconditioning was able to ameliorate radiation-induced lung injury assessed by histopathological evaluation. In conclusion, ozone oxidative preconditioning, repeated low-dose intraperitoneal administration of ozone, did not exacerbate radiation-induced lung injury, and, on the contrary, it provided protection against radiation-induced lung damage.

  9. 40 CFR 1065.518 - Engine preconditioning.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... engine and begin the cold soak as described in § 1065.530(a)(1). (2) Hot-start transient cycle... same ones that apply for emission testing: (1) Cold-start transient cycle. Precondition the engine by running at least one hot-start transient cycle. We will precondition your engine by running two...

  10. Evaluation of formaldehyde and VOCs emission factors from paints in a small chamber: the effects of preconditioning time and coating weight.

    PubMed

    Kim, Jin-A; Kim, Sumin; Kim, Hyun-Joong; Kim, Yong-Shik

    2011-03-15

    The aims of this study were to improve the emission test method for the 20 L small chamber standardized in Korea using paints and to develop an optical test method for paints. The emission factors of the total volatile organic compounds (TVOC) and formaldehyde from oil-based paints, emulsion paints and water-dispersion paints coated at 300 g/m(2) and cured for 24 (48)h were determined using the 20 L small chamber method. The emission factors of TVOC and formaldehyde from all paints under steady state conditions were determined after 7 days with 24 (48)h of curing. The Korean standards require that paints be measured and analyzed on the third day after a test. However, the emission factors of TVOC and formaldehyde from the paints only began to stabilize 7 days after installing the samples. Until now, the emission test results have been reported mainly as concentration vs. time or emission factor vs. time profiles of TVOC and formaldehyde. The emission factors of the target volatile organic compounds (VOCs) and aldehyde types were obtained under specific test conditions according to the different coating weights. For all target volatile organic compounds and aldehyde types examined, the paint coating weight had an effect on emission. Copyright © 2010 Elsevier B.V. All rights reserved.

  11. Caffeine prevents protection in two human models of ischemic preconditioning.

    PubMed

    Riksen, Niels P; Zhou, Zhigang; Oyen, Wim J G; Jaspers, Rogier; Ramakers, Bart P; Brouwer, Rene M H J; Boerman, Otto C; Steinmetz, Neil; Smits, Paul; Rongen, Gerard A

    2006-08-15

    We studied whether caffeine impairs protection by ischemic preconditioning (IP) in humans. Ischemic preconditioning is critically dependent on adenosine receptor stimulation. We hypothesize that the adenosine receptor antagonist caffeine blocks the protective effect of IP. In vivo ischemia-reperfusion injury was assessed in the thenar muscle by 99mTc-annexin A5 scintigraphy. Forty-two healthy volunteers performed forearm ischemic exercise. In 24 subjects, this was preceded by a stimulus for IP. In a randomized double-blinded design, the subjects received caffeine (4 mg/kg) or saline intravenously before the experiment. At reperfusion, 99mTc-annexin A5 was administered intravenously. Targeting of annexin was quantified by region-of-interest analysis, and expressed as percentage difference between experimental and contralateral hand. In vitro, we assessed recovery of contractile function of human atrial trabeculae, harvested during heart surgery, as functional end point of ischemia-reperfusion injury. Field-stimulated contraction was quantified at baseline and after simulated ischemia-reperfusion, in a paired approach with and without 5 min of IP, in the presence (n=13) or absence (n = 17) of caffeine (10 mg/l). Ischemic preconditioning reduced annexin targeting in the absence of caffeine (from 13 +/- 3% to 7 +/- 1% at 1 h, and from 19 +/- 2% to 9 +/- 3% at 4 h after reperfusion, p = 0.006), but not after caffeine administration (targeting 11 +/- 2% and 16 +/- 3% at 1 and 4 h). In vitro, IP improved post-ischemic functional recovery in the control group, but not in the caffeine group (8 +/- 3% vs. -8 +/- 5%, p=0.003). Caffeine abolishes IP in 2 human models at a dose equivalent to the drinking of 2 to 4 cups of coffee. (The Effect of Caffeine on Ischemic Preconditioning; http://clinicaltrials.gov/ct/show/NCT00184912?order=1; NCT00184912).

  12. Blocking brain-derived neurotrophic factor inhibits injury-induced hyperexcitability of hippocampal CA3 neurons.

    PubMed

    Gill, Raminder; Chang, Philip K-Y; Prenosil, George A; Deane, Emily C; McKinney, Rebecca A

    2013-12-01

    Brain trauma can disrupt synaptic connections, and this in turn can prompt axons to sprout and form new connections. If these new axonal connections are aberrant, hyperexcitability can result. It has been shown that ablating tropomyosin-related kinase B (TrkB), a receptor for brain-derived neurotrophic factor (BDNF), can reduce axonal sprouting after hippocampal injury. However, it is unknown whether inhibiting BDNF-mediated axonal sprouting will reduce hyperexcitability. Given this, our purpose here was to determine whether pharmacologically blocking BDNF inhibits hyperexcitability after injury-induced axonal sprouting in the hippocampus. To induce injury, we made Schaffer collateral lesions in organotypic hippocampal slice cultures. As reported by others, we observed a 50% reduction in axonal sprouting in cultures treated with a BDNF blocker (TrkB-Fc) 14 days after injury. Furthermore, lesioned cultures treated with TrkB-Fc were less hyperexcitable than lesioned untreated cultures. Using electrophysiology, we observed a two-fold decrease in the number of CA3 neurons that showed bursting responses after lesion with TrkB-Fc treatment, whereas we found no change in intrinsic neuronal firing properties. Finally, evoked field excitatory postsynaptic potential recordings indicated an increase in network activity within area CA3 after lesion, which was prevented with chronic TrkB-Fc treatment. Taken together, our results demonstrate that blocking BDNF attenuates injury-induced hyperexcitability of hippocampal CA3 neurons. Axonal sprouting has been found in patients with post-traumatic epilepsy. Therefore, our data suggest that blocking the BDNF-TrkB signaling cascade shortly after injury may be a potential therapeutic target for the treatment of post-traumatic epilepsy.

  13. 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

  14. Hypoxia-inducible factor-1alpha blocks differentiation of malignant gliomas.

    PubMed

    Lu, Huimin; Li, Yan; Shu, Minfeng; Tang, Jianjun; Huang, Yijun; Zhou, Yuxi; Liang, Yingjie; Yan, Guangmei

    2009-12-01

    Aberrant differentiation is a characteristic feature of neoplastic transformation, while hypoxia in solid tumors is believed to be linked to aggressive behavior and poor prognosis. However, the possible relationship between hypoxia and differentiation in malignancies remains poorly defined. Here we show that rat C6 and primary human malignant glioma cells can be induced to differentiate into astrocytes by the well-known adenylate cyclase activator forskolin. However, hypoxia-inducible factor-1alpha expression stimulated by the hypoxia mimetics cobalt chloride or deferoxamine blocks this differentiation and this effectiveness is reversible upon withdrawal of the hypoxia mimetics. Importantly, knockdown of hypoxia inducible factor-1alpha by RNA interference restores the differentiation capabilities of the cells, even in the presence of cobalt chloride, whereas stabilization of hypoxia-inducible factor-1alpha through retarded ubiquitination by von Hippel-Lindau tumor suppressor gene silence abrogates the induced differentiation. Moreover, targeting of HIF-1 using chetomin, a disrupter of HIF-1 binding to its transcriptional co-activator CREB-binding protein (CBP)/p300, abolishes the differentiation-inhibitory effect of hypoxia-inducible factor-1alpha. Administration of chetomin in combination with forskolin significantly suppresses malignant glioma growth in an in vivo xenograft model. Analysis of 95 human glioma tissues revealed an increase of hypoxia-inducible factor-1alpha protein expression with progressing tumor grade. Taken together, these findings suggest a key signal transduction pathway involving hypoxia-inducible factor-1alpha that contributes to a differentiation defect in malignant gliomas and sheds new light on the differentiation therapy of solid tumors by targeting hypoxia-inducible factor-1alpha.

  15. IXOLARIS, A TISSUE FACTOR INHIBITOR, BLOCKS PRIMARY TUMOR GROWTH AND ANGIOGENESIS IN A GLIOBLASTOMA MODEL

    PubMed Central

    Carneiro-Lobo, Tatiana C.; Konig, Sandra; Machado, Daniel E.; Nasciutti, Luiz E.; Forni, Maria Fernanda; Francischetti, Ivo M.B.; Sogayar, Mari C.; Monteiro, Robson Q.

    2010-01-01

    Summary Background The expression levels of the clotting initiator protein Tissue Factor (TF) correlates with vessel density and the histological malignancy grade of glioma patients. Increased procoagulant tonus in high grade tumors (glioblastomas) also indicate a potential role for TF in progression of this disease, and suggest that anticoagulants could be used as adjuvants for its treatment. Objectives We hypothesized that blocking of TF activity with the tick anticoagulant Ixolaris might interfere with glioblastoma progression. Methods and results TF was identified in U87-MG cells by flow-cytometric and functional assays (extrinsic tenase). In addition, flow-cytometric analysis demonstrated the exposure of phosphatidylserine in the surface of U87-MG cells which supported the assembly of intrinsic tenase (FIXa/FVIIIa/FX) and prothrombinase (FVa/FXa/prothrombin) complexes, accounting for the production of FXa and thrombin, respectively. Ixolaris effectively blocked the in vitro TF-dependent procoagulant activity of U87-MG human glioblastoma cell line and attenuated multimolecular coagulation complexes assembly. Notably, Ixolaris inhibited in vivo tumorigenic potential of U87-MG cells in nude mice, without observable bleeding. This inhibitory effect of Ixolaris on tumor growth was associated with downregulation of VEGF and reduced tumor vascularization. Conclusion Our results suggest that Ixolaris might be a promising agent for anti-tumor therapy of human glioblastoma. PMID:19624457

  16. Proliferative and Invasive Effects of Progesterone-Induced Blocking Factor in Human Glioblastoma Cells

    PubMed Central

    Hansberg-Pastor, Valeria

    2017-01-01

    Progesterone-induced blocking factor (PIBF) is a progesterone (P4) regulated protein expressed in different types of high proliferative cells including astrocytomas, the most frequent and aggressive brain tumors. It has been shown that PIBF increases the number of human astrocytoma cells. In this work, we evaluated PIBF regulation by P4 and the effects of PIBF on proliferation, migration, and invasion of U87 and U251 cells, both derived from human glioblastomas. PIBF mRNA expression was upregulated by P4 (10 nM) from 12 to 24 h. Glioblastoma cells expressed two PIBF isoforms, 90 and 57 kDa. The content of the shorter isoform was increased by P4 at 24 h, while progesterone receptor antagonist RU486 (10 μM) blocked this effect. PIBF (100 ng/mL) increased the number of U87 cells on days 4 and 5 of treatment and induced cell proliferation on day 4. Wound-healing assays showed that PIBF increased the migration of U87 (12–48 h) and U251 (24 and 48 h) cells. Transwell invasion assays showed that PIBF augmented the number of invasive cells in both cell lines at 24 h. These data suggest that PIBF promotes proliferation, migration, and invasion of human glioblastoma cells. PMID:28168193

  17. 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

    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.

  18. Mifepristone causing complete remission of rapidly advancing leukemia with measurement of progesterone-induced blocking factor.

    PubMed

    Check, Jerome H; Check, Diane; Cohen, Rachael; Sarumi, Mojirayo

    2014-05-01

    Mifepristone has been demonstrated to cause palliation from murine and human cancer, even in cancers not known to be positive for expression of progesterone receptors. The aim of the present study was to determine if rapidly advancing chronic lymphocytic leukemia responds to mifepristone therapy, and if so, is this effect related to increased expression of the progesterone-induced blocking factor? An 81-year-old woman with chronic lymphocytic leukemia whose condition progressed to the acute rapidly progressing stage agreed to be exclusively treated orally with 200 mg mifepristone daily. The patient showed a dramatic improvement after a short exposure time to mifepristone. Complete remission has persisted so far for 12 months on exclusive mifepristone therapy. Her PIBF levels were normal before mifepristone therapy and did not change after treatment. Mifepristone can provide marked improvement of human leukemia even in the absence of increased serum PIBF levels.

  19. Human thoracic duct cannulation: manipulation of tumor-specific blocking factors in a patient with malignant melanoma.

    PubMed

    Isbister, W H; Noonan, F P; Halliday, W J; Clunie, G J

    1975-05-01

    Thoracic duct lymph was drained for 28 days from a patient with disseminated malignant melanoma. Lymphocytes were separated from the lymph by centrifugation, and returned to the patient daily. Biochemical and hematologic parameters were monitored in blood and lymph, and were maintained at satisfactory levels throughout the period. Cell-mediated immunity and specific blocking activity directed against melanoma antigens were examined by the leukocyte adherence inhibition test. Blocking factors in drained lymph fell to undetectable levels after 6 days' thoracic duct drainage, whereas it took 9 days for serum blocking factors to fall to similar levels. Peripheral blood leukocytes demonstrated cell-mediated immunity against melanoma antigens before and throughout the period of drainage, except for the immediate postoperative period. Within 24 hours of closure of the thoracic duct fistula, serum blocking activity had returned, and 17 days later the patient died.

  20. 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.

  1. 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.

  2. 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

  3. 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.

  4. 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.

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

    PubMed

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

    2015-09-08

    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.

  6. Atorvastatin preconditioning improves the forward blood flow in the no-reflow rats.

    PubMed

    Shao, Liang; Zhang, Yong; Ma, Aiqun; Zhang, Ping; Wu, Dayin; Li, Wenzhu; Wang, Jue; Liu, Kun; Wang, Zhaohui

    2014-02-01

    Atorvastatin is not only an antilipemic but also used as an anti-inflammatory medicine in heart disease. Our working hypothesis was that atorvastatin preconditioning could improve the forward blood flow in the no-reflow rats associated with inflammation. We investigated that two doses of atorvastatin preconditioning (20 and 5 mg/kg/day) could alleviate deterioration of early cardiac diastolic function in rats with inflammation detected by echocardiography and haemodynamics. This benefit was obtained from the effect of atorvastatin preconditioning on improving forward blood flow and preserving the infarct cardiomyocytes, which was estimated by Thioflavin S and TTC staining in rats with myocardial ischemia/reperfusion. Subsequently, the improving of forward blood flow was ascribed to reduction of microthrombus in microvascular and myocardial fibrosis observed by MSB and Masson's trichrome staining with atorvastatin preconditioning. Ultimately, we found that atorvastatin preconditioning could reduce inflammation factor, such as tumor necrosis factor-α and fibrinogen-like protein 2, both in myocardial and in mononuclear cells, which probably attribute to microcirculation dysfunction in no-reflow rats detected by immunohistochemistry staining, western blot, and ELISA detection, respectively. In conclusion, atorvastatin preconditioning could alleviate deterioration of early cardiac diastolic function and improve the forward blood flow in the no-reflow rats attributing to reduction of TNF-α and fgl-2 expression.

  7. 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

  8. Molecular mechanisms of ischemic preconditioning in the kidney

    PubMed Central

    Haase, Volker H.

    2015-01-01

    More effective therapeutic strategies for the prevention and treatment of acute kidney injury (AKI) are needed to improve the high morbidity and mortality associated with this frequently encountered clinical condition. Ischemic and/or hypoxic preconditioning attenuates susceptibility to ischemic injury, which results from both oxygen and nutrient deprivation and accounts for most cases of AKI. While multiple signaling pathways have been implicated in renoprotection, this review will focus on oxygen-regulated cellular and molecular responses that enhance the kidney's tolerance to ischemia and promote renal repair. Central mediators of cellular adaptation to hypoxia are hypoxia-inducible factors (HIFs). HIFs play a crucial role in ischemic/hypoxic preconditioning through the reprogramming of cellular energy metabolism, and by coordinating adenosine and nitric oxide signaling with antiapoptotic, oxidative stress, and immune responses. The therapeutic potential of HIF activation for the treatment and prevention of ischemic injuries will be critically examined in this review. PMID:26311114

  9. Generalized block-lifting factorization of M-channel biorthogonal filter banks for lossy-to-lossless image coding.

    PubMed

    Suzuki, Taizo; Ikehara, Masaaki; Nguyen, Truong Q

    2012-07-01

    Generalized block-lifting factorization of M-channel (M > 2) biorthogonal filter banks (BOFBs) for lossy-to-lossless image coding is presented in this paper. Since the proposed block-lifting structure is more general than the conventional lifting factorizations and does NOT require many restrictions such as paraunitary, number of channels, and McMillan degree in each building block unlike the conventional lifting factorizations, its coding gain is higher than that of the previous methods. Several proposed BOFBs are designed and applied to image coding. Comparing the results with conventional lossy-to-lossless image coding structures, including the 5/3- and 9/7-tap discrete wavelet transforms in JPEG 2000 and a 4 × 8 hierarchical lapped biorthogonal transform in JPEG XR, the proposed BOFBs achieve better result in both objective measure and perceptual visual quality for the images with a lot of high-frequency components.

  10. 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.

  11. 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.

  12. Pharmacologic preconditioning with berberine attenuating ischemia-induced apoptosis and promoting autophagy in neuron

    PubMed Central

    Zhang, Qichun; Bian, Huimin; Guo, Liwei; Zhu, Huaxu

    2016-01-01

    Pharmacologic preconditioning is an intriguing and emerging approach adopted to prevent injury of ischemia/reperfusion. Neuroprotection is the cardinal effect of these pleiotropic actions of berberine. Here we investigated that whether berberine could acts as a preconditioning stimuli contributing to attenuate hypoxia-induced neurons death as well. Male Sprague-Dawley rats of middle cerebral artery occlusion (MCAO) and rat primary cortical neurons undergoing oxygen and glucose deprivation (OGD) were preconditioned with berberine (40 mg/kg, for 24 h in vivo, and 10-6 mol/L, for 2 h in vitro, respectively). The neurological deficits and cerebral water contents of MCAO rats were evaluated. The autophagy and apoptosis were further determined in primary neurons in vitro. Berberine preconditioning (BP) was then shown to ameliorate the neurological deficits, decrease cerebral water content and promote neurogenesis of MCAO rats. Decreased LDH release from OGD-treated neurons was observed via BP, which was blocked by LY294002 (20 µmol/L), GSK690693 (10 µmol/L), or YC-1 (25 µmol/L). Furthermore, BP stimulated autophagy and inhibited apoptosis via modulated the autophagy-associated proteins LC 3, Beclin-1 and p62, and apoptosis-modulating proteins caspase 3, caspase 8, caspase 9, PARP and BCL-2/Bax. In conclusion, berberine acts as a stimulus of preconditioning that exhibits neuroprotection via promoting autophagy and decreasing anoxia-induced apoptosis. PMID:27158406

  13. 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

  14. 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

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

    PubMed

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

    2015-09-29

    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.

  16. 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.

  17. Effect of remote ischemic preconditioning on kidney injury among high-risk patients undergoing cardiac surgery: a randomized clinical trial.

    PubMed

    Zarbock, Alexander; Schmidt, Christoph; Van Aken, Hugo; Wempe, Carola; Martens, Sven; Zahn, Peter K; Wolf, Britta; Goebel, Ulrich; Schwer, Christian I; Rosenberger, Peter; Haeberle, Helene; Görlich, Dennis; Kellum, John A; Meersch, Melanie

    2015-06-02

    preconditioning on myocardial infarction, stroke, or mortality. Remote ischemic preconditioning significantly attenuated the release of urinary insulinlike growth factor-binding protein 7 and tissue inhibitor of metalloproteinases 2 after surgery (remote ischemic preconditioning, 0.36 vs control, 0.97 ng/mL2/1000; difference, 0.61; 95% CI, 0.27-0.86; P < .001). No adverse events were reported with remote ischemic preconditioning. Among high-risk patients undergoing cardiac surgery, remote ischemic preconditioning compared with no ischemic preconditioning significantly reduced the rate of acute kidney injury and use of renal replacement therapy. The observed reduction in the rate of acute kidney injury and the need for renal replacement warrants further investigation. German Clinical Trials Register Identifier: DRKS00005333.

  18. Hypoxic Preconditioning Increases Survival and Pro-Angiogenic Capacity of Human Cord Blood Mesenchymal Stromal Cells In Vitro

    PubMed Central

    Bader, Andreas Matthäus; Klose, Kristin; Bieback, Karen; Korinth, Dirk; Schneider, Maria; Seifert, Martina; Choi, Yeong-Hoon; Kurtz, Andreas; Falk, Volkmar; Stamm, Christof

    2015-01-01

    Hypoxic preconditioning was shown to improve the therapeutic efficacy of bone marrow-derived multipotent mesenchymal stromal cells (MSCs) upon transplantation in ischemic tissue. Given the interest in clinical applications of umbilical cord blood-derived MSCs, we developed a specific hypoxic preconditioning protocol and investigated its anti-apoptotic and pro-angiogenic effects on cord blood MSCs undergoing simulated ischemia in vitro by subjecting them to hypoxia and nutrient deprivation with or without preceding hypoxic preconditioning. Cell number, metabolic activity, surface marker expression, chromosomal stability, apoptosis (caspases-3/7 activity) and necrosis were determined, and phosphorylation, mRNA expression and protein secretion of selected apoptosis and angiogenesis-regulating factors were quantified. Then, human umbilical vein endothelial cells (HUVEC) were subjected to simulated ischemia in co-culture with hypoxically preconditioned or naïve cord blood MSCs, and HUVEC proliferation was measured. Migration, proliferation and nitric oxide production of HUVECs were determined in presence of cord blood MSC-conditioned medium. Cord blood MSCs proved least sensitive to simulated ischemia when they were preconditioned for 24 h, while their basic behavior, immunophenotype and karyotype in culture remained unchanged. Here, “post-ischemic” cell number and metabolic activity were enhanced and caspase-3/7 activity and lactate dehydrogenase release were reduced as compared to non-preconditioned cells. Phosphorylation of AKT and BAD, mRNA expression of BCL-XL, BAG1 and VEGF, and VEGF protein secretion were higher in preconditioned cells. Hypoxically preconditioned cord blood MSCs enhanced HUVEC proliferation and migration, while nitric oxide production remained unchanged. We conclude that hypoxic preconditioning protects cord blood MSCs by activation of anti-apoptotic signaling mechanisms and enhances their angiogenic potential. Hence, hypoxic preconditioning

  19. 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.

  20. 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.

  1. 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.

  2. 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.

  3. Blocking of tumor necrosis factor activity promotes natural repair of osteochondral defects in rabbit knee

    PubMed Central

    2009-01-01

    Background and purpose Osteochondral defects have a limited capacity for repair. We therefore investigated the effects of tumor necrosis factor (TNF) signal blockade by etanercept (human recombinant soluble TNF receptor) on the repair of osteochondral defects in rabbit knees. Material and methods Osteochondral defects (5 mm in diameter) were created in the femoral patellar groove in rabbits. Soon after the procedure, a first subcutaneous injection of etanercept was performed. This single injection or, alternatively, 4 injections in total (twice a week for 2 weeks) were given. Each of these 2 groups was divided further into 3 subgroups: a low-dose group (0.05 μg/kg), an intermediate-dose group (0.4 μ g/kg), and a high-dose group (1.6 μ g /kg) with 19 rabbits in each. As a control, 19 rabbits were injected with water alone. The rabbits in each subgroup were killed 4 weeks (6 rabbits), 8 weeks (6 rabbits), or 24 weeks (7 rabbits) after surgery and repair was assessed histologically. Results Histological examination revealed that the natural process of repair of the osteochondral defects was promoted by 4 subcutaneous injections of intermediate-dose etanercept and by 1 or 4 injections of high-dose etanercept at the various time points examined postoperatively (4, 8, and 24 weeks). Western blot showed that rabbit TNFα had a high affinity for etanercept. Interpretation Blocking of TNF by etanercept enabled repair of osteochondral defects in rabbit knee. Anti-TNF therapy could be a strategy for the use of tissue engineering for bone and cartilage repair. PMID:19916697

  4. DEMONSTRATION OF A BLOCKING FACTOR IN THE PLASMA AND SPINAL FLUID OF PATIENTS WITH SUBACUTE SCLEROSING PANENCEPHALITIS

    PubMed Central

    Ahmed, Aftab; Strong, Douglas M.; Sell, Kenneth W.; Thurman, Gary B.; Knudsen, Richard C.; Wistar, Richard; Grace, William R.

    1974-01-01

    Conflicting reports on the immune responsiveness of patients with subacute sclerosing panencephalitis (SSPE) have been reported. This report shows that the leucocytes from four SSPE patients exhibited strong sensitivity to both measles and SSPE virus preparations as measured by the macrophage migration inhibition test, mixed lymphocyte virus infected cell culture test, and the lymphotoxin assay. Earlier suggestions that a factor may be operating to suppress cellular reactivity are confirmed by the demonstration that the response of lymphocytes from SSPE patients could be blocked by the addition of SSPE spinal fluid or plasma. It was determined that the blocking factor was stable at –20°C, heat labile at 56°C for 30 minutes, trypsin and neuraminadase sensitive, and had a mol wt greater than 150,000 as determined by Sephadex G-200 gel chromatography. The blocking factor appeared to be specific for SSPE virus and did not block the response of lymphocytes to nonspecific mitogenic agents and other viral and bacterial agents. PMID:4593239

  5. Mitochondrial preconditioning: a potential neuroprotective strategy.

    PubMed

    Correia, Sónia C; Carvalho, Cristina; Cardoso, Susana; Santos, Renato X; Santos, Maria S; Oliveira, Catarina R; Perry, George; Zhu, Xiongwei; Smith, Mark A; Moreira, Paula I

    2010-01-01

    Mitochondria have long been known as the powerhouse of the cell. However, these organelles are also pivotal players in neuronal cell death. Mitochondrial dysfunction is a prominent feature of chronic brain disorders, including Alzheimer's disease (AD) and Parkinson's disease (PD), and cerebral ischemic stroke. Data derived from morphologic, biochemical, and molecular genetic studies indicate that mitochondria constitute a convergence point for neurodegeneration. Conversely, mitochondria have also been implicated in the neuroprotective signaling processes of preconditioning. Despite the precise molecular mechanisms underlying preconditioning-induced brain tolerance are still unclear, mitochondrial reactive oxygen species generation and mitochondrial ATP-sensitive potassium channels activation have been shown to be involved in the preconditioning phenomenon. This review intends to discuss how mitochondrial malfunction contributes to the onset and progression of cerebral ischemic stroke and AD and PD, two major neurodegenerative disorders. The role of mitochondrial mechanisms involved in the preconditioning-mediated neuroprotective events will be also discussed. Mitochondrial targeted preconditioning may represent a promising therapeutic weapon to fight neurodegeneration.

  6. Cyclic mechanical preconditioning improves engineered muscle contraction.

    PubMed

    Moon, Du Geon; Christ, George; Stitzel, Joel D; Atala, Anthony; Yoo, James J

    2008-04-01

    The inability to engineer clinically relevant functional muscle tissue remains a major hurdle to successful skeletal muscle reconstructive procedures. This article describes an in vitro preconditioning protocol that improves the contractility of engineered skeletal muscle after implantation in vivo. Primary human muscle precursor cells (MPCs) were seeded onto collagen-based acellular tissue scaffolds and subjected to cyclic strain in a computer-controlled bioreactor system. Control constructs (static culture conditions) were run in parallel. Bioreactor preconditioning produced viable muscle tissue constructs with unidirectional orientation within 5 days, and in vitro-engineered constructs were capable of generating contractile responses after 3 weeks of bioreactor preconditioning. MPC-seeded constructs preconditioned in the bioreactor for 1 week were also implanted onto the latissimus dorsi muscle of athymic mice. Analysis of tissue constructs retrieved 1 to 4 weeks postimplantation showed that bioreactor-preconditioned constructs, but not statically cultured control tissues, generated tetanic and twitch contractile responses with a specific force of 1% and 10%, respectively, of that observed on native latissimus dorsi. To our knowledge, this is the largest force generated for tissue-engineered skeletal muscle on an acellular scaffold. This finding has important implications to the application of tissue engineering and regenerative medicine to skeletal muscle replacement and reconstruction.

  7. Minocycline-preconditioned neural stem cells enhance neuroprotection after ischemic stroke in rats.

    PubMed

    Sakata, Hiroyuki; Niizuma, Kuniyasu; Yoshioka, Hideyuki; Kim, Gab Seok; Jung, Joo Eun; Katsu, Masataka; Narasimhan, Purnima; Maier, Carolina M; Nishiyama, Yasuhiro; Chan, Pak H

    2012-03-07

    Transplantation of neural stem cells (NSCs) offers a novel therapeutic strategy for stroke; however, massive grafted cell death following transplantation, possibly due to a hostile host brain environment, lessens the effectiveness of this approach. Here, we have investigated whether reprogramming NSCs with minocycline, a broadly used antibiotic also known to possess cytoprotective properties, enhances survival of grafted cells and promotes neuroprotection in ischemic stroke. NSCs harvested from the subventricular zone of fetal rats were preconditioned with minocycline in vitro and transplanted into rat brains 6 h after transient middle cerebral artery occlusion. Histological and behavioral tests were examined from days 0-28 after stroke. For in vitro experiments, NSCs were subjected to oxygen-glucose deprivation and reoxygenation. Cell viability and antioxidant gene expression were analyzed. Minocycline preconditioning protected the grafted NSCs from ischemic reperfusion injury via upregulation of Nrf2 and Nrf2-regulated antioxidant genes. Additionally, preconditioning with minocycline induced the NSCs to release paracrine factors, including brain-derived neurotrophic factor, nerve growth factor, glial cell-derived neurotrophic factor, and vascular endothelial growth factor. Moreover, transplantation of the minocycline-preconditioned NSCs significantly attenuated infarct size and improved neurological performance, compared with non-preconditioned NSCs. Minocycline-induced neuroprotection was abolished by transfecting the NSCs with Nrf2-small interfering RNA before transplantation. Thus, preconditioning with minocycline, which reprograms NSCs to tolerate oxidative stress after ischemic reperfusion injury and express higher levels of paracrine factors through Nrf2 up-regulation, is a simple and safe approach to enhance the effectiveness of transplantation therapy in ischemic stroke.

  8. The dual role of prostaglandin E(2) in excitotoxicity and preconditioning-induced neuroprotection.

    PubMed

    Gendron, Tania F; Brunette, Eric; Tauskela, Joseph S; Morley, Paul

    2005-07-04

    Cyclooxygenase-2 is harmful in models of cerebral ischemia yet plays a protective role in preconditioning-induced ischemic tolerance in the heart. This study examined the mechanisms underlying cyclooxygenase-2-mediated neurotoxicity and preconditioning-induced neuroprotection in an in vitro model of cerebral ischemia. Inhibition of cyclooxygenase-2 protects cortical neuronal cultures from death induced by oxygen-glucose deprivation and reduces oxygen-glucose deprivation-induced increases in intracellular Ca(2+) ([Ca(2+)](i)). In the present study, we determined if prostaglandin E(2) (PGE(2)) is responsible for this cyclooxygenase-2-mediated effect. Rat cortical cultures expressed mRNA for the prostanoid EP(1)-EP(4) receptors. PGE(2) reversed the attenuation in [Ca(2+)](i) and the protection offered by cyclooxygenase-2 inhibition during oxygen-glucose deprivation. These effects likely occur via activation of the prostanoid EP(1) receptor since blocking this receptor during oxygen-glucose deprivation reduced [Ca(2+)](i) and neurotoxicity. Next, we considered if the moderate activation of this pathway, by preconditioning cultures with sub-lethal oxygen-glucose deprivation, influenced the development of tolerance to an otherwise lethal oxygen-glucose deprivation insult, 48 h later. Inhibition of cyclooxygenase-2 during oxygen-glucose deprivation-preconditioning abolished preconditioning-induced protection. Furthermore, cultures were rendered tolerant to oxygen-glucose deprivation by the transient exposure to exogenous PGE(2) 24 h prior to the insult, indicating that this product of the cyclooxygenase-2 pathway is sufficient to induce ischemic tolerance. This study shows that cyclooxygenase-2 and PGE(2) are involved in both oxygen-glucose deprivation-induced neurotoxicity and preconditioning-induced neuroprotection. While neurotoxic in the context of lethal oxygen-glucose deprivation, the moderate activation of this signalling pathway confers ischemic tolerance.

  9. Mechanical preconditioning enables electrophysiologic coupling of skeletal myoblast cells to myocardium.

    PubMed

    Neef, Klaus; Choi, Yeong-Hoon; Srinivasan, Sureshkumar Perumal; Treskes, Philipp; Cowan, Douglas B; Stamm, Christof; Rubach, Martin; Adelmann, Roland; Wittwer, Thorsten; Wahlers, Thorsten

    2012-11-01

    The effect of mechanical preconditioning on skeletal myoblasts in engineered tissue constructs was investigated to resolve issues associated with conduction block between skeletal myoblast cells and cardiomyocytes. Murine skeletal myoblasts were used to generate engineered tissue constructs with or without application of mechanical strain. After in vitro myotube formation, engineered tissue constructs were co-cultured for 6 days with viable embryonic heart slices. With the use of sharp electrodes, electrical coupling between engineered tissue constructs and embryonic heart slices was assessed in the presence or absence of pharmacologic agents. The isolation and expansion procedure for skeletal myoblasts resulted in high yields of homogeneously desmin-positive (97.1% ± 0.1%) cells. Mechanical strain was exerted on myotubes within engineered tissue constructs during gelation of the matrix, generating preconditioned engineered tissue constructs. Electrical coupling between preconditioned engineered tissue constructs and embryonic heart slices was observed; however, no coupling was apparent when engineered tissue constructs were not subjected to mechanical strain. Coupling of cells from engineered tissue constructs to cells in embryonic heart slices showed slower conduction velocities than myocardial cells with the embryonic heart slices (preconditioned engineered tissue constructs vs embryonic heart slices: 0.04 ± 0.02 ms vs 0.10 ± 0.05 ms, P = .011), lower maximum stimulation frequencies (preconditioned engineered tissue constructs vs embryonic heart slices: 4.82 ± 1.42 Hz vs 10.58 ± 1.56 Hz; P = .0009), and higher sensitivities to the gap junction inhibitor (preconditioned engineered tissue constructs vs embryonic heart slices: 0.22 ± 0.07 mmol/L vs 0.93 ± 0.15 mmol/L; P = .0004). We have generated skeletal myoblast-based transplantable grafts that electrically couple to myocardium. Copyright © 2012 The American Association for Thoracic Surgery. Published by

  10. 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.

  11. 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.

  12. Lipopolysaccharide preconditioning facilitates M2 activation of resident microglia after spinal cord injury.

    PubMed

    Hayakawa, Kentaro; Okazaki, Rentaro; Morioka, Kazuhito; Nakamura, Kozo; Tanaka, Sakae; Ogata, Toru

    2014-12-01

    The inflammatory response following spinal cord injury (SCI) has both harmful and beneficial effects; however, it can be modulated for therapeutic benefit. Endotoxin/lipopolysaccharide (LPS) preconditioning, a well-established method for modifying the immune reaction, has been shown to attenuate damage induced by stroke and brain trauma in rodent models. Although such effects likely are conveyed by tissue-repairing functions of the inflammatory response, the mechanisms that control the effects have not yet been elucidated. The present study preconditioned C57BL6/J mice with 0.05 mg/kg of LPS 48 hr before inducing contusion SCI to investigate the effect of LPS preconditioning on the activation of macrophages/microglia. We found that LPS preconditioning promotes the polarization of M1/M2 macrophages/microglia toward an M2 phenotype in the injured spinal cord on quantitative real-time polymerase chain reaction, enzyme-linked immunosorbent assay, and immunohistochemical analyses. Flow cytometric analyses reveal that LPS preconditioning facilitates M2 activation in resident microglia but not in infiltrating macrophages. Augmented M2 activation was accompanied by vascularization around the injured lesion, resulting in improvement in both tissue reorganization and functional recovery. Furthermore, we found that M2 activation induced by LPS preconditioning is regulated by interleukin-10 gene expression, which was preceded by the transcriptional activation of interferon regulatory factor (IRF)-3, as demonstrated by Western blotting and an IRF-3 binding assay. Altogether, our findings demonstrate that LPS preconditioning has a therapeutic effect on SCI through the modulation of M1/M2 polarization of resident microglia. The present study suggests that controlling M1/M2 polarization through endotoxin signal transduction could become a promising therapeutic strategy for various central nervous system diseases. © 2014 Wiley Periodicals, Inc.

  13. Preconditions for successful advance care planning in nursing homes: A systematic review.

    PubMed

    Gilissen, Joni; Pivodic, Lara; Smets, Tinne; Gastmans, Chris; Vander Stichele, Robert; Deliens, Luc; Van den Block, Lieve

    2017-01-01

    There is growing evidence of the potential effectiveness of advance care planning. Yet important knowledge gaps remain regarding the preconditions for successful implementation of advance care planning in the nursing home setting. We aim to identify the preconditions related to successful advance care planning in the nursing home setting. By specifying those, we would be able to make well-founded choices for the future design and planning of advance care planning intervention programs. A systematic review. PubMed, PsycINFO, EMBASE and CINAHL. Two authors independently screened publications. One author assessed methodological quality and extracted textual data, which was double-checked for a random sample. We extracted textual data and used thematic synthesis to identify "preconditions", defined as requirements, conditions and elements necessary to achieve the desired outcome of advance care planning, i.e. attaining concordance between residents' preferences and actual care or treatment received at the end of life. Based on 38 publications, we identified 17 preconditions at five different levels: resident, family, health-care professional, facility and community. Most preconditions were situated on multiple levels but the majority addressed professionals and the nursing home itself. We summarized preconditions in five domains: to have sufficient knowledge and skills, to be willing and able to participate in advance care planning, to have good relationships, to have an administrative system in place, and contextual factors supporting advance care planning within the nursing home. There are multiple preconditions related to successfully implementing advance care planning in the complex nursing home setting that operate at micro, meso and macro level. Future interventions need to address these multiple domains and levels in a whole-system approach in order to be better implementable and more sustainable, while simultaneously target the important role of the health

  14. Preconditioning with a decoupled rowwise ordering on the CM-5

    SciTech Connect

    Toledo, S.

    1995-12-01

    Decoupled rowwise ordering is an ordering scheme for 2-dimensional grids, which is tailored for preconditioning 5-point difference equations arising from discretizations of partial differential equations. This paper describes the ordering scheme and implementations of a conjugate gradient solver and SSOR preconditioners which use the decoupled rowwise and the red black ordering schemes on the CM-5 parallel supercomputer. The rowwise decoupled preconditioner leads to faster convergence than the red black preconditioner, and it reduces the solution time by a factor of 1.5 to 2.5 over a nonpreconditioned solver on a variety of test problems.

  15. Role of decoy molecules in neuronal ischemic preconditioning

    PubMed Central

    Panneerselvam, Mathivadhani; Patel, Piyush M.; Roth, David M.; Kidd, Michael W.; Chin-Lee, Blake; Head, Brian P.; Niesman, Ingrid R.; Inoue, Satoki; Patel, Hemal H.; Davis, Daniel P.

    2011-01-01

    Decoy receptors bind with TNF related apoptosis inducing ligands (TRAIL) but do not contain the cytoplasmic domains necessary to transduce apoptotic signals. We hypothesized that decoy receptors may confer neuronal protection against lethal ischemia after ischemic preconditioning (IPC). Mixed cortical neurons were exposed to IPC one day prior to TRAIL treatment or lethal ischemia. IPC increased decoy receptor but reduced death receptor expression compared to lethal ischemia. IPC-induced increase in decoy receptor expression was reduced by prior treatment with CAPE, a nuclear factor-kappa B inhibitor (NFκB). Expression of decoy molecules, dependent on NFκB, may mediate neuronal survival induced by IPC. PMID:21315738

  16. 40 CFR 1066.816 - Vehicle preconditioning for FTP testing.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 33 2014-07-01 2014-07-01 false Vehicle preconditioning for FTP testing. 1066.816 Section 1066.816 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED... § 1066.816 Vehicle preconditioning for FTP testing. Precondition the test vehicle before the FTP...

  17. 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.

  18. Exercise preconditioning improves traumatic brain injury outcomes.

    PubMed

    Taylor, Jordan M; Montgomery, Mitchell H; Gregory, Eugene J; Berman, Nancy E J

    2015-10-05

    To determine whether 6 weeks of exercise performed prior to traumatic brain injury (TBI) could improve post-TBI behavioral outcomes in mice, and if exercise increases neuroprotective molecules (vascular endothelial growth factor-A [VEGF-A], erythropoietin [EPO], and heme oxygenase-1 [HO-1]) in brain regions responsible for movement (sensorimotor cortex) and memory (hippocampus). 120 mice were randomly assigned to one of four groups: (1) no exercise+no TBI (NOEX-NOTBI [n=30]), (2) no exercise+TBI (NOEX-TBI [n=30]), (3) exercise+no TBI (EX-NOTBI [n=30]), and (4) exercise+TBI (EX-TBI [n=30]). The gridwalk task and radial arm water maze were used to evaluate sensorimotor and cognitive function, respectively. Quantitative real time polymerase chain reaction and immunostaining were performed to investigate VEGF-A, EPO, and HO-1 mRNA and protein expression in the right cerebral cortex and ipsilateral hippocampus. EX-TBI mice displayed reduced post-TBI sensorimotor and cognitive deficits when compared to NOEX-TBI mice. EX-NOTBI and EX-TBI mice showed elevated VEGF-A and EPO mRNA in the cortex and hippocampus, and increased VEGF-A and EPO staining of sensorimotor cortex neurons 1 day post-TBI and/or post-exercise. EX-TBI mice also exhibited increased VEGF-A staining of hippocampal neurons 1 day post-TBI/post-exercise. NOEX-TBI mice demonstrated increased HO-1 mRNA in the cortex (3 days post-TBI) and hippocampus (3 and 7 days post-TBI), but HO-1 was not increased in mice that exercised. Improved TBI outcomes following exercise preconditioning are associated with increased expression of specific neuroprotective genes and proteins (VEGF-A and EPO, but not HO-1) in the brain. Copyright © 2015 Elsevier B.V. All rights reserved.

  19. Exercise Preconditioning Improves Traumatic Brain Injury Outcomes

    PubMed Central

    Taylor, Jordan M.; Montgomery, Mitchell H.; Gregory, Eugene J.; Berman, Nancy E.J.

    2015-01-01

    Purpose To determine whether 6 weeks of exercise performed prior to traumatic brain injury (TBI) could improve post-TBI behavioral outcomes in mice, and if exercise increases neuroprotective molecules (vascular endothelial growth factor-A [VEGF-A], erythropoietin [EPO], and heme oxygenase-1 [HO-1]) in brain regions responsible for movement (sensorimotor cortex) and memory (hippocampus). Methods 120 mice were randomly assigned to one of four groups: 1) no exercise + no TBI (NOEX-NOTBI [n=30]), 2) no exercise + TBI (NOEX-TBI [n=30]), 3) exercise + no TBI (EX-NOTBI [n=30]), and 4) exercise + TBI (EX-TBI [n=30]). The gridwalk task and radial arm water maze were used to evaluate sensorimotor and cognitive function, respectively. Quantitative real time polymerase chain reaction and immunostaining were performed to investigate VEGF-A, EPO, and HO-1 mRNA and protein expression in the right cerebral cortex and ipsilateral hippocampus. Results EX-TBI mice displayed reduced post-TBI sensorimotor and cognitive deficits when compared to NOEX-TBI mice. EX-NOTBI and EX-TBI mice showed elevated VEGF-A and EPO mRNA in the cortex and hippocampus, and increased VEGF-A and EPO staining of sensorimotor cortex neurons 1 day post-TBI and/or post-exercise. EX-TBI mice also exhibited increased VEGF-A staining of hippocampal neurons 1 day post-TBI/post-exercise. NOEX-TBI mice demonstrated increased HO-1 mRNA in the cortex (3 days post-TBI) and hippocampus (3 and 7 days post-TBI), but HO-1 was not increased in mice that exercised. Conclusions Improved TBI outcomes following exercise preconditioning are associated with increased expression of specific neuroprotective genes and proteins (VEGF-A and EPO, but not HO-1) in the brain. PMID:26165153

  20. 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.

  1. 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.

  2. 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,…

  3. Preconditioning and tolerance against cerebral ischaemia

    PubMed Central

    Dirnagl, Ulrich; Becker, Kyra; Meisel, Andreas

    2009-01-01

    Neuroprotection and brain repair in patients after acute brain damage are still major unfulfilled medical needs. Pharmacological treatments are either ineffective or confounded by adverse effects. Consequently, endogenous mechanisms by which the brain protects itself against noxious stimuli and recovers from damage are being studied. Research on preconditioning, also known as induced tolerance, over the past decade has resulted in various promising strategies for the treatment of patients with acute brain injury. Several of these strategies are being tested in randomised clinical trials. Additionally, research into preconditioning has led to the idea of prophylactically inducing protection in patients such as those undergoing brain surgery and those with transient ischaemic attack or subarachnoid haemorrhage who are at high risk of brain injury in the near future. In this Review, we focus on the clinical issues relating to preconditioning and tolerance in the brain; specifically, we discuss the clinical situations that might benefit from such procedures. We also discuss whether preconditioning and tolerance occur naturally in the brain and assess the most promising candidate strategies that are being investigated. PMID:19296922

  4. 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…

  5. Neuroprotective Effects of Peptides during Ischemic Preconditioning.

    PubMed

    Zarubina, I V; Shabanov, P D

    2016-02-01

    Experiments on rats showed that neurospecific protein preparations reduce the severity of neurological deficit, restore the structure of individual behavior of the animals with different hypoxia tolerance, and exert antioxidant action during chronic ischemic damage to the brain unfolding during the early and late phases of ischemic preconditioning.

  6. 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…

  7. Factor levels for density comparisons in the split-block spacing design

    Treesearch

    Kurt H. Riitters; Brian J. Stanton; Robbert H. Walkup

    1989-01-01

    The split-block spacing design is a compact test of the effects of within-row and between-row spacings. But the sometimes awkward analysis of density (i.e., trees/ha) effects may deter use of the design. The analysis is simpler if the row spacings are chosen to obtain a balanced set of equally spaced density and rectangularity treatments. A spacing study in poplar (...

  8. Hammerhead ribozyme targeting connective tissue growth factor mRNA blocks transforming growth factor-beta mediated cell proliferation.

    PubMed

    Blalock, Timothy D; Yuan, Rong; Lewin, Alfred S; Schultz, Gregory S

    2004-06-01

    Excessive scarring following trauma or surgery of cornea, conjunctiva or retina can greatly impair visual outcome. At present, no agents are clinically available that selectively reduce activity of genes that regulate fibrosis. Connective tissue growth factor (CTGF) has been linked to fibrosis in several tissues, including cornea and conjunctiva. In this study, hammerhead ribozymes targeting CTGF mRNA were synthesized, kinetic parameters were measured, and the effect on TGF-beta-mediated cell proliferation was measured in cultured human fibroblasts. The mRNA sequence of human CTGF was scanned for potential hammerhead ribozyme cleavage sites, and predicted secondary folding structures around the sites were calculated. Synthetic 12mer ribozymes and 33mer oligonucleotide mRNA targets corresponding to two sites were synthesized, and kinetic constants calculated from Hanes-Wolff plots of in vitro cleavage reactions. The ribozyme with higher percentage cleavage and kinetic rate was cloned into an expression plasmid (pTR-UF21) and stably transfected into cultured human fibroblasts. An inactive ribozyme plasmid served as a negative control. The effects of the ribozyme on expression of TGF-beta-induced CTGF mRNA and protein levels were measured using ELISA and real-time TaqMan quantitative RT-PCR. Finally, the effect of the CTGF ribozyme on TGF-beta-mediated proliferation of fibroblasts was measured using a non-radioactive cell proliferation microtiter assay. Of the eight potential hammerhead ribozyme cleavage sites in human CTGF mRNA, two sites (CHR 745, and CHR 859) were identified with optimal secondary folding. CHR 859 cleaved 94% of the target mRNA, compared to 46% cleavage for CHR 745 after 16 hr of reaction. CHR 859 had a K(m) of 1.56 microM and a K(cat) of 2.97 min(-1), while CHR 745 had a K(m) of 7.80 microM and a K(cat) of 5.7 min(-1). The turnover numbers (K(cat)/K(m)) of CHR 859 and CHR 745 were 1.9 x 10(6) M min(-1) and 7.4 x 10(5) M min(-1), respectively

  9. Neuroprotective Effect of Antioxidants and Moderate Hypoxia as Combined Preconditioning in Cerebral Ischemia.

    PubMed

    Levchenkova, O S; Novikov, V E; Parfenov, E A; Kulagin, K N

    2016-12-01

    We studied combined effect of moderate hypoxia and compounds pQ-4, pQ-915, pQ-1032, and pQ-1104 on neurological deficit and survival of rats after bilateral ligation of common carotid arteries. Preconditioning including moderate hypoxia and treatment with compound pQ-4 produced a neuroprotective effect and increased animal survival during the early (by 51%) and late (by 33.5%) periods of modeled ischemia and reduced neurological deficit (by 50% and 41%, respectively). Moreover, this combination of preconditioning factors prevented postischemic excessive activation of free radical oxidation in brain hemispheres and blood serum.

  10. 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

  11. 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.

  12. Hypoxic preconditioning of human cardiosphere-derived cell sheets enhances cellular functions via activation of the PI3K/Akt/mTOR/HIF-1α pathway

    PubMed Central

    Tanaka, Yuya; Hosoyama, Tohru; Mikamo, Akihito; Kurazumi, Hiroshi; Nishimoto, Arata; Ueno, Koji; Shirasawa, Bungo; Hamano, Kimikazu

    2017-01-01

    Cell sheet technology is a promising therapeutic strategy for the treatment of ischemic diseases such as myocardial infarction. We recently developed a novel protocol, termed “hypoxic preconditioning,” capable of augmenting the therapeutic efficacy of cell sheets. Following this protocol, the pro-angiogenic and anti-fibrotic activity of cell sheets were enhanced by brief incubation of cell sheets under hypoxic culture conditions. However, the precise molecular mechanism underlying the hypoxic preconditioning of cell sheets is unclear. In the present study, we examined signal transducers in cell sheets to identify those responsive to hypoxic preconditioning, using cardiosphere-derived cell (CDC) sheets. We initially tested whether sheet-like structures were suitable for hypoxic preconditioning by comparing them with individual cells. Hypoxic preconditioning was more effective in sheeted cells than in individual cells. Expression of hypoxia inducible factor-1α (HIF-1α) and mammalian target of rapamycin (mTOR) were induced upon hypoxic preconditioning of cell sheets, as was the phosphoinositide 3-kinase (PI3K)/Akt pathway. In addition, hypoxic preconditioning increased phosphorylation of epidermal growth factor receptor (EGFR) and heat shock protein 60 (HSP60) in CDC sheets. Our findings provide novel insights into the utility of hypoxic preconditioning in cell sheet-based technologies for the treatment of ischemic diseases. PMID:28337294

  13. 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.

  14. Two functional epitopes of pigment epithelial-derived factor block angiogenesis and induce differentiation in prostate cancer.

    PubMed

    Filleur, Stephanie; Volz, Karl; Nelius, Thomas; Mirochnik, Yelena; Huang, Hanhua; Zaichuk, Tetiana A; Aymerich, Maria S; Becerra, Sofia P; Yap, Ronald; Veliceasa, Dorina; Shroff, Emelyn H; Volpert, Olga V

    2005-06-15

    Pigment epithelial-derived factor (PEDF), an angiogenesis inhibitor with neurotrophic properties, balances angiogenesis in the eye and blocks tumor progression. Its neurotrophic function and the ability to block vascular leakage is replicated by the PEDF 44-mer peptide (residues 58-101). We analyzed PEDFs' three-dimensional structure and identified a potential receptor-binding surface. Seeking PEDF-based antiangiogenic agents we generated and tested peptides representing the middle and lower regions of this surface. We identified previously unknown antiangiogenic epitopes consisting of the 34-mer (residues 24-57) and a shorter proximal peptide (TGA, residues 16-26) with the critical stretch L19VEEED24 and a fragment within the 44-mer (ERT, residues 78-94), which retained neurotrophic activity. The 34-mer and TGA, but not the 44-mer reproduced PEDF angioinhibitory signals hinged on c-jun-NH2-kinase-dependent nuclear factor of activated T cell deactivation and caused apoptosis. Conversely, the ERT, but not the 34-mer/TGA induced neuronal differentiation. For the 44-mer/ERT, we showed a novel ability to cause neuroendocrine differentiation in prostate cancer cells. PEDF and the peptides bound endothelial and PC-3 prostate cancer cells. Bound peptides were displaced by PEDF, but not by each other, suggesting multiple receptors. PEDF and its active fragments blocked tumor formation when conditionally expressed by PC-3 cells. The 34- and 44-mer used distinct mechanisms: the 34-mer acted on endothelial cells, blocked angiogenesis, and induced apoptosis whereas 44-mer prompted neuroendocrine differentiation in cancer cells. Our results map active regions for the two PEDF functions, signaling via distinct receptors, identify candidate peptides, and provide their mechanism of action for future development of PEDF-based tumor therapies.

  15. Safety of tumour necrosis factor and interleukin-1 blocking agents in rheumatic diseases.

    PubMed

    Botsios, Costantino

    2005-03-01

    The three licensed TNF(alpha) blocking agents (etanercept, infliximab, adalimumab) and the recombinant form of human interleukin-1-receptor antagonist (anakinra) have all been shown to be effective in patients with chronic rheumatic autoimmune diseases; they have also been associated with certain types of serious adverse events. As expected, much of the information on serious events have accumulated during the post-marketing period. Certain serious, but uncommon, adverse events have been observed with all three TNF(alpha) blocking agents, including serious bacterial infections, tuberculosis (TB) and certain opportunistic infections, demyelinating syndromes, and lupus-like reactions. These data suggest that these adverse reactions may be related to blockade of TNF(alpha) and may therefore represent class effects of these agents. However, the severity and degree of risk may not be the same with all three agents. Blockade of interleukin-1 activity with anakinra appears, at present, to be relatively safe. The safety profile of these products will continue to be developed through the use of the registry, periodic safety updates from the passive surveillance program, and safety data from controlled trials of biological therapy for other diseases. Physicians should minimize risks by patient selection and screening for opportunistic infections. Moreover, the choice of the biological agent must be tailored to minimize risks and maximize benefits.

  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. 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.

  18. Prothymosin-alpha preconditioning activates TLR4-TRIF signaling to induce protection of ischemic retina.

    PubMed

    Halder, Sebok Kumar; Matsunaga, Hayato; Ishii, Ken J; Ueda, Hiroshi

    2015-12-01

    preconditioning-induced prevention of retinal ischemic damage is mediated by selective activation of the TIR-domain-containing adapter-inducing interferon-β (TRIF)- interferon regulatory factor 3 (IRF3) pathway downstream of toll-like receptor 4 (TLR4) in microglia, resulting in up-regulation of TRIF-IRF3-dependent protective genes and down-regulation of myeloid differentiation primary response gene 88 (MyD88)-Nuclear factor (NF)κB-dependent injury genes. Detailed investigations would be helpful to test the efficacy of ProTα as a therapeutic agent for the prevention of ischemic disorders.

  19. 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

  20. Interleukin 6-preconditioned neural stem cells reduce ischaemic injury in stroke mice.

    PubMed

    Sakata, Hiroyuki; Narasimhan, Purnima; Niizuma, Kuniyasu; Maier, Carolina M; Wakai, Takuma; Chan, Pak H

    2012-11-01

    Transplantation of neural stem cells provides a promising therapy for stroke. Its efficacy, however, might be limited because of massive grafted-cell death after transplantation, and its insufficient capability for tissue repair. Interleukin 6 is a pro-inflammatory cytokine involved in the pathogenesis of various neurological disorders. Paradoxically, interleukin 6 promotes a pro-survival signalling pathway through activation of signal transducer and activator of transcription 3. In this study, we investigated whether cellular reprogramming of neural stem cells with interleukin 6 facilitates the effectiveness of cell transplantation therapy in ischaemic stroke. Neural stem cells harvested from the subventricular zone of foetal mice were preconditioned with interleukin 6 in vitro and transplanted into mouse brains 6 h or 7 days after transient middle cerebral artery occlusion. Interleukin 6 preconditioning protected the grafted neural stem cells from ischaemic reperfusion injury through signal transducer and activator of transcription 3-mediated upregulation of manganese superoxide dismutase, a primary mitochondrial antioxidant enzyme. In addition, interleukin 6 preconditioning induced secretion of vascular endothelial growth factor from the neural stem cells through activation of signal transducer and activator of transcription 3, resulting in promotion of angiogenesis in the ischaemic brain. Furthermore, transplantation of interleukin 6-preconditioned neural stem cells significantly attenuated infarct size and improved neurological performance compared with non-preconditioned neural stem cells. This interleukin 6-induced amelioration of ischaemic insults was abolished by transfecting the neural stem cells with signal transducer and activator of transcription 3 small interfering RNA before transplantation. These results indicate that preconditioning with interleukin 6, which reprograms neural stem cells to tolerate oxidative stress after ischaemic reperfusion

  1. Identifying factors affecting the safety of mid-block bicycle lanes considering mixed 2-wheeled traffic flow.

    PubMed

    Bai, Lu; Chan, Ching-Yao; Liu, Pan; Xu, Chengcheng

    2017-10-03

    Electric bikes (e-bikes) have been one of the fastest growing trip modes in Southeast Asia over the past 2 decades. The increasing popularity of e-bikes raised some safety concerns regarding urban transport systems. The primary objective of this study was to identify whether and how the generalized linear regression model (GLM) could be used to relate cyclists' safety with various contributing factors when riding in a mid-block bike lane. The types of 2-wheeled vehicles in the study included bicycle-style electric bicycles (BSEBs), scooter-style electric bicycles (SSEBs), and regular bicycles (RBs). Traffic conflict technology was applied as a surrogate measure to evaluate the safety of 2-wheeled vehicles. The safety performance model was developed by adopting a generalized linear regression model for relating the frequency of rear-end conflicts between e-bikes and regular bikes to the operating speeds of BSEBs, SSEBs, and RBs in mid-block bike lanes. The frequency of rear-end conflicts between e-bikes and bikes increased with an increase in the operating speeds of e-bikes and the volume of e-bikes and bikes and decreased with an increase in the width of bike lanes. The large speed difference between e-bikes and bikes increased the frequency of rear-end conflicts between e-bikes and bikes in mid-block bike lanes. A 1% increase in the average operating speed of e-bikes would increase the expected number of rear-end conflicts between e-bikes and bikes by 1.48%. A 1% increase in the speed difference between e-bikes and bikes would increase the expected number of rear-end conflicts between e-bikes/bikes by 0.16%. The conflict frequency in mid-block bike lanes can be modeled using generalized linear regression models. The factors that significantly affected the frequency of rear-end conflicts included the operating speeds of e-bikes, the speed difference between e-bikes and regular bikes, the volume of e-bikes, the volume of bikes, and the width of bike lanes. The

  2. Mitochondria in the middle: exercise preconditioning protection of striated muscle

    PubMed Central

    Rodriguez, Dinah A.; Hord, Jeffrey M.

    2016-01-01

    Abstract Cellular and physiological adaptations to an atmosphere which became enriched in molecular oxygen spurred the development of a layered system of stress protection, including antioxidant and stress response proteins. At physiological levels reactive oxygen and nitrogen species regulate cell signalling as well as intracellular and intercellular communication. Exercise and physical activity confer a variety of stressors on skeletal muscle and the cardiovascular system: mechanical, metabolic, oxidative. Transient increases of stressors during acute bouts of exercise or exercise training stimulate enhancement of cellular stress protection against future insults of oxidative, metabolic and mechanical stressors that could induce injury or disease. This phenomenon has been termed both hormesis and exercise preconditioning (EPC). EPC stimulates transcription factors such as Nrf‐1 and heat shock factor‐1 and up‐regulates gene expression of a cadre of cytosolic (e.g. glutathione peroxidase and heat shock proteins) and mitochondrial adaptive or stress proteins (e.g. manganese superoxide dismutase, mitochondrial KATP channels and peroxisome proliferator activated receptor γ coactivator‐1 (PGC‐1)). Stress response and antioxidant enzyme inducibility with exercise lead to protection against striated muscle damage, oxidative stress and injury. EPC may indeed provide significant clinical protection against ischaemia–reperfusion injury, Type II diabetes and ageing. New molecular mechanisms of protection, such as δ‐opioid receptor regulation and mitophagy, reinforce the notion that mitochondrial adaptations (e.g. heat shock proteins, antioxidant enzymes and sirtuin‐1/PGC‐1 signalling) are central to the protective effects of exercise preconditioning. PMID:27060608

  3. Effect of Thermal Preconditioning Before Excimer Laser Photoablation

    PubMed Central

    Kim, Joon Mo; Park, Woo Chan; Seo, Jeong-Sun; Chang, Hae Ran

    2004-01-01

    The purposes of this study were to assess the expression patterns of heat shock proteins (Hsps), after eyeball heating or cooling, and to elucidate their relationships with corneal wound healing and intraocular complications after excimer laser treatment. Experimental mice were grouped into three according to local pretreatment type: heating, cooling, and control groups. The preconditioning was to apply saline eyedrops onto the cornea prior to photoablation. Following photoablation, we evaluated corneal wound healing, corneal opacity and lens opacity. Hsp expression patterns were elucidated with Western blot and immunohistochemical staining. The heating and cooling groups recovered more rapidly, and showed less corneal and lens opacity than the control group. In the heating and cooling groups, there were more expressions of Hsps in the cornea and lens than in the control group. These results were confirmed in the Hsp 70.1 knockout mouse model. Our study showed that Hsps were induced by the heating or cooling preconditioning, and appeared to be a major factor in protecting the cornea against serious thermal damage. Induced Hsps also seemed to play an important role in rapid wound healing, and decreased corneal and lens opacity after excimer laser ablation. PMID:15201513

  4. Acupuncture for preconditioning of expectancy and/or Pavlovian extinction.

    PubMed

    Lundeberg, Thomas; Lund, Iréne

    2008-12-01

    Both specific and non-specific factors, as well as the therapist, may play a role in acupuncture therapy. Recent results suggest that verum acupuncture has specific physiological effects and that patients expectations and belief regarding a potentially beneficial treatment modulate activity in the reward and self-appraisal systems in the brain. We suggest that acupuncture treatment may partly be regarded and used as an intervention that preconditions expectancy, which results in both conditional reflexes and conditioning of expected reward and self-appraisal. If so, acupuncture should preferably be applied before the start of the specific treatment (drug or behavioural intervention which is given with the intention of achieving a specific outcome) to enhance the specific and non-specific effects. This hypothesis is further supported by the suggestions that acupuncture may be viewed as a neural stimulus that triggers Pavlovian extinction. If this is the case, acupuncture should preferably be applied repeatedly (ie in a learning process) before the start of the specific treatment to initiate the extinction of previous unpleasant associations like pain or anxiety. Our clinical data suggest that acupuncture may precondition expectancy and conditional reflexes as well as induce Pavlovian extinction. Based on the above we suggest that acupuncture should be tried (as an adjunct) before any specific therapy.

  5. Physiology and pharmacology of myocardial preconditioning.

    PubMed

    Raphael, Jacob

    2010-03-01

    Perioperative myocardial ischemia and infarction are not only major sources of morbidity and mortality in patients undergoing surgery but also important causes of prolonged hospital stay and resource utilization. Ischemic and pharmacological preconditioning and postconditioning have been known for more than two decades to provide protection against myocardial ischemia and reperfusion and limit myocardial infarct size in many experimental animal models, as well as in clinical studies (1-3). This paper will review the physiology and pharmacology of ischemic and drug-induced preconditioning and postconditioning of the myocardium with special emphasis on the mechanisms by which volatile anesthetics provide myocardial protection. Insights gained from animal and clinical studies will be presented and reviewed and recommendations for the use of perioperative anesthetics and medications will be given.

  6. The effect of brain death in rat steatotic and non-steatotic liver transplantation with previous ischemic preconditioning.

    PubMed

    Jiménez-Castro, Mónica B; Meroño, Noelia; Mendes-Braz, Mariana; Gracia-Sancho, Jordi; Martínez-Carreres, Laia; Cornide-Petronio, Maria Eugenia; Casillas-Ramirez, Araní; Rodés, Juan; Peralta, Carmen

    2015-01-01

    Most liver grafts undergoing transplantation derive from brain dead donors, which may also show hepatic steatosis, being both characteristic risk factors in liver transplantation. Ischemic preconditioning shows benefits when applied in non-brain dead clinical situations like hepatectomies, whereas it has been less promising in the transplantation from brain dead patients. This study examined how brain death affects preconditioned steatotic and non-steatotic liver grafts undergoing transplantation. Steatotic and non-steatotic grafts from non-brain dead and brain dead-donors were cold stored for 6h and then transplanted. After 2, 4, and 16 h of reperfusion, hepatic damage was analysed. In addition, two therapeutic strategies, ischemic preconditioning and/or acetylcholine pre-treatment, and their underlying mechanisms were characterized. Preconditioning benefits in non-brain dead donors were associated with nitric oxide and acetylcholine generation. In brain dead donors, preconditioning generated nitric oxide but did not promote acetylcholine upregulation, and this resulted in inflammation and damage. Acetylcholine treatment in brain dead donors, through PKC, increased antioxidants and reduced lipid peroxidation, nitrotyrosines and neutrophil accumulation, altogether protecting against damage. The combination of acetylcholine and preconditioning conferred stronger protection against damage, oxidative stress and neutrophil accumulation than acetylcholine treatment alone. These superior beneficial effects were due to a selective preconditioning-mediated generation of nitric oxide and regulation of PPAR and TLR4 pathways, which were not observed when acetylcholine was administered alone. Our findings propose the combination of acetylcholine+preconditioning as a feasible and highly protective strategy to reduce the adverse effects of brain death and to ultimately improve liver graft quality. Copyright © 2014 European Association for the Study of the Liver. Published by

  7. Modal preconditioning of Galerkin spectral methods: Dual bookkeeping for the Delves-Freeman iteration

    NASA Astrophysics Data System (ADS)

    Huang, Zhu; Boyd, John P.

    2015-11-01

    Fourier-Galerkin discretizations of PDEs can often be preconditioned by a matrix that is the union of a dense M × M matrix plus a large matrix that is either diagonal or banded with small bandwidth. This was suggested forty years ago by L.M. Delves. For our two-dimensional example, the preconditioned iteration converges geometrically fast to machine precision in less than ten iterations. If the residual of the partial differential equation is evaluated by Fast Fourier Transform (FFT), the cost scales almost linearly in the number of unknowns. On a 6144 × 6144 grid, the computation needed less than an hour in Matlab on a laptop. The dense block requires a total degree ordering; the FFT evaluation of the residual requires speedometer ordering of the Fourier coefficient matrix. We show that this dual bookkeeping is essential but not difficult.

  8. 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.

  9. Integrated assessment of behavioral and environmental risk factors for Lyme disease infection on Block Island, Rhode Island.

    PubMed

    Finch, Casey; Al-Damluji, Mohammed Salim; 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.

  10. Silymarin and its constituents in cardiac preconditioning.

    PubMed

    Zholobenko, A; Modriansky, M

    2014-09-01

    Silymarin, a standardised extract of Silybum marianum (milk thistle), comprises mainly of silybin, with dehydrosilybin (DHSB), quercetin, taxifolin, silychristin and a number of other compounds which are known to possess a range of salutary effects. Indeed, there is evidence for their role in reducing tumour growth, preventing liver toxicity, and protecting a number of organs against ischemic damage. The hepatoprotective effects of silymarin, especially in preventing Amanita and alcohol intoxication induced damage to the liver, are a well established fact. Likewise, there is weighty evidence that silymarin possesses antimicrobial and anticancer activities. Additionally, it has emerged that in animal models, silymarin can protect the heart, brain, liver and kidneys against ischemia reperfusion injury, probably by preconditioning. The mechanisms of preconditioning are, in general, well studied, especially in the heart. On the other hand, the mechanism by which silymarin protects the heart from ischemia remains largely unexplored. This review, therefore, focuses on evaluating existing studies on silymarin induced cardioprotection in the context of the established mechanisms of preconditioning. Copyright © 2014. Published by Elsevier B.V.

  11. Lck activation mediates neuroprotection during ischemic preconditioning

    PubMed Central

    Bae, Ok-Nam; Rajanikant, Krishnamurthy; Min, Jiangyong; Smith, Jeremy; Baek, Seung-Hoon; Serfozo, Kelsey; Hejabian, Siamak; Lee, Ki Yong; Kassab, Mounzer; Majid, Arshad

    2012-01-01

    The molecular mechanisms underlying preconditioning (PC), a powerful endogenous neuroprotective phenomenon, remain to be fully elucidated. Once identified, these endogenous mechanisms could be manipulated for therapeutic gain. We investigated whether Lck, a member of the Src kinases family, mediates PC. We employed both in vitro primary cortical neurons and in vivo mouse cerebral focal ischemia models of preconditioning, cellular injury and neuroprotection. Genetically engineered mice deficient in LcK, gene silencing using siRNA and pharmacological approaches were used. Cortical neurons preconditioned with sub-lethal exposure to NMDA or oxygen glucose deprivation (OGD) exhibited enhanced Lck kinase activity, and were resistant to injury on subsequent exposure to lethal levels of NMDA or OGD. Lck gene silencing using siRNA abolished tolerance against both stimuli. Lck−/− mice or neurons isolated from Lck−/− mice did not exhibit PC-induced tolerance. An Lck antagonist administered to wild-type mice significantly attenuated the neuroprotective effect of PC in the mouse focal ischemia model. Using pharmacological and gene silencing strategies, we also showed that PKCε is an upstream regulator of Lck, and Fyn is a downstream target of Lck. We have discovered that Lck plays an essential role in PC in both cellular and animal models of stroke. Our data also show that the PKCε-Lck-Fyn axis is a key mediator of PC. These findings provide new opportunities for stroke therapy development. PMID:22623673

  12. Anthrax lethal factor (LF) mediated block of the anthrax protective antigen (PA) ion channel: effect of ionic strength and voltage.

    PubMed

    Neumeyer, Tobias; Tonello, Fiorella; Dal Molin, Federica; Schiffler, Bettina; Orlik, Frank; Benz, Roland

    2006-03-07

    The anthrax toxin complex consists of three different molecules, protective antigen (PA), lethal factor (LF), and edema factor (EF). The activated form of PA, PA(63), forms heptamers that insert at low pH in biological membranes forming ion channels and that are necessary to translocate EF and LF in the cell cytosol. LF and EF are intracellular active enzymes that inhibit the host immune system promoting bacterial outgrowth. Here, PA(63) was reconstituted into artificial lipid bilayer membranes and formed ion-permeable channels. The heptameric PA(63) channel contains a binding site for LF on the cis side of the channel. Full-size LF was found to block the PA(63) channel in a dose- and ionic-strength-dependent way with half-saturation constants in the nanomolar concentration range. The binding curves suggest a 1:1 relationship between (PA(63))(7) and bound LF that blocks the channel. The presence of a His(6) tag at the N-terminal end of LF strongly increases the affinity of LF toward the PA(63) channel, indicating that the interaction between LF and the PA(63) channel occurs at the N terminus of the enzyme. The LF-mediated block of the PA(63)-induced membrane conductance is highly asymmetric with respect to the sign of the applied transmembrane potential. The result suggested that the PA(63) heptamers contain a high-affinity binding site for LF inside domain 1 or the channel vestibule and that the binding is ionic-strength-dependent.

  13. 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.

  14. Aerodynamic shape optimization using preconditioned conjugate gradient methods

    NASA Technical Reports Server (NTRS)

    Burgreen, Greg W.; Baysal, Oktay

    1993-01-01

    In an effort to further improve upon the latest advancements made in aerodynamic shape optimization procedures, a systematic study is performed to examine several current solution methodologies as applied to various aspects of the optimization procedure. It is demonstrated that preconditioned conjugate gradient-like methodologies dramatically decrease the computational efforts required for such procedures. The design problem investigated is the shape optimization of the upper and lower surfaces of an initially symmetric (NACA-012) airfoil in inviscid transonic flow and at zero degree angle-of-attack. The complete surface shape is represented using a Bezier-Bernstein polynomial. The present optimization method then automatically obtains supercritical airfoil shapes over a variety of freestream Mach numbers. Furthermore, the best optimization strategy examined resulted in a factor of 8 decrease in computational time as well as a factor of 4 decrease in memory over the most efficient strategies in current use.

  15. 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.

  16. Evaluation of a new assay kit for intrinsic factor blocking antibody (type I) as an aid in the diagnosis of pernicious anemia.

    PubMed

    Chen, W L; Morishita, R; Eguchi, T; Kawai, T; Uchino, H

    1985-10-01

    Sera from 39 patients with pernicious anemia and 251 patients with various other diseases and 42 healthy normal subjects were tested for intrinsic factor blocking antibody by a Corning commercial kit. Twenty-five (64%) out of 39 pernicious anemia patients showed a positive reaction to the intrinsic factor blocking antibody. The positive incidence of intrinsic factor blocking antibody by this method agreed well with the results obtained in this laboratory over the past 10 years using the charcoal method. No sera from normal subjects tested were positive for the intrinsic factor blocking antibody. All 226 sera with vitamin B12 levels less than 3,500 pg/ml which came from patients without pernicious anemia, were negative for the intrinsic factor blocking antibody. In 15 sera with B12 levels greater than 3,500 pg/ml from patients who received recent B12 medications, 11 sera showed false positive results. On the other hand, no false positive results were obtained by this method in 10 sera with endogenous serum B12 levels greater than 3,500 pg/ml collected from patients with chronic myelogenous leukemia. It is reasonable to presume that this assay is clinically useful for detection of intrinsic factor blocking antibody in the diagnosis of pernicious anemia, if false positive results due to B12 medication are excluded.

  17. Ischemic preconditioning in the hippocampus of a knockout mouse lacking SUR1-based K(ATP) channels.

    PubMed

    Muñoz, Alvaro; Nakazaki, Mitsuhiro; Goodman, J Clay; Barrios, Roberto; Onetti, Carlos G; Bryan, Joseph; Aguilar-Bryan, Lydia

    2003-01-01

    ATP-sensitive K+ (K(ATP)) channels have been implicated in the mechanism of neuronal ischemic preconditioning. To evaluate the role of neuronal/beta-cell-type K(ATP) channels, SUR1 null (Sur1KO) mice lacking (K(IR)6.x/SUR1)(4) K(ATP) channels were subjected to a preconditioning protocol with the use of double carotid occlusion. Wild-type C57BL/6 and Sur1KO mice were subjected to a double carotid block for 40 minutes with or without a 20-minute preconditioning block. After a 10-day reperfusion period, damage was assessed histologically in the hippocampal CA1, CA2, and CA3 areas and in the dentate gyrus. The neuroprotective effects of intracerebroventricular injections of diazoxide, which selectively affects mitochondria versus opening SUR1-type K(ATP) channels, and 5-hydroxydecanoate, a selective blocker of mitoK(ATP) channels, were evaluated with the same protocol. Neurons in the CA1 region of both Sur1KO and wild-type animals subjected to a 20-minute ischemic insult were protected equally from neuronal damage produced by a subsequent 40-minute ischemic period. Pretreatment with diazoxide protected both Sur1KO and wild-type neurons, while 5-hydroxydecanoate augmented neurodegeneration in both strains of animals when administered before a 20-minute bout of ischemia. SUR1-based K(ATP) channels are not obligatory for neuronal preconditioning or augmentation of neurodegeneration by 5-hydroxydecanoate.

  18. 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.

  19. Preconditioned minimal residual methods for Chebyshev spectral calculations

    NASA Technical Reports Server (NTRS)

    Canuto, C.; Quarteroni, A.

    1985-01-01

    The problem of preconditioning the pseudospectral Chebyshev approximation of an elliptic operator is considered. The numerical sensitiveness to variations of the coefficients of the operator are investigated for two classes of preconditioning matrices: one arising from finite differences, the other from finite elements. The preconditioned system is solved by a conjugate gradient type method, and by a Dufort-Frankel method with dynamical parameters. The methods are compared on some test problems with the Richardson method and with the minimal residual Richardson method.

  20. 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. Copyright © 2016 Elsevier Inc. All rights reserved.

  1. 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

  2. Cooperation of Cytokine Signaling with Chimeric Transcription Factors in Leukemogenesis: PML-Retinoic Acid Receptor Alpha Blocks Growth Factor-Mediated Differentiation

    PubMed Central

    Phan, Vernon T.; Shultz, David B.; Truong, Bao-Tran H.; Blake, Timothy J.; Brown, Anna L.; Gonda, Thomas J.; Beau, Michelle M. Le; Kogan, Scott C.

    2003-01-01

    We utilized a mouse model of acute promyelocytic leukemia (APL) to investigate how aberrant activation of cytokine signaling pathways interacts with chimeric transcription factors to generate acute myeloid leukemia. Expression in mice of the APL-associated fusion, PML-RARA, initially has only modest effects on myelopoiesis. Whereas treatment of control animals with interleukin-3 (IL-3) resulted in expanded myelopoiesis without a block in differentiation, PML-RARA abrogated differentiation that normally characterizes the response to IL-3. Retroviral transduction of bone marrow with an IL-3-expressing retrovirus revealed that IL-3 and promyelocytic leukemia-retinoic acid receptor alpha (PML-RARα) combined to generate a lethal leukemia-like syndrome in <21 days. We also observed that a constitutively activated mutant IL-3 receptor, βcV449E, cooperated with PML-RARα in leukemogenesis, whereas a different activated mutant, βcI374N, did not. Analysis of additional mutations introduced into βcV449E showed that, although tyrosine phosphorylation of βc is necessary for cooperation, the Src homology 2 domain-containing transforming protein binding site is dispensable. Our results indicate that chimeric transcription factors can block the differentiative effects of growth factors. This combination can be potently leukemogenic, but the particular manner in which these types of mutations interact determines the ability of such combinations to generate acute myeloid leukemia. PMID:12808098

  3. 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.

  4. 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.

  5. 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.

  6. Matrix preconditioning: a robust operation for optical linear algebra processors.

    PubMed

    Ghosh, A; Paparao, P

    1987-07-15

    Analog electrooptical processors are best suited for applications demanding high computational throughput with tolerance for inaccuracies. Matrix preconditioning is one such application. Matrix preconditioning is a preprocessing step for reducing the condition number of a matrix and is used extensively with gradient algorithms for increasing the rate of convergence and improving the accuracy of the solution. In this paper, we describe a simple parallel algorithm for matrix preconditioning, which can be implemented efficiently on a pipelined optical linear algebra processor. From the results of our numerical experiments we show that the efficacy of the preconditioning algorithm is affected very little by the errors of the optical system.

  7. 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

  8. A Heparin-Mimicking Block Copolymer Both Stabilizes and Increases the Activity of Fibroblast Growth Factor 2 (FGF2)

    PubMed Central

    2016-01-01

    Fibroblast growth factor 2 (FGF2) is a protein involved in cellular functions in applications such as wound healing and tissue regeneration. Stabilization of this protein is important for its use as a therapeutic since the native protein is unstable during storage and delivery. Additionally, the ability to increase the activity of FGF2 is important for its application, particularly in chronic wound healing and the treatment of various ischemic conditions. Here we report a heparin mimicking block copolymer, poly(styrenesulfonate-co-poly(ethylene glycol) methyl ether methacrylate)-b-vinyl sulfonate) (p(SS-co-PEGMA)-b-VS, that contains a segment that enhances the stability of FGF2 and one that binds to the FGF2 receptor. The FGF2 conjugate retained activity after exposure to refrigeration (4 °C) and room temperature (23 °C) for 7 days, while unmodified FGF2 was inactive after these standard storage conditions. A cell study performed with a cell line lacking native heparan sulfate proteoglycans indicated that the conjugated block copolymer facilitated binding of FGF2 to its receptor similar to the addition of heparin to FGF2. A receptor-based enzyme-linked immunosorbant assay (ELISA) confirmed the results. The conjugate also increased the migration of endothelial cells by 80% compared to FGF2 alone. Additionally, the FGF2-p(SS-co-PEGMA)-b-VS stimulated endothelial cell sprouting 250% better than FGF2 at low concentration. These data verify that this rationally designed protein-block copolymer conjugate enhances receptor binding, cellular processes such as migration and tube-like formation, and stability, and suggest that it may be useful for applications in biomaterials, tissue regeneration, and wound healing. PMID:27580376

  9. Nonsteroidal anti-inflammatory drugs attenuate proliferation of colonic carcinoma cells by blocking epidermal growth factor-induced Ca++ mobilization.

    PubMed

    Kokoska, E R; Smith, G S; Miller, T A

    2000-01-01

    Numerous studies suggest that nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit colorectal carcinogenesis. We have previously reported that NSAIDs, in human colonic carcinoma cells (Caco-2), attenuate epidermal growth factor (EGF)-induced cellular proliferation through a process independent of their inhibitory effects on prostaglandin synthesis. Furthermore, separate studies have also suggested that NSAIDs inhibit EGF-induced store-operated Ca++ influx. Thus we developed the hypothesis that NSAIDs may limit the activity of EGF by altering intracellular Ca++ ([Ca++]i) mobilization. Serum-deprived Caco-2 cells were employed for all experimentation. [Ca++]i was measured with Fluo-3 and extracellular Ca++ influx was monitored by quenching Fluo-3 fluorescence with Mn++. Proliferation was quantitated with two assays: cellular nucleic acid and total protein content. Caco-2 cells exposed to EGF demonstrated an initial increase in [Ca++]i which was blocked by neomycin, an inhibitor of IPsubscript 3 generation, and the phospholipase C inhibitor U73122 but not U73343 (inactive control). This was followed by sustained extracellular Ca++ influx, which was attenuated with calcium-free buffer (-Ca++), the store- operated Ca++ channel blocker lanthanum, indomethacin, ibuprofen, and aspirin. In subsequent studies, cells were treated with either serum-free media or EGF +/- the aforementioned inhibitors, and again serum starved. Cells exposed to EGF +/- the inactive phospholipase C inhibitor U73343 demonstrated a significant increase in nucleic acid and protein. However, proliferation induced by EGF was not observed when [Ca++]i elevation was prevented by blocking either internal Ca++ store release via phospholipase C/IPsubscript 3 or sustained Ca++ influx through store-operated Ca++ channels. Sustained [Ca++]i elevation, as induced by EGF, appears to be required for mitogenesis. These data support our premise that one mechanism whereby NSAIDs may attenuate colonic neoplasia is

  10. Iterated preconditioned LSQR method for inverse problems on unstructured grids

    NASA Astrophysics Data System (ADS)

    Arridge, S. R.; Betcke, M. M.; Harhanen, L.

    2014-06-01

    This article presents a method for solving large-scale linear inverse imaging problems regularized with a nonlinear, edge-preserving penalty term such as total variation or the Perona-Malik technique. Our method is aimed at problems defined on unstructured meshes, where such regularizers naturally arise in unfactorized form as a stiffness matrix of an anisotropic diffusion operator and factorization is prohibitively expensive. In the proposed scheme, the nonlinearity is handled with lagged diffusivity fixed point iteration, which involves solving a large-scale linear least squares problem in each iteration. Because the convergence of Krylov methods for problems with discontinuities is notoriously slow, we propose to accelerate it by means of priorconditioning (Bayesian preconditioning). priorconditioning is a technique that, through transformation to the standard form, embeds the information contained in the prior (Bayesian interpretation of a regularizer) directly into the forward operator and thence into the solution space. We derive a factorization-free preconditioned LSQR algorithm (MLSQR), allowing implicit application of the preconditioner through efficient schemes such as multigrid. The resulting method is also matrix-free i.e. the forward map can be defined through its action on a vector. We illustrate the performance of the method on two numerical examples. Simple 1D-deblurring problem serves to visualize the discussion throughout the paper. The effectiveness of the proposed numerical scheme is demonstrated on a three-dimensional problem in fluorescence diffuse optical tomography with total variation regularization derived algebraic multigrid preconditioner, which is the type of large scale, unstructured mesh problem, requiring matrix-free and factorization-free approaches that motivated the work here.

  11. [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.

  12. Nimotuzumab, an antitumor antibody that targets the epidermal growth factor receptor, blocks ligand binding while permitting the active receptor conformation.

    PubMed

    Talavera, Ariel; Friemann, Rosmarie; Gómez-Puerta, Silvia; Martinez-Fleites, Carlos; Garrido, Greta; Rabasa, Ailem; López-Requena, Alejandro; Pupo, Amaury; Johansen, Rune F; Sánchez, Oliberto; Krengel, Ute; Moreno, Ernesto

    2009-07-15

    Overexpression of the epidermal growth factor (EGF) receptor (EGFR) in cancer cells correlates with tumor malignancy and poor prognosis for cancer patients. For this reason, the EGFR has become one of the main targets of anticancer therapies. Structural data obtained in the last few years have revealed the molecular mechanism for ligand-induced EGFR dimerization and subsequent signal transduction, and also how this signal is blocked by either monoclonal antibodies or small molecules. Nimotuzumab (also known as h-R3) is a humanized antibody that targets the EGFR and has been successful in the clinics. In this work, we report the crystal structure of the Fab fragment of Nimotuzumab, revealing some unique structural features in the heavy variable domain. Furthermore, competition assays show that Nimotuzumab binds to domain III of the extracellular region of the EGFR, within an area that overlaps with both the surface patch recognized by Cetuximab (another anti-EGFR antibody) and the binding site for EGF. A computer model of the Nimotuzumab-EGFR complex, constructed by docking and molecular dynamics simulations and supported by mutagenesis studies, unveils a novel mechanism of action, with Nimotuzumab blocking EGF binding while still allowing the receptor to adopt its active conformation, hence warranting a basal level of signaling.

  13. Matrix metalloproteinase inhibition delays wound healing and blocks latent transforming growth factor-β1 promoted myofibroblast formation and function

    PubMed Central

    Mirastschijski, Ursula; Schnabel, Reinhild; Claes, Juliane; Schneider, Wolfgang; Ågren, Magnus S.; Haaksma, Carol; Tomasek, James J.

    2010-01-01

    The ability to regulate wound contraction is critical for wound healing as well as for pathological contractures. Matrix metalloproteinases (MMPs) have been demonstrated to be obligatory for normal wound healing. This study examined the effect the broad-spectrum MMP inhibitor BB-94 has when applied topically to full-thickness skin excisional wounds in rats and its ability to inhibit the promotion of myofibroblast formation and function by latent transforming-growth factor-β1 (TGF-β1). BB-94 delayed wound contraction, as well as all other associated aspects of wound healing examined, including myofibroblast formation, stromal cell proliferation, blood vessel formation, and epithelial wound coverage. Interestingly, BB-94 dramatically increased the level of latent and active MMP-9. The increased levels of active MMP-9 may eventually overcome the ability of BB-94 to inhibit this MMP and may explain why wound contraction and other associated events of wound healing were only delayed and not completely inhibited. BB-94 was also found to inhibit the ability of latent TGF-β1 to promote the formation and function of myofibroblasts. These results suggest that BB-94 could delay wound closure through a two-fold mechanism; by blocking keratinocyte migration and thereby blocking necessary keratinocyte-fibroblast interactions needed for myofibroblast formation and by inhibiting the activation of latent TGF-β1. PMID:20409148

  14. Methamphetamine Preconditioning Causes Differential Changes in Striatal Transcriptional Responses to Large Doses of the Drug

    PubMed Central

    Cadet, Jean Lud; Brannock, Christie; Ladenheim, Bruce; McCoy, Michael T.; Beauvais, Genevieve; Hodges, Amber B.; Lehrmann, Elin; Wood, William H.; Becker, Kevin G.; Krasnova, Irina N.

    2010-01-01

    Methamphetamine (METH) is a toxic drug of abuse, which can cause significant decreases in the levels of monoamines in various brain regions. However, animals treated with progressively increasing doses of METH over several weeks are protected against the toxic effects of the drug. In the present study, we tested the possibility that this pattern of METH injections might be associated with transcriptional changes in the rat striatum, an area of the brain which is known to be very sensitive to METH toxicity and which is protected by METH preconditioning. We found that the presence and absence of preconditioning followed by injection of large doses of METH caused differential expression in different sets of striatal genes. Quantitative PCR confirmed METH-induced changes in some genes of interest. These include small heat shock 27 kD proteins 1 and 2 (HspB1 and HspB2), brain derived neurotrophic factor (BDNF), and heme oxygenase-1 (Hmox-1). Our observations are consistent with previous studies which have reported that ischemic or pharmacological preconditioning can cause reprogramming of gene expression after lethal ischemic insults. These studies add to the growing literature on the effects of preconditioning on the brain transcriptome. PMID:21731535

  15. Macrophage migration inhibitory factor antagonist blocks the development of endometriosis in vivo.

    PubMed

    Khoufache, Khaled; Bazin, Sylvie; Girard, Karine; Guillemette, Julie; Roy, Marie-Christine; Verreault, Jean-Pierre; Al-Abed, Yousef; Foster, Warren; Akoum, Ali

    2012-01-01

    Endometriosis, a disease of reproductive age women, is a major cause of infertility, menstrual disorders and pelvic pain. Little is known about its etiopathology, but chronic pelvic inflammation is a common feature in affected women. Beside symptomatic treatment of endometriosis-associated pain, only two main suboptimal therapeutic approaches (hormonal and invasive surgery) are generally recommended to patients and no specific targeted treatment is available. Our studies led to the detection of a marked increase in the expression of macrophage migration inhibitory factor (MIF) in the eutopic endometrium, the peripheral blood and the peritoneal fluid of women with endometriosis, and in early, vascularized and active endometriotic lesions. Herein, we developed a treatment model of endometriosis, where human endometrial tissue was first allowed to implant into the peritoneal cavity of nude mice, to assess in vivo the effect of a specific antagonist of MIF (ISO-1) on the progression of endometriosis and evaluate its efficacy as a potential therapeutic tool. Administration of ISO-1 led to a significant decline of the number, size and in situ dissemination of endometriotic lesions. We further showed that ISO-1 may act by significantly inhibiting cell adhesion, tissue remodeling, angiogenesis and inflammation as well as by altering the balance of pro- and anti-apoptotic factors. Actually, mice treatment with ISO-1 significantly reduced the expression of cell adhesion receptors αv and ß3 integrins (P<0.05), matrix metalloproteinases (MMP) 2 and 9 (P<0.05), vascular endothelial cell growth factor (VEGF) (P<0.01), interleukin 8 (IL8) (P<0.05), cyclooxygenease (COX)2 (P<0.001) and the anti-apoptotic protein Bcl2 (P<0.01), but significantly induced the expression of Bax (P<0.05), a potent pro-apoptotic protein. These data provide evidence that specific inhibition of MIF alters endometriotic tissue growth and progression in vivo and may represent a promising potential

  16. Macrophage Migration Inhibitory Factor Antagonist Blocks the Development of Endometriosis In Vivo

    PubMed Central

    Khoufache, Khaled; Bazin, Sylvie; Girard, Karine; Guillemette, Julie; Roy, Marie-Christine; Verreault, Jean-Pierre; Al-Abed, Yousef; Foster, Warren; Akoum, Ali

    2012-01-01

    Endometriosis, a disease of reproductive age women, is a major cause of infertility, menstrual disorders and pelvic pain. Little is known about its etiopathology, but chronic pelvic inflammation is a common feature in affected women. Beside symptomatic treatment of endometriosis-associated pain, only two main suboptimal therapeutic approaches (hormonal and invasive surgery) are generally recommended to patients and no specific targeted treatment is available. Our studies led to the detection of a marked increase in the expression of macrophage migration inhibitory factor (MIF) in the eutopic endometrium, the peripheral blood and the peritoneal fluid of women with endometriosis, and in early, vascularized and active endometriotic lesions. Herein, we developed a treatment model of endometriosis, where human endometrial tissue was first allowed to implant into the peritoneal cavity of nude mice, to assess in vivo the effect of a specific antagonist of MIF (ISO-1) on the progression of endometriosis and evaluate its efficacy as a potential therapeutic tool. Administration of ISO-1 led to a significant decline of the number, size and in situ dissemination of endometriotic lesions. We further showed that ISO-1 may act by significantly inhibiting cell adhesion, tissue remodeling, angiogenesis and inflammation as well as by altering the balance of pro- and anti-apoptotic factors. Actually, mice treatment with ISO-1 significantly reduced the expression of cell adhesion receptors αv and ß3 integrins (P<0.05), matrix metalloproteinases (MMP) 2 and 9 (P<0.05), vascular endothelial cell growth factor (VEGF) (P<0.01), interleukin 8 (IL8) (P<0.05), cyclooxygenease (COX)2 (P<0.001) and the anti-apoptotic protein Bcl2 (P<0.01), but significantly induced the expression of Bax (P<0.05), a potent pro-apoptotic protein. These data provide evidence that specific inhibition of MIF alters endometriotic tissue growth and progression in vivo and may represent a promising potential

  17. 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.

  18. The progesterone receptor antagonist mifepristone does not lower serum progesterone induced blocking factor (PIBF) in the presence of progesterone.

    PubMed

    Check, J H; DiAntonio, G; DiAntonio, A; Duroseau, M

    2016-01-01

    To determine if mifepristone can lower serum levels of a progesterone (P) induced immunomodulatory protein believed to be needed for the fetus to escape immune surveillance. A female volunteer had her serum P induced blocking factor (PIBF) increased by ingestion of oral micronized P. While remaining on P mifepristone, 200 mg/day was given for six days when another serum PIBF level was obtained. The serum PIBF was 273 ng/ml after five days of oral micronized P. It increased further to 737 ng/ml despite taking six days of 200 mg mifepristone. The mechanism for inducing abortion by mifepristone does not seem to be related to decreasing serum levels of PIBF. This does not eliminate the possibility that the mechanism involves reducing the intracytoplasmic PIBF levels.

  19. Preconditioning, postconditioning and their application to clinical cardiology.

    PubMed

    Kloner, Robert A; Rezkalla, Shereif H

    2006-05-01

    Ischemic preconditioning is a well-established phenomenon first described in experimental preparations in which brief episodes of ischemia/reperfusion applied prior to a longer coronary artery occlusion reduce myocardial infarct size. There are ample correlates of ischemic preconditioning in the clinical realm. Preconditioning mimetic agents that stimulate the biochemical pathways of ischemic preconditioning and protect the heart without inducing ischemia have been examined in numerous experimental studies. However, despite the effectiveness of ischemic preconditioning and preconditioning mimetics for protecting ischemic myocardium, there are no preconditioning-based therapies that are routinely used in clinical medicine at the current time. Part of the problem is the need to administer therapy prior to the known ischemic event. Other issues are that percutaneous coronary intervention technology has advanced so far (with the development of stents and drug-eluting stents) that ischemic preconditioning or preconditioning mimetics have not been needed in most interventional cases. Recent clinical trials such as AMISTAD I and II (Acute Myocardial Infarction STudy of ADenosine) suggest that some preconditioning mimetics may reduce myocardial infarct size when given along with reperfusion or, as in the IONA trial, have benefit on clinical events when administered chronically in patients with known coronary artery disease. It is possible that some of the benefit described for adenosine in the AMISTAD 1 and 2 trials represents a manifestation of the recently described postconditioning phenomenon. It is probable that postconditioning--in which reperfusion is interrupted with brief coronary occlusions and reperfusion sequences--is more likely than preconditioning to be feasible as a clinical application to patients undergoing percutaneous coronary intervention for acute myocardial infarction.

  20. 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.

  1. 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.

  2. 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.

  3. Fast permutation preconditioning for fractional diffusion equations.

    PubMed

    Wang, Sheng-Feng; Huang, Ting-Zhu; Gu, Xian-Ming; Luo, Wei-Hua

    2016-01-01

    In this paper, an implicit finite difference scheme with the shifted Grünwald formula, which is unconditionally stable, is used to discretize the fractional diffusion equations with constant diffusion coefficients. The coefficient matrix possesses the Toeplitz structure and the fast Toeplitz matrix-vector product can be utilized to reduce the computational complexity from [Formula: see text] to [Formula: see text], where N is the number of grid points. Two preconditioned iterative methods, named bi-conjugate gradient method for Toeplitz matrix and bi-conjugate residual method for Toeplitz matrix, are proposed to solve the relevant discretized systems. Finally, numerical experiments are reported to show the effectiveness of our preconditioners.

  4. Review of Preconditioning Methods for Fluid Dynamics

    DTIC Science & Technology

    1992-09-01

    applies equally to all preconditioners e.g. that of Van Leer et. al. which will now be presented. The Van Leer, Lee, Roe preconditioning [55] for...a(dd an artificial viscosity. Accuracy is im1proved for low Mach number flows if the preconditioner is applied only to t lie physical convective and...w j u()s M4u’, h)t appe~var .Jtwurrral ()f C(’oII~putationial Phyisic ,". 11 Iý ( -ltrii. AX .. A .\\itinfi c 7(/Alt .1/1( 1dfr *Si/’olil nq li(o1/ itp

  5. Inhibition of nuclear factor-kappaB suppresses peritoneal dissemination of gastric cancer by blocking cancer cell adhesion.

    PubMed

    Mino, Kazuhiro; Ozaki, Michitaka; Nakanishi, Kazuaki; Haga, Sanae; Sato, Masanori; Kina, Masaya; Takahashi, Masato; Takahashi, Norihiko; Kataoka, Akihiko; Yanagihara, Kazuyoshi; Ochiya, Takahiro; Kamiyama, Toshiya; Umezawa, Kazuo; Todo, Satoru

    2011-05-01

    Currently, patients with peritoneal dissemination of gastric cancer must accept a poor prognosis because there is no standard effective therapy. To inhibit peritoneal dissemination it is important to inhibit interactions between extracellular matrices (ECM) and cell surface integrins, which are important for cancer cell adhesion. Although nuclear factor-kappa B (NF-κB) is involved in various processes in cancer progression, its involvement in the expression of integrins has not been elucidated. We used a novel NF-κB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), to study whether NF-κB blocks cancer cell adhesion via integrins in a gastric cancer dissemination model in mice and found that DHMEQ is a potent suppressor of cancer cell dissemination. Dehydroxymethylepoxyquinomicin suppressed the NF-κB activity of human gastric cancer cells NUGC-4 and 44As3Luc and blocked the adhesion of cancer cells to ECM when compared with the control. Dehydroxymethylepoxyquinomicin also inhibited expression of integrin (α2, α3, β1) in in vitro studies. In the in vivo model, we injected 44As3Luc cells pretreated with DHMEQ into the peritoneal cavity of mice and performed peritoneal lavage after the injection of cancer cells. Viable cancer cells in the peritoneal cavities were evaluated sequentially by in vivo imaging. In mice injected with DHMEQ-pretreated cells and lavaged, live cancer cells in the peritoneum were significantly reduced compared with the control, and these mice survived longer. These results indicate that DHMEQ could inhibit cancer cell adhesion to the peritoneum possibly by suppressing integrin expression. Nuclear factor-kappa B inhibition may be a new therapeutic option for suppressing postoperative cancer dissemination.

  6. Role of kinins in the endothelial protective effect of ischaemic preconditioning

    PubMed Central

    Bouchard, Jean-François; Chouinard, Jérôme; Lamontagne, Daniel

    1998-01-01

    The aim of this study was to assess whether the protective effect of ischaemic preconditioning on endothelial function in coronary arteries of the rat involves kinins. Isolated hearts of the rat were exposed to a 30-min low-flow ischaemia (flow rate of 1 ml min−1) followed by 20-min reperfusion, after which coronaries were precontracted with 0.1 μM U-46619, and the response to the endothelium-dependent vasodilator, 5-hydroxytryptamine (5-HT, 10 μM), compared to that of the endothelium-independent vasodilator, sodium nitroprusside (SNP, 3 μM). In untreated hearts, ischaemia-reperfusion diminished selectively 5-HT-induced vasodilatation, compared with time-matched sham hearts. The vasodilatation to SNP was unaffected after ischaemia-reperfusion. Preconditioning (5 min of zero-flow ischaemia followed by 10 min reperfusion) in untreated hearts preserved the vasodilatation produced by 5-HT. Blockade of B1 and B2 receptors with either 3 nM [Lys0, Leu8, des-Arg9]-bradykinin (LLDBK) or 10 nM Hoe 140 (icatibant), respectively, (started 15 min before ischaemic preconditioning or a corresponding sham period and stopped just before the 20-min reperfusion period) had no effect on the vasodilatation produced by either 5-HT or SNP in sham hearts. Pretreatment with Hoe 140 did not block the protective effect of ischaemic preconditioning on the 5-HT vasodilatation. In contrast, LLDBK halved the protective effect of ischaemic preconditioning on endothelium-dependent vasodilatation. Perfusion with either bradykinin or des-Arg9-bradykinin (1 nM) 30 min before and lasting throughout the ischaemia protected the endothelium. In conclusion, ischaemic preconditioning affords protection to the endothelial function in coronary resistance arteries of the rat partly by activation of B1 receptors. Although exogenous BK perfusion can protect the endothelium, B2 receptors do not play an important role in this protection in the rat isolated heart. PMID:9504381

  7. 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

    2015-07-03

    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.

  8. 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

  9. Increased sensitivity of detection of the blocking (type I) anti-intrinsic factor antibody.

    PubMed

    Nimo, R E; Carmel, R

    1987-12-01

    Increasing the ratio of test serum to the intrinsic factor (IF) antigen should increase the sensitivity of anti-IF antibody assay, a useful, specific tool for diagnosing pernicious anemia. We therefore designed an assay in which this ratio was increased 25-fold over that of our current standard assay and 1,000-fold over that of most described methods. This assay was then compared with our standard assay, with one of the original assays, and with a commercial kit. Both of our assays, especially the newer sensitive method, detected antibody in much greater dilutions of positive serum than the other assays. The sensitive assay also detected antibody in 17% of pernicious anemia sera negative by our standard technique. We calculated that anti-IF antibody can be detected with the sensitive assay in 78% of our patients with pernicious anemia, compared with 73% by our standard assay, 65% by the commercial kit, and 61% by the original method of Gottlieb and colleagues. No antibody was detected in 35 control sera with the new assay, which suggests that the increased sensitivity did not come at the expense of diminished specificity. The increased sensitivity enhances the value of the anti-IF antibody as a major screening and diagnostic tool in pernicious anemia.

  10. Development of an Epidermal Growth Factor Derivative with EGFR Blocking Activity

    PubMed Central

    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

  11. Limb remote-preconditioning protects against focal ischemia in rats and contradicts the dogma of therapeutic time windows for preconditioning.

    PubMed

    Ren, C; Gao, X; Steinberg, G K; Zhao, H

    2008-02-19

    Remote ischemic preconditioning is an emerging concept for stroke treatment, but its protection against focal stroke has not been established. We tested whether remote preconditioning, performed in the ipsilateral hind limb, protects against focal stroke and explored its protective parameters. Stroke was generated by a permanent occlusion of the left distal middle cerebral artery (MCA) combined with a 30 min occlusion of the bilateral common carotid arteries (CCA) in male rats. Limb preconditioning was generated by 5 or 15 min occlusion followed with the same period of reperfusion of the left hind femoral artery, and repeated for two or three cycles. Infarct was measured 2 days later. The results showed that rapid preconditioning with three cycles of 15 min performed immediately before stroke reduced infarct size from 47.7+/-7.6% of control ischemia to 9.8+/-8.6%; at two cycles of 15 min, infarct was reduced to 24.7+/-7.3%; at two cycles of 5 min, infarct was not reduced. Delayed preconditioning with three cycles of 15 min conducted 2 days before stroke also reduced infarct to 23.0+/-10.9%, but with two cycles of 15 min it offered no protection. The protective effects at these two therapeutic time windows of remote preconditioning are consistent with those of conventional preconditioning, in which the preconditioning ischemia is induced in the brain itself. Unexpectedly, intermediate preconditioning with three cycles of 15 min performed 12 h before stroke also reduced infarct to 24.7+/-4.7%, which contradicts the current dogma for therapeutic time windows for the conventional preconditioning that has no protection at this time point. In conclusion, remote preconditioning performed in one limb protected against ischemic damage after focal cerebral ischemia.

  12. Cocaine- and alcohol-mediated expression of inducible transcription factors is blocked by pentobarbital anesthesia.

    PubMed

    Ryabinin, A E; Wang, Y M; Bachtell, R K; Kinney, A E; Grubb, M C; Mark, G P

    2000-09-22

    Identifying the neurocircuitry involved in behavioral responses to drugs of abuse is an important step towards understanding the mechanisms of drug addiction. The present study sought to distinguish brain regions involved in pharmacological effects of cocaine and ethanol from secondary effects by administering these drugs in the presence or absence of pentobarbital anesthesia. Changes in neuronal activity were assessed by immunohistochemical analysis of expression of an inducible transcription factor (ITF), c-Fos, in the brain of rats habituated to repeated pentobarbital anesthesia or saline administration. Cocaine administration (15 mg/kg, i.v.) in non-anesthetized animals produced a strong induction of c-Fos in the striatum and large number of other brain areas. Ethanol administration (2 g/kg, i.p.) induced c-Fos in a smaller number of characteristic brain areas, including the central nucleus of amygdala and paraventricular nucleus of hypothalamus. However, neither of these drugs was able to induce c-Fos in pentobarbital-anesthetized rats (50 mg/kg, i.v.). The suppressive effects of pentobarbital were not specific to c-Fos, such that pentobarbital also suppressed expression of ITFs FosB and Egr1 in the striatum of cocaine-treated rats. On the other hand, pentobarbital by itself strongly induced c-Fos expression in the lateral habenula of saline-, cocaine-, and ethanol-injected rats. It is not clear whether the suppressive effects of anesthesia on ITF expression in other areas are mediated by activation of lateral habenula, or are independent of this event. Our data suggest that in the absence of conscious awareness of drug-associated cues, cocaine and alcohol activate only a fraction of the neural elements engaged in the unanesthetized state.

  13. A preconditioned formulation of the Cauchy-Riemann equations

    NASA Technical Reports Server (NTRS)

    Phillips, T. N.

    1983-01-01

    A preconditioning of the Cauchy-Riemann equations which results in a second-order system is described. This system is shown to have a unique solution if the boundary conditions are chosen carefully. This choice of boundary condition enables the solution of the first-order system to be retrieved. A numerical solution of the preconditioned equations is obtained by the multigrid method.

  14. 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...

  15. 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...

  16. 40 CFR 86.532-78 - 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. 86.532-78... (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, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 19 2014-07-01 2014-07-01 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. 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...

  19. Protective role of vitamin E preconditioning of human dermal fibroblasts against thermal stress in vitro.

    PubMed

    Butt, Hira; Mehmood, Azra; Ali, Muhammad; Tasneem, Saba; Anjum, Muhammad Sohail; Tarar, Moazzam N; Khan, Shaheen N; Riazuddin, Sheikh

    2017-09-01

    Oxidative microenvironment of burnt skin restricts the outcome of cell based therapies of thermal skin injuries. The aim of this study was to precondition human dermal fibroblasts with an antioxidant such as vitamin E to improve their survival and therapeutic abilities in heat induced oxidative in vitro environment. Fibroblasts were treated with 100μM vitamin E for 24h at 37°C followed by heat shock for 10min at 51°C in fresh serum free medium. Preconditioning with vitamin E reduced cell injury as demonstrated by decreased expression of annexin-V, cytochrome p450 (CYP450) mediated oxidative reactions, senescence and release of lactate dehydrogenase (LDH) accomplished by down-regulated expression of pro-apoptotic BAX gene. Vitamin E preconditioned cells exhibited remarkable improvement in cell viability, release of paracrine factors such as epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), stromal derived factor-1alpha (SDF-1α) and also showed significantly up-regulated levels of PCNA, VEGF, BCL-XL, FGF7, FGF23, FLNβ and Col7α genes presumably through activation of phosphatidylinositol 3-kinase (PI3-K)/Akt pathway. The results suggest that pretreatment of fibroblasts with vitamin E prior to transplantation in burnt skin speeds up the wound healing process by improving the antioxidant scavenging responses in oxidative environment of transplanted burn wounds. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. Mitochondria-specific transgenic overexpression of connexin-43 simulates preconditioning-induced cytoprotection of stem cells

    PubMed Central

    Lu, Gang; Haider, Husnain Kh; Porollo, Aleksey; Ashraf, Muhammad

    2010-01-01

    Aims We previously reported that preconditioning of stem cells with insulin-like growth factor-1 (IGF-1) translocated connexin-43 (Cx-43) into mitochondria, causing cytoprotection. We posit that these preconditioning effects could be simulated by mitochondria-specific overexpression of Cx-43. Methods and results During IGF-1-induced preconditioning of C57black/6 mouse bone marrow stem cell antigen-1+ (Sca-1+) cells, Cx-43 was mainly translocated onto the mitochondrial inner membrane, which was abrogated by an extracellular signal-regulated kinases 1 and 2 (ERK1/2) blocker PD98059. To investigate the role of mitochondrial Cx-43, we successfully designed a vector coding for full-length mouse Cx-43 with a mitochondria-targeting sequence (mito-Cx-43) and cloned into a shuttle vector (pShuttle-IRES-hrGFP-1) for mitochondria-specific overexpression of Cx-43 (mito-Cx-43). Sca-1+ cells with mito-Cx-43 reduced cytosolic accumulation of cytochrome c, lowered caspase-3 activity, and improved survival during index oxygen–glucose deprivation as determined by terminal deoxynucleotidyl transferase dUTP nick-end labelling and lactate dehydrogenase assays. Computational analysis revealed a B-cell lymphoma-2 (Bcl-2) homology domain-3 (BH3) motif in Cx-43 with a conserved pattern of amino acids consistent with the Bcl-2 family that regulated cytochrome c release. Moreover, computational secondary structure prediction indicated an extended α-helix in this region, a known condition for BH3-driven protein–protein interactions. Conclusion Cx-43 translocation into mitochondria during preconditioning was ERK1/2-dependent. Expression of mito-Cx-43 simulated the cytoprotective effects of preconditioning in stem cells. Structural features of Cx-43 were shared with the Bcl-2 family as determined by computational analysis. PMID:20833648

  1. Mitochondria-specific transgenic overexpression of connexin-43 simulates preconditioning-induced cytoprotection of stem cells.

    PubMed

    Lu, Gang; Haider, Husnain Kh; Porollo, Aleksey; Ashraf, Muhammad

    2010-11-01

    We previously reported that preconditioning of stem cells with insulin-like growth factor-1 (IGF-1) translocated connexin-43 (Cx-43) into mitochondria, causing cytoprotection. We posit that these preconditioning effects could be simulated by mitochondria-specific overexpression of Cx-43. During IGF-1-induced preconditioning of C57black/6 mouse bone marrow stem cell antigen-1(+) (Sca-1(+)) cells, Cx-43 was mainly translocated onto the mitochondrial inner membrane, which was abrogated by an extracellular signal-regulated kinases 1 and 2 (ERK1/2) blocker PD98059. To investigate the role of mitochondrial Cx-43, we successfully designed a vector coding for full-length mouse Cx-43 with a mitochondria-targeting sequence (mito-Cx-43) and cloned into a shuttle vector (pShuttle-IRES-hrGFP-1) for mitochondria-specific overexpression of Cx-43 (mito-Cx-43). Sca-1(+) cells with mito-Cx-43 reduced cytosolic accumulation of cytochrome c, lowered caspase-3 activity, and improved survival during index oxygen-glucose deprivation as determined by terminal deoxynucleotidyl transferase dUTP nick-end labelling and lactate dehydrogenase assays. Computational analysis revealed a B-cell lymphoma-2 (Bcl-2) homology domain-3 (BH3) motif in Cx-43 with a conserved pattern of amino acids consistent with the Bcl-2 family that regulated cytochrome c release. Moreover, computational secondary structure prediction indicated an extended α-helix in this region, a known condition for BH3-driven protein-protein interactions. Cx-43 translocation into mitochondria during preconditioning was ERK1/2-dependent. Expression of mito-Cx-43 simulated the cytoprotective effects of preconditioning in stem cells. Structural features of Cx-43 were shared with the Bcl-2 family as determined by computational analysis.

  2. 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.

  3. Inhalational Anesthetics as Preconditioning Agents in Ischemic Brain

    PubMed Central

    Wang, Lan; Traystman, Richard J.; Murphy, Stephanie J.

    2008-01-01

    SUMMARY While many pharmacological agents have been shown to protect the brain from cerebral ischemia in animal models, none have translated successfully to human patients. One potential clinical neuroprotective strategy in humans may involve increasing the brain’s tolerance to ischemia by pre-ischemic conditioning (preconditioning). There are many methods to induce tolerance via preconditioning such as: ischemia itself, pharmacological, hypoxia, endotoxin, and others. Inhalational anesthetic agents have also been shown to result in brain preconditioning. Mechanisms responsible for brain preconditioning are many, complex, and unclear and may involve Akt activation, ATP-sensitive potassium channels, and nitric oxide, amongst many others. Anesthetics, however, may play an important and unique role as preconditioning agents, particularly during the perioperative period. PMID:17962069

  4. Preconditioning Newton-Krylor Methods for Variably Saturated Flow

    SciTech Connect

    Woodward, C.; Jones, J

    2000-01-07

    In this paper, we compare the effectiveness of three preconditioning strategies in simulations of variably saturated flow. Using Richards' equation as our model, we solve the nonlinear system using a Newton-Krylov method. Since Krylov solvers can stagnate, resulting in slow convergence, we investigate different strategies of preconditioning the Jacobian system. Our work uses a multigrid method to solve the preconditioning systems, with three different approximations to the Jacobian matrix. One approximation lags the nonlinearities, the second results from discarding selected off-diagonal contributions, and the third matrix considered is the full Jacobian. Results indicate that although the Jacobian is more accurate, its usage as a preconditioning matrix should be limited, as it requires much more storage than the simpler approximations. Also, simply lagging the nonlinearities gives a preconditioning matrix that is almost as effective as the full Jacobian but much easier to compute.

  5. Characterization of Inhibitory Anti-insulin-like Growth Factor Receptor Antibodies with Different Epitope Specificity and Ligand-blocking Properties

    PubMed Central

    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

    2009-01-01

    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 μm) 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 leads

  6. 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.

  7. Generation of tumour-necrosis-factor-alpha-specific affibody molecules capable of blocking receptor binding in vitro.

    PubMed

    Jonsson, Andreas; Wållberg, Helena; Herne, Nina; Ståhl, Stefan; Frejd, Fredrik Y

    2009-08-17

    Affibody molecules specific for human TNF-alpha (tumour necrosis factor-alpha) were selected by phage-display technology from a library based on the 58-residue Protein A-derived Z domain. TNF-alpha is a proinflammatory cytokine involved in several inflammatory diseases and, to this day, four TNF-alpha-blocking protein pharmaceuticals have been approved for clinical use. The phage selection generated 18 unique cysteine-free affibody sequences of which 12 were chosen, after sequence cluster analysis, for characterization as proteins. Biosensor binding studies of the 12 Escherichia coli-produced and IMAC (immobilized-metal-ion affinity chromatography)-purified affibody molecules revealed three variants that demonstrated the strongest binding to human TNF-alpha. These three affibody molecules were subjected to kinetic binding analysis and also tested for their binding to mouse, rat and pig TNF-alpha. For ZTNF-alpha:185, subnanomolar affinity (KD=0.1-0.5 nM) for human TNF-alpha was demonstrated, as well as significant binding to TNF-alpha from the other species. Furthermore, the binding site was found to overlap with the binding site for the TNF-alpha receptor, since this interaction could be efficiently blocked by the ZTNF-alpha:185 affibody. When investigating six dimeric affibody constructs with different linker lengths, and one trimeric construct, it was found that the inhibition of the TNF-alpha binding to its receptor could be further improved by using dimers with extended linkers and/or a trimeric affibody construct. The potential implication of the results for the future design of affibody-based reagents for the diagnosis of inflammation is discussed.

  8. Factors determining the magnitude of the pre-ejection leftward septal motion in left bundle branch block.

    PubMed

    Remme, Espen W; Niederer, Steven; Gjesdal, Ola; Russell, Kristoffer; Hyde, Eoin R; Smith, Nicolas; Smiseth, Otto A

    2016-12-01

    An abnormal large leftward septal motion prior to ejection is frequently observed in left bundle branch block (LBBB) patients. This motion has been proposed as a predictor of response to cardiac resynchronization therapy (CRT). Our goal was to investigate factors that influence its magnitude. Left (LVP) and right ventricular (RVP) pressures and left ventricular (LV) volume were measured in eight canines. After induction of LBBB, LVP and, hence, the transmural septal pressure (PLV-RV = LVP-RVP) increased more slowly (P < 0.01) during the phase when septum moved leftwards. A biventricular finite-element LBBB simulation model confirmed that the magnitude of septal leftward motion depended on reduced rise of PLV-RV. The model showed that leftward septal motion was decreased with shorter activation delay, reduced global or right ventricular (RV) contractility, septal infarction, or when the septum was already displaced into the LV at end diastole by RV volume overload. Both experiments and simulations showed that pre-ejection septal hypercontraction occurs, in part, because the septum performs more of the work pushing blood towards the mitral valve leaflets to close them as the normal lateral wall contribution to this push is lost. Left bundle branch block lowers afterload against pre-ejection septal contraction, expressed as slowed rise of PLV-RV, which is a main cause and determinant of the magnitude of leftward septal motion. The motion may be small or absent due to septal infarct, impaired global or RV contractility or RV volume overload, which should be kept in mind if this motion is to be used in evaluation of CRT response. © The Author 2015. Published by Oxford University Press on behalf of the European Society of Cardiology.

  9. Green tea polyphenols precondition against cell death induced by oxygen-glucose deprivation via stimulation of laminin receptor, generation of reactive oxygen species, and activation of protein kinase Cε.

    PubMed

    Gundimeda, Usha; McNeill, Thomas H; Elhiani, Albert A; Schiffman, Jason E; Hinton, David R; Gopalakrishna, Rayudu

    2012-10-05

    As the development of synthetic drugs for the prevention of stroke has proven challenging, utilization of natural products capable of preconditioning neuronal cells against ischemia-induced cell death would be a highly useful complementary approach. In this study using an oxygen-glucose deprivation and reoxygenation (OGD/R) model in PC12 cells, we show that 2-day pretreatment with green tea polyphenols (GTPP) and their active ingredient, epigallocatechin-3-gallate (EGCG), protects cells from subsequent OGD/R-induced cell death. A synergistic interaction was observed between GTPP constituents, with unfractionated GTPP more potently preconditioning cells than EGCG. GTPP-induced preconditioning required the 67-kDa laminin receptor (67LR), to which EGCG binds with high affinity. 67LR also mediated the generation of reactive oxygen species (ROS) via activation of NADPH oxidase. An exogenous ROS-generating system bypassed 67LR to induce preconditioning, suggesting that sublethal levels of ROS are indeed an important mediator in GTPP-induced preconditioning. This role for ROS was further supported by the fact that antioxidants blocked GTPP-induced preconditioning. Additionally, ROS induced an activation and translocation of protein kinase C (PKC), particularly PKCε from the cytosol to the membrane/mitochondria, which was also blocked by antioxidants. The crucial role of PKC in GTPP-induced preconditioning was supported by use of its specific inhibitors. Preconditioning was increased by conditional overexpression of PKCε and decreased by its knock-out with siRNA. Collectively, these results suggest that GTPP stimulates 67LR and thereby induces NADPH oxidase-dependent generation of ROS, which in turn induces activation of PKC, particularly prosurvival isoenzyme PKCε, resulting in preconditioning against cell death induced by OGD/R.

  10. Green Tea Polyphenols Precondition against Cell Death Induced by Oxygen-Glucose Deprivation via Stimulation of Laminin Receptor, Generation of Reactive Oxygen Species, and Activation of Protein Kinase Cϵ

    PubMed Central

    Gundimeda, Usha; McNeill, Thomas H.; Elhiani, Albert A.; Schiffman, Jason E.; Hinton, David R.; Gopalakrishna, Rayudu

    2012-01-01

    As the development of synthetic drugs for the prevention of stroke has proven challenging, utilization of natural products capable of preconditioning neuronal cells against ischemia-induced cell death would be a highly useful complementary approach. In this study using an oxygen-glucose deprivation and reoxygenation (OGD/R) model in PC12 cells, we show that 2-day pretreatment with green tea polyphenols (GTPP) and their active ingredient, epigallocatechin-3-gallate (EGCG), protects cells from subsequent OGD/R-induced cell death. A synergistic interaction was observed between GTPP constituents, with unfractionated GTPP more potently preconditioning cells than EGCG. GTPP-induced preconditioning required the 67-kDa laminin receptor (67LR), to which EGCG binds with high affinity. 67LR also mediated the generation of reactive oxygen species (ROS) via activation of NADPH oxidase. An exogenous ROS-generating system bypassed 67LR to induce preconditioning, suggesting that sublethal levels of ROS are indeed an important mediator in GTPP-induced preconditioning. This role for ROS was further supported by the fact that antioxidants blocked GTPP-induced preconditioning. Additionally, ROS induced an activation and translocation of protein kinase C (PKC), particularly PKCϵ from the cytosol to the membrane/mitochondria, which was also blocked by antioxidants. The crucial role of PKC in GTPP-induced preconditioning was supported by use of its specific inhibitors. Preconditioning was increased by conditional overexpression of PKCϵ and decreased by its knock-out with siRNA. Collectively, these results suggest that GTPP stimulates 67LR and thereby induces NADPH oxidase-dependent generation of ROS, which in turn induces activation of PKC, particularly prosurvival isoenzyme PKCϵ, resulting in preconditioning against cell death induced by OGD/R. PMID:22879598

  11. Ischemic preconditioning, retinal neuroprotection and histone deacetylase activities.

    PubMed

    Fan, Jie; Alsarraf, Oday; Chou, C James; Yates, Phillip W; Goodwin, Nicole C; Rice, Dennis S; Crosson, Craig E

    2016-05-01

    Increased histone deacetylase (HDAC) activity and the resulting dysregulation of protein acetylation is an integral event in retinal degenerations associated with ischemia and ocular hypertension. This study investigates the role of preconditioning on the process of acetylation in ischemic retinal injury. Rat eyes were unilaterally subjected to retinal injury by 45 min of acute ischemia, and retinal neuroprotection induced by 5 min of an ischemic preconditioning (IPC) event. HDAC activity was evaluated by a fluorometric enzymatic assay with selective isoform inhibitors. Retinal localization of acetylated histone-H3 was determined by immunohistochemistry on retina cross sections. Cleaved caspase-3 level was evaluated by Western blots. Electroretinogram (ERG) analyses were used to assess differences in retinal function seven days following ischemic injury. In control eyes, analysis of HDAC isoforms demonstrated that HDAC1/2 accounted for 28.4 ± 1.6%, HDAC3 for 42.4 ± 1.5% and HDAC6 activity 27.3 ± 3.5% of total activity. Following ischemia, total Class-I HDAC activity increased by 21.2 ± 6.2%, and this increase resulted solely from a rise in HDAC1/2 activity. No change in HDAC3 activity was measured. Activity of Class-II HDACs and HDAC8 was negligible. IPC stimulus prior to ischemic injury also suppressed the rise in Class-I HDAC activity, cleaved caspase-3 levels, and increased acetylated histone-H3 in the retina. In control animals 7 days post ischemia, ERG a- and b-wave amplitudes were significantly reduced by 34.9 ± 3.1% and 42.4 ± 6.3%, respectively. In rats receiving an IPC stimulus, the ischemia-induced decline in ERG a- and b-wave amplitudes was blocked. Although multiple HDACs were detected in the retina, these studies provide evidence that hypoacetylation associated with ischemic injury results from the selective rise in HDAC1/2 activity and that neuroprotection induced by IPC is mediated in part by suppressing HDAC activity. Copyright

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

    PubMed

    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.

  13. Reliability computation from reliability block diagrams

    NASA Technical Reports Server (NTRS)

    Chelson, P. O.; Eckstein, E. Y.

    1975-01-01

    Computer program computes system reliability for very general class of reliability block diagrams. Four factors are considered in calculating probability of system success: active block redundancy, standby block redundancy, partial redundancy, and presence of equivalent blocks in the diagram.

  14. Thermal preconditioning of mountain permafrost towards instability

    NASA Astrophysics Data System (ADS)

    Hauck, Christian; Etzelmüller, Bernd; Hilbich, Christin; Isaksen, Ketil; Mollaret, Coline; Pellet, Cécile; Westermann, Sebastian

    2017-04-01

    Warming permafrost has been detected worldwide in recent years and is projected to continue during the next century as shown in many modelling studies from the polar and mountain regions. In mountain regions, this can lead to potentially hazardous impacts on short time-scales by an increased tendency for slope instabilities. However, the time scale of permafrost thaw and the role of the ice content for determining the strength and rate of permafrost warming and degradation (= development of talik) are still unclear, especially in highly heterogeneous terrain. Observations of permafrost temperatures near the freezing point show complex inter-annual responses to climate forcing due to latent heat effects during thawing and the influence of the snow-cover, which is formed and modulated by highly non-linear processes itself. These effects are complicated by 3-dimensional hydrological processes and interactions between snow melt, infiltration and drainage which may also play an important role in the triggering of mass movements in steep permafrost slopes. In this contribution we demonstrate for the first time a preconditioning effect within near-surface layers in mountain permafrost that causes non-linear degradation and accelerates permafrost thaw. We hypothesise that an extreme regional or global temperature anomaly, such as the Central European summers 2003 and 2015 or the Northern European summers 2006 and 2014, will enhance permafrost degradation if the active layer and the top of the permafrost layer are already preconditioned, i.e. have reduced latent heat content. This preconditioning can already be effectuated by a singular warm year, leading to exceptionally strong melting of the ground ice in the near-surface layers. On sloping terrain and in a context of quasi-continuous atmospheric warming, this ice-loss can be considered as irreversible, as a large part of the melted water will drain/evaporate during the process, and the build-up of an equivalent amount of

  15. A practical approach to remote ischemic preconditioning and ischemic preconditioning against myocardial ischemia/reperfusion injury

    PubMed Central

    Totzeck, Matthias; Hendgen-Cotta, Ulrike B.; French, Brent A.; Rassaf, Tienush

    2016-01-01

    Although urgently needed in clinical practice, a cardioprotective therapeutic approach against myocardial ischemia/ reperfusion injury remains to be established. Remote ischemic preconditioning (rIPC) and ischemic preconditioning (IPC) represent promising tools comprising three entities: the generation of a protective signal, the transfer of the signal to the target organ, and the response to the transferred signal resulting in cardioprotection. However, in light of recent scientific advances, many controversies arise regarding the efficacy of the underlying signaling. We here show methods for the generation of the signaling cascade by rIPC as well as IPC in a mouse model for in vivo myocardial ischemia/ reperfusion injury using highly reproducible approaches. This is accomplished by taking advantage of easily applicable preconditioning strategies compatible with the clinical setting. We describe methods for using laser Doppler perfusion imaging to monitor the cessation and recovery of perfusion in real time. The effects of preconditioning on cardiac function can also be assessed using ultrasound or magnetic resonance imaging approaches. On a cellular level, we confirm how tissue injury can be monitored using histological assessment of infarct size in conjunction with immunohistochemistry to assess both aspects in a single specimen. Finally, we outline, how the rIPC-associated signaling can be transferred to the target cell via conservation of the signal in the humoral (blood) compartment. This compilation of experimental protocols including a conditioning regimen comparable to the clinical setting should proof useful to both beginners and experts in the field of myocardial infarction, supplying information for the detailed procedures as well as troubleshooting guides. PMID:28066791

  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. Microglia preconditioned by oxygen-glucose deprivation promote functional recovery in ischemic rats

    PubMed Central

    Kanazawa, Masato; Miura, Minami; Toriyabe, Masafumi; Koyama, Misaki; Hatakeyama, Masahiro; Ishikawa, Masanori; Nakajima, Takashi; Onodera, Osamu; Takahashi, Tetsuya; Nishizawa, Masatoyo; Shimohata, Takayoshi

    2017-01-01

    Cell-therapies that invoke pleiotropic mechanisms may facilitate functional recovery in stroke patients. We hypothesized that a cell therapy using microglia preconditioned by optimal oxygen-glucose deprivation (OGD) is a therapeutic strategy for ischemic stroke because optimal ischemia induces anti-inflammatory M2 microglia. We first delineated changes in angiogenesis and axonal outgrowth in the ischemic cortex using rats. We found that slight angiogenesis without axonal outgrowth were activated at the border area within the ischemic core from 7 to 14 days after ischemia. Next, we demonstrated that administration of primary microglia preconditioned by 18 hours of OGD at 7 days prompted functional recovery at 28 days after focal cerebral ischemia compared to control therapies by marked secretion of remodelling factors such as vascular endothelial growth factor, matrix metalloproteinase-9, and transforming growth factor-β polarized to M2 microglia in vitro/vivo. In conclusion, intravascular administration of M2 microglia preconditioned by optimal OGD may be a novel therapeutic strategy against ischemic stroke. PMID:28195185

  18. 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.

  19. Sarcosine preconditioning induces ischemic tolerance against global cerebral ischemia.

    PubMed

    Pinto, M C X; Simão, F; da Costa, F L P; Rosa, D V; de Paiva, M J N; Resende, R R; Romano-Silva, M A; Gomez, M V; Gomez, R S

    2014-06-20

    Brain ischemic tolerance is an endogenous protective mechanism activated by a preconditioning stimulus that is closely related to N-methyl-d-aspartate receptor (NMDAR). Glycine transporter type 1 (GlyT-1) inhibitors potentiate NMDAR and suggest an alternative strategy for brain preconditioning. The aim of this work was to evaluate the effects of brain preconditioning induced by sarcosine, a GlyT-1 inhibitor, against global cerebral ischemia and its relation to NMDAR. Sarcosine was administered over 7 days (300 or 500 mg/kg/day, ip) before the induction of a global cerebral ischemia model in Wistar rats (male, 8-week-old). It was observed that sarcosine preconditioning reduced cell death in rat hippocampi submitted to cerebral ischemia. Hippocampal levels of glycine were decreased in sarcosine-treated animals, which was associated with a reduction of [(3)H] glycine uptake and a decrease in glycine transporter expression (GlyT-1 and GlyT-2). The expression of glycine receptors and the NR1 and NR2A subunits of NMDAR were not affected by sarcosine preconditioning. However, sarcosine preconditioning reduced the expression of the NR2B subunits of NMDAR. In conclusion, these data demonstrate that sarcosine preconditioning induces ischemic tolerance against global cerebral ischemia and this neuroprotective state is associated with changes in glycine transport and reduction of NR2B-containing NMDAR expression. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

  20. Remote ischemic preconditioning enhances fracture healing

    PubMed Central

    Çatma, Mehmet Faruk; Şeşen, Hakan; Aydın, Aytekin; Ünlü, Serhan; Demirkale, İsmail; Altay, Murat

    2015-01-01

    Purpose We hypothesized that RIP accelerates fracture healing. Methods Rats (n = 48) were used for the technique of ischemic preconditioning involved applying 35 min of intermittent pneumatic tourniquet for 7 cycles of 5 min each to the fractured hind limb. Results We observed greater callus maturity in RIP group at first week after fracture when compared to controls (p < 0,0001). The serum MDA levels demonstrated statistically lower values at the RIP group at the first week after fracture; however, there were not significant differences at 3rd and 5th weeks (p = 0.0001, p = 0.725, p = 0.271, respectively). Conclusions Greater callus maturity was obtained in RIP group. PMID:26566314

  1. Remote ischaemic preconditioning: closer to the mechanism?

    PubMed Central

    Gleadle, Jonathan M.; Mazzone, Annette

    2016-01-01

    Brief periods of ischaemia followed by reperfusion of one tissue such as skeletal muscle can confer subsequent protection against ischaemia-induced injury in other organs such as the heart. Substantial evidence of this effect has been accrued in experimental animal models. However, the translation of this phenomenon to its use as a therapy in ischaemic disease has been largely disappointing without clear evidence of benefit in humans. Recently, innovative experimental observations have suggested that remote ischaemic preconditioning (RIPC) may be largely mediated through hypoxic inhibition of the oxygen-sensing enzyme PHD2, leading to enhanced levels of alpha-ketoglutarate and subsequent increases in circulating kynurenic acid (KYNA). These observations provide vital insights into the likely mechanisms of RIPC and a route to manipulating this mechanism towards therapeutic benefit by direct alteration of KYNA, alpha-ketoglutarate levels, PHD inhibition, or pharmacological targeting of the incompletely understood cardioprotective mechanism activated by KYNA. PMID:28163901

  2. 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. Copyright © 2014 Elsevier B.V. All rights reserved.

  3. 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

  4. Pigment Epithelium-derived Factor (PEDF) Blocks Wnt3a Protein-induced Autophagy in Pancreatic Intraepithelial Neoplasms.

    PubMed

    Gong, Jingjing; Belinsky, Glenn; Sagheer, Usman; Zhang, Xuchen; Grippo, Paul J; Chung, Chuhan

    2016-10-14

    An increase in autophagy characterizes pancreatic carcinogenesis, but the signals that regulate this process are incompletely understood. Because canonical Wnt/β-catenin signaling is necessary for the transition from early to advanced pancreatic intraepithelial neoplasia (PanIN) lesions, we assessed whether Wnt ligands and endogenous inhibitors of Wnt signaling modulate autophagy. In this study, canonical Wnt3a ligand induced autophagy markers and vacuoles in murine PanIN cells. Furthermore, pigment epithelium-derived factor (PEDF), a secreted glycoprotein known for its anti-tumor properties, blocked Wnt3a-directed induction of autophagy proteins. Autophagy inhibition was complemented by reciprocal regulation of the oxidative stress enzymes, superoxide dismutase 2 (SOD2) and catalase. Transcriptional control of Sod2 expression was mediated by PEDF-induced NFκB nuclear translocation. PEDF-dependent SOD2 expression in PanIN lesions was recapitulated in a murine model of PanIN formation where PEDF was deleted. In human PanIN lesions, co-expression of PEDF and SOD2 was observed in the majority of early PanIN lesions (47/50, 94%), whereas PEDF and SOD2 immunolocalization in high-grade human PanIN-2/3 was uncommon (7/50, 14%). These results indicate that PEDF regulates autophagy through coordinate Wnt signaling blockade and NFκB activation.

  5. Leukemia inhibitory factor is expressed by the preimplantation uterus and selectively blocks primitive ectoderm formation in vitro.

    PubMed Central

    Shen, M M; Leder, P

    1992-01-01

    Among its many activities, leukemia inhibitory factor (LIF) can maintain embryonic stem cell monolayers in a pluripotent undifferentiated state. Presuming that this might reflect its physiologic role during embryogenesis, we have examined LIF expression in the embryonic environment by RNase protection assays and have determined its in vitro effect on differentiating embryonic stem cell embryoid bodies. Of all adult tissues analyzed, LIF transcripts appear only in the uterus, where their level fluctuates with the estrous cycle, peaking after ovulation. LIF expression continues in the uteri of pregnant and pseudopregnant females, with a relative peak when blastocysts are normally present. As for its effects on in vitro differentiation, we have found that LIF blocks embryoid body differentiation only partially, yet in a precise manner. Using molecular markers to follow the differentiation of defined cell types, we demonstrate that LIF selectively inhibits the formation of primitive ectoderm, while permitting the differentiation of primitive endoderm. These results suggest a specific role for LIF in preimplantation mouse development. Images PMID:1518852

  6. 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

  7. 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.

  8. H2O2 preconditioning modulates phase II enzymes through p38 MAPK and PI3K/Akt activation.

    PubMed

    Angeloni, Cristina; Motori, Elisa; Fabbri, Daniele; Malaguti, Marco; Leoncini, Emanuela; Lorenzini, Antonello; Hrelia, Silvana

    2011-06-01

    Ischemic preconditioning is a complex cardioprotective phenomenon that involves adaptive changes in cells and molecules and occurs in a biphasic pattern: an early phase after 1-2 h and a late phase after 12-24 h. While it is widely accepted that reactive oxygen species are strongly involved in triggering ischemic preconditiong, it is not clear if they play a major role in the early or late phase of preconditioning and which are the mechanisms involved. The present study was designed to investigate the mechanisms behind H(2)O(2)-induced cardioprotection in rat neonatal cardiomyocytes. We focused on antioxidant and phase II enzymes and their modulation by protein kinase signaling pathways and nuclear-factor-E(2)-related factor-1 (Nrf1) and Nrf2. H(2)O(2) preconditioning was able to counteract oxidative stress more effectively in the late than in the early phase of adaptation. In particular, H(2)O(2) preconditioning counteracted oxidative stress-induced apoptosis by decreasing caspase-3 activity, increasing Bcl2 expression and selectively increasing the expression and activity of antioxidant and phase II enzymes through Nrf1 and Nrf2 translocation to the nucleus. The downregulation of Nrf1 and Nrf2 by small interfering RNA reduced the expression level of phase II enzymes. Specific inhibitors of phosphatidylinositol 3-kinase/Akt and p38 MAPK activation partially reduced the cardioprotection elicited by H(2)O(2) preconditioning and the induction and activity of phase II enzymes. These findings demonstrate, for the first time, a key role for Nrf1, and not only for Nrf2, in the induction of phase II enzymes triggered by H(2)O(2) preconditioning.

  9. Preconditioned Minimal Residual Methods for Chebyshev Spectral Caluclations

    NASA Technical Reports Server (NTRS)

    Canuto, C.; Quarteroni, A.

    1983-01-01

    The problem of preconditioning the pseudospectral Chebyshev approximation of an elliptic operator is considered. The numerical sensitiveness to variations of the coefficients of the operator are investigated for two classes of preconditioning matrices: one arising from finite differences, the other from finite elements. The preconditioned system is solved by a conjugate gradient type method, and by a DuFort-Frankel method with dynamical parameters. The methods are compared on some test problems with the Richardson method and with the minimal residual Richardson method.

  10. Preconditioning principles for preventing sports injuries in adolescents and children.

    PubMed

    Dollard, Mark D; Pontell, David; Hallivis, Robert

    2006-01-01

    Preseason preconditioning can be accomplished well over a 4-week period with a mandatory period of rest as we have discussed. Athletic participation must be guided by a gradual increase of skills performance in the child assessed after a responsible preconditioning program applying physiologic parameters as outlined. Clearly, designing a preconditioning program is a dynamic process when accounting for all the variables in training discussed so far. Despite the physiologic demands of sport and training, we still need to acknowledge the psychologic maturity and welfare of the child so as to ensure that the sport environment is a wholesome and emotionally rewarding experience.

  11. Loss of Ribosomal Protein L11 Blocks Stress Activation of the Bacillus subtilis Transcription Factor ςB

    PubMed Central

    Zhang, Shuyu; Scott, Janelle M.; Haldenwang, W. G.

    2001-01-01

    ςB, the general stress response sigma factor of Bacillus subtilis, is activated when the cell's energy levels decline or the bacterium is exposed to environmental stress (e.g., heat shock, ethanol). Physical stress activates ςB through a collection of regulatory kinases and phosphatases (the Rsb proteins) which catalyze the release of ςB from an anti-ςB factor inhibitor. The means by which diverse stresses communicate with the Rsb proteins is unknown; however, a role for the ribosome in this process was suggested when several of the upstream members of the ςB stress activation cascade (RsbR, -S, and -T) were found to cofractionate with ribosomes in crude B. subtilis extracts. We now present evidence for the involvement of a ribosome-mediated process in the stress activation of ςB. B. subtilis strains resistant to the antibiotic thiostrepton, due to the loss of ribosomal protein L11 (RplK), were found to be blocked in the stress activation of ςB. Neither the energy-responsive activation of ςB nor stress-dependent chaperone gene induction (a ςB-independent stress response) was inhibited by the loss of L11. The Rsb proteins required for stress activation of ςB are shown to be active in the RplK− strain but fail to be triggered by stress. The data demonstrate that the B. subtilis ribosomes provide an essential input for the stress activation of ςB and suggest that the ribosomes may themselves be the sensors for stress in this system. PMID:11244072

  12. Mesenchymal Stem/Stromal Cells in Regenerative Medicine: Can Preconditioning Strategies Improve Therapeutic Efficacy?

    PubMed Central

    Schäfer, Richard; Spohn, Gabriele; Baer, Patrick C.

    2016-01-01

    Mesenchymal stem/stromal cells (MSCs) are becoming increasingly important for the development of cell therapeutics in regenerative medicine. Featuring immunomodulatory potential as well as secreting a variety of trophic factors, MSCs showed remarkable therapeutic effects in numerous preclinical disease models. However, sustainable translation of MSC therapies to the clinic is hampered by heterogeneity of MSCs and non-standardized in vitro culture technologies. Moreover, potent MSC therapeutics require MSCs with maximum regenerative capacity. There is growing evidence that in vitro preconditioning strategies of MSCs can optimize their therapeutic potential. In the following we will discuss achievements and challenges of the development of MSC therapies in regenerative medicine highlighting specific in vitro preconditioning strategies prior to cell transplantation to increase their therapeutic efficacy. PMID:27721701

  13. Lattice Boltzmann model for exterior flows with an annealing preconditioning method.

    PubMed

    Liu, Bo; Khalili, Arzhang

    2009-06-01

    In this paper we propose a highly efficient and stable lattice Boltzmann method for solving low Reynolds number exterior flows using a preconditioning technique. The present method is based on replacing the constant preconditioning parameter (gamma) within uniform grids [Guo, Phys. Rev. E 70, 066706 (2004)] by a space- and time-dependent one in a nested mesh-refined domain. To do this, for the transition from a fine to the neighboring coarser grid, gamma has been divided by a factor K , which is large initially and anneals stepwise to a small value after some iterations. With this technique, more than one order of magnitude larger convergence rate can be achieved, and several orders of magnitude larger system size can be treated.

  14. 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

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

    PubMed

    Zhao, Zaorui; Sabirzhanov, Boris; Wu, Junfang; Faden, Alan I; Stoica, Bogdan A

    2015-09-01

    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.

  16. 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.

  17. Flagellin preconditioning enhances the efficacy of mesenchymal stem cells in an irradiation-induced proctitis model.

    PubMed

    Linard, Christine; Strup-Perrot, Carine; Lacave-Lapalun, Jean-Victor; Benderitter, Marc

    2016-09-01

    The success of mesenchymal stem cell transplantation for proctitis depends not only on cell donors but also on host microenvironmental factors, which play a major role in conditioning mesenchymal stem cell immunosuppressive action and repair. This study sought to determine if flagellin, a TLR5 ligand, can enhance the mesenchymal stem cell treatment efficacy in radiation-induced proctitis. With the use of a colorectal model of 27 Gy irradiation in rats, we investigated and compared the effects on immune capacity and remodeling at 28 d after irradiation of the following: 1) systemic mesenchymal stem cell (5 × 10(6)) administration at d 7 after irradiation, 2) administration of flagellin at d 3 and systemic mesenchymal stem cell administration at d 7, and 3) in vitro preconditioning of mesenchymal stem cells with flagellin, 24 h before their administration on d 7. The mucosal CD8(+) T cell population was normalized after treatment with flagellin-preconditioned mesenchymal stem cells or flagellin plus mesenchymal stem cells, whereas mesenchymal stem cells alone did not alter the radiation-induced elevation of CD8(+) T cell frequency. Mesenchymal stem cell treatment returned the irradiation-elevated frequency of CD25(+) cells in the mucosa-to-control levels, whereas both flagellin-preconditioned mesenchymal stem cell and flagellin-plus-mesenchymal stem cell treatment each significantly increased not only CD25(+) cell frequency but also forkhead box p3 and IL-2Rα expression. Specifically, IL-10 was overexpressed after flagellin-preconditioned mesenchymal stem cell treatment. Analysis of collagen expression showed that the collagen type 1/collagen type 3 ratio, an indicator of wound-healing maturation, was low in the irradiated and mesenchymal stem cell-treated groups and returned to the normal level only after the flagellin-preconditioned mesenchymal stem cell treatment. This was associated with a reduction in myofibroblast accumulation. In a proctitis model, flagellin-preconditioned

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

    NASA Astrophysics Data System (ADS)

    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.

  19. 40 CFR 1065.516 - Sample system decontamination and preconditioning.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... Cycles § 1065.516 Sample system decontamination and preconditioning. This section describes how to manage... purified air or nitrogen. (3) When calculating zero emission levels, apply all applicable...

  20. 40 CFR 86.132-00 - Vehicle preconditioning.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... (CONTINUED) CONTROL OF EMISSIONS FROM NEW AND IN-USE HIGHWAY VEHICLES AND ENGINES Emission Regulations for... manufacturer has concerns about fuel effects on adaptive memory systems, a manufacturer may precondition a test...

  1. 40 CFR 86.132-00 - Vehicle preconditioning.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... (CONTINUED) CONTROL OF EMISSIONS FROM NEW AND IN-USE HIGHWAY VEHICLES AND ENGINES Emission Regulations for... manufacturer has concerns about fuel effects on adaptive memory systems, a manufacturer may precondition a test...

  2. 40 CFR 86.132-00 - Vehicle preconditioning.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... (CONTINUED) CONTROL OF EMISSIONS FROM NEW AND IN-USE HIGHWAY VEHICLES AND ENGINES Emission Regulations for... manufacturer has concerns about fuel effects on adaptive memory systems, a manufacturer may precondition a test...

  3. 40 CFR 86.132-00 - Vehicle preconditioning.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... (CONTINUED) CONTROL OF EMISSIONS FROM NEW AND IN-USE HIGHWAY VEHICLES AND ENGINES Emission Regulations for... manufacturer has concerns about fuel effects on adaptive memory systems, a manufacturer may precondition a test...

  4. 40 CFR 86.132-00 - Vehicle preconditioning.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... (CONTINUED) CONTROL OF EMISSIONS FROM NEW AND IN-USE HIGHWAY VEHICLES AND ENGINES Emission Regulations for... manufacturer has concerns about fuel effects on adaptive memory systems, a manufacturer may precondition a test...

  5. 33 CFR 183.320 - Preconditioning for tests.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... Engines of 2 Horsepower or Less General § 183.320 Preconditioning for tests. A boat must meet the... be sealed. (f) The boat must be keel down in the water. (g) The boat must be swamped, allowing...

  6. 33 CFR 183.320 - Preconditioning for tests.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... Engines of 2 Horsepower or Less General § 183.320 Preconditioning for tests. A boat must meet the... be sealed. (f) The boat must be keel down in the water. (g) The boat must be swamped, allowing...

  7. Heme oxygenase-1 could mediate the protective effects of hyperbaric oxygen preconditioning against hepatic ischemia-reperfusion injury in rats.

    PubMed

    Liu, Yi; Sun, Xue-Jun; Liu, Ji; Kang, Zhi-Min; Deng, Xiao-Ming

    2011-10-01

    1. Heme oxygenase 1 (HO-1) has been shown to play a pivotal role in the maintenance of cellular homeostasis when the liver undergoes sublethal stress, such as ischaemia-reperfusion (I/R) injury. In the present study, we investigated the protective role of HO-1 in hyperbaric oxygen (HBO) preconditioning against liver injury after I/R. 2. A total hepatic ischaemia (30 min) and reperfusion (60 min) injury model in rats was used in the present study. Preconditioned groups were exposed to HBO 24 h prior to the induction of I/R injury. Other groups were injected with zinc protoporphyrin IX (ZnPP) intraperitoneally 1 h before I/R to inhibit HO-1 activity. At the end of the reperfusion period, blood and liver samples were collected for the analysis of liver injury markers, morphological changes, and HO-1 expression and activity in the liver. 3. In untreated rats, I/R induced an increase in hepatic injury markers, such as plasma transaminases, inflammatory cytokines (tumour necrosis factor-α and interleukin-1β), and tissue malondialdehyde. However, HBO preconditioning attenuated the I/R-induced increases in these hepatic injury markers, and prevented both the necrosis and apoptosis of hepatocytes induced by I/R injury. Furthermore, HBO preconditioning significantly increased HO-1 mRNA and protein levels in the liver. In rats in which HO-1 activity had been inhibited with ZnPP pretreatment, the protective effects of HBO preconditioning against I/R injury were abolished. 4. In conclusion, HBO preconditioning can protect the liver against I/R injury and it appears that this effect might be mediated by the induction of HO-1.

  8. Remote ischemic preconditioning improves the cognitive function of elderly patients following colon surgery: A randomized clinical trial.

    PubMed

    He, Zhenqiu; Xu, Nan; Qi, Sihua

    2017-04-01

    Cognitive function impairment is one of the most common complications in elderly patients after surgery, and an ideal nonpharmacological therapy has not yet been identified. Thus, we hypothesized that remote ischemic preconditioning could improve cognitive functions in elderly patients after surgery and investigated the mechanism underlying this effect. Ninety patients classified as American Society of Anaesthesiologists (ASA) physical status of 2 or 3 and aged 65 to 75 years who were scheduled for elective colon surgery under general anesthesia were randomly allocated to either a remote ischemic preconditioning group (Group R, n = 45) or a control group (Group C, n = 45). Remote ischemic preconditioning was performed by applying a static pressure of 200 mm Hg with a blood pressure cuff wrapped around the right upper limb for 3 ischemia cycles of 5 minutes each. The Montreal Cognitive Assessment (MoCA) scores between the 2 groups were not significantly different on the day before surgery or the seventh day after surgery, but the scores on the first day after surgery (26.87 ± 0.84 vs 25.96 ± 0.85, P < .001) and third day after surgery (27.49 ± 0.66 vs 27.02 ± 0.92, P = .009) were significantly higher for Group R than those for Group C. Moreover, remote ischemic preconditioning markedly decreased the serum concentrations of the interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and S100B proteins compared with the control group (P < .001). Remote ischemic preconditioning improves postoperative cognitive function in elderly patients following colon surgery. The cognitive protective effects of remote ischemic preconditioning are partially related to the inhibition of inflammation.

  9. Perceptual learning transfer: Salience of the common element as a factor contributing to the intermixed/blocked effect.

    PubMed

    Artigas, Antonio A; Prados, Jose

    2014-10-01

    Rats received intermixed or blocked preexposure to 2 similar flavor compounds, AX and BX. Following preexposure, conditioning trials took place in which a novel compound stimulus NX was paired with an illness-induced unconditioned stimulus. Animals that were given intermixed preexposure to AX and BX showed lower generalization of the aversive response conditioned to NX to a new compound, ZX, than animals that were given blocked preexposure. The results support the proposal that intermixed preexposure reduces the salience of the common element X to a greater extent than blocked preexposure. The way in which current theories of perceptual learning can predict a differential salience of X after intermixed and blocked preexposure is discussed.

  10. Hypoxic preconditioning enhances the therapeutic potential of the secretome from cultured human mesenchymal stem cells in experimental traumatic brain injury.

    PubMed

    Chang, Ching-Ping; Chio, Chung-Ching; Cheong, Chong-Un; Chao, Chien-Ming; Cheng, Bor-Chieh; Lin, Mao-Tsun

    2013-02-01

    Bone-marrow-derived human MSCs (mesenchymal stem cells) support repair when administered to animals with TBI (traumatic brain injury) in large part through secreted trophic factors. We directly tested the ability of the culture medium (or secretome) collected from human MSCs under normoxic or hypoxic conditions to protect neurons in a rat model of TBI. Concentrated conditioned medium from cultured human MSCs or control medium was infused through the tail vein of rats subjected to TBI. We have demonstrated that MSCs cultured in hypoxia were superior to those cultured in normoxia in inducing expression of both HGF (hepatocyte growth factor) and VEGF (vascular endothelial growth factor) in the cultured medium. We showed further that rats treated with the secretome from both normoxic- and hypoxic-preconditioned MSCs performed significantly better than the controls in both motor and cognitive functional test. Subsequent post-mortem evaluation of brain damage at the 4-day time point confirmed that both normoxic- and hypoxic-preconditioned MSC secretome-treated rats had significantly greater numbers of newly forming neurons, but significantly less than the controls in brain damaged volume and apoptosis. The TBI rats treated with hypoxic-preconditioned MSC secretome performed significantly better in both motor and cognitive function tests and neurogenesis, and had significantly less brain damage than the TBI rats treated with the normoxic-preconditioned MSC secretome. Collectively, these findings suggest that MSCs secrete bioactive factors, including HGF and VEGF, that stimulate neurogenesis and improve outcomes of TBI in a rat model. Hypoxic preconditioning enhances the secretion of these bioactive factors from the MSCs and the therapeutic potential of the cultured MSC secretome in experimental TBI.

  11. Hypercholesterolemia abrogates sevoflurane-induced delayed preconditioning against myocardial infarct in rats by alteration of nitric oxide synthase signaling.

    PubMed

    Zhang, Feng-Jiang; Ma, Lei-Lei; Wang, Wen-Na; Qian, Ling-Bo; Yang, Mei-Juan; Yu, Jing; Chen, Gang; Yu, Li-Na; Yan, Min

    2012-05-01

    among all groups. The expression of myocardial phosphorylated endothelial NOS, Bcl-2, and phosphorylated Bad in normocholesterolemic rats was not affected by delayed sevoflurane preconditioning but was decreased in the hypercholesterolemic control group, and this was not reversed by sevoflurane, compared with the normocholesterolemic control group. Taken together, these results indicate that sevoflurane preconditioning exerts delayed cardioprotection against IR injury in normocholesterolemic rats, which is blocked by hypercholesterolemia potentially via interference with the iNOS/mitochondrial ATP-dependent K⁺ channel pathway.

  12. Effect of early pregnancy on the expression of progesterone receptor and progesterone-induced blocking factor in ovine lymph node.

    PubMed

    Yang, Ling; Zang, Shengqin; Bai, Ying; Yao, Xiaolei; Zhang, Leying

    2017-04-15

    Lymph nodes are the sites where the immune reaction or suppression takes place. Progesterone (P4) exerts an essential effect of the immunomodulation on the maternal uterus during early pregnancy in ruminants. At present study, the inguinal lymph nodes were obtained at day 16 of non-pregnancy, days 13, 16 and 25 of pregnancy (n = 3 for each group) in ewes, and RT-PCR assay, western blot and immunohistochemistry analysis were used to analyze to the effect of early pregnancy on the expression of P4 receptor (PGR) and progesterone-induced blocking factor (PIBF) in the lymph nodes. Our results showed that the PGR and PIBF mRNA were up-regulated in the lymph nodes in pregnant ewes, and the PGR isoform (60 kDa) and the PIBF variant (75 kDa) were expressed constantly in the lymph nodes. However, there was no expression of the PGR isoform (40 kDa) and the PIBF variant (48 kDa) at day 16 of the estrous cycle. The immunohistochemistry results confirmed that the PGR and PIBF proteins were limited to the subcapsular sinus and trabeculae in the cortex, medullary sinuses, and were localized in the cytoplasm of the specific cells. This paper reports for the first time that early pregnancy exerts its effect on the specific cells in the lymph nodes through P4, which results in the up-regulated expression of the PGR mRNA and 40 kDa isoform, the PIBF mRNA and 48 kDa variant, and is involved in the immunoregulation of the lymph nodes through a cytosolic pathway in ewes. Copyright © 2017 Elsevier Inc. All rights reserved.

  13. Human amniotic fluid stem cell preconditioning improves their regenerative potential.

    PubMed

    Rota, Cinzia; Imberti, Barbara; Pozzobon, Michela; Piccoli, Martina; De Coppi, Paolo; Atala, Anthony; Gagliardini, Elena; Xinaris, Christodoulos; Benedetti, Valentina; Fabricio, Aline S C; Squarcina, Elisa; Abbate, Mauro; Benigni, Ariela; Remuzzi, Giuseppe; Morigi, Marina

    2012-07-20

    Human amniotic fluid stem (hAFS) cells, a novel class of broadly multipotent stem cells that share characteristics of both embryonic and adult stem cells, have been regarded as promising candidate for cell therapy. Taking advantage by the well-established murine model of acute kidney injury (AKI), we studied the proregenerative effect of hAFS cells in immunodeficient mice injected with the nephrotoxic drug cisplatin. Infusion of hAFS cells in cisplatin mice improved renal function and limited tubular damage, although not to control level, and prolonged animal survival. Human AFS cells engrafted injured kidney predominantly in peritubular region without acquiring tubular epithelial markers. Human AFS cells exerted antiapoptotic effect, activated Akt, and stimulated proliferation of tubular cells possibly via local release of factors, including interleukin-6, vascular endothelial growth factor, and stromal cell-derived factor-1, which we documented in vitro to be produced by hAFS cells. The therapeutic potential of hAFS cells was enhanced by cell pretreatment with glial cell line-derived neurotrophic factor (GDNF), which markedly ameliorated renal function and tubular injury by increasing stem cell homing to the tubulointerstitial compartment. By in vitro studies, GDNF increased hAFS cell production of growth factors, motility, and expression of receptors involved in cell homing and survival. These findings indicate that hAFS cells can promote functional recovery and contribute to renal regeneration in AKI mice via local production of mitogenic and prosurvival factors. The effects of hAFS cells can be remarkably enhanced by GDNF preconditioning.

  14. Human Amniotic Fluid Stem Cell Preconditioning Improves Their Regenerative Potential

    PubMed Central

    Rota, Cinzia; Imberti, Barbara; Pozzobon, Michela; Piccoli, Martina; De Coppi, Paolo; Atala, Anthony; Gagliardini, Elena; Xinaris, Christodoulos; Benedetti, Valentina; Fabricio, Aline S.C.; Squarcina, Elisa; Abbate, Mauro; Benigni, Ariela; Remuzzi, Giuseppe

    2012-01-01

    Human amniotic fluid stem (hAFS) cells, a novel class of broadly multipotent stem cells that share characteristics of both embryonic and adult stem cells, have been regarded as promising candidate for cell therapy. Taking advantage by the well-established murine model of acute kidney injury (AKI), we studied the proregenerative effect of hAFS cells in immunodeficient mice injected with the nephrotoxic drug cisplatin. Infusion of hAFS cells in cisplatin mice improved renal function and limited tubular damage, although not to control level, and prolonged animal survival. Human AFS cells engrafted injured kidney predominantly in peritubular region without acquiring tubular epithelial markers. Human AFS cells exerted antiapoptotic effect, activated Akt, and stimulated proliferation of tubular cells possibly via local release of factors, including interleukin-6, vascular endothelial growth factor, and stromal cell–derived factor-1, which we documented in vitro to be produced by hAFS cells. The therapeutic potential of hAFS cells was enhanced by cell pretreatment with glial cell line–derived neurotrophic factor (GDNF), which markedly ameliorated renal function and tubular injury by increasing stem cell homing to the tubulointerstitial compartment. By in vitro studies, GDNF increased hAFS cell production of growth factors, motility, and expression of receptors involved in cell homing and survival. These findings indicate that hAFS cells can promote functional recovery and contribute to renal regeneration in AKI mice via local production of mitogenic and prosurvival factors. The effects of hAFS cells can be remarkably enhanced by GDNF preconditioning. PMID:22066606

  15. 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.

  16. 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

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

    PubMed

    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 min 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.

  18. 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…

  19. 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…

  20. Growth differentiation factor (GDF)-15 blocks norepinephrine-induced myocardial hypertrophy via a novel pathway involving inhibition of epidermal growth factor receptor transactivation.

    PubMed

    Xu, Xin-ye; Nie, Ying; Wang, Fang-fang; Bai, Yan; Lv, Zhi-zhen; Zhang, You-yi; Li, Zi-jian; Gao, Wei

    2014-04-04

    Accumulating evidence suggests that growth differentiation factor 15 (GDF-15) is associated with the severity and prognosis of various cardiovascular diseases. However, the effect of GDF-15 on the regulation of cardiac remodeling is still poorly understood. In this present study, we demonstrate that GDF-15 blocks norepinephrine (NE)-induced myocardial hypertrophy through a novel pathway involving inhibition of EGFR transactivation. Both in vivo and in vitro assay indicate that NE was able to stimulate the synthesis of GDF-15. The up-regulation of GDF-15 feedback inhibits NE-induced myocardial hypertrophy, including quantitation of [(3)H]leucine incorporation, protein/DNA ratio, cell surface area, and ANP mRNA level. Further research shows that GDF-15 could inhibit the phosphorylation of EGF receptor and downstream kinases (AKT and ERK1/2) induced by NE. Clinical research also shows that serum GDF-15 levels in hypertensive patients were significant higher than in healthy volunteers and were positively correlated with the thickness of the posterior wall of the left ventricle, interventricular septum, and left ventricular mass, as well as the serum level of norepinephrine. In conclusion, NE induces myocardial hypertrophy and up-regulates GDF-15, and this up-regulation of GDF-15 negatively regulates NE-induced myocardial hypertrophy by inhibiting EGF receptor transactivation following NE stimulation.

  1. Efficacy of continuous epidural block in acute herpes zoster: Incidence and predictive factors of postherpetic neuralgia, a retrospective single-center study.

    PubMed

    Kim, Yoo Na; Kim, Dae Woo; Kim, Eung Don

    2016-08-01

    The aim of the present study was to investigate efficacy of continuous epidural block for prevent postherpetic neuralgia (PHN) progression in cases of acute herpes zoster with severe pain and also to identify predictive factors for PHN in such conditions.We retrospectively analyzed the clinical data of patients with herpes zoster who underwent continuous epidural block between March 2013 and October 2015. Time points were set as 1 month, 3 months, and 6 months after zoster onset. PHN was defined as the presence of pain with NRS ≥3 at certain time points.The incidence of developing PHN was 38.1%, 27.0%, and 19.0% 1 month, 3 months, and 6 months after zoster onset, respectively. Age and duration of catheterization were predictive factors for PHN at 1 month. Age, duration of catheterization, and NRS at first visit were identified as predictive factors for PHN at 3 months. Presence of diabetes, duration of catheterization, and NRS during catheterization were significant predictive factors for PHN at 6 months.The incidence of PHN is higher in zoster patients with severe pain that requires continuous epidural block compared to incidence in the general population. Advanced age and severe initial pain intensity were predictive factors of PHN development. Prolonged catheterization resulting from weak response to treatment strongly suggested progression to PHN.

  2. Remote ischemic preconditioning on neovascularization and follicle viability on ovary autotransplantation in rats.

    PubMed

    Damous, L L; Silva, S M; Simões, R S; Morello, R J; Carbonel, A P F; Simões, M J; Montero, E F S

    2008-04-01

    Verify the optimum remote vascular occlusion time to reduce ovarian injury in autologous transplants in rats. Twenty-four adult female rats were assigned to four groups: GC (control group): bilateral oophorectomy followed by ovary transplant; GIPC (ischemic preconditioning group): remote ischemic preconditioning at the iliac artery for 5, 10, and 15 minutes (GIPC-5, GIPC-20, and GIPC-15) previous to bilateral oophorectomy and ovarian transplantation. The right ovary was fixed in the retroperitoneum. Euthanasia was performed 4 days after the surgical procedure. The follicles were counted and classified as developing versus atretic. The immunohistochemical assay identified vascular factor of endothelial growth (VEGF) in the ovarian stroma and assessed the proliferation capacity by means of the Ki-67 in the ovarian follicles. Every group showed an inflammatory infiltrate, luteous body, and ovarian follicles in several phases of development. The ischemic preconditioning groups displayed greater amounts of viable ovarian follicles and increased vascularization and vasodilatation than the control group. GIPC-15 showed the highest amount of viable follicles compared to the others (P < .05 GIPC-15 vs GC; GIPC-15 vs GIPC-5). More VEGF-labeled cells were observed in GIPC-10 than the control group (P < .05, GIPC-10 vs GC). The proliferation index assessed by Ki-67 marking showed GC: 80%; GIPC-5: 76%; GIPC-10: 67%; and GIPC-15: 64% (P > .05). The PCI-15 cohort seem to be the most adequate timing to achieve functional support and preservation of a greater number of viable ovarian follicles.

  3. Pre-conditioning with low-level laser (light) therapy: light before the storm.

    PubMed

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

    2014-12-01

    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.

  4. Geranylgeranylacetone preconditioning may attenuate heat-induced inflammation and multiorgan dysfunction in rats.

    PubMed

    Zhao, Yong-Qi; Gao, Jun-Tao; Liu, Shou-Hong; Wu, Yan; Lin, Mao-Tsun; Fan, Ming

    2010-01-01

    Geranylgeranylacetone, an acyclic isoprenoid, is a non-toxic inducer of heat shock protein (HSP)70. HSP70 overproduction is associated with heat tolerance in rats. This study aimed to investigate whether geranylgeranylacetone preconditioning of rats reduced heat-induced inflammation and multiple organ dysfunction. Anaesthetised rats were given vehicle or geranylgeranylacetone (800 mg/kg) orally. After 48 h they were exposed to ambient temperature of 43 degrees C for 70 min to induce heatstroke. Another group of rats kept at room temperature were used as normothermic controls. Vehicle-treated rats all succumbed to heat stress; their survival time was 25 +/- 4 min. Pretreatment with geranylgeranylacetone significantly increased survival time to 92 +/- 15 min. Compared with normothermic controls, all vehicle-treated heatstroke rats displayed hepatic and renal dysfunction (e.g. increased plasma levels of serum urea nitrogen, creatinine, aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase) and active inflammation (e.g. increased plasma and brain levels of interleukin-1 beta, tumour necrosis factor-alpha and interleukin-6). These heat-stress response indicators were all significantly suppressed by geranylgeranylacetone pretreatment. In addition, the plasma and brain levels of interleukin-10 (an anti-inflammatory cytokine) and brain levels of HSP70 were significantly increased after geranylgeranylacetone preconditioning during heatstroke. Geranylgeranylacetone preconditioning attenuates heat-induced inflammation and multiorgan dysfunction in rats.

  5. 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

  6. Exploring the Role of TRPV and CGRP in Adenosine Preconditioning and Remote Hind Limb Preconditioning-Induced Cardioprotection in Rats.

    PubMed

    Singh, Amritpal; Randhawa, Puneet Kaur; Bali, Anjana; Singh, Nirmal; Jaggi, Amteshwar Singh

    2017-02-14

    The cardioprotective effects of remote hind limb preconditioning (RIPC) are well known, but mechanisms by which protection occurs still remain to be explored. Therefore, the present study was designed to investigate the role of TRPV and CGRP in adenosine and remote preconditioning-induced cardioprotection, using sumatriptan, a CGRP release inhibitor and ruthenium red, a TRPV inhibitor, in rats. For remote preconditioning, a pressure cuff was tied around the hind limb of the rat and was inflated with air up to 150 mmHg to produce ischemia in the hind limb and during reperfusion pressure was released. Four cycles of ischemia and reperfusion, each consisting of 5 min of inflation and 5 min of deflation of pressure cuff were used to produce remote limb preconditioning. An ex vivo Langendorff's isolated rat heart model was used to induce ischemia reperfusion injury by 30 min of global ischemia followed by 120 min of reperfusion. RIPC demonstrated a significant decrease in ischemia reperfusion-induced significant myocardial injury in terms of increase in LDH, CK, infarct size and decrease in LVDP, +dp/dtmax and -dp/dtmin. Moreover, pharmacological preconditioning with adenosine produced cardioprotective effects in a similar manner to RIPC. Pretreatment with sumatriptan, a CGRP release blocker, abolished RIPC and adenosine preconditioning-induced cardioprotective effects. Administration of ruthenium red, a TRPV inhibitor, also abolished adenosine preconditioning-induced cardioprotection. It may be proposed that the cardioprotective effects of adenosine and remote preconditioning are possibly mediated through activation of a TRPV channels and consequent, release of CGRP.

  7. 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.

  8. 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.

  9. Methamphetamine Preconditioning Alters Midbrain Transcriptional Responses to Methamphetamine-Induced Injury in the Rat Striatum

    PubMed Central

    Cadet, Jean Lud; McCoy, Michael T.; Cai, Ning Sheng; Krasnova, Irina N.; Ladenheim, Bruce; Beauvais, Genevieve; Wilson, Natascha; Wood, William; Becker, Kevin G.; Hodges, Amber B.

    2009-01-01

    Methamphetamine (METH) is an illicit drug which is neurotoxic to the mammalian brain. Numerous studies have revealed significant decreases in dopamine and serotonin levels in the brains of animals exposed to moderate-to-large METH doses given within short intervals of time. In contrast, repeated injections of small nontoxic doses of the drug followed by a challenge with toxic METH doses afford significant protection against monoamine depletion. The present study was undertaken to test the possibility that repeated injections of the drug might be accompanied by transcriptional changes involved in rendering the nigrostriatal dopaminergic system refractory to METH toxicity. Our results confirm that METH preconditioning can provide significant protection against METH-induced striatal dopamine depletion. In addition, the presence and absence of METH preconditioning were associated with substantial differences in the identity of the genes whose expression was affected by a toxic METH challenge. Quantitative PCR confirmed METH-induced changes in genes of interest and identified additional genes that were differentially impacted by the toxic METH challenge in the presence of METH preconditioning. These genes include small heat shock 27 kD 27 protein 2 (HspB2), thyrotropin-releasing hormone (TRH), brain derived neurotrophic factor (BDNF), c-fos, and some encoding antioxidant proteins including CuZn superoxide dismutase (CuZnSOD), glutathione peroxidase (GPx)-1, and heme oxygenase-1 (Hmox-1). These observations are consistent, in part, with the transcriptional alterations reported in models of lethal ischemic injuries which are preceded by ischemic or pharmacological preconditioning. Our findings suggest that multiple molecular pathways might work in tandem to protect the nigrostriatal dopaminergic pathway against the deleterious effects of the toxic psychostimulant. Further analysis of the molecular and cellular pathways regulated by these genes should help to provide some

  10. Peoniflorin suppresses tumor necrosis factor-α induced chemokine production in human dermal microvascular endothelial cells by blocking nuclear factor-κB and ERK pathway.

    PubMed

    Chen, Tao; Guo, Zai-Pei; Jiao, Xiao-Yan; Jia, Rui-Zhen; Zhang, Yu-Hong; Li, Jing-Yi; Huang, Xu-Lei; Liu, Hong-Jie

    2011-07-01

    Peoniflorin (PF) extracted from the root of Paeonia lactiflora pall displays anti-inflammation and antioxidant properties in several animal models. Chemokines are vital for directing the movement of circulating leukocytes to the sites of inflammation and are involved in the pathogenesis of various inflammatory skin diseases. Herein, we investigated the effects and potential mechanisms of PF on tumor necrosis factor-α (TNF-α) induced chemokine production in human dermal microvascular endothelial cells. Human dermal microvascular endothelial cell line (HMEC-1) was treated by TNF-α with or without PF. PF markedly attenuated TNF-α-induced chemokines (including CCL2, CCL5, CCL20, CXCL8, CXCL16 and CX3CL1) mRNA expression in HMEC-1. PF also reduced the secretion of these chemokines in culture supernatants. In addition, endothelial activation in the presence of PF markedly blocked the chemotactic activities of TNF-α-stimulated HMEC-1 supernatant on promyelocytic leukemia cell line (HL-60) or the acute mature monocytic leukemia cell line (THP-1) cell migration. Furthermore, Western blot data revealed TNF-α upregulated phosphorylation of inhibitor of κB-α (IκBα) and phosphorylation of extracellular signal-regulated kinase (ERK)1/2, which was almost completely reversed by PF. Finally, PF inhibited nuclear factor-κB (NF-κB) nuclear translocation to the nucleus. Taken together, our data provide the first evidence that PF has an anti-inflammatory ability against TNF-α-induced chemokine production and leukocyte migration, which may be at least partly related to the inhibition of NF-κB and ERK pathway. PF may be a candidate medicine for the treatment of inflammatory skin diseases.

  11. 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.

  12. Preconditioning and postconditioning: new strategies for cardioprotection.

    PubMed

    Hausenloy, D J; Yellon, D M

    2008-06-01

    Despite optimal therapy, the morbidity and mortality of coronary heart disease (CHD) remains significant, particularly in patients with diabetes or the metabolic syndrome. New strategies for cardioprotection are therefore required to improve the clinical outcomes in patients with CHD. Ischaemic preconditioning (IPC) as a cardioprotective strategy has not fulfilled it clinical potential, primarily because of the need to intervene before the index ischaemic event, which is impossible to predict in patients presenting with an acute myocardial infarction (AMI). However, emerging studies suggest that IPC-induced protection is mediated in part by signalling transduction pathways recruited at time of myocardial reperfusion, creating the possibility of harnessing its cardioprotective potential by intervening at time of reperfusion. In this regard, the recently described phenomenon of ischaemic postconditioning (IPost) has attracted great interest, particularly as it represents an intervention, which can be applied at time of myocardial reperfusion for patients presenting with an AMI. Interestingly, the signal transduction pathways, which underlie its protection, are similar to those recruited by IPC, creating a potential common cardioprotective pathway, which can be recruited at time of myocardial reperfusion, through the use of appropriate pharmacological agents given as adjuvant therapy to current myocardial reperfusion strategies such as thrombolysis and primary percutaneous coronary intervention for patients presenting with an AMI. This article provides a brief overview of IPC and IPost and describes the common signal transduction pathway they both appear to recruit at time of myocardial reperfusion, the pharmacological manipulation of which has the potential to generate new strategies for cardioprotection.

  13. Ischemic Preconditioning Mediates Neuroprotection against Ischemia in Mouse Hippocampal CA1 Neurons by Inducing Autophagy.

    PubMed

    Gao, Chunlin; Cai, Ying; Zhang, Xuebin; Huang, Huiling; Wang, Jin; Wang, Yajing; Tong, Xiaoguang; Wang, Jinhuan; Wu, Jialing

    2015-01-01

    The hippocampal CA1 region is sensitive to hypoxic and ischemic injury but can be protected by ischemic preconditioning (IPC). However, the mechanism through which IPC protects hippocampal CA1 neurons is still under investigation. Additionally, the role of autophagy in determining the fate of hippocampal neurons is unclear. Here, we examined whether IPC induced autophagy to alleviate hippocampal CA1 neuronal death in vitro and in vivo with oxygen glucose deprivation (OGD) and bilateral carotid artery occlusion (BCCAO) models. Survival of hippocampal neurons increased from 51.5% ± 6.3% in the non-IPC group (55 min of OGD) to 77.3% ± 7.9% in the IPC group (15 min of OGD, followed by 55 min of OGD 24 h later). The number of hippocampal CA1 layer neurons increased from 182 ± 26 cells/mm2 in the non-IPC group (20 min of BCCAO) to 278 ± 55 cells/mm2 in the IPC group (1 min × 3 BCCAO, followed by 20 min of BCCAO 24 h later). Akt phosphorylation and microtubule-associated protein light chain 3 (LC3)-II/LC3-I expression were increased in the preconditioning group. Moreover, the protective effects of IPC were abolished only by inhibiting the activity of autophagy, but not by blocking the activation of Akt in vitro. Using in vivo experiments, we found that LC3 expression was upregulated, accompanied by an increase in neuronal survival in hippocampal CA1 neurons in the preconditioning group. The neuroprotective effects of IPC on hippocampal CA1 neurons were completely inhibited by treatment with 3-MA. In contrast, hippocampal CA3 neurons did not show changes in autophagic activity or beneficial effects of IPC. These data suggested that IPC may attenuate ischemic injury in hippocampal CA1 neurons through induction of Akt-independent autophagy.

  14. Ischemic Preconditioning Mediates Neuroprotection against Ischemia in Mouse Hippocampal CA1 Neurons by Inducing Autophagy

    PubMed Central

    Zhang, Xuebin; Huang, Huiling; Wang, Jin; Wang, Yajing; Tong, Xiaoguang; Wang, Jinhuan; Wu, Jialing

    2015-01-01

    The hippocampal CA1 region is sensitive to hypoxic and ischemic injury but can be protected by ischemic preconditioning (IPC). However, the mechanism through which IPC protects hippocampal CA1 neurons is still under investigation. Additionally, the role of autophagy in determining the fate of hippocampal neurons is unclear. Here, we examined whether IPC induced autophagy to alleviate hippocampal CA1 neuronal death in vitro and in vivo with oxygen glucose deprivation (OGD) and bilateral carotid artery occlusion (BCCAO) models. Survival of hippocampal neurons increased from 51.5% ± 6.3% in the non-IPC group (55 min of OGD) to 77.3% ± 7.9% in the IPC group (15 min of OGD, followed by 55 min of OGD 24 h later). The number of hippocampal CA1 layer neurons increased from 182 ± 26 cells/mm2 in the non-IPC group (20 min of BCCAO) to 278 ± 55 cells/mm2 in the IPC group (1 min × 3 BCCAO, followed by 20 min of BCCAO 24 h later). Akt phosphorylation and microtubule-associated protein light chain 3 (LC3)-II/LC3-I expression were increased in the preconditioning group. Moreover, the protective effects of IPC were abolished only by inhibiting the activity of autophagy, but not by blocking the activation of Akt in vitro. Using in vivo experiments, we found that LC3 expression was upregulated, accompanied by an increase in neuronal survival in hippocampal CA1 neurons in the preconditioning group. The neuroprotective effects of IPC on hippocampal CA1 neurons were completely inhibited by treatment with 3-MA. In contrast, hippocampal CA3 neurons did not show changes in autophagic activity or beneficial effects of IPC. These data suggested that IPC may attenuate ischemic injury in hippocampal CA1 neurons through induction of Akt-independent autophagy. PMID:26325184

  15. Ischemic preconditioning of one forearm enhances static and dynamic apnea.

    PubMed

    Kjeld, Thomas; Rasmussen, Mads Reinholdt; Jattu, Timo; Nielsen, Henning Bay; Secher, Niels Henry

    2014-01-01

    Ischemic preconditioning enhances ergometer cycling and swimming performance. We evaluated whether ischemic preconditioning of one forearm (four times for 5 min) also affects static breath hold and underwater swimming, whereas the effect of similar preconditioning on ergometer rowing served as control because the warm-up for rowing regularly encompasses intense exercise and therefore reduced muscle oxygenation. Six divers performed a dry static breath hold, 11 divers swam underwater in an indoor pool, and 14 oarsmen rowed "1000 m" on an ergometer. Ischemic preconditioning reduced the forearm oxygen saturation from 65% ± 7% to 19% ± 7% (mean ± SD; P < 0.001), determined using spatially resolved near-infrared spectroscopy. During the breath hold (315 s, range = 280-375 s), forearm oxygenation decreased to 29% ± 10%; and in preparation for rowing, right thigh oxygenation decreased from 66% ± 7% to 33% ± 14% (P < 0.05). Ischemic preconditioning prolonged the breath hold from 279 ± 72 to 327 ± 39 s, and the underwater swimming distance from 110 ± 16 to 119 ± 14 m (P < 0.05) and also the rowing time was reduced (from 186.5 ± 3.6 to 185.7 ± 3.6 s; P < 0.05). We conclude that while the effect of ischemic preconditioning (of one forearm) on ergometer rowing was minimal, probably because of reduced muscle oxygenation during the warm-up, ischemic preconditioning does enhance both static and dynamic apnea, supporting that muscle ischemia is an important preparation for physical activity.

  16. Preconditioning Strategies in Elastic Full Waveform Inversion.

    NASA Astrophysics Data System (ADS)

    Matharu, G.; Sacchi, M. D.

    2016-12-01

    Elastic full waveform inversion (FWI) is inherently more non-linear than its acoustic counterpart, a property that stems from the increased model space of the problem. Whereas acoustic media can be parametrized by density and P-wave velocity, visco-elastic media are parametrized by density, attenuation and 21 independent coefficients of the elastic tensor. Imposing assumptions of isotropy and perfect elasticity to simplify the physics, reduces the number of independent parameters required to characterize a medium. Isotropic, elastic media can be parametrized in terms of density and the Lamé parameters. The different parameters can exhibit trade-off that manifest as attributes in the data. In the context of FWI, this means that certain parameters cannot be uniquely resolved. An ideal model update in full waveform inversion is equivalent to a Newton step. Explicit computation of the Hessian and its inverse is not computationally feasible in elastic FWI. The inverse Hessian scales the gradients to account for trade-off between parameters as well as compensating for inadequate illumination related to source-receiver coverage. Gradient preconditioners can be applied to mimic the action of the inverse Hessian and partially correct for inaccuracies in the gradient. In this study, we investigate the effects of model reparametrization by recasting a regularized form of the least-squares waveform misfit into a preconditioned formulation. New model parameters are obtained by applying invertible weighting matrices to the model vector. The weighting matrices are related to estimates of the prior model covariance matrix and incorporate information about spatially variant correlations of model parameters as well as correlations between independent parameters. We compare the convergence of conventional FWI to FWI after model reparametrization.

  17. 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

  18. Human bone marrow-derived mesenchymal stem cells display enhanced clonogenicity but impaired differentiation with hypoxic preconditioning.

    PubMed

    Boyette, Lisa B; Creasey, Olivia A; Guzik, Lynda; Lozito, Thomas; Tuan, Rocky S

    2014-02-01

    Stem cells are promising candidate cells for regenerative applications because they possess high proliferative capacity and the potential to differentiate into other cell types. Mesenchymal stem cells (MSCs) are easily sourced but do not retain their proliferative and multilineage differentiative capabilities after prolonged ex vivo propagation. We investigated the use of hypoxia as a preconditioning agent and in differentiating cultures to enhance MSC function. Culture in 5% ambient O(2) consistently enhanced clonogenic potential of primary MSCs from all donors tested. We determined that enhanced clonogenicity was attributable to increased proliferation, increased vascular endothelial growth factor secretion, and increased matrix turnover. Hypoxia did not impact the incidence of cell death. Application of hypoxia to osteogenic cultures resulted in enhanced total mineral deposition, although this effect was detected only in MSCs preconditioned in normoxic conditions. Osteogenesis-associated genes were upregulated in hypoxia, and alkaline phosphatase activity was enhanced. Adipogenic differentiation was inhibited by exposure to hypoxia during differentiation. Chondrogenesis in three-dimensional pellet cultures was inhibited by preconditioning with hypoxia. However, in cultures expanded under normoxia, hypoxia applied during subsequent pellet culture enhanced chondrogenesis. Whereas hypoxic preconditioning appears to be an excellent way to expand a highly clonogenic progenitor pool, our findings suggest that it may blunt the differentiation potential of MSCs, compromising their utility for regenerative tissue engineering. Exposure to hypoxia during differentiation (post-normoxic expansion), however, appears to result in a greater quantity of functional osteoblasts and chondrocytes and ultimately a larger quantity of high-quality differentiated tissue.

  19. 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

  20. Preconditioning chemotherapy with cisplatin enhances the antitumor activity of cytokine-induced killer cells in a murine melanoma model.

    PubMed

    Chen, Jing; Huang, Xiang; Huang, Guichun; Chen, Yitian; Chen, Longbang; Song, Haizhu

    2012-04-01

    Accumulating evidence has indicated that preconditioning chemotherapy could eliminate the suppressive factors in antitumor immune response, thereby leading to the full release of the efficacy of the subsequent immunotherapy. In this study, a single subtoxic dose (5 mg/kg, intraperitoneally) of cisplatin was chosen as the preconditioning chemotherapy in combination with cytokine-induced killer (CIK) cells (4×10(6), intravenously) to treat the murine B16 melanoma xenografts. It was found that cisplatin pretreatment could enhance the antitumor activity of CIK cells. To explore the potential mechanisms underlying the efficacy-enhancing effect of cisplatin, the in vivo trafficking and distribution of the infused CIK cells were traced. It was found that cisplatin could augment the homing ability of CIK cells into the tumor, tumor-draining lymph nodes (TDLNs), and spleen tissues. The endogenous effector cells, CD3(+) T lymphocytes also had an increased accumulation in the tumor and TDLNs after cisplatin precondition. Moreover, cisplatin could also modulate the percentages of myeloid cells, thus encouraging immune responses by increasing the percentages of dendritic cells and relieving the immunosuppression by preferentially eliminating the myeloid-derived suppressor cells. In conclusion, our findings suggested that cisplatin preconditioning chemotherapy could enhance the antitumor activity of CIK cells in a murine melanoma model, and this efficacy-enhancing effect was attributed to the augmented homing ability of exogenous and endogenous effector cells and the modulation of the myeloid cells.

  1. Up-regulation of heme oxygenase-1 by isoflurane preconditioning during tolerance against neuronal injury induced by oxygen glucose deprivation.

    PubMed

    Li, Qifang; Zhu, Yesen; Jiang, Hong; Xu, Hui; Liu, Heping

    2008-09-01

    Heme oxygenase (HO) is the rate-limiting enzyme in the degradation of heme to produce bile pigments and carbon monoxide. The HO-1 isozyme is induced by a variety of factors such as heat, heme, ischemia, and hydrogen peroxide. In recent years, mounting findings have suggested that HO-1 has a neuroprotective activity against ischemic injury. The neuroprotective role of isoflurane, a commonly used anesthetic, has been well documented, but little is known about the underlying mechanisms involved. Recently, isoflurane has been shown to up-regulate HO-1 in the liver. In this study, we show that isoflurane preconditioning promotes the survival of cultured ischemic hippocampal neurons by increasing the number of surviving neurons and their viability. Further study by reverse transcription-polymerase chain reaction and Western blot analysis showed that isoflurane preconditioning significantly increases HO-1 expression in oxygen glucose deprivation (OGD)-induced neuronal injury. Furthermore, inhibition of HO activity by tin protoporphyrin partially abolishes isoflurane preconditioning's protective effect as measured by lactate dehydrogenase release in OGD neurons. These findings indicated that the neuroprotective role of isoflurane preconditioning against OGD-induced injury might be associated with its role in up-regulating HO-1 in ischemic neurons.

  2. 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

  3. Limb ischemic preconditioning protects against contrast-induced nephropathy via renalase.

    PubMed

    Wang, Feng; Yin, Jianyong; Lu, Zeyuan; Zhang, Guangyuan; Li, Junhui; Xing, Tao; Zhuang, Shougang; Wang, Niansong

    2016-07-01

    Clinical trials shows that remote ischemic preconditioning (IPC) can protect against contrast induced nephropathy (CIN) in risky patients, however, the exact mechanism is unclear. In this study, we explored whether renalase, an amine oxidase that has been previously shown to mediate reno-protection by local IPC, would also mediate the same effect elicited by remote IPC in animal model. Limb IPC was performed for 24h followed by induction of CIN. Our results indicated that limb IPC prevented renal function decline, attenuated tubular damage and reduced oxidative stress and inflammation in the kidney. All those beneficial effects were abolished by silencing of renalase with siRNA. This suggests that similar to local IPC, renalase is also critically involved in limb IPC-elicited reno-protection. Mechanistic studies showed that limb IPC increased TNFα levels in the muscle and blood, and up-regulated renalase and phosphorylated IκBα expression in the kidney. Pretreatment with TNFα antagonist or NF-κB inhibitor, largely blocked renalase expression. Besides, TNFα preconditioning increased expression of renal renalase in vivo and in vitro, and attenuated H2O2 induced apoptosis in renal tubular cells. Collectively, our results suggest that limb IPC-induced reno-protection in CIN is dependent on increased renalase expression via activation of the TNFα/NF-κB pathway.

  4. 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

  5. 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.

  6. Retrospective analysis of risk factors and predictors of intraoperative complications in neuraxial blocks at Faculdade de Medicina de Botucatu-UNESP.

    PubMed

    Pereira, Ivan Dias Fernandes; Grando, Marcela Miguel; Vianna, Pedro Thadeu Galvão; Braz, José Reinaldo Cerqueira; Castiglia, Yara Marcondes Machado; Vane, Luís Antônio; Módolo, Norma Sueli Pinheiro; do Nascimento, Paulo; Amorim, Rosa Beatriz; Rodrigues, Geraldo Rolim; Braz, Leandro Gobbo; Ganem, Eliana Marisa

    2011-01-01

    Cardiovascular changes associated with neuraxial blocks are a cause of concern due to their frequency and because some of them can be considered physiological effects triggered by the sympathetic nervous system blockade. The objective of this study was to evaluate intraoperative cardiovascular complications and predictive factors associated with neuraxial blocks in patients ≥ 18 years of age undergoing non-obstetric procedures over an 18-year period in a tertiary university hospital--HCFMB-UNESP. A retrospective analysis of the following complications was undertaken: hypertension, hypotension, sinus bradycardia, and sinus tachycardia. These complications were correlated with anesthetic technique, physical status (ASA), age, gender, and preoperative co-morbidities. The Tukey test for comparisons among proportions and logistic regression was used for statistical analysis. 32,554 patients underwent neuraxial blocks. Intraoperative complications mentioned included hypotension (n=4,109), sinus bradycardia (n=1,107), sinus tachycardia (n=601), and hypertension (n=466). Hypotension was seen more often in patients undergoing continuous subarachnoid anesthesia (29.4%, OR=2.39), ≥ 61 years of age, and female (OR=1.27). Intraoperative hypotension and bradycardia were the complications observed more often. Hypotension was related to anesthetic technique (CSA), increased age, and female. Tachycardia and hypertension may not have been directly related to neuraxial blocks. Copyright © 2011 Elsevier Editora Ltda. All rights reserved.

  7. Corsi's block-tapping task: standardization and location in factor space with the WAIS-R for two normal samples of older adults.

    PubMed

    Saggino, Aristide; Balsamo, Michela; Grieco, Anna; Cerbone, Maria Rosaria; Raviele, Nicla Nicolina

    2004-06-01

    Corsi's block-tapping task and WAIS-R were administered to two Italian samples of 200 normal older adults (aged 65-74 years and 75-100 years). Corsi's reliabilities and standardization data are shown. Additionally, Corsi's location in the factor space of cognitive abilities represented by the 11 WAIS-R subtests is presented. Corsi's test seems to be a reliable one for older Italians. It seems also to be a measure of general intelligence in those 65-74 years of age and a measure of the Freedom from Distractibility factor in subjects 75 years and older.

  8. Local anaesthetics and additives for spinal anaesthesia--characteristics and factors influencing the spread and duration of the block.

    PubMed

    Pitkänen, Mikko; Rosenberg, Per H

    2003-09-01

    Different characteristics of patients and local anaesthetic formulations will influence the spread of spinal anaesthesia. The predictability of the spread of spinal anaesthesia can be improved by altering both baricity of the solution, and the position of the patient during the intrathecal local anaesthetic injection. The role of adrenaline and clonidine in prolonging the block and associated side effects is discussed. The role of opioids added to local anaesthetic solutions is discussed from a cost/benefit point of view.

  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. 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…

  11. 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

  12. 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.

  13. 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.

  14. 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.

  15. 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.

  16. 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

  17. 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.

  18. 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.

  19. 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.

  20. Optimal bounds for solving tridiagonal systems with preconditioning

    SciTech Connect

    Zellini, P. )

    1988-10-01

    Let (1) Tx=f be a linear tridiagonal system system of n equations in the unknown x/sub 1/, ..., x/sub n/. It is proved that 3n-2 (nonscalar) multiplications/divisions are necessary to solve (1) in a straight-line program excluding divisions by elements of f. This bound is optimal if the cost of preconditioning of T is not counted. Analogous results are obtained in case (i) T is bidiagonal and (ii) T and f are both centrosymmetric. The existence of parallel algorithms to solve (1) with preconditioning and with minimal multiplicative redundancy is also discussed.

  1. Hyperbaric oxygen preconditioning: a reliable option for neuroprotection

    PubMed Central

    Hu, Qin; Manaenko, Anatol; Matei, Nathanael; Guo, Zhenni; Xu, Ting; Tang, Jiping; Zhang, John H.

    2016-01-01

    Brain injury is the leading cause of death and disability worldwide and clinically there is no effective therapy for neuroprotection. Hyperbaric oxygen preconditioning (HBO-PC) has been experimentally demonstrated to be neuroprotective in several models and has shown efficiency in patients undergoing on-pump coronary artery bypass graft (CABG) surgery. Compared with other preconditioning stimuli, HBO is benign and has clinically translational potential. In this review, we will summarize the results in experimental brain injury and clinical studies, elaborate the mechanisms of HBO-PC, and discuss regimes and opinions for future interventions in acute brain injury. PMID:27826420

  2. 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.

  3. 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.

  4. Hypoxia Pre-Conditioned Embryonic Mesenchymal Stem Cell Secretome Reduces IL-10 Production by Peripheral Blood Mononuclear Cells

    PubMed Central

    Lotfinia, Majid; Lak, Shirin; Ghahhari, Nastaran Mohammadi; Johari, Behrooz; Maghsood, Faezeh; Parsania, Sara; Tabrizi, Bahareh Sadegh; Kadivar, Mehdi

    2017-01-01

    Background: Mesenchymal stem cells (MSCs) are important candidates for MSC-based cellular therapy. Current paradigm states that MSCs support local progenitor cells in damaged tissue through paracrine signaling. Therefore, the study of paracrine effects and secretome of MSCs could lead to the appreciation of mechanisms and molecules associated with the therapeutic effects of these cells. This study analyzed anti-inflammatory and immune-modulatory effects of MSC secretomes derived from embryonic stem cells (ESCs) and bone marrow cells after hypoxia and normoxia preconditioning. Methods: ESCs differentiated into MSCs and characterized by flow cytometry as well as by differentiation into adipocytes and osteoblasts. The experimental groups were consisted of individual groups of ESC-MSCs and BM-MSCs (bone marrow-derived mesenchymal stromal cells), which were preconditioned with either hypoxia or normoxia for 24, 48 and 72 h. After collecting the cell-free medium from each treatment, secretomes were concentrated by centrifugal filters. Using a peripheral blood mononuclear cell (PBMC) assay and ELISA, IL-10 concentration in PBMCs was evaluated after their incubation with different secretomes from preconditioned and non-preconditioned MSCs. Results: A significant difference was observed between ESC-MSC normoxia and ESC-MSC hypoxia in IL-10 concentration, and normoxia secretomes increased IL-10 secretion from PBMCs. Moreover, the strongest IL-10 secretion from PBMCs could be detected after the stimulation by ESC-MSC conditioned secretomes, but not BM-MSC conditioned medium. Conclusions: Human hypoxia preconditioned ESC-MSC secretome indicated stronger immune-modulatory effects compared to BM-MSC conditioned medium. It could be suggested that induced MSCs confer less immune-modulatory effects but produce more inflammatory molecules such as tumor necrosis factor α, which needs further investigation. PMID:27132108

  5. Heme oxygenase-1 mediated memorial and revivable protective effect of ischemic preconditioning on brain injury.

    PubMed

    Le, Li-Li; Li, Xue-Yi; Meng, Dan; Liang, Qiu-Jun; Wang, Xin-Hong; Li, Ning; Quan, Jing; Xiang, Meng; Jiang, Mei; Sun, Jian; Chen, Si-Feng

    2013-12-01

    Ischemic preconditioning (IPC) has short-term benefits for stroke patients. However, if IPC protective effect is memorial and the role of the intracellular protective protein heme oxygenase-1 (HO-1) is not known. Ischemic preconditioning and the corresponding sham control were achieved by blocking the blood flow of the left internal carotid artery for 20 min and 2 second, respectively, in rats. Both IPC and sham-operated animals were divided into three groups and treated with PBS, the HO-1 inducer hemin, and the HO-1 inhibitor Znpp. Three weeks after IPC, brain ischemia-reperfusion injury was achieved by left middle cerebral artery obstruction for 45 min followed by 24-h reperfusion. 2,3,5-triphenyltetrazolium chloride staining and neurological dysfunction scoring showed IPC significantly reduced brain infarct area and improved neurological function occurred 3 weeks after IPC. Hemin treatment promoted whereas ZnPP blocked the benefits of IPC. Immunohistochemical analysis and Western blotting showed that the expression of HO-1 was higher in the border zone than in the necrotic core zone. The memorial IPC protection is independent of adenosine receptor A1R and A2aR expressions. We found for the first time that the protective effect of IPC can be remembered to protect brain injury occurred after acute response disappear. The results indicate that interventional treatment can achieve protective effect for future cerebral injury not only through interventional treatment itself but also through the memorial and revivable IPC, eliminating the concern that temporary ischemia caused by interventional treatment may leave harmful effect in the brain. © 2013 John Wiley & Sons Ltd.

  6. 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.

  7. 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.

  8. 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.

  9. Lower extremity mechanics during landing after a volleyball block as a risk factor for anterior cruciate ligament injury.

    PubMed

    Zahradnik, David; Jandacka, Daniel; Uchytil, Jaroslav; Farana, Roman; Hamill, Joseph

    2015-02-01

    To compare lower extremity mechanics and energy absorption during two types of landing after a successful or unsuccessful block in volleyball and assess the risks of anterior cruciate ligament (ACL) injury. Cohort study. Fourteen elite male volleyball players (aged 24.5 ± 4.6 years; height 1.94 ± 0.06 m; mass 86.6 ± 7.6 kg). Subjects were required to land on force platforms using stick landing or step-back landing (with the right lower extremity stepping back away from the net) techniques after performing a standing block jump movement. Vertical ground reaction force (body weight); knee flexion (degrees); knee moments (Nm/kg); and hip, knee and ankle energy absorption (J/kg). The right lower extremity showed a greater first peak of vertical ground reaction force, a greater valgus moment, lower energy absorption by the knee, and higher energy absorption by the hip and ankle joints during step-back landing. The lower extremity may be exposed to a greater risk of ACL injury when stepping back from the net during the initial impact phase after a step-back landing. Copyright © 2014 Elsevier Ltd. All rights reserved.

  10. Laboratory investigation of the factors impact on bubble size, pore blocking and enhanced oil recovery with aqueous Colloidal Gas Aphron.

    PubMed

    Shi, Shenglong; Wang, Yefei; Li, Zhongpeng; Chen, Qingguo; Zhao, Zenghao

    Colloidal Gas Aphron as a mobility control in enhanced oil recovery is becoming attractive; it is also designed to block porous media with micro-bubbles. In this paper, the effects of surfactant concentration, polymer concentration, temperature and salinity on the bubble size of the Colloidal Gas Aphron were studied. Effects of injection rates, Colloidal Gas Aphron fluid composition, heterogeneity of reservoir on the resistance to the flow of Colloidal Gas Aphron fluid through porous media were investigated. Effects of Colloidal Gas Aphron fluid composition and temperature on residual oil recovery were also studied. The results showed that bubble growth rate decreased with increasing surfactant concentration, polymer concentration, and decreasing temperature, while it decreased and then increased slightly with increasing salinity. The obvious increase of injection pressure was observed as more Colloidal Gas Aphron fluid was injected, indicating that Colloidal Gas Aphron could block the pore media effectively. The effectiveness of the best blend obtained through homogeneous sandpack flood tests was modestly improved in the heterogeneous sandpack. The tertiary oil recovery increased 26.8 % by Colloidal Gas Aphron fluid as compared to 20.3 % by XG solution when chemical solution of 1 PV was injected into the sandpack. The maximum injected pressure of Colloidal Gas Aphron fluid was about three times that of the XG solution. As the temperature increased, the Colloidal Gas Aphron fluid became less stable; the maximum injection pressure and tertiary oil recovery of Colloidal Gas Aphron fluid decreased.

  11. 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.

  12. 33 CFR 183.220 - Preconditioning for tests.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... and outside of the boat, either over the sides, through a hull opening, or both. Entrapped air in the... (CONTINUED) BOATING SAFETY BOATS AND ASSOCIATED EQUIPMENT Flotation Requirements for Outboard Boats Rated for Engines of More Than 2 Horsepower General § 183.220 Preconditioning for tests. A boat must meet the...

  13. 33 CFR 183.220 - Preconditioning for tests.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... and outside of the boat, either over the sides, through a hull opening, or both. Entrapped air in the... (CONTINUED) BOATING SAFETY BOATS AND ASSOCIATED EQUIPMENT Flotation Requirements for Outboard Boats Rated for Engines of More Than 2 Horsepower General § 183.220 Preconditioning for tests. A boat must meet the...

  14. 33 CFR 183.320 - Preconditioning for tests.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... to flow between the inside and the outside of the boat, either over the sides, through a hull opening... (CONTINUED) BOATING SAFETY BOATS AND ASSOCIATED EQUIPMENT Flotation Requirements for Outboard Boats Rated for Engines of 2 Horsepower or Less General § 183.320 Preconditioning for tests. A boat must meet the...

  15. 33 CFR 183.320 - Preconditioning for tests.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... to flow between the inside and the outside of the boat, either over the sides, through a hull opening... (CONTINUED) BOATING SAFETY BOATS AND ASSOCIATED EQUIPMENT Flotation Requirements for Outboard Boats Rated for Engines of 2 Horsepower or Less General § 183.320 Preconditioning for tests. A boat must meet the...

  16. 33 CFR 183.320 - Preconditioning for tests.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... to flow between the inside and the outside of the boat, either over the sides, through a hull opening... (CONTINUED) BOATING SAFETY BOATS AND ASSOCIATED EQUIPMENT Flotation Requirements for Outboard Boats Rated for Engines of 2 Horsepower or Less General § 183.320 Preconditioning for tests. A boat must meet the...

  17. 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.

  18. Applying polynomial filtering to mass preconditioned Hybrid Monte Carlo

    NASA Astrophysics Data System (ADS)

    Haar, Taylor; Kamleh, Waseem; Zanotti, James; Nakamura, Yoshifumi

    2017-06-01

    The use of mass preconditioning or Hasenbusch filtering in modern Hybrid Monte Carlo simulations is common. At light quark masses, multiple filters (three or more) are typically used to reduce the cost of generating dynamical gauge fields; however, the task of tuning a large number of Hasenbusch mass terms is non-trivial. The use of short polynomial approximations to the inverse has been shown to provide an effective UV filter for HMC simulations. In this work we investigate the application of polynomial filtering to the mass preconditioned Hybrid Monte Carlo algorithm as a means of introducing many time scales into the molecular dynamics integration with a simplified parameter tuning process. A generalized multi-scale integration scheme that permits arbitrary step-sizes and can be applied to Omelyan-style integrators is also introduced. We find that polynomial-filtered mass-preconditioning (PF-MP) performs as well as or better than standard mass preconditioning, with significantly less fine tuning required.

  19. 40 CFR 1066.407 - Vehicle preparation and preconditioning.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 34 2012-07-01 2012-07-01 false Vehicle preparation and...) AIR POLLUTION CONTROLS VEHICLE-TESTING PROCEDURES Vehicle Preparation and Running a Test § 1066.407 Vehicle preparation and preconditioning. This section describes steps to take before measuring exhaust...

  20. 40 CFR 1066.407 - Vehicle preparation and preconditioning.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 34 2013-07-01 2013-07-01 false Vehicle preparation and...) AIR POLLUTION CONTROLS VEHICLE-TESTING PROCEDURES Vehicle Preparation and Running a Test § 1066.407 Vehicle preparation and preconditioning. This section describes steps to take before measuring exhaust...

  1. 33 CFR 183.220 - Preconditioning for tests.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... (CONTINUED) BOATING SAFETY BOATS AND ASSOCIATED EQUIPMENT Flotation Requirements for Outboard Boats Rated for Engines of More Than 2 Horsepower General § 183.220 Preconditioning for tests. A boat must meet the... boat. (b) The boat must be loaded with a quantity of weight that, when submerged, is equal to the sum...

  2. Preconditioning with cobalt chloride modifies pain perception in mice.

    PubMed

    Alexa, Teodora; Luca, Andrei; Dondas, Andrei; Bohotin, Catalina Roxana

    2015-04-01

    Cobalt chloride (CoCl2) modifies mitochondrial permeability and has a hypoxic-mimetic effect; thus, the compound induces tolerance to ischemia and increases resistance to a number of injury types. The aim of the present study was to investigate the effects of CoCl2 hypoxic preconditioning for three weeks on thermonociception, somatic and visceral inflammatory pain, locomotor activity and coordination in mice. A significant pronociceptive effect was observed in the hot plate and tail flick tests after one and two weeks of CoCl2 administration, respectively (P<0.001). Thermal hyperalgesia (Plantar test) was present in the first week, but recovered by the end of the experiment. Contrary to the hyperalgesic effect on thermonociception, CoCl2 hypoxic preconditioning decreased the time spent grooming the affected area in the second phase of the formalin test on the orofacial and paw models. The first phase of formalin-induced pain and the writhing test were not affected by CoCl2 preconditioning. Thus, the present study demonstrated that CoCl2 preconditioning has a dual effect on pain, and these effects should be taken into account along with the better-known neuro-, cardio- and renoprotective effects of CoCl2.

  3. 40 CFR 86.232-94 - 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. 86.232-94... (CONTINUED) CONTROL OF EMISSIONS FROM NEW AND IN-USE HIGHWAY VEHICLES AND ENGINES Emission Regulations for 1994 and Later Model Year Gasoline-Fueled New Light-Duty Vehicles, New Light-Duty Trucks and New...

  4. 40 CFR 86.1774-99 - Vehicle preconditioning.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 20 2012-07-01 2012-07-01 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...

  5. 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...

  6. 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...

  7. 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...

  8. 33 CFR 183.220 - Preconditioning for tests.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... Engines of More Than 2 Horsepower General § 183.220 Preconditioning for tests. A boat must meet the... be keel down in the water. (g) The boat must be swamped, allowing water to flow between the inside... flooded portion of the boat must be eliminated. (h) Water must flood the two largest air chambers and...

  9. 33 CFR 183.220 - Preconditioning for tests.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... Engines of More Than 2 Horsepower General § 183.220 Preconditioning for tests. A boat must meet the... be keel down in the water. (g) The boat must be swamped, allowing water to flow between the inside... flooded portion of the boat must be eliminated. (h) Water must flood the two largest air chambers and...

  10. 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 Emission...

  11. No influence of ischemic preconditioning on running economy.

    PubMed

    Kaur, Gungeet; Binger, Megan; Evans, Claire; Trachte, Tiffany; Van Guilder, Gary P

    2017-02-01

    Many of the potential performance-enhancing properties of ischemic preconditioning suggest that the oxygen cost for a given endurance exercise workload will be reduced, thereby improving the economy of locomotion. The aim of this study was to identify whether ischemic preconditioning improves exercise economy in recreational runners. A randomized sham-controlled crossover study was employed in which 18 adults (age 27 ± 7 years; BMI 24.6 ± 3 kg/m(2)) completed two, incremental submaximal (65-85% VO2max) treadmill running protocols (3 × 5 min stages from 7.2-14.5 km/h) coupled with indirect calorimetry to assess running economy following ischemic preconditioning (3 × 5 min bilateral upper thigh ischemia) and sham control. Running economy was expressed as mlO2/kg/km and as the energy in kilocalories required to cover 1 km of horizontal distance (kcal/kg/km). Ischemic preconditioning did not influence steady-state heart rate, oxygen consumption, minute ventilation, respiratory exchange ratio, energy expenditure, and blood lactate. Likewise, running economy was similar (P = 0.647) between the sham (from 201.6 ± 17.7 to 204.0 ± 16.1 mlO2/kg/km) and ischemic preconditioning trials (from 202.8 ± 16.2 to 203.1 ± 15.6 mlO2/kg/km). There was no influence (P = 0.21) of ischemic preconditioning on running economy expressed as the caloric unit cost (from 0.96 ± 0.12 to 1.01 ± 0.11 kcal/kg/km) compared with sham (from 1.00 ± 0.10 to 1.00 ± 0.08 kcal/kg/km). The properties of ischemic preconditioning thought to affect exercise performance at vigorous to severe exercise intensities, which generate more extensive physiological challenge, are ineffective at submaximal workloads and, therefore, do not change running economy.

  12. Time-derivative preconditioning method for multicomponent flow

    NASA Astrophysics Data System (ADS)

    Housman, Jeffrey Allen

    A time-derivative preconditioned system of equations suitable for the numerical simulation of single component and multicomponent inviscid flows at all speeds is formulated. The system is shown to be hyperbolic in time and remain well-posed at low Mach numbers, allowing an efficient time marching solution strategy to be utilized from transonic to incompressible flow speeds. For multicomponent flow at low speed, a preconditioned nonconservative discretization scheme is described which preserves pressure and velocity equilibrium across fluid interfaces, handles sharp liquid/gas interfaces with large density ratios, while remaining well-conditioned for time marching methods. The method is then extended to transonic and supersonic flows using a hybrid conservative/nonconservative formulation which retains the pressure/velocity equilibrium property and converges to the correct weak solution when shocks are present. In order to apply the proposed model to complex flow applications, the overset grid methodology is used where the equations are transformed to a nonorthogonal curvilinear coordinate system and discretized on structured body-fitted curvilinear grids. The multicomponent model and its extension to homogeneous multiphase mixtures is discussed and the hyperbolicity of the governing equations is demonstrated. Low Mach number perturbation analysis is then performed on the system of equations and a local time-derivative preconditioning matrix is derived allowing time marching numerical methods to remain efficient at low speeds. Next, a particular time marching numerical method is presented along with three discretization schemes for the convective terms. These include a conservative preconditioned Roe type method, a nonconservative preconditioned Split Coefficient Matrix (SCM) method, and hybrid formulation which combines the conservative and nonconservative schemes using a simple switching function. A characteristic boundary treatment which includes time

  13. Rhodopseudomonas sphaeroides lipid A derivatives block in vitro induction of tumor necrosis factor and endotoxin tolerance by smooth lipopolysaccharide and monophosphoryl lipid A.

    PubMed Central

    Henricson, B E; Perera, P Y; Qureshi, N; Takayama, K; Vogel, S N

    1992-01-01

    Rhodopseudomonas (Rhodobacter) sphaeroides diphosphoryl lipid A is a relatively inert species of lipid A but has been shown to antagonize the effects of toxic lipopolysaccharide (LPS) both in vivo and in vitro. The antagonist and its monophosphoryl derivative were examined for the ability to block tumor necrosis factor synthesis and reverse tolerance induction in vitro in macrophage cultures stimulated with bioactive preparations of smooth LPS, rough LPS, diphosphoryl lipid A, and monophosphoryl lipid A. Inhibition of agonist activity and reversal of tolerance by these novel penta-acylated lipid A antagonists provides new insight into macrophage-LPS interactions. PMID:1398939

  14. Hypoxic-preconditioning induces neuroprotection against hypoxia-ischemia in newborn piglet brain.

    PubMed

    Ara, Jahan; Fekete, Saskia; Frank, Melissa; Golden, Jeffrey A; Pleasure, David; Valencia, Ignacio

    2011-08-01

    Preconditioning-induced ischemic tolerance has been documented in the newborn brain, however, the signaling mechanisms of this preconditioning require further elucidation. The aims of this study were to develop a hypoxic-preconditioning (PC) model of ischemic tolerance in the newborn piglet, which emulates important clinical similarities to human situation of birth asphyxia, and to characterize some of the molecular mechanisms shown to be implicated in PC-induced neuroprotection in rodent models. One day old piglets were subjected to PC (8% O2/92% N2) for 3 h and 24 h later were exposed to hypoxia-ischemia (HI) produced by a combination of hypoxia (5% FiO2) for a period of 30 min and ischemia induced by a period of hypotension (10 min of reduced mean arterial blood pressure; ≤70% of baseline). Neuropathologic analysis and unbiased stereology, conducted at 24 h, 3 and 7 days of recovery following HI, indicated a substantial reduction in the severity of brain damage in PC piglets compared to non-PC piglets (P<0.05). PC significantly increased the mRNA expression of hypoxia-inducible factor-1α (HIF-1α) and its target gene, vascular endothelial growth factor (VEGF) at 0 h, 6h, 24 h, 3 and 7 days of recovery. Immunoblot analysis demonstrated that PC resulted in HIF-1α protein stabilization and accumulation in nuclear extracts of cerebral cortex of newborn piglet brain compared to normoxic controls. Protein levels of VEGF increased in a time-dependent manner in both cortex and hippocampus following PC. Double-immunolabeling indicated that VEGF is mainly expressed in neurons, endothelial cells and astroglia. Our study demonstrates for the first time the protective efficacy of PC against hypoxic-ischemic injury in newborn piglet model, which recapitulates many pathophysiological features of asphyxiated human neonates. Furthermore, as has been shown in rodent models of preconditioning, our results suggest that PC-induced protection in neonatal piglets may involve

  15. Metabolomic Analysis of Two Different Models of Delayed Preconditioning

    PubMed Central

    Bravo, Claudio; Kudej, Raymond K.; Yuan, Chujun; Yoon, Seonghun; Ge, Hui; Park, Ji Yeon; Tian, Bin; Stanley, William C.; Vatner, Stephen F.; Vatner, Dorothy E.; Yan, Lin

    2013-01-01

    Recently we described an ischemic preconditioning induced by repetitive coronary stenosis, which is induced by 6 episodes of non-lethal ischemia over 3 days, and which also resembles the hibernating myocardium phenotype. When compared with traditional second window of ischemic preconditioning using DNA microarrays, many genes which differed in the repetitive coronary stenosis appeared targeted to metabolism. Accordingly, the goal of this study was to provide a more in depth analysis of changes in metabolism in the different models of delayed preconditioning, i.e., second window and repetitive coronary stenosis. This was accomplished using a metabolomic approach based on liquid chromatography-mass spectrometry (LC-MS) and gas chromatography-mass spectrometry (GC-MS) techniques. Myocardial samples from the ischemic section of porcine hearts subjected to both models of late preconditioning were compared against sham controls. Interestingly, although both models involve delayed preconditioning, their metabolic signatures were radically different; of the total number of metabolites that changed in both models (135 metabolites) only 7 changed in both models, and significantly more, p<0.01, were altered in the repetitive coronary stenosis (40%) than in the second window (8.1%). The most significant changes observed were in energy metabolism, e.g., phosphocreatine was increased 4 fold and creatine kinase activity increased by 27.2%, a pattern opposite from heart failure, suggesting that the repetitive coronary stenosis and potentially hibernating myocardium have enhanced stress resistance capabilities. The improved energy metabolism could also be a key mechanism contributing to the cardioprotection observed in the repetitive coronary stenosis and in hibernating myocardium. PMID:23127662

  16. Priming of the Cells: Hypoxic Preconditioning for Stem Cell Therapy.

    PubMed

    Wei, Zheng Z; Zhu, Yan-Bing; Zhang, James Y; McCrary, Myles R; Wang, Song; Zhang, Yong-Bo; Yu, Shan-Ping; Wei, Ling

    2017-10-05

    Stem cell-based therapies are promising in regenerative medicine for protecting and repairing damaged brain tissues after injury or in the context of chronic diseases. Hypoxia can induce physiological and pathological responses. A hypoxic insult might act as a double-edged sword, it induces cell death and brain damage, but on the other hand, sublethal hypoxia can trigger an adaptation response called hypoxic preconditioning or hypoxic tolerance that is of immense importance for the survival of cells and tissues. This review was based on articles published in PubMed databases up to August 16, 2017, with the following keywords: "stem cells," "hypoxic preconditioning," "ischemic preconditioning," and "cell transplantation." Original articles and critical reviews on the topics were selected. Hypoxic preconditioning has been investigated as a primary endogenous protective mechanism and possible treatment against ischemic injuries. Many cellular and molecular mechanisms underlying the protective effects of hypoxic preconditioning have been identified. In cell transplantation therapy, hypoxic pretreatment of stem cells and neural progenitors markedly increases the survival and regenerative capabilities of these cells in the host environment, leading to enhanced therapeutic effects in various disease models. Regenerative treatments can mobilize endogenous stem cells for neurogenesis and angiogenesis in the adult brain. Furthermore, transplantation of stem cells/neural progenitors achieves therapeutic benefits via cell replacement and/or increased trophic support. Combinatorial approaches of cell-based therapy with additional strategies such as neuroprotective protocols, anti-inflammatory treatment, and rehabilitation therapy can significantly improve therapeutic benefits. In this review, we will discuss the recent progress regarding cell types and applications in regenerative medicine as well as future applications.

  17. Review of Hydraulic Fracturing for Preconditioning in Cave Mining

    NASA Astrophysics Data System (ADS)

    He, Q.; Suorineni, F. T.; Oh, J.

    2016-12-01

    Hydraulic fracturing has been used in cave mining for preconditioning the orebody following its successful application in the oil and gas industries. In this paper, the state of the art of hydraulic fracturing as a preconditioning method in cave mining is presented. Procedures are provided on how to implement prescribed hydraulic fracturing by which effective preconditioning can be realized in any in situ stress condition. Preconditioning is effective in cave mining when an additional fracture set is introduced into the rock mass. Previous studies on cave mining hydraulic fracturing focused on field applications, hydraulic fracture growth measurement and the interaction between hydraulic fractures and natural fractures. The review in this paper reveals that the orientation of the current cave mining hydraulic fractures is dictated by and is perpendicular to the minimum in situ stress orientation. In some geotechnical conditions, these orientation-uncontrollable hydraulic fractures have limited preconditioning efficiency because they do not necessarily result in reduced fragmentation sizes and a blocky orebody through the introduction of an additional fracture set. This implies that if the minimum in situ stress orientation is vertical and favors the creation of horizontal hydraulic fractures, in a rock mass that is already dominated by horizontal joints, no additional fracture set is added to that rock mass to increase its blockiness to enable it cave. Therefore, two approaches that have the potential to create orientation-controllable hydraulic fractures in cave mining with the potential to introduce additional fracture set as desired are proposed to fill this gap. These approaches take advantage of directional hydraulic fracturing and the stress shadow effect, which can re-orientate the hydraulic fracture propagation trajectory against its theoretical predicted direction. Proppants are suggested to be introduced into the cave mining industry to enhance the

  18. Neuromuscular block.

    PubMed

    Bowman, W C

    2006-01-01

    Descriptions of the South American arrow poisons known as curares were reported by explorers in the 16th century, and their site of action in producing neuromuscular block was determined by Claude Bernard in the mid-19th century. Tubocurarine, the most important curare alkaloid, played a large part in experiments to determine the role of acetylcholine in neuromuscular transmission, but it was not until after 1943 that neuromuscular blocking drugs became established as muscle relaxants for use during surgical anaesthesia. Tubocurarine causes a number of unwanted effects, and there have been many attempts to replace it. The available drugs fall into two main categories: the depolarising blocking drugs and the nondepolarising blocking drugs. The former act by complex mixed actions and are now obsolete with the exception of suxamethonium, the rapid onset and brief duration of action of which remain useful for intubation at the start of surgical anaesthesia. The nondepolarising blocking drugs are reversible acetylcholine receptor antagonists. The main ones are the atracurium group, which possess a built-in self-destruct mechanism that makes them specially useful in kidney or liver failure, and the vecuronium group, which are specially free from unwanted side effects. Of this latter group, the compound rocuronium is of special interest because its rapid onset of action allows it to be used for intubation, and there is promise that its duration of action may be rapidly terminated by a novel antagonist, a particular cyclodextrin, that chelates the drug, thereby removing it from the acetylcholine receptors.

  19. 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.

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

    PubMed

    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 (CoCl₂), a hypoxia mimetic, stabilizes HIF-1, which otherwise is degraded in normoxic conditions. We studied the effects of hypoxia preconditioning by CoCl₂ 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. CoCl₂ 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 CoCl₂ 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.

  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. In vitro hypoxic preconditioning of embryonic stem cells as a strategy of promoting cell survival and functional benefits after transplantation into the ischemic rat brain.

    PubMed

    Theus, Michelle Hedrick; Wei, Ling; Cui, Lin; Francis, Kevin; Hu, Xinyang; Keogh, Christine; Yu, Shan Ping

    2008-04-01

    Hypoxic preconditioning (HP) and stem cell transplantation have been extensively studied as individual therapies for ischemic stroke. The present investigation is an initial effort to combine these methods to achieve increased therapeutic effects after brain ischemia. Sublethal in vitro hypoxia pretreatment significantly enhanced the tolerance of neurally-differentiating embryonic stem (ES) cells and primary bone marrow mesenchymal stem cells (BMSC) to apoptotic cell death (40-50% reduction in cell death and caspase-3 activation). The HP protective effects on cultured cells lasted for at least 6 days. HP increased secretion of erythropoietin (EPO) and upregulated expression of bcl-2, hypoxia-inducible factor (HIF-1alpha), erythropoietin receptor (EPOR), neurofilament (NF), and synaptophysin in ES cell-derived neural progenitor cells (ES-NPCs). The HP cytoprotective effect was diminished by blocking EPOR, while pretreatment of ES-NPCs with recombinant human EPO mimicked the HP effect. HP-primed ES-NPCs survived better 3 days after transplantation into the ischemic brain (30-40% reduction in cell death and caspase-3 activation). Finally, transplanted HP-primed ES-NPCs exhibited extensive neuronal differentiation in the ischemic brain, accelerated and enhanced recovery of sensorimotor function when compared to transplantation of non-HP-treated ES-NPCs. The cell-priming strategy aimed to promote transplanted cell survival and their tissue repair capability provides a simple yet effective way of optimizing cell transplantation therapy.

  3. Cardiac mast cell stabilization and cardioprotective effect of ischemic preconditioning in isolated rat heart.

    PubMed

    Parikh, V; Singh, M

    1998-05-01

    This study was designed to investigate the effect of disodium cromoglycate (DSCG), a mast cell stabilizer, on cardioprotective effect of ischemic preconditioning. Isolated rat heart was subjected to 30 min of global ischemia followed by 30 min of reperfusion. Ischemic preconditioning was provided by four episodes of 5-min global ischemia followed by 5 min of reperfusion before sustained ischemia. Ischemic preconditioning and DSCG (10 and 100 microM) treatment markedly decreased the release of lactate dehydrogenase (LDH) and creatine kinase (CK) in coronary effluent and percentage incidence of ventricular premature beats (VPBs) and ventricular tachycardia/fibrillation (VT/VF) during reperfusion. Ischemic preconditioning and DSCG treatment also significantly reduced ischemia/reperfusion-induced mast cell peroxidase (MPO) release, a marker of mast cell degranulation. A significant increase in MPO release was observed immediately after ischemic preconditioning, and the release was found to be inhibited in hearts perfused with DSCG (10 and 100 microM) during ischemic preconditioning. DSCG administered during ischemic preconditioning (DSCG in ischemic preconditioning) attenuated the cardioprotective and antiarrhythmic effects of ischemic preconditioning. DSCG in ischemic preconditioning produced no marked effect on ischemia/reperfusion-induced MPO release. These findings tentatively suggest that DSCG administration during ischemic preconditioning abolishes its cardioprotective effect, perhaps by stabilizing resident cardiac mast cells.

  4. Preconditioning of Human Mesenchymal Stem Cells to Enhance Their Regulation of the Immune Response

    PubMed Central

    Ogay, Vyacheslav; Nurgozhin, Talgat; Jumabay, Medet

    2016-01-01

    Mesenchymal stem cells (MSCs) have attracted the attention of researchers and clinicians for their ability to differentiate into a number of cell types, participate in tissue regeneration, and repair the damaged tissues by producing various growth factors and cytokines, as well as their unique immunoprivilege in alloreactive hosts. The immunomodulatory functions of exogenous MSCs have been widely investigated in immune-mediated inflammatory diseases and transplantation research. However, a harsh environment at the site of tissue injury/inflammation with insufficient oxygen supply, abundance of reactive oxygen species, and presence of other harmful molecules that damage the adoptively transferred cells collectively lead to low survival and engraftment of the transferred cells. Preconditioning of MSCs ex vivo by hypoxia, inflammatory stimulus, or other factors/conditions prior to their use in therapy is an adaptive strategy that prepares MSCs to survive in the harsh environment and to enhance their regulatory function of the local immune responses. This review focuses on a number of approaches in preconditioning human MSCs with the goal of augmenting their capacity to regulate both innate and adaptive immune responses. PMID:27822228

  5. 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

  6. A projected preconditioned conjugate gradient algorithm for computing many extreme eigenpairs of a Hermitian matrix [A projected preconditioned conjugate gradient algorithm for computing a large eigenspace of a Hermitian matrix

    SciTech Connect

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

    2015-02-25

    Here, 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.

  7. Curcumin Suppresses T Cell Activation by Blocking Ca2+ Mobilization and Nuclear Factor of Activated T Cells (NFAT) Activation

    PubMed Central

    Kliem, Christian; Merling, Anette; Giaisi, Marco; Köhler, Rebecca; Krammer, Peter H.; Li-Weber, Min

    2012-01-01

    Curcumin is the active ingredient of the spice turmeric and has been shown to have a number of pharmacologic and therapeutic activities including antioxidant, anti-microbial, anti-inflammatory, and anti-carcinogenic properties. The anti-inflammatory effects of curcumin have primarily been attributed to its inhibitory effect on NF-κB activity due to redox regulation. In this study, we show that curcumin is an immunosuppressive phytochemical that blocks T cell-activation-induced Ca2+ mobilization with IC50 = ∼12.5 μm and thereby prevents NFAT activation and NFAT-regulated cytokine expression. This finding provides a new mechanism for curcumin-mediated anti-inflammatory and immunosuppressive function. We also show that curcumin can synergize with CsA to enhance immunosuppressive activity because of different inhibitory mechanisms. Furthermore, because Ca2+ is also the secondary messenger crucial for the TCR-induced NF-κB signaling pathway, our finding also provides another mechanism by which curcumin suppresses NF-κB activation. PMID:22303019

  8. Ozone protects rat heart against ischemia-reperfusion injury: A role for oxidative preconditioning in attenuating mitochondrial injury.

    PubMed

    Meng, Weixin; Xu, Ying; Li, Dandan; Zhu, Erjun; Deng, Li; Liu, Zonghong; Zhang, Guowei; Liu, Hongyu

    2017-04-01

    Ischemia-reperfusion injury (IRI) is a major cause of cardiac dysfunction during cardiovascular surgery, heart transplantation and cardiopulmonary bypass procedures. The purpose of the present study was to explore, firstly, whether ozone induces oxidative preconditioning by activation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and, secondly, whether ozone oxidative preconditioning (OzoneOP) can protect the heart against IRI by attenuating mitochondrial damage. Rats were subjected to 30min of cardiac ischemia followed by 2h of reperfusion, with or without prior OzoneOP (100μg/kg/day) for 5 days. Antioxidant capacity, myocardial apoptosis and mitochondrial damage were evaluated and compared at the end of reperfusion. OzoneOP was found to increase antioxidant capacity and to protect the myocardium against IRI by attenuating mitochondrial damage and myocardial apoptosis. The study suggests a potential role for OzoneOP in protecting the heart against IRI during cardiovascular surgery, cardiopulmonary bypass procedures or transplantation.

  9. Block People.

    ERIC Educational Resources Information Center

    Peterson, Rayma

    1999-01-01

    Discusses an activity in which students in an after-school art class drew one another on pieces of 2-by-4 scrap lumber in order to create a class portrait in three dimensions. Stresses that the portraits on the wood blocks were done in-the-round, or each side was covered. (CMK)

  10. Block Busters.

    ERIC Educational Resources Information Center

    Noblitt, Bill

    1994-01-01

    A number of college publications editors and designers share their secrets for coping with writer's block and other forms of creative anxiety. Suggested techniques include a change of scenery, guarding one's time, sharing ideas with others, thorough research, and organization. (MSE)

  11. Strategies for Study of Neuroprotection from Cold-preconditioning

    PubMed Central

    Mitchell, Heidi M.; White, David M.; Kraig, Richard P.

    2010-01-01

    Neurological injury is a frequent cause of morbidity and mortality from general anesthesia and related surgical procedures that could be alleviated by development of effective, easy to administer and safe preconditioning treatments. We seek to define the neural immune signaling responsible for cold-preconditioning as means to identify novel targets for therapeutics development to protect brain before injury onset. Low-level pro-inflammatory mediator signaling changes over time are essential for cold-preconditioning neuroprotection. This signaling is consistent with the basic tenets of physiological conditioning hormesis, which require that irritative stimuli reach a threshold magnitude with sufficient time for adaptation to the stimuli for protection to become evident. Accordingly, delineation of the immune signaling involved in cold-preconditioning neuroprotection requires that biological systems and experimental manipulations plus technical capacities are highly reproducible and sensitive. Our approach is to use hippocampal slice cultures as an in vitro model that closely reflects their in vivo counterparts with multi-synaptic neural networks influenced by mature and quiescent macroglia / microglia. This glial state is particularly important for microglia since they are the principal source of cytokines, which are operative in the femtomolar range. Also, slice cultures can be maintained in vitro for several weeks, which is sufficient time to evoke activating stimuli and assess adaptive responses. Finally, environmental conditions can be accurately controlled using slice cultures so that cytokine signaling of cold-preconditioning can be measured, mimicked, and modulated to dissect the critical node aspects. Cytokine signaling system analyses require the use of sensitive and reproducible multiplexed techniques. We use quantitative PCR for TNF-α to screen for microglial activation followed by quantitative real-time qPCR array screening to assess tissue

  12. Strategies for study of neuroprotection from cold-preconditioning.

    PubMed

    Mitchell, Heidi M; White, David M; Kraig, Richard P

    2010-09-02

    Neurological injury is a frequent cause of morbidity and mortality from general anesthesia and related surgical procedures that could be alleviated by development of effective, easy to administer and safe preconditioning treatments. We seek to define the neural immune signaling responsible for cold-preconditioning as means to identify novel targets for therapeutics development to protect brain before injury onset. Low-level pro-inflammatory mediator signaling changes over time are essential for cold-preconditioning neuroprotection. This signaling is consistent with the basic tenets of physiological conditioning hormesis, which require that irritative stimuli reach a threshold magnitude with sufficient time for adaptation to the stimuli for protection to become evident. Accordingly, delineation of the immune signaling involved in cold-preconditioning neuroprotection requires that biological systems and experimental manipulations plus technical capacities are highly reproducible and sensitive. Our approach is to use hippocampal slice cultures as an in vitro model that closely reflects their in vivo counterparts with multi-synaptic neural networks influenced by mature and quiescent macroglia/microglia. This glial state is particularly important for microglia since they are the principal source of cytokines, which are operative in the femtomolar range. Also, slice cultures can be maintained in vitro for several weeks, which is sufficient time to evoke activating stimuli and assess adaptive responses. Finally, environmental conditions can be accurately controlled using slice cultures so that cytokine signaling of cold-preconditioning can be measured, mimicked, and modulated to dissect the critical node aspects. Cytokine signaling system analyses require the use of sensitive and reproducible multiplexed techniques. We use quantitative PCR for TNF-α to screen for microglial activation followed by quantitative real-time qPCR array screening to assess tissue-wide cytokine

  13. Remote Ischemic Preconditioning and Outcomes of Cardiac Surgery.

    PubMed

    Hausenloy, Derek J; Candilio, Luciano; Evans, Richard; Ariti, Cono; Jenkins, David P; Kolvekar, Shyam; Knight, Rosemary; Kunst, Gudrun; Laing, Christopher; Nicholas, Jennifer; Pepper, John; Robertson, Steven; Xenou, Maria; Clayton, Tim; Yellon, Derek M

    2015-10-08

    Whether remote ischemic preconditioning (transient ischemia and reperfusion of the arm) can improve clinical outcomes in patients undergoing coronary-artery bypass graft (CABG) surgery is not known. We investigated this question in a randomized trial. We conducted a multicenter, sham-controlled trial involving adults at increased surgical risk who were undergoing on-pump CABG (with or without valve surgery) with blood cardioplegia. After anesthesia induction and before surgical incision, patients were randomly assigned to remote ischemic preconditioning (four 5-minute inflations and deflations of a standard blood-pressure cuff on the upper arm) or sham conditioning (control group). Anesthetic management and perioperative care were not standardized. The combined primary end point was death from cardiovascular causes, nonfatal myocardial infarction, coronary revascularization, or stroke, assessed 12 months after randomization. We enrolled a total of 1612 patients (811 in the control group and 801 in the ischemic-preconditioning group) at 30 cardiac surgery centers in the United Kingdom. There was no significant difference in the cumulative incidence of the primary end point at 12 months between the patients in the remote ischemic preconditioning group and those in the control group (212 patients [26.5%] and 225 patients [27.7%], respectively; hazard ratio with ischemic preconditioning, 0.95; 95% confidence interval, 0.79 to 1.15; P=0.58). Furthermore, there were no significant between-group differences in either adverse events or the secondary end points of perioperative myocardial injury (assessed on the basis of the area under the curve for the high-sensitivity assay of serum troponin T at 72 hours), inotrope score (calculated from the maximum dose of the individual inotropic agents administered in the first 3 days after surgery), acute kidney injury, duration of stay in the intensive care unit and hospital, distance on the 6-minute walk test, and quality of life

  14. Sca-1+ stem cell survival and engraftment in the infarcted heart: dual role for preconditioning induced connexin-43

    PubMed Central

    Lu, Gang; Haider, Husnain Kh; Jiang, Shujia; Ashraf, Muhammad

    2009-01-01

    Background We report that elevated connexin-43 (Cx-43) in stem cells preconditioned with insulin like growth factor-1 (IGF-1) is cytoprotective and reprograms the cells for cardiomyogenic differentiation. Methods and Results Sca-1+ cells were preconditioned with 100nM IGF-1 for 30-minutes followed by 8-hours (h) of oxygen glucose deprivation (OGD) to assess the cytoprotective effects of preconditioning. LDH release assay, cytochrome-c release and mitochondrial membrane potential assay showed improved survival of preconditioned Sca-1+ cells (PCSca-1+) under OGD as compared to non-preconditioned Sca-1+ cells (non-PCSca-1+) via PI3K/Akt dependent caspase-3 downregulation. We observed PI3K/Akt dependent upregulation of cardiac specific markers including MEF-2c (2.5-fold), GATA4 (3.1-fold) and Cx-43 (3.5-fold). Cx-43 inhibition with specific RNAi reduced the cell survival under OGD and post-transplantation. In vivo studies were performed in a female rat model of acute myocardial infarction (n=78). Animals were grouped to receive intramyocardially 70μl DMEM without cells (group-1), or containing male 1×106 non-PCSca-1+ (group-2) or PCSca-1+ (group-3) cells labeled with PKH26. Survival of the PCSca-1+ was 5.5-fold higher in group-3 compared to group-2 on 7-days post-transplantation. Confocal imaging after actinin and Cx-43 specific immunostaining showed extensive engraftment and myogenic differentiation of PCSca-1+. As compared to group-2, group-3 showed increased blood vessel density (22.3±1.7/microscopic field, p<0.0001) and attenuated infarction size (23.3±3.6%; p=0.002). Heart function indices including ejection fraction (56.2±3.5; p=0.029) and fractional shortening (24.3±2.1; p=0.03) were improved in group-3 compared to group-2. Conclusions Preconditioning with IGF-1 reprograms Sca-1+ for pro-survival signaling and cardiomyogenic differentiation with an important role for Cx-43 in this process. PMID:19414636

  15. Neuraxial blocks and spinal haematoma: Review of 166 case reports published 1994-2015. Part 1: Demographics and risk-factors.

    PubMed

    Lagerkranser, Michael

    2017-04-01

    Bleeding into the vertebral canal causing a spinal haematoma (SH) is a rare but serious complication to central neuraxial blocks (CNB). Of all serious complications to CNBs such as meningitis, abscess, cardiovascular collapse, and nerve injury, neurological injury associated with SH has the worst prognosis for permanent harm. Around the turn of the millennium, the first guidelines were published that aimed to reduce the risk of this complication. These guidelines are based on known risk factors for SH, rather than evidence from randomised, controlled trials (RCTs). RCTs, and therefore meta-analysis of RCTs, are not appropriate for identifying rare events. Analysing published case reports of rare complications may at least reveal risk factors and can thereby improve management of CNBs. The aims of the present review were to analyse case reports of SH after CNBs published between 1994 and 2015, and compare these with previous reviews of case reports. MEDLINE and EMBASE were used for identifying case reports published in English, German, or Scandinavian languages, using appropriate search terms. Reference lists were also scrutinised for case reports. Twenty different variables from each case were specifically searched for and filled out on an Excel spreadsheet, and incidences were calculated using the number of informative reports as denominator for each variable. Altogether 166 case reports on spinal haematoma after CNB published during the years between 1994 and 2015 were collected. The annual number of case reports published during this period almost trebled compared with the two preceding decades. This trend continued even after the first guidelines on safe practice of CNBs appeared around year 2000, although more cases complied with such guidelines during the second half of the observation period (2005-2015) than during the first half. Three types of risk factors dominated: (1) Patient-related risk factors such as haemostatic and spinal disorders, (2) CNB

  16. Antibiotic-induced immediate type hypersensitivity is a risk factor for positive allergy skin tests for neuromuscular blocking agents.

    PubMed

    Hagau, Natalia; Gherman, Nadia; Cocis, Mihaela; Petrisor, Cristina

    2016-01-01

    Skin tests for neuromuscular blocking agents (NMBAs) are not currently recommended for the general population undergoing general anaesthesia. In a previous study we have reported a high incidence of positive allergy tests for NMBAs in patients with a positive history of non-anaesthetic drug allergy, a larger prospective study being needed to confirm those preliminary results. The objective of this study was to compare the skin tests results for patients with a positive history of antibiotic-induced immediate type hypersensitivity reactions to those of controls without drug allergies. Ninety eight patients with previous antibiotic hypersensitivity and 72 controls were prospectively included. Skin tests were performed for atracurium, pancuronium, rocuronium, and suxamethonium. We found 65 positive skin tests from the 392 tests performed in patients with a positive history of antibiotic hypersensitivity (1 6.58%) and 23 positive skin tests from the 288 performed in controls (7.98%), the two incidences showing significant statistical difference (p = 0.0011). The relative risk for having a positive skin test for NMBAs for patients versus controls was 1.77 (1.15-2.76). For atracurium, skin tests were more often positive in patients with a positive history of antibiotic hypersensitivity versus controls (p = 0.02). For pancuronium, rocuronium and suxamethonium the statistical difference was not attained (p-values 0.08 for pancuronium, 0.23 for rocuronium, and 0.26 for suxamethonium). Patients with a positive history of antibiotic hypersensitivity seem to have a higher incidence of positive skin tests for NMBAs. They might represent a group at higher risk for developing intraoperative anaphylaxis compared to the general population. Copyright © 2015 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

  17. An interleukin-1 receptor antagonist blocks lipopolysaccharide-induced colony-stimulating factor production and early endotoxin tolerance.

    PubMed Central

    Henricson, B E; Neta, R; Vogel, S N

    1991-01-01

    In this report, administration of a recombinant interleukin-1 receptor antagonist protein to mice was found to inhibit induction of colony-stimulating factor as well as induction of early endotoxin tolerance by lipopolysaccharide. These findings provide direct evidence that interleukin-1 is an intermediate in these two lipopolysaccharide-induced phenomena. PMID:1825485

  18. Hyperbaric Oxygen Preconditioning Attenuates Myocardium Ischemia-Reperfusion Injury Through Upregulation of Heme Oxygenase 1 Expression: PI3K/Akt/Nrf2 Pathway Involved.

    PubMed

    Yin, Xuesong; Wang, Xiaofeng; Fan, Zhixin; Peng, Chenghai; Ren, Zhongqiao; Huang, Le; Liu, Zhuang; Zhao, Kan

    2015-07-01

    With the rise of the burden of ischemic heart disease, both clinical and economic evidence show a desperate need to protect the heart against myocardium ischemia-reperfusion injury-related complications following cardiac surgery or percutaneous coronary intervention. However, there is no effective intervention for myocardium ischemia-reperfusion injury as yet. We pretreated mice with 4 daily 2.0 absolute atmosphere (ATA) hyperbaric oxygen, then observed its effects on heart function parameters and infarct size following in situ ischemia-reperfusion. Multiple oxidative and inflammation products were measured in the myocardium. Next, we investigated the expression of heme oxygenase 1 (HO-1), phosphatidylinositol 3-kinase (PI3K)/serine/threonine protein kinase (Akt) pathway, and NF-E2-related factor 2 (Nrf2) in the presence of myocardium ischemia-reperfusion injury, hyperbaric oxygen preconditioning, and their inhibitors and their effects on heart function parameters. Hyperbaric oxygen preconditioning ameliorated the cardiac function and histological alterations induced by myocardium ischemia-reperfusion injury, decreased oxidative products and proinflammatory cytokine. Hyperbaric oxygen preconditioning increased expression of HO-1, which was suppressed by PI3K inhibitor LY294002, Nrf2 knockout, and Akt inhibitor triciribine. The expression of Nrf2 was enhanced by hyperbaric oxygen preconditioning, but decreased by LY294002 and triciribine. The Akt was also activated by hyperbaric oxygen preconditioning but suppressed by LY294002. The hemodynamic assays showed that cardiac function was suppressed by LY294002, Nrf2 knockout, and triciribine. These data present a novel signaling mechanism by which hyperbaric oxygen preconditioning protects myocardium ischemia-reperfusion injury via PI3K/Akt/Nrf2-dependent antioxidant defensive system. © The Author(s) 2015.

  19. Acute ischemic preconditioning of skeletal muscle prior to flap elevation augments muscle-flap survival.

    PubMed

    Carroll, C M; Carroll, S M; Overgoor, M L; Tobin, G; Barker, J H

    1997-07-01

    Ischemic preconditioning of the myocardium with repeated brief periods of ischemia and reperfusion prior to prolonged ischemia significantly reduces subsequent myocardial infarction. Following ischemic preconditioning, two "windows of opportunity" (early and late) exist, during which time prolonged ischemia can occur with reduced infarction size. The early window occurs at approximately 4 hours and the late window at 24 hours following ischemic preconditioning of the myocardium. We investigated if ischemic preconditioning of skeletal muscle prior to flap creation improved subsequent flap survival and perfusion immediately or 24 hours following ischemic preconditioning. Currently, no data exist on the utilization of ischemic preconditioning in this fashion. The animal model used was the latissimus dorsi muscle of adult male Sprague-Dawley rats. Animals were assigned to three groups, and the right or left latissimus dorsi muscle was chosen randomly in each animal. Group 1 (n = 12) was the control group, in which the entire latissimus dorsi muscle was elevated acutely without ischemic preconditioning. Group 2 (n = 8) investigated the effects of ischemic preconditioning in the early window. In this group, the latissimus dorsi muscle was elevated immediately following preconditioning. Group 3 (n = 8) investigated the effects of ischemic preconditioning in the late window, with elevation of the latissimus dorsi muscle 24 hours following ischemic preconditioning. The preconditioning regimen used in groups 2 and 3 was two 30-minute episodes of normothermic global ischemia with intervening 10-minute episodes of reperfusion. Latissimus dorsi muscle ischemia was created by occlusion of the thoracodorsal artery and vein and the intercostal perforators, after isolation of the muscle on these vessels. Muscle perfusion was assessed by a laser-Doppler perfusion imager. One week after flap elevation, muscle necrosis was quantified in all groups by means of computer-assisted digital

  20. Cardiac-specific overexpression of caveolin-3 induces endogenous cardiac protection by mimicking ischemic preconditioning

    PubMed Central

    Tsutsumi, Yasuo M.; Horikawa, Yousuke T.; Jennings, Michelle M.; Kidd, Michael W.; Niesman, Ingrid R.; Yokoyama, Utako; Head, Brian P.; Hagiwara, Yasuko; Ishikawa, Yoshihiro; Miyanohara, Atsushi; Patel, Piyush M.; Insel, Paul A.; Patel, Hemal H.; Roth, David M.

    2009-01-01

    Background Caveolae, lipid-rich microdomains of the sarcolemma, localize and enrich cardiac protective signaling molecules. Caveolin-3 (Cav-3), the dominant isoform in cardiac myocytes, is a determinant of caveolae formation. We hypothesized that cardiac myocyte-specific overexpression of Cav-3 would enhance the formation of caveolae and augment cardiac protection in vivo. Methods and Results Ischemic preconditioning (IPC) in vivo increased formation of caveolae. Adenovirus for Cav-3 increased caveolar formation and phosphorylation of survival kinases in cardiac myocytes. A transgenic (TG) mouse with cardiac myocyte-specific overexpression of Cav-3 (Cav-3 OE) showed enhanced formation of caveolae on the sarcolemma. Cav-3 OE mice subjected to ischemia/reperfusion injury had a significantly reduced infarct size relative to TGneg mice. Endogenous cardiac protection in Cav-3 OE mice was similar to wild-type mice undergoing IPC; no increased protection was observed in preconditioned Cav-3 OE mice. Cav-3 knockout mice did not show endogenous protection and showed no protection in response to IPC. Cav-3 OE mouse hearts had increased basal Akt and GSK3β phosphorylation comparable to wild-type mice exposed to IPC. Wortmannin, a PI3K inhibitor, attenuated basal phosphorylation of Akt and GSK3β and blocked cardiac protection in Cav-3 OE mice. Cav-3 OE mice had improved functional recovery and reduced apoptosis at 24 h of reperfusion. Conclusion Expression of caveolin-3 is both necessary and sufficient for cardiac protection, a conclusion that unites long-standing ultrastructural and molecular observations in the ischemic heart. The current results indicate that increased expression of caveolins, apparently via actions that depend on PI3K, has the potential to protect hearts exposed to ischemia-reperfusion injury. PMID:18936328

  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. Immunotherapy of human tumour xenografts overexpressing the EGF receptor with rat antibodies that block growth factor-receptor interaction.

    PubMed Central

    Modjtahedi, H.; Eccles, S.; Box, G.; Styles, J.; Dean, C.

    1993-01-01

    Athymic mice bearing xenografts of human tumours that overexpress the receptor (EGFR) for EGF and TGF alpha have been used to evaluate the therapeutic potential of three new rat monoclonal antibodies (mAbs) directed against two distinct epitopes on the extracellular domain of the human EGFR. The antibodies, ICR16 (IgG2a), ICR62 (IgG2b) and ICR64 (IgG1), have been shown (Modjtahedi et al., 1993) to be potent inhibitors of the growth in vitro of a number of human squamous cell carcinomas because they block receptor-ligand interaction. When given i.p. at 200 micrograms dose, the three antibodies were found to induce complete regression of xenografts of the HN5 tumour if treatment with antibody commenced at the time of tumour implantation (total doses: ICR16, 3.0 mg; ICR62, 1.2 mg; ICR64, 2.2 mg). More importantly when treatment was delayed until the tumours were established (mean diam. 0.5 cm) both ICR16 and ICR62 induced complete or almost complete regression of the tumours. Furthermore, treatment with a total dose of only 0.44 mg of ICR62 was found to induce complete remission of xenografts of the breast carcinoma MDA-MB 468, but ICR16 was less effective at this dose of antibody and only 4/8 tumours regressed completely. ICR16 and ICR62 were poor inhibitors of the growth in vitro of the vulval carcinoma A431, but both induced a substantial delay in the growth of xenografts of this tumour and 4/8 tumours regressed completely in the mice treated with ICR62 (total dose 2.2 mg). Although ICR16 and ICR64 were more effective than ICR62 as growth inhibitors in vitro, ICR62 was found to be substantially better at inducing regression of the tumour xenografts due perhaps to additional activation of host immune effector functions by the IgG2b antibody. We conclude that these antibodies may be useful therapeutic agents that can be used alone without conjugation to other cytotoxic moieties. PMID:7679281

  3. Superoxide dismutase abolishes the platelet-derived growth factor-induced release of prostaglandin E2 by blocking induction of nitric oxide synthase: role of superoxide.

    PubMed

    Kelner, M J; Uglik, S F

    1995-09-10

    The ability of platelet-derived growth factor (PDGF) to induce prostaglandin E2 (PGE2) release in fibroblasts is abolished when copper-zinc superoxide dismutase activity is increased by transfection of an expression vector. The effect is specific to copper-zinc superoxide dismutase as glutathione peroxidase-overexpressing NIH3T3 cells, again produced by transfection of an expression vector, retain the ability to release PGE2 in response to growth factor stimulation. The defect in PDGF-induced PGE2 release occurs prior to action of prostaglandin H synthase/cyclooxygenase as release of arachadonic acid (in response to PDGF) does not occur in the superoxide dismutase-overexpressing clones. The defect in PDGF-induced release of PGE2 in superoxide dismutase-overexpressing clones differs from the defect found in pEJ-ras-transformed clones. The parent cells, the glutathione peroxidase-expressing cells, and the superoxide dismutase-overexpressing cells all release PGE2 in response to exogenous nitric oxide, whereas the pEJ-ras-transformed cells do not. The glutathione peroxidase-expressing cells also retained the ability to release nitrite in response to PDGF, whereas the superoxide dismutase-expressing clones do not. PDGF stimulates nitric oxide synthase activity in NIH3T3 cells, but not in the superoxide dismutase-expressing clones. These results indicate that superoxide dismutase overexpression blocks the PDGF-induced release of PGE2 by blocking induction of nitric oxide synthase. This indicates that the increase of nitric oxide synthase induced by PDGF is mediated in part by production of superoxide. These findings link cellular oxygen radical homeostasis to three different classes of messenger molecules (growth factors, nitric oxide, and prostaglandins).

  4. Experimental investigation on preconditioned rate induced tipping in a thermoacoustic system.

    PubMed

    Tony, J; Subarna, S; Syamkumar, K S; Sudha, G; Akshay, S; Gopalakrishnan, E A; Surovyatkina, E; Sujith, R I

    2017-07-14

    Many systems found in nature are susceptible to tipping, where they can shift from one stable dynamical state to another. This shift in dynamics can be unfavorable in systems found in various fields ranging from ecology to finance. Hence, it is important to identify the factors that can lead to tipping in a physical system. Tipping can mainly be brought about by a change in parameter or due to the influence of external fluctuations. Further, the rate at which the parameter is varied also determines the final state that the system attains. Here, we show preconditioned rate induced tipping in experiments and in a theoretical model of a thermoacoustic system. We provide a specific initial condition (preconditioning) and vary the parameter at a rate higher than a critical rate to observe tipping. We find that the critical rate is a function of the initial condition. Our study is highly relevant because the parameters that dictate the asymptotic behavior of many physical systems are temporally dynamic.

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

    PubMed

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

    2014-04-01

    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.

  6. VEGF released by deferoxamine preconditioned mesenchymal stem cells seeded on collagen-GAG substrates enhances neovascularization

    PubMed Central

    Wahl, Elizabeth A.; Schenck, Thilo L.; Machens, Hans-Günther; Balmayor, Elizabeth R.

    2016-01-01

    Hypoxia preconditioning of mesenchymal stem cells (MSCs) has been shown to promote wound healing through HIF-1α stabilization. Preconditioned MSCs can be applied to three-dimensional biomaterials to further enhance the regenerative properties. While environmentally induced hypoxia has proven difficult in clinical settings, this study compares the wound healing capabilities of adipose derived (Ad) MSCs seeded on a collagen-glycosaminoglycan (GAG) dermal substrate exposed to either environmental hypoxia or FDA approved deferoxamine mesylate (DFO) to stabilize HIF-1α for wound healing. The release of hypoxia related reparative factors by the cells on the collagen-GAG substrate was evaluated to detect if DFO produces results comparable to environmentally induced hypoxia to facilitate optimal clinical settings. VEGF release increased in samples exposed to DFO. While the SDF-1α release was lower in cells exposed to environmental hypoxia in comparison to cells cultured in DFO in vitro. The AdMSC seeded biomaterial was further evaluated in a murine model. The implants where harvested after 1 days for histological, inflammatory, and protein analysis. The application of DFO to the cells could mimic and enhance the wound healing capabilities of environmentally induced hypoxia through VEGF expression and promises a more viable option in clinical settings that is not merely restricted to the laboratory. PMID:27830734

  7. Finding Chemical Reaction Paths with a Multilevel Preconditioning Protocol

    DOE PAGES

    Kale, Seyit; Sode, Olaseni; Weare, Jonathan; ...

    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

  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. 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

  10. 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.

  11. 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.

  12. HMC algorithm with multiple time scale integration and mass preconditioning

    NASA Astrophysics Data System (ADS)

    Urbach, C.; Jansen, K.; Shindler, A.; Wenger, U.

    2006-01-01

    We present a variant of the HMC algorithm with mass preconditioning (Hasenbusch acceleration) and multiple time scale integration. We have tested this variant for standard Wilson fermions at β=5.6 and at pion masses ranging from 380 to 680 MeV. We show that in this situation its performance is comparable to the recently proposed HMC variant with domain decomposition as preconditioner. We give an update of the "Berlin Wall" figure, comparing the performance of our variant of the HMC algorithm to other published performance data. Advantages of the HMC algorithm with mass preconditioning and multiple time scale integration are that it is straightforward to implement and can be used in combination with a wide variety of lattice Dirac operators.

  13. Investigation of reperfusion injury and ischemic preconditioning in microsurgery.

    PubMed

    Wang, Wei Zhong

    2009-01-01

    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 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 and preconditioning-induced protection in the fields relevant to microsurgery.

  14. Preconditioned lattice-Boltzmann method for steady flows

    NASA Astrophysics Data System (ADS)

    Guo, Zhaoli; Zhao, T. S.; Shi, Yong

    2004-12-01

    In this paper we propose a preconditioned lattice Boltzmann (LB) method for steady incompressible flows. For steady flows, the macroscopic equations derived from this LB model are equivalent to those from the standard LB model, but with an improved eigenvalue system. The proposed model can be viewed as an explicit solver for preconditioned compressible Navier-Stokes equations. Linear stability analysis is performed and the results show that the stability of the model is the same as that of the standard LB model for low Mach numbers. The proposed model retains the structure of the standard LB model and, hence, possesses all the advantages. Numerical tests show that the convergence rate can be enhanced as much as an order of magnitude compared to the standard lattice Boltzmann method. The accuracy of the solutions is improved as well.

  15. Transforming Growth Factor β Blocks Tec Kinase Phosphorylation, Ca2+ Influx, and NFATc Translocation Causing Inhibition of T Cell Differentiation

    PubMed Central

    Chen, Chang-Hung; Seguin-Devaux, Carole; Burke, Nancy A.; Oriss, Timothy B.; Watkins, Simon C.; Clipstone, Neil; Ray, Anuradha

    2003-01-01

    Transforming growth factor (TGF)-β inhibits T cell proliferation and differentiation. TGF-β has been shown to inhibit the expression of transcription factors such as GATA-3 and T-bet that play important roles in T cell differentiation. Here we show that TGF-β inhibits T cell differentiation at a more proximal step. An early event during T cell activation is increased intracellular calcium levels. Calcium influx in activated T cells and the subsequent activation of transcription factors such as NFATc, events essential for T cell differentiation, are modulated by the Tec kinases that are downstream of the T cell receptor and CD28. We show that in stimulated CD4+ T cells, TGF-β inhibits phosphorylation and activation of the Tec kinase Itk, increase in intracellular Ca2+ levels, NFATc translocation, and activation of the mitogen-activated protein kinase ERK that together regulate T cell differentiation. Our studies suggest that by inhibiting Itk, and consequently Ca2+ influx, TGF-β limits T cell differentiation along both the Th1 and Th2 lineages. PMID:12810687

  16. 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

  17. Peripheral vascular disease as remote ischemic preconditioning, for acute stroke.

    PubMed

    Connolly, Mark; Bilgin-Freiert, Arzu; Ellingson, Benjamin; Dusick, Joshua R; Liebeskind, David; Saver, Jeff; Gonzalez, Nestor R

    2013-10-01

    Remote ischemic preconditioning (RIPC) is a powerful endogenous mechanism whereby a brief period of ischemia is capable of protecting remote tissues from subsequent ischemic insult. While this phenomenon has been extensively studied in the heart and brain in animal models, little work has been done to explore the effects of RIPC in human patients with acute cerebral ischemia. This study investigates whether chronic peripheral hypoperfusion, in the form of pre-existing arterial peripheral vascular disease (PVD) that has not been surgically treated, is capable of inducing neuroprotective effects for acute ischemic stroke. Individuals with PVD who had not undergone prior surgical treatment were identified from a registry of stroke patients. A control group within the same database was identified by matching patient's demographics and risk factors. The two groups were compared in terms of outcome by NIH Stroke Scale (NIHSS), modified Rankin scale (mRS), mortality, and volume of infarcted tissue at presentation and at discharge. The matching algorithm identified 26 pairs of PVD-control patients (9 pairs were female and 17 pairs were male). Age range was 20-93 years (mean 73). The PVD group was found to have significantly lower NIHSS scores at admission (NIHSS≤4: PVD 47.1%, control 4.35%, p<0.003), significantly more favorable outcomes at discharge (mRS≤2: PVD 30.8%, control 3.84%, p<0.012), and a significantly lower mortality rate (PVD 26.9%, control 57.7%, p=0.024). Mean acute stroke volume at admission and at discharge were significantly lower for the PVD group (admission: PVD 39.6 mL, control 148.3 mL, p<0.005 and discharge: PVD 111.7 mL, control 275 mL, p<0.001). Chronic limb hypoperfusion induced by PVD can potentially produce a neuroprotective effect in acute ischemic stroke. This effect resembles the neuroprotection induced by RIPC in preclinical models. Copyright © 2013 Elsevier B.V. All rights reserved.

  18. Major Ozonated Autohemotherapy Preconditioning Ameliorates Kidney Ischemia-Reperfusion Injury.

    PubMed

    Sancak, Eyup Burak; Turkön, Hakan; Çukur, Selma; Erimsah, Sevilay; Akbas, Alpaslan; Gulpinar, Murat Tolga; Toman, Huseyin; Sahin, Hasan; Uzun, Metehan

    2016-02-01

    Medical ozone has therapeutic properties as an antimicrobial, anti-inflammatory, modulator of antioxidant defense system. Major ozonated autohemotherapy (MOA) is a new therapeutic approach that is widely used in the treatment of many diseases. The objective of the present study was to determine whether preischemic application of MOA would attenuate renal ischemia-reperfusion injury (IRI) in rabbits. Twenty-four male New Zealand white rabbits were divided into four groups, each including six animals: (1) Sham-operated group, (2) Ozone group (the MOA group without IRI), (3) IR group (60 min ischemia followed by 24 h reperfusion), and (4) IR + MOA group (MOA group). The effects of MOA were examined by use of hematologic and biochemical parameters consisting of neutrophil to lymphocyte ratio (NLR), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), ischemia-modified albumin (IMA), total antioxidant status (TAS), total oxidant status (TOS), and oxidative stress index (OSI). In addition, the histopathological changes including the tubular brush border loss (TBBL), tubular cast (TC), tubular necrosis (TN), intertubular hemorrhage and congestion (IHC), dilatation of bowman space (DBS), and interstitial inflammatory cells infiltration (IECI) were evaluated. In the IR group, compared to the Sham group, biochemical parameters indicating oxidative stress, NLR, IL-6, TNF-α, IMA, TOS, and OSI have increased. MOA reduced inflammation and oxidative stress parameters. Although TAS values have decreased in the IR group and increased in the MOA-pretreated group, no significant changes in TAS values were detected between the IR and MOA groups. The total score was obtained by summing all the scores from morphological kidney damage markers. The total score has increased with IR damage when compared with the Sham group (13.83 ± 4.30 vs 1.51 ± 1.71; p = 0.002). But, the total score has decreased significantly after application of MOA (5.01 ± 1.49; p = 0.002; compared

  19. Chemogenetic silencing of neurons in retrosplenial cortex disrupts sensory preconditioning.

    PubMed

    Robinson, Siobhan; Todd, Travis P; Pasternak, Anna R; Luikart, Bryan W; Skelton, Patrick D; Urban, Daniel J; Bucci, David J

    2014-08-13

    An essential aspect of episodic memory is the formation of associations between neutral sensory cues in the environment. In light of recent evidence that this critical aspect of learning does not require the hippocampus, we tested the involvement of the retrosplenial cortex (RSC) in this process using a chemogenetic approach that allowed us to temporarily silence neurons along the entire rostrocaudal extent of the RSC. A viral vector containing the gene for a synthetic inhibitory G-protein-coupled receptor (hM4Di) was infused into RSC. When the receptor was later activated by systemic injection of clozapine-N-oxide, neural activity in RSC was transiently silenced (confirmed using a patch-clamp procedure). Rats expressing hM4Di and control rats were trained in a sensory preconditioning procedure in which a tone and light were paired on some trials and a white noise stimulus was presented alone on the other trials during the Preconditioning phase. Thus, rats were given the opportunity to form an association between a tone and a light in the absence of reinforcement. Later, the light was paired with food. During the test phase when the auditory cues were presented alone, controls exhibited more conditioned responding during presentation of the tone compared with the white noise reflecting the prior formation of a tone-light association. Silencing RSC neurons during the Preconditioning phase prevented the formation of an association between the tone and light and eliminated the sensory preconditioning effect. These findings indicate that RSC may contribute to episodic memory formation by linking essential sensory stimuli during learning. Copyright © 2014 the authors 0270-6474/14/3410982-07$15.00/0.

  20. CaMeL: Learning Method Preconditions for HTN Planning

    DTIC Science & Technology

    2006-01-01

    CaMeL : Learning Method Preconditions for HTN Planning Okhtay Ilghami and Dana S. Nau Department of Computer Science University of Maryland College...algorithm, named CaMeL , based on this formalism. We present theo- retical results about CaMeL’s soundness, completeness, and convergence properties...We also report experimental results about its speed of convergence under different conditions. The experimental results suggest that CaMeL has the

  1. 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.

  2. 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

  3. Exercise and Cardiac Preconditioning Against Ischemia Reperfusion Injury

    PubMed Central

    Quindry, John C; Hamilton, Karyn L

    2013-01-01

    Cardiovascular disease (CVD), including ischemia reperfusion (IR) injury, remains a major cause of morbidity and mortality in industrialized nations. Ongoing research is aimed at uncovering therapeutic interventions against IR injury. Regular exercise participation is recognized as an important lifestyle intervention in the prevention and treatment of CVD and IR injury. More recent understanding reveals that moderate intensity aerobic exercise is also an important experimental model for understanding the cellular mechanisms of cardioprotection against IR injury. An important discovery in this regard was the observation that one-to-several days of exercise will attenuate IR injury. This phenomenon has been observed in young and old hearts of both sexes. Due to the short time course of exercise induced protection, IR injury prevention must be mediated by acute biochemical alterations within the myocardium. Research over the last decade reveals that redundant mechanisms account for exercise induced cardioprotection against IR. While much is now known about exercise preconditioning against IR injury, many questions remain. Perhaps most pressing, is what mechanisms mediate cardioprotection in aged hearts and what sex-dependent differences exist. Given that that exercise preconditioning is a polygenic effect, it is likely that multiple mediators of exercise induced cardioprotection have yet to be uncovered. Also unknown, is whether post translational modifications due to exercise are responsible for IR injury prevention. This review will provide an overview the major mechanisms of IR injury and exercise preconditioning. The discussion highlights many promising avenues for further research and describes how exercise preconditioning may continue to be an important scientific paradigm in the translation of cardioprotection research to the clinic. PMID:23909636

  4. 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.

  5. Transforming Growth Factor-β Regulation of Epithelial Tight Junction Proteins Enhances Barrier Function and Blocks Enterohemorrhagic Escherichia coli O157:H7-Induced Increased Permeability

    PubMed Central

    Howe, Kathryn L.; Reardon, Colin; Wang, Arthur; Nazli, Aisha; McKay, Derek M.

    2005-01-01

    Enterohemorrhagic Escherichia coli O157:H7 (EHEC) is an enteric pathogen that causes potentially fatal symptoms after intimate adhesion, modulation of intestinal epithelial signal transduction, and alteration of epithelial function (eg, barrier disruption). Although the epithelial barrier is critical to gut homeostasis, only a few agents, such as transforming growth factor (TGF)-β, can enhance or protect epithelial barrier function. Our aims were to delineate the mechanism(s) behind TGF-β-induced barrier enhancement and to determine whether TGF-β could prevent EHEC-induced barrier disruption. Using monolayers of the human T84 colonic epithelial cell line, we found that TGF-β induced a significant increase in transepithelial electrical resistance (a measure of paracellular permeability) through activation of ERK MAPK and SMAD signaling pathways and up-regulation of the tight junction protein claudin-1. Additionally, TGF-β pretreatment of epithelia blocked the decrease in transepithelial electrical resistance and the increase in transepithelial passage of [3H]-mannitol caused by EHEC infection. EHEC infection was associated with reduced expression of zonula occludens-1, occludin, and claudin-2 (but not claudin-1 or claudin-4); TGF-β pretreatment prevented these changes. These studies provide insight into EHEC pathogenesis by illustrating the mechanisms underlying TGF-β-induced epithelial barrier enhancement and identifying TGF-β as an agent capable of blocking EHEC-induced increases in epithelial permeability via maintenance of claudin-2, occludin, and zonula occludens-1 levels. PMID:16314472

  6. Conjugate-gradient preconditioning methods for shift-variant PET image reconstruction.

    PubMed

    Fessler, J A; Booth, S D

    1999-01-01

    Gradient-based iterative methods often converge slowly for tomographic image reconstruction and image restoration problems, but can be accelerated by suitable preconditioners. Diagonal preconditioners offer some improvement in convergence rate, but do not incorporate the structure of the Hessian matrices in imaging problems. Circulant preconditioners can provide remarkable acceleration for inverse problems that are approximately shift-invariant, i.e., for those with approximately block-Toeplitz or block-circulant Hessians. However, in applications with nonuniform noise variance, such as arises from Poisson statistics in emission tomography and in quantum-limited optical imaging, the Hessian of the weighted least-squares objective function is quite shift-variant, and circulant preconditioners perform poorly. Additional shift-variance is caused by edge-preserving regularization methods based on nonquadratic penalty functions. This paper describes new preconditioners that approximate more accurately the Hessian matrices of shift-variant imaging problems. Compared to diagonal or circulant preconditioning, the new preconditioners lead to significantly faster convergence rates for the unconstrained conjugate-gradient (CG) iteration. We also propose a new efficient method for the line-search step required by CG methods. Applications to positron emission tomography (PET) illustrate the method.

  7. Preconditioning reduces myocardial complement gene expression in vivo.

    PubMed

    Tanhehco, E J; Yasojima, K; McGeer, P L; McGeer, E G; Lucchesi, B R

    2000-09-01

    This investigation examined the effect of preconditioning in an in vivo model of ischemia-reperfusion injury. Anesthetized New Zealand White rabbits underwent 30 min of regional myocardial ischemia followed by 2 h of reperfusion. Hearts preconditioned with two cycles of 5 min ischemia-10 min reperfusion (IPC) or with the ATP-sensitive K (K(ATP)) channel opener, diazoxide (10 mg/kg), exhibited significantly (P < 0.05) smaller infarcts compared with control. These treatments also significantly (P < 0.001 to P < 0.05) reduced C1q, C1r, C3, C8, and C9 mRNA in the areas at risk (AAR). The K(ATP) channel blocker 5-hydroxydecanoate (5-HD; 10 mg/kg) attenuated infarct size reduction elicited by IPC and diazoxide treatment. 5-HD partially reversed the decrease in complement expression caused by IPC but not diazoxide. There were no significant differences in complement gene expression in the nonrisk regions and livers of all groups. Western blot analysis revealed that IPC also reduced membrane attack complex expression in the AAR. The data demonstrate that preconditioning significantly decreases reperfusion-induced myocardial complement expression in vivo.

  8. Thermal Preconditioning of MIMS Type K Thermocouples to Reduce Drift

    NASA Astrophysics Data System (ADS)

    Webster, E. S.

    2017-01-01

    Type K thermocouples are the most widely used temperature sensors in industry and are often used in the convenient mineral-insulated metal-sheathed (MIMS) format. The MIMS format provides almost total immunity to oxide-related drift in the 800°C-1000°C range. However, crystalline ordering of the atomic structure causes drift in the range 200°C-600°C. Troublesomely, the effects of this ordering are reversible, leading to hysteresis in some applications. Typically, MIMS cable is subjected to a post-manufacturing high-temperature recrystallization anneal to remove cold-work and place the thermocouple in a `known state.' However, variations in the temperatures and times of these exposures can lead to variations in the `as-received state.' This study gives guidelines on the best thermal preconditioning of 3 mm MIMS Type K thermocouples in order to minimize drift and achieve the most reproducible temperature measurements. Experimental results demonstrate the consequences of using Type K MIMS thermocouples in different states, including the as-received state, after a high-temperature recrystallization anneal and after preconditioning anneals at 200°C, 300°, 400°C and and 500°C. It is also shown that meaningful calibration is possible with the use of regular preconditioning anneals.

  9. Preconditioned alternating projection algorithms for maximum a posteriori ECT reconstruction

    NASA Astrophysics Data System (ADS)

    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 constraint 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 PAPA. 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.

  10. Positive feedback induced memory effect in ischemic preconditioning.

    PubMed

    Shi, Jichen; Xu, Jian; Zhang, Xiaorong; Yang, Ling

    2012-05-07

    The memory of ischemic preconditioning remains a great mystery. Brief preconditioning (several sequential regional ischemia/reperfusion in minutes) can induce a two-phase protection that lasts up to 3 days. Thus comes the so-called memory of preconditioning. This memory effect has been attributed to a feed-forward signaling cascade. But recent experimental observations suggest that intra-mitochondrial positive feedback may be responsible for sustaining the protective effect. The link between positive feedback and memory is yet to be determined. In this study, we used a mathematical model to describe the way in which positive feedback induces memory in the first window of cardioprotection, and we derived an explicit relationship between the memory duration and the strength of the positive feedback. Our major findings are: (1) that positive feedback relying on a hysteresis response provides an effective way of prolonging protection up to any length; and (2) that the stronger the positive feedback, the longer the memory duration. Furthermore, compared with the feed-forward signaling cascade, positive feedback may be more favored by natural systems because of its robustness and high efficiency. The mechanisms described in this study have important implications for developments of experimental approaches as well as therapeutic strategies. Copyright © 2012 Elsevier Ltd. All rights reserved.

  11. Financial preconditions for successful community initiatives for the uninsured.

    PubMed

    Song, Paula H; Smith, Dean G

    2007-01-01

    Community-based initiatives are increasingly being implemented as a strategy to address the health needs of the community, with a growing body of evidence on successes of various initiatives. This study addresses financial status indicators (preconditions) that might predict where community-based initiatives might have a better chance for success. We evaluated five community-based initiatives funded by the Communities in Charge (CIC) program sponsored by the Robert Wood Johnson Foundation. These initiatives focus on increasing access by easing financial barriers to care for the uninsured. At each site, we collected information on financial status indicators and interviewed key personnel from health services delivery and financing organizations. With full acknowledgment of the caveats associated with generalizations based on a small number of observations, we suggest four financial preconditions associated with successful initiation of CIC programs: (1) uncompensated care levels that negatively affect profitability, (2) reasonable financial stability of providers, (3) stable health insurance market, and (4) the potential to create new sources of funding. In general, sites that demonstrate successful program initiation are financially stressed enough by uncompensated care to gain the attention of local healthcare providers. However, they are not so strained and so concerned about revenue sources that they cannot afford to participate in the initiative. In addition to political and managerial indicators, we suggest that planning for community-based initiatives should include financial indicators of current health services delivery and financing organizations and consideration of whether they meet preconditions for success.

  12. Lentiviral Delivery of Small Hairpin RNA Targeting Connective Tissue Growth Factor Blocks Profibrotic Signaling in Tenon's Capsule Fibroblasts.

    PubMed

    Lei, Dawei; Dong, Changgui; Wu, William Ka Kei; Dong, Aimeng; Li, Tingting; Chan, Matthew T V; Zhou, Xinrong; Yuan, Huiping

    2016-10-01

    Trabeculectomy is a surgical procedure for lowering intraocular pressure in glaucoma patients, in which excessive scarring leading to failure of the filtering bleb adversely affects the surgical outcome. Heightened Tenon's capsule fibroblast (TCF) proliferation and extracellular matrix (ECM) deposition are implicated in this process but endogenous factors that regulate TCF functions remain largely elusive. This study sought to elucidate the role of connective tissue growth factor (CTGF) in the regulation of TCF phenotypes and signaling. Expression of CTGF in scarring and nonscarring Tenon's capsules was measured by real-time PCR and immunofluorescence. Knockdown of CTGC was achieved by lentivirus delivery of small-hairpin RNA. Cell proliferation was measured by CCK8, cell cycle progression, and apoptosis by flow cytometry, adhesion, migration, and invasion of TCF by functional assays in vitro. Proteins and cytokines related to fibrosis were measured by Western blot and ELISA, respectively. Expression of CTGF was significantly upregulated in scarring Tenon's capsules and their isolated fibroblasts when compared with the nonfibrotic counterparts. Functionally, targeting CTGF with lentivirus-delivered small-hairpin RNA inhibited the proliferation, adhesion, migration, and invasion of TCFs, accompanied by downregulation of p38 and nuclear factor-κB as well as matrix metalloproteinase-2, cyclin D1, and collagen I. In addition, lentiviral targeting of CTGF reduced the release of fibrosis-related cytokines from TCFs and inhibited TCF-conditioned, medium-induced macrophage chemotaxis. Our study supports a crucial role of CTGF in the regulation of TCF proliferation and ECM deposition. Targeting CTGF using lentiviral vector may be a promising approach for preventing excessive scarring after trabeculectomy.

  13. Organ fibrosis inhibited by blocking transforming growth factor-β signaling via peroxisome proliferator-activated receptor γ agonists.

    PubMed

    Deng, Yi-Lei; Xiong, Xian-Ze; Cheng, Nan-Sheng

    2012-10-01

    Organ fibrosis has been viewed as one of the major medical problems, which can lead to progressive dysfunction of the liver, lung, kidney, skin, heart, and eventually death of patients. Fibrosis is initiated by a variety of pathological, physiological, biochemical, and physical factors. Regardless of their different etiologies, they all share a common pathogenetic process: excessive activation of the key profibrotic cytokine, transforming growth factor-beta (TGF-beta). Peroxisome proliferator-activated receptor gamma (PPARgamma), a ligand-activated transcription factor of the nuclear receptor superfamily, has received particular attention in recent years, because the activation of PPARgamma by both natural and synthetic agonists could effectively inhibit TGF-beta-induced profibrotic effects in many organs. The English-language medical databases, PubMed, Elsevier and SpringerLink were searched for articles on PPARgamma, TGF-beta, and fibrosis, and related topics. TGF-beta is recognized as a key profibrotic cytokine. Excessive activation of TGF-beta increases synthesis of extracellular matrix proteins and decreases their degradation, associated with a gradual destruction of normal tissue architecture and function, whereas PPARgamma agonists inhibit TGF-beta signal transduction and are effective antifibrogenic agents in many organs including the liver, lung, kidney, skin and heart. The main antifibrotic activity of PPARgamma agonists is to suppress the TGF-beta signaling pathway by so-called PPARgamma-dependent effect. In addition, PPARgamma agonists, especially 15d-PGJ2, also exert potentially antifibrotic activity independent of PPARgamma activation. TGF-beta1/Smads signaling not only plays many essential roles in multiple developmental processes, but also forms cross-talk networks with other signal pathways, and their inhibition by PPARgamma agonists certainly affects the cytokine networks and causes non-suspected side-effects. Anti-TGF-beta therapies with

  14. Brain-Derived Neurotrophic Factor Knockdown Blocks the Angiogenic and Protective Effects of Angiotensin Modulation After Experimental Stroke.

    PubMed

    Fouda, Abdelrahman Y; Alhusban, Ahmed; Ishrat, Tauheed; Pillai, Bindu; Eldahshan, Wael; Waller, Jennifer L; Ergul, Adviye; Fagan, Susan C

    2017-01-01

    Angiotensin type 1 receptor blockers (ARBs) have been shown to be neuroprotective and neurorestorative in experimental stroke. The mechanisms proposed include anti-inflammatory, antiapoptotic effects, as well as stimulation of endogenous trophic factors leading to angiogenesis and neuroplasticity. We aimed to investigate the involvement of the neurotrophin, brain-derived neurotrophic factor (BDNF), in ARB-mediated functional recovery after stroke. To achieve this aim, Wistar rats received bilateral intracerebroventricular (ICV) injections of short hairpin RNA (shRNA) lentiviral particles or nontargeting control (NTC) vector, to knock down BDNF in both hemispheres. After 14 days, rats were subjected to 90-min middle cerebral artery occlusion (MCAO) and received the ARB, candesartan, 1 mg/kg, or saline IV at reperfusion (one dose), then followed for another 14 days using a battery of behavioral tests. BDNF protein expression was successfully reduced by about 70 % in both hemispheres at 14 days after bilateral shRNA lentiviral particle injection. The NTC group that received candesartan showed better functional outcome as well as increased vascular density and synaptogenesis as compared to saline treatment. BDNF knockdown abrogated the beneficial effects of candesartan on neurobehavioral outcome, vascular density, and synaptogenesis. In conclusion, BDNF is directly involved in candesartan-mediated functional recovery, angiogenesis, and synaptogenesis.

  15. 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

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

    PubMed

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

    2004-02-01

    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. To analyze the protective role of ozone oxidative preconditioning against cisplatin-induced nephrotoxicity. 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. 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. Intrarectal ozone therapy prevented effectively the renal antioxidant unbalance induced by cisplatin treatment.

  17. Crotalus atrox venom preconditioning increases plasma fibrinogen and reduces perioperative hemorrhage in a rat model of surgical brain injury

    PubMed Central

    Kim, Cherine H.; McBride, Devin W.; Raval, Ronak; Sherchan, Prativa; Hay, Karen L.; Gren, Eric C. K.; Kelln, Wayne; Lekic, Tim; Hayes, William K.; Bull, Brian S.; Applegate, Richard; Tang, Jiping; Zhang, John H.

    2017-01-01

    Perioperative bleeding is a potentially devastating complication in neurosurgical patients, and plasma fibrinogen concentration has been identified as a potential modifiable risk factor for perioperative bleeding. The aim of this study was to evaluate preconditioning with Crotalus atrox venom (Cv-PC) as potential preventive therapy for reducing perioperative hemorrhage in the rodent model of surgical brain injury (SBI). C. atrox venom contains snake venom metalloproteinases that cleave fibrinogen into fibrin split products without inducing clotting. Separately, fibrinogen split products induce fibrinogen production, thereby elevating plasma fibrinogen levels. Thus, the hypothesis was that preconditioning with C. atrox venom will produce fibrinogen spilt products, thereby upregulating fibrinogen levels, ultimately improving perioperative hemostasis during SBI. We observed that Cv-PC SBI animals had significantly reduced intraoperative hemorrhage and postoperative hematoma volumes compared to those of vehicle preconditioned SBI animals. Cv-PC animals were also found to have higher levels of plasma fibrinogen at the time of surgery, with unchanged prothrombin time. Cv-PC studies with fractions of C. atrox venom suggest that snake venom metalloproteinases are largely responsible for the improved hemostasis by Cv-PC. Our findings indicate that Cv-PC increases plasma fibrinogen levels and may provide a promising therapy for reducing perioperative hemorrhage in elective surgeries. PMID:28102287

  18. Spontaneous In Vivo Chondrogenesis of Bone Marrow-Derived Mesenchymal Progenitor Cells by Blocking Vascular Endothelial Growth Factor Signaling.

    PubMed

    Marsano, Anna; Medeiros da Cunha, Carolina M; Ghanaati, Shahram; Gueven, Sinan; Centola, Matteo; Tsaryk, Roman; Barbeck, Mike; Stuedle, Chiara; Barbero, Andrea; Helmrich, Uta; Schaeren, Stefan; Kirkpatrick, James C; Banfi, Andrea; Martin, Ivan

    2016-12-01

    : Chondrogenic differentiation of bone marrow-derived mesenchymal stromal/stem cells (MSCs) can be induced by presenting morphogenetic factors or soluble signals but typically suffers from limited efficiency, reproducibility across primary batches, and maintenance of phenotypic stability. Considering the avascular and hypoxic milieu of articular cartilage, we hypothesized that sole inhibition of angiogenesis can provide physiological cues to direct in vivo differentiation of uncommitted MSCs to stable cartilage formation. Human MSCs were retrovirally transduced to express a decoy soluble vascular endothelial growth factor (VEGF) receptor-2 (sFlk1), which efficiently sequesters endogenous VEGF in vivo, seeded on collagen sponges and immediately implanted ectopically in nude mice. Although naïve cells formed vascularized fibrous tissue, sFlk1-MSCs abolished vascular ingrowth into engineered constructs, which efficiently and reproducibly developed into hyaline cartilage. The generated cartilage was phenotypically stable and showed no sign of hypertrophic evolution up to 12 weeks. In vitro analyses indicated that spontaneous chondrogenic differentiation by blockade of angiogenesis was related to the generation of a hypoxic environment, in turn activating the transforming growth factor-β pathway. These findings suggest that VEGF blockade is a robust strategy to enhance cartilage repair by endogenous or grafted mesenchymal progenitors. This article outlines the general paradigm of controlling the fate of implanted stem/progenitor cells by engineering their ability to establish specific microenvironmental conditions rather than directly providing individual morphogenic cues. Chondrogenic differentiation of mesenchymal stromal/stem cells (MSCs) is typically targeted by morphogen delivery, which is often associated with limited efficiency, stability, and robustness. This article proposes a strategy to engineer MSCs with the capacity to establish specific

  19. 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

  20. Heartland virus NSs protein disrupts host defenses by blocking the TBK1 kinase-IRF3 transcription factor interaction and signaling required for interferon induction.

    PubMed

    Ning, Yun-Jia; Feng, Kuan; Min, Yuan-Qin; Deng, Fei; Hu, Zhihong; Wang, Hualin

    2017-10-06

    Heartland virus (HRTV) is a pathogenic phlebovirus related to the severe fever with thrombocytopenia syndrome virus (SFTSV), another phlebovirus causing life-threatening disease in humans. Previous findings have suggested that SFTSV can antagonize the host interferon (IFN) system via viral nonstructural protein (NSs)-mediated sequestration of antiviral signaling proteins into NSs-induced inclusion bodies. However, whether and how HRTV counteracts the host innate immunity is unknown. Here, we report that HRTV NSs (HNSs) also antagonizes IFN and cytokine induction and bolsters viral replication, although no noticeable inclusion body formation was observed in HNSs-expressing cells. Furthermore, HNSs inhibited the virus-triggered activation of IFN-β promoter by specifically targeting the IFN-stimulated response element but not the NF-κB response element. Consistently, HNSs blocked the phosphorylation and nuclear translocation of IFN regulatory factor 3 (IRF3, an IFN-stimulated response element-activating transcription factor). Reporter gene assays next showed that HNSs blockades the antiviral signaling mediated by RIG-I-like receptors likely at the level of TANK-binding kinase 1 (TBK1). Indeed, HNSs strongly interacts with TBK1 as indicated by confocal microscopy and pulldown analyses, and we also noted that the scaffold dimerization domain of TBK1 is required for the TBK1-HNSs interaction. Finally, pulldown assays demonstrated that HNSs expression dose-dependently diminishes a TBK1-IRF3 interaction, further explaining the mechanism for HNSs function. Collectively, these data suggest that HNSs, an antagonist of host innate immunity, interacts with TBK1 and thereby hinders the association of TBK1 with its substrate IRF3, thus blocking IRF3 activation and transcriptional induction of the cellular antiviral responses. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  1. Techniques and Software for Monolithic Preconditioning of Moderately-sized Geodynamic Stokes Flow Problems

    NASA Astrophysics Data System (ADS)

    Sanan, Patrick; May, Dave A.; Schenk, Olaf; Bollhöffer, Matthias

    2017-04-01

    Geodynamics simulations typically involve the repeated solution of saddle-point systems arising from the Stokes equations. These computations often dominate the time to solution. Direct solvers are known for their robustness and ``black box'' properties, yet exhibit superlinear memory requirements and time to solution. More complex multilevel-preconditioned iterative solvers have been very successful for large problems, yet their use can require more effort from the practitioner in terms of setting up a solver and choosing its parameters. We champion an intermediate approach, based on leveraging the power of modern incomplete factorization techniques for indefinite symmetric matrices. These provide an interesting alternative in situations in between the regimes where direct solvers are an obvious choice and those where complex, scalable, iterative solvers are an obvious choice. That is, much like their relatives for definite systems, ILU/ICC-preconditioned Krylov methods and ILU/ICC-smoothed multigrid methods, the approaches demonstrated here provide a useful addition to the solver toolkit. We present results with a simple, PETSc-based, open-source Q2-Q1 (Taylor-Hood) finite element discretization, in 2 and 3 dimensions, with the Stokes and Lamé (linear elasticity) saddle point systems. Attention is paid to cases in which full-operator incomplete factorization gives an improvement in time to solution over direct solution methods (which may not even be feasible due to memory limitations), without the complication of more complex (or at least, less-automatic) preconditioners or smoothers. As an important factor in the relevance of these tools is their availability in portable software, we also describe open-source PETSc interfaces to the factorization routines.

  2. 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…

  3. 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…

  4. A Staphylococcus aureus TIR domain protein virulence factor blocks TLR2-mediated NF-κB signaling.

    PubMed

    Askarian, Fatemeh; van Sorge, Nina M; Sangvik, Maria; Beasley, Federico C; Henriksen, Jørn R; Sollid, Johanna U E; van Strijp, Jos A G; Nizet, Victor; Johannessen, Mona

    2014-01-01

    Signaling through Toll-like receptors (TLRs), crucial molecules in the induction of host defense responses, requires adaptor proteins that contain a Toll/interleukin-1 receptor (TIR) domain. The pathogen Staphylococcus aureus produces several innate immune-evasion molecules that interfere with the host's innate immune response. A database search analysis suggested the presence of a gene encoding a homologue of the human TIR domain in S. aureus MSSA476 which was named staphylococcal TIR domain protein (TirS). Ectopic expression of TirS in human embryonic kidney, macrophage and keratinocyte cell lines interfered with signaling through TLR2, including MyD88 and TIRAP, NF-κB and/or mitogen-activated protein kinase pathways. Moreover, the presence of TirS reduced the levels of cytokines MCP-1 and G-CSF secreted in response to S. aureus. The effects on NF-κB pathway were confirmed using S. aureus MSSA476 wild type, an isogenic mutant MSSA476ΔtirS, and complemented MSSA476ΔtirS +pTirS in a Transwell system where bacteria and host cells were physically separated. Finally, in a systematic mouse infection model, TirS promoted bacterial accumulation in several organs 4 days postinfection. The results of this study reveal a new S. aureus virulence factor that can interfere with PAMP-induced innate immune signaling in vitro and bacterial survival in vivo.

  5. 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.

  6. S. aureus blocks efferocytosis of neutrophils by macrophages through the activity of its virulence factor alpha toxin

    PubMed Central

    Cohen, Taylor S.; Jones-Nelson, Omari; Hotz, Meghan; Cheng, Lily; Miller, Lloyd S.; Suzich, JoAnn; Stover, C. Kendall; Sellman, Bret R.

    2016-01-01

    Bacterial pneumonia, such as those caused by Staphylococcus aureus, is associated with an influx of inflammatory neutrophils into the lung tissue and airways. Regulation and clearance of recruited neutrophils is essential for preventing tissue damage by “friendly fire”, a responsibility of macrophages in a process called efferocytosis. We hypothesized that S. aureus impairs efferocytosis by alveolar macrophages (AMs) through the activity of the secreted virulence factor alpha toxin (AT), which has been implicated in altering the antimicrobial function of AMs. Infection of mice lacking AMs resulted in significantly increased numbers of neutrophils in the lung, while clearance of neutrophils delivered intranasally into uninfected mice was reduced in AM depleted animals. In vitro, sublytic levels of AT impaired uptake of apoptotic neutrophils by purified AMs. In vivo, the presence of AT reduced uptake of neutrophils by AMs. Differential uptake of neutrophils was not due to changes in either the CD47/CD172 axis or CD36 levels. AT significantly reduced lung expression of CCN1 and altered AM surface localization of DD1α, two proteins known to influence efferocytosis. We conclude that AT may contribute to tissue damage during S. aureus pneumonia by inhibiting the ability of AM to clear neutrophils at the site of infection. PMID:27739519

  7. Renal fibrosis is not reduced by blocking transforming growth factor-β signaling in matrix-producing interstitial cells.

    PubMed

    Neelisetty, Surekha; Alford, Catherine; Reynolds, Karen; Woodbury, Luke; Nlandu-Khodo, Stellor; Yang, Haichun; Fogo, Agnes B; Hao, Chuan-Ming; Harris, Raymond C; Zent, Roy; Gewin, Leslie

    2015-09-01

    Transforming growth factor-β (TGF-β) strongly promotes renal tubulointerstitial fibrosis, but the cellular target that mediates its profibrotic actions has not been clearly identified. While in vitro data suggest that TGF-β-induced matrix production is mediated by renal fibroblasts, the role of these cells in TGF-β-dependent tubulointerstitial fibrosis following renal injury is not well defined. To address this, we deleted the TGF-β type II receptor in matrix-producing interstitial cells using two different inducible Cre models: COL1A2-Cre with a mesenchymal enhancer element and tenascin-Cre that targets medullary interstitial cells, and either the mouse unilateral ureteral obstruction or the aristolochic acid renal injury model. Renal interstitial cells lacking the TGF-β receptor had significantly impaired collagen I production, but, unexpectedly, overall tissue fibrosis was unchanged in the conditional knockouts after renal injury. Thus, abrogating TGF-β signaling in matrix-producing interstitial cells is not sufficient to reduce fibrosis after renal injury.

  8. Renal fibrosis is not reduced by blocking transforming growth factor-β signaling in matrix-producing interstitial cells

    PubMed Central

    Neelisetty, Surekha; Alford, Catherine; Reynolds, Karen; Woodbury, Luke; Nlandu-khodo, Stellor; Yang, Haichun; Fogo, Agnes B.; Hao, Chuan-Ming; Harris, Raymond C.; Zent, Roy; Gewin, Leslie

    2015-01-01

    Transforming growth factor-β (TGF-β) strongly promotes renal tubulointerstitial fibrosis, but the cellular target that mediates its profibrotic actions has not been clearly identified. While in vitro data suggest that TGF-β-induced matrix production is mediated by renal fibroblasts, the role of these cells in TGF-β-dependent tubulointerstitial fibrosis following renal injury is not well defined. To address this, we deleted the TGF-β type II receptor in matrix-producing interstitial cells using two different inducible Cre models: COL1A2-Cre with a mesenchymal enhancer element and tenascin-Cre which targets medullary interstitial cells and either the mouse unilateral ureteral obstruction or aristolochic acid renal injury model. Renal interstitial cells lacking the TGF-β receptor had significantly impaired collagen I production, but unexpectedly, overall tissue fibrosis was unchanged in the conditional knockouts after renal injury. Thus, abrogating TGF-β signaling in matrix-producing interstitial cells is not sufficient to reduce fibrosis after renal injury. PMID:25760325

  9. Reactive Oxygen Species and Mitochondrial KATP Channels Mediate Helium-Induced Preconditioning Against Myocardial Infarction In Vivo

    PubMed Central

    Pagel, Paul S.; Krolikowski, John G.; Pratt, Phillip F.; Shim, Yon Hee; Amour, Julien; Warltier, David C.; Weihrauch, Dorothee

    2008-01-01

    Objectives Helium produces preconditioning by activating prosurvival kinases, but the roles of reactive oxygen species (ROS) or mitochondrial KATP channels in this process are unknown. We tested the hypothesis that ROS and mitochondrial KATP channels mediate helium-induced preconditioning in vivo. Design Randomized, prospective study. Setting University research laboratory. Participants Male New Zealand white rabbits. Interventions Rabbits (n=64) were instrumented for measurement of systemic hemodynamics and subjected to a 30 min left anterior descending coronary artery (LAD) occlusion and 3 h reperfusion. In separate experimental groups, rabbits (n=7 or 8 per group) were randomly assigned to receive 0.9% saline (control) or three cycles of 70% helium-30% oxygen administered for 5 min interspersed with 5 min of an air-oxygen mixture before LAD occlusion with or without the ROS scavengers N-acetylcysteine (NAC; 150 mg/kg) or N-2-mercaptoproprionyl glycine (2-MPG; 75 mg/kg), or the mitochondrial KATP antagonist 5-hydroxydecanoate (5-HD; 5 mg/kg). Statistical analysis of data was performed with analysis of variance for repeated measures followed by Bonferroni's modification of Student's t test. Measurements and Main Results Myocardial infarct size was determined using triphenyltetrazolium chloride staining and presented as a percentage of the left ventricular area at risk. Helium significantly (P<0.05) reduced infarct size (23±4% of the area at risk; mean±SD) compared with control (46±3%). NAC, 2-MPG, and 5-HD did not affect irreversible ischemic injury when administered alone (49±5, 45±6, and 45±3%), but these drugs blocked reductions in infarct size produced by helium (45±4, 45±2, and 44±3%). Conclusions The results suggest that ROS and mitochondrial KATP channels mediate helium-induced preconditioning in vivo. PMID:18662630

  10. Small-molecule factor D inhibitors selectively block the alternative pathway of complement in paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome.

    PubMed

    Yuan, Xuan; Gavriilaki, Eleni; Thanassi, Jane A; Yang, Guangwei; Baines, Andrea C; Podos, Steven D; Huang, Yongqing; Huang, Mingjun; Brodsky, Robert A

    2017-03-01

    Paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome are diseases of excess activation of the alternative pathway of complement that are treated with eculizumab, a humanized monoclonal antibody against the terminal complement component C5. Eculizumab must be administered intravenously, and moreover some patients with paroxysmal nocturnal hemoglobinuria on eculizumab have symptomatic extravascular hemolysis, indicating an unmet need for additional therapeutic approaches. We report the activity of two novel small-molecule inhibitors of the alternative pathway component Factor D using in vitro correlates of both paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome. Both compounds bind human Factor D with high affinity and effectively inhibit its proteolytic activity against purified Factor B in complex with C3b. When tested using the traditional Ham test with cells from paroxysmal nocturnal hemoglobinuria patients, the Factor D inhibitors significantly reduced complement-mediated hemolysis at concentrations as low as 0.01 μM. Additionally the compound ACH-4471 significantly decreased C3 fragment deposition on paroxysmal nocturnal hemoglobinuria erythrocytes, indicating a reduced potential relative to eculizumab for extravascular hemolysis. Using the recently described modified Ham test with serum from patients with atypical hemolytic uremic syndrome, the compounds reduced the alternative pathway-mediated killing of PIGA-null reagent cells, thus establishing their potential utility for this disease of alternative pathway of complement dysregulation and validating the modified Ham test as a system for pre-clinical drug development for atypical hemolytic uremic syndrome. Finally, ACH-4471 blocked alternative pathway activity when administered orally to cynomolgus monkeys. In conclusion, the small-molecule Factor D inhibitors show potential as oral therapeutics for human diseases driven by the alternative pathway of complement

  11. Rectal Delivery of a DNAzyme That Specifically Blocks the Transcription Factor GATA3 and Reduces Colitis in Mice.

    PubMed

    Popp, Vanessa; Gerlach, Katharina; Mott, Stefanie; Turowska, Agnieszka; Garn, Holger; Atreya, Raja; Lehr, Hans-Anton; Ho, I-Cheng; Renz, Harald; Weigmann, Benno; Neurath, Markus F

    2017-01-01

    GATA3 is a transcription factor that regulates T-cell production of cytokines. We investigated the role of GATA3 in development of colitis in mice. We performed quantitative polymerase chain reaction and immunofluorescence analyses of colon tissues from patients with Crohn's disease (n = 61) or ulcerative colitis (UC, n = 74) or from patients without inflammatory bowel diseases (n = 22), to measure levels of GATA3. Colitis was induced by administration of oxazolone or 2,4,6-trinitrobenzenesulfonic acid to control mice, mice with T-cell-specific deletion of GATA3, and mice with deletion of tumor necrosis factor receptor (TNFR) 1 and TNFR2 (TNFR double knockouts); some mice were given a GATA3-specific DNAzyme (hgd40) or a control DNAzyme via intrarectal administration, or systemic injections of an antibody to TNF before or during sensitization and challenge phase of colitis induction. Colon tissues were collected and immunofluorescence and histochemical analyses were performed. Lamina propria mononuclear cells and T cells were isolated and analyzed by flow cytometry or cytokine assays. Colonic distribution of labeled DNAzyme and inflammation were monitored by in vivo imaging (endoscopy) of mice. Levels of GATA3 messenger RNA were higher in colon tissues from patients with UC, but not ileal Crohn's disease, than control tissues; levels of GATA3 correlated with levels of inflammatory cytokines (interleukin [IL] 9, IL17A, IL6, IL5, IL4, IL13, and TNF). We observed increased expression of GATA3 by lamina propria T cells from mice with colitis compared with controls. Mice with T-cell-specific deletion of GATA3 did not develop colitis and their colonic tissues did not produce inflammatory cytokines (IL6, IL9, or IL13). The DNAzyme hgd40 inhibited expression of GATA3 messenger RNA by unstimulated and stimulated T cells, and distributed throughout the inflamed colons of mice with colitis. Colon tissues from mice given hgd40 had reduced expression of GATA3 messenger RNA

  12. Semi-coarsening AMLI preconditioning of higher order elliptic problems

    NASA Astrophysics Data System (ADS)

    Kraus, J.; Lymbery, M.; Margenov, S.

    2012-10-01

    The present paper presents the construction of a robust multilevel preconditioner for anisotropic bicubic finite element (FE) elliptic problems. More precisely, the behavior of the constant in the strengthened CBS inequality, which is important for studying (approximate) block factorizations of FE stiffness matrices, is analyzed in the case when the underlying conforming FE space consists of piecewise bicubic functions, and is decomposed according to hierarchical splittings that are based on semi-coarsening of the FE mesh. The presented theoretical estimates are further confirmed by numerically computed CBS constants for a rich set of parameters (coarsening factor and anisotropy ratio). The problem of solving efficiently systems with the pivot block matrices arising in the hierarchical basis two-level matrices is also addressed in this paper. Finally, combining the proven uniform estimates with the theory of the Algebraic Multilevel Iteration (AMLI) methods an optimal order multilevel algorithm whose total computational cost is proportional to the size of the discrete problem with a proportionality constant independent of the anisotropy ratio is obtained.

  13. 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

  14. 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.

  15. Antiviral activity of the "Virus Blocking Factor" (VBF) derived i.a. from Pelargonium extract and Sambucus juice against different human-pathogenic cold viruses in vitro.

    PubMed

    Fal, Andrzej M; Conrad, Frank; Schönknecht, Karina; Sievers, Hartwig; Pawińska, Anna

    2016-01-01

    The in-vitro antiviral activity of the "Virus Blocking Factor" (VBF), a combination of Pelargonium extract and Sambucus juice with addition of Betaglucan 1,3 / 1,6, Zincum gluconium, Acidum ascorbicum, was studied against human pathogenic viruses: Influenza A H1N1 (FluA H1N1), Rhinovirus B subtype 14 (HRV14), Respiratory Syncytial Virus (RSV), Parainfluenzavirus subtype 3 (Para 3), and Adenovirus C subtype 5 (Adeno 5). Antiviral activity was assessed using plaque-reduction assays after adding the test substance post infection of the MDCK, HeLa and HEp-2 cells with the viruses. Ribavirin Virazol and - in case of Adenovirus an internal laboratory standard - were used as positive controls. Cytotoxic effects of VBF and VBF Control onto the virus permissive MDCK, HeLa and HEp-2 cells were examined. Non-toxic concentrations of VBF were determined by the Methylthiazoletetrazolium test (MTT-Test). In all antiviral studies VBF showed (2.1%) a dose-dependent antiviral activity against FluA H1N1 and HRV14 at non-toxic concentrations. A very strong effect was demonstrated in concentrations of 2.5% and 1.25% where replication of H1N1 and HRV14 was nearly completely blocked. Dose-dependent antiviral activity was detectable against RSV in a concentration range of 1.25% to 0.63% of the test item. Due to toxic side effects of a 2.5% concentration at least a "minor effect" of about 30% (1.25% solution) against Para 3 infected HEp-2 cells could be determined. Concerning Adeno 5 not any antiviral activity could be demonstrated in all studies with all tested substance concentrations of VBF. VBF Control did not show any cytotoxicity and antiviral effects. Further research is needed to elucidate clinical effect of VBF.

  16. Antiviral activity of the "Virus Blocking Factor" (VBF) derived i.a. from Pelargonium extract and Sambucus juice against different human-pathogenic cold viruses in vitro.

    PubMed

    Fal, Andrzej M; Conrad, Frank; Schönknecht, Karina; Sievers, Hartwig; Pawińska, Anna

    The in-vitro antiviral activity of the "Virus Blocking Factor" (VBF), a combination of Pelargonium extract and Sambucus juice with addition of Betaglucan 1,3 / 1,6, Zincum gluconium, Acidum ascorbicum, was studied against human pathogenic viruses: Influenza A H1N1 (FluA H1N1), Rhinovirus B subtype 14 (HRV14), Respiratory Syncytial Virus (RSV), Parainfluenzavirus subtype 3 (Para 3), and Adenovirus C subtype 5 (Adeno 5). Antiviral activity was assessed using plaque-reduction assays after adding the test substance post infection of the MDCK, HeLa and HEp-2 cells with the viruses. Ribavirin Virazol and - in case of Adenovirus an internal laboratory standard - were used as positive controls. Cytotoxic effects of VBF and VBF Control onto the virus permissive MDCK, HeLa and HEp-2 cells were examined. Non-toxic concentrations of VBF were determined by the Methylthiazoletetrazolium test (MTT-Test). In all antiviral studies VBF showed (2.1%) a dose-dependent antiviral activity against FluA H1N1 and HRV14 at non-toxic concentrations. A very strong effect was demonstrated in concentrations of 2.5% and 1.25% where replication of H1N1 and HRV14 was nearly completely blocked. Dose-dependent antiviral activity was detectable against RSV in a concentration range of 1.25% to 0.63% of the test item. Due to toxic side effects of a 2.5% concentration at least a "minor effect" of about 30% (1.25% solution) against Para 3 infected HEp-2 cells could be determined. Concerning Adeno 5 not any antiviral activity could be demonstrated in all studies with all tested substance concentrations of VBF. VBF Control did not show any cytotoxicity and antiviral effects. Further research is needed to elucidate clinical effect of VBF.

  17. Overexpression of actin-depolymerizing factor blocks oxidized low-density lipoprotein-induced mouse brain microvascular endothelial cell barrier dysfunction.

    PubMed

    Wang, Jun; Sun, Lu; Si, Yan-Fang; Li, Bao-Min

    2012-12-01

    The aim of present work was to elucidate the role of actin-depolymerizing factor (ADF), an important regulator of actin cytoskeleton, in the oxidized low-density lipoprotein (ox-LDL)-induced blood-brain barrier (BBB) disruption. The primary mouse brain microvascular endothelial cells (MBMECs) were exposed to ox-LDL. Treatment with LDL served as control. It was found that ADF mRNA level and protein expression were decreased when exposed to ox-LDL in MBMECs. Then, we investigated the influence of ADF overexpression on ox-LDL-treated MBMECs. Structurally, overexpression of ADF inhibited ox-LDL-induced F-actin formation. Functionally, overexpression of ADF attenuated ox-LDL-induced disruption of endothelial barrier marked by restoration of transendothelial electrical resistance, permeability of Evans Blue and expression of tight junction-associated proteins including ZO-1 and occludin, and blocked ox-LDL-induced oxidative stress marked by inhibition of reactive oxygen species (ROS) formation and activity of NADPH oxidase and Nox2 expression. However, overexpression of ADF in control cells had no significant effect on endothelial permeability and ROS formation. In conclusion, overexpression of ADF blocks ox-LDL-induced disruption of endothelial barrier. In addition, siRNA-mediated downregulation of ADF expression aggravated ox-LDL-induced disruption of endothelial barrier and ROS formation. These findings identify ADF as a key signaling molecule in the regulation of BBB integrity and suggest that ADF might be used as a target to modulate diseases accompanied by ox-LDL-induced BBB compromise.

  18. 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

  19. 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

  20. 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.

  1. Selective inhibition of extracellular signal-regulated kinases 1/2 blocks nerve growth factor to brain-derived neurotrophic factor signaling and suppresses the development of and reverses already established pain behavior in rats.

    PubMed

    Matsuoka, Y; Yang, J

    2012-03-29

    Brain-derived neurotrophic factor (BDNF) plays a key role in the development of pathological pain. Although it is known that nerve growth factor (NGF) induces BDNF mRNA through extracellular signal-regulated kinases (ERK), whether ERK1/2 or ERK5, two closely related members of the ERK family, mediate this signal is still unclear because classical MEK inhibitors block both pathways. We studied the involvement of ERK-signaling in NGF induction of BDNF in PC12 cells, cultured dorsal root ganglia neurons, and in rats subjected to neuropathic pain models using ERK1/2- and ERK5-specific tools. Selective activation of ERK1/2 upregulated BDNF mRNA in PC12 cells, whereas selective ERK5 activation did not. AZD6244, a potent selective inhibitor of ERK1/2 activation, blocked NGF induction of BDNF mRNA in vitro suggesting that NGF induction of BDNF is mediated by ERK1/2. siRNA experiments indicated that both ERK1 or ERK2 can signal suggesting that both pathways must be blocked to prevent NGF-induced increase in BDNF mRNA. I.p. injection of AZD6244 prevented the development of pain in rats subjected to the chronic constriction injury and reversed already established pain in the spared nerve injury model. Immunohistochemical studies showed decreased phospho-ERK1/2-immunoreactivity in dorsal root ganglia and BDNF immunoreactivity in ipsilateral spinal dorsal horn in the drug-treated rats. Our results suggest the possible use of AZD6244, already in human clinical trials as an anticancer agent, for the treatment of pathological pain.

  2. 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.

  3. 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.

  4. Transplantation of hypoxic preconditioned neural stem cells benefits functional recovery via enhancing neurotrophic secretion after spinal cord injury in rats.

    PubMed

    Fan, Wei-Li; Liu, Peng; Wang, Guan; Pu, Jung-Ang; Xue, Xin; Zhao, Jian-Hua

    2017-09-08

    Spinal cord injury (SCI) is a debilitating, costly, and common pathological condition that affects the function of central nervous system (CNS). To date, there are few promising therapeutic strategies available for SCI. To look for a suitable therapeutic strategy, we have developed a sublethal hypoxic preconditioning procedure using Fluorescence-activated cell sorting (FACS) analysis, LDH releasing and cell viability assays in vitro. Meanwhile, we have examined the benefits of neural stem cells (NSCs) transplantation prior to hypoxic preconditioning on functional recovery and potential mechanism via MRI screening, H&E and Nissl staining, immunofluorescence staining and Elisa assays. Our data showed that transplantation of hypoxic prconditioned NSCs could enhance neuronal survival, especially 5-TH(+) and ChAT(+) neurons, in the injured spinal cord to reinforce functional benefits. The hypoxia exposure upregulated HIF-1α, neurotrophic and growth factors including neurotrophin-3 (NT-3), glial cell-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) in vitro and in vivo. Furthermore, functional recovery, including locomotor and hypersensitivities to mechanical and thermal stimulation assessed via behavioral and sensory tests, improved significantly in rats with engraftment of NSCs after hypoxia exposure from day 14 post-SCI, compared with the control and N-NSCs groups. In short, the approach employed in this study could result in functional recovery via upregulating neurotrophic and growth factors, which implies that hypoxic preconditioning strategy could serve as an effective and feasible strategy for cell-based therapy in the treatment of SCI in rats. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  5. Local heat preconditioning in skin sparing mastectomy: a pilot study.

    PubMed

    Mehta, Saahil; Rolph, Rachel; Cornelius, Victoria; Harder, Yves; Farhadi, Jian

    2013-12-01

    Experimental data has shown an association with a reduction of flap necrosis after local heat-application to a supraphysiological level resulting from the up-regulation of heat shock proteins, such as HSP-32. The proteins maintained capillary perfusion and increased tissue tolerance to ischaemia. The purpose of this translational study was to evaluate the effect of local heat preconditioning before skin sparing mastectomy and immediate breast reconstruction. A prospective non-randomised trial was performed from July 2009-April 2010. 50 consecutive patients at risk of skin flap necrosis (BMI >30, sternal-to-nipple distance>26 cm or breast size>C-cup) were included. Twenty-five patients were asked to heat-precondition their breast 24-h prior to surgery using a hot water bottle with a water temperature of 43 °C (thermometers provided), in three 30-min cycles interrupted by spontaneous cooling to room temperature. Skin flap necrosis was defined by the need for surgical debridement. LDI images were taken pre- and post-mastectomy to demonstrate an increase in tissue vascularity. 36% of women (n=25) without local heat-treatment developed skin flap necrosis, 12% developed skin flap necrosis in the treatment group, resulting in a 24% difference (n=25; p=0.047 (95%CI 1%-47%)). LDI scanning of the heated breast demonstrated an increase in vascularity compared to the contralateral non-heated breast. Median length of inpatient stay for treatment group was 4 days (95%CI(4, 7)), controls 8 days (95%CI(8, 9) (p=<0.001)). The data suggests that in selected cases, local heat preconditioning is a simple and non-invasive method of reducing skin necrosis and length of hospital stay following skin sparing mastectomy. ACTRN12612001197820. II. Copyright © 2013 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.

  6. Hyperbaric Oxygen Preconditioning Provides Preliminary Protection Against Doxorubicin Cardiotoxicity

    PubMed Central

    Tezcan, Orhan; Karahan, Oguz; Alan, Mustafa; Ekinci, Cenap; Yavuz, Celal; Demirtas, Sinan; Ekinci, Aysun; Caliskan, Ahmet

    2017-01-01

    Background Doxorubicin (DOX) is generally recognized to have important cardiotoxic side effects. Studies are contradictory about the interaction between hyperbaric oxygen (HBO2) therapy and doxorubicin-induced cardiomyotoxicity. Recent data suggests that HBO2 therapy can lead to preconditioning of myocardium while generating oxidative stress. Herein we have investigated the effect of HBO2 therapy in a DOX-induced cardiomyocyte injury animal model. Methods Twenty-one rats were divided into three equal groups as follows: 1) Group 1 is a control group (without any intervention), used for evaluating the basal cardiac structures and determining the normal value of cardiacs and serum oxidative markers; 2) Group 2 is the doxorubicin group (single dose i.p. 20 mg/kg doxorubicin) for detecting the cardiotoxic and systemic effects of doxorubicin; 3) Group 3 is the doxorubicin and HBO2 group (100% oxygen at 2.5 atmospheric for 90 minutes, daily), for evaluating the effect of HBO2 in doxorubicin induced cardiotoxicity. At the end of the protocols, the hearts were harvested and blood samples (2 ml) were obtained. Results The doxorubicin treated animals (Group 2) had increased oxidative stress markers (both cardiac and serum) and severe cardiac injury as compared to the basal findings in the control group. Nevertheless, the highest cardiac oxidative stress index was detected in Group 3 (control vs. Group 3, p = 0.01). However, histological examination revealed that cardiac structures were well preserved in Group 3 when compared with Group 2. Conclusions Our results suggest that HBO2 preconditioning appears to be protective in the doxorubicin-induced cardiotoxicity model. Future studies are required to better elucidate the basis of this preconditioning effect of HBO2. PMID:28344418

  7. 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

  8. 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.

  9. 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

  10. 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

  11. Factorizing the factorization - a spectral-element solver for elliptic equations with linear operation count

    NASA Astrophysics Data System (ADS)

    Huismann, Immo; Stiller, Jörg; Fröhlich, Jochen

    2017-10-01

    The paper proposes a novel factorization technique for static condensation of a spectral-element discretization matrix that yields a linear operation count of just 13N multiplications for the residual evaluation, where N is the total number of unknowns. In comparison to previous work it saves a factor larger than 3 and outpaces unfactored variants for all polynomial degrees. Using the new technique as a building block for a preconditioned conjugate gradient method yields linear scaling of the runtime with N which is demonstrated for polynomial degrees from 2 to 32. This makes the spectral-element method cost effective even for low polynomial degrees. Moreover, the dependence of the iterative solution on the element aspect ratio is addressed, showing only a slight increase in the number of iterations for aspect ratios up to 128. Hence, the solver is very robust for practical applications.

  12. 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

  13. Delayed myocardial preconditioning induced by cobalt chloride in the rat: HIF-1α and iNOS involvement.

    PubMed

    Belaidi, Elise; Beguin, Pauline C; Levy, Patrick; Ribuot, Christophe; Godin-Ribuot, Diane

    2012-08-01

    We previously reported that acute exposure to intermittent hypoxia results in delayed cardioprotection against ischemia/reperfusion (I/R) injury and that the hypoxia-inducible factor (HIF)-1α, a transcriptional factor stabilized by hypoxia, as well as inducible nitric oxide synthase (iNOS) play a key role in this form of preconditioning. As cobalt chloride (CoCl(2)) is known to promote HIF-1α stabilization by inhibiting prolyl hydroxylase activity, we hypothesized that CoCl(2) could mimic the cardioprotective effects of hypoxia. Two groups of rats were administered 30 mg/kg twice of CoCl(2) or sterile water. Twenty-four hours later, hearts were perfused in Langendorff mode and subjected to an I/R protocol. Infarct size and functional recovery were studied. The role of iNOS was assessed by measuring myocardial iNOS content and by observing the effects of the iNOS inhibitor aminoguanidine (Ag, 100 μm, prior to ischemia). The role of HIF-1α was investigated by preventing its stabilization using cadmium chloride (CdCl(2), 1 mg/kg), administered 1 h before cobalt treatment. Treatment by CoCl(2) significantly reduced myocardial infarction by 33% and increased coronary flow (CF) at reperfusion by 27% compared with control rats, and this was accompanied by a threefold increase in myocardial iNOS content. CdCl(2) pretreatment and Ag perfusion abolished the beneficial effects on both infarct size and CF. Thus, the hypoxia-sensitive transcription factor HIF-1α and iNOS appear to play a pivotal role in the delayed pharmacological myocardial preconditioning induced by cobalt, thus mimicking the effects of hypoxic preconditioning. These results underscore the importance of prolyl hydroxylases as potential therapeutic targets for cardioprotection.

  14. [Hypoxic preconditioning of stem cells as a new approach to increase the efficacy of cell therapy for myocardial infarction].

    PubMed

    Maslov, L N; Podoksenov, Iu K; Portnichenko, A G; Naumova, A V

    2013-01-01

    During the last decade, stem cell research has developed at an accelerated pace. Various types of stem cells have been tested for myocardial infarction therapy. Despite the preclinical benefits of cell therapy success in clinical trials remains modest. The main obstacles to regeneration of the infarcted heart using stem cells are: 1) not every stem cell type can differentiate into cardiomyocytes; and 2) low survival rates of transplanted cells, due to the harsh environment of the infarcted myocardium. Hypoxic preconditioning (HP) has been shown to improve transplantation efficacy of mesenchymal stem cells and cardiac progenitor cells in animal models of myocardial infarction. It has also been shown that transplantation of preconditioned cells decreases infarct size, prevents postinfarction remodeling of the heart, and positively modulates development of ischemic cardiomyopathy. Hypoxic preconditioning also prevents extensive death of transplanted cells due to necrosis and apoptosis during long-term hypoxia or oxidative stress. The protective effect of HP is based on three main processes: (1) modification of cell phenotypes to help survival during hypoxia (enhancement of HIF-1alpha expression, ERK1/2 and Akt activation, enhancement of erythropoietin receptor expression and erythropoietin production, and an elevation in levels of antiapoptotic proteins Bcl-2 and Bcl-xL); (2) upregulation of various secretable factors including the vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF), and expression of VEGF-2 and HGF-receptors; (3) enhancement in the formation of CXCR4 and CXCR7 receptors, which play an important role in mobilization and homing of stem cells in the ischemic region.

  15. Remote Ischemic Preconditioning Protects Retinal Photoreceptors: Evidence From a Rat Model of Light-Induced Photoreceptor Degeneration.

    PubMed

    Brandli, Alice; Johnstone, Daniel M; Stone, Jonathan

    2016-10-01

    To test whether remote ischemic preconditioning (RIP) is protective to photoreceptors, in a light damage model, and to identify mechanisms involved. A pressure cuff was used to induce ischemia (2 × 5 minutes) in one hind limb of 4- to 6-month-old albino Sprague-Dawley rats raised in dim, cyclic light (12 hours 5 lux, 12 hours dark). Immediately following the ischemia, rats were exposed to bright continuous light (1000 lux) for 24 hours. After 7-day survival in dim, cyclic light conditions, retinal function was assessed using the flash electroretinogram (ERG) and retinal structure was examined for photoreceptor survival and death, as well as for stress. Messenger RNA and protein expression of growth factors and brain-derived neurotrophic factor (BDNF) receptors was also assessed at 7-day survival. Bright light exposure reduced the amplitude of the a- and b-waves of the ERG, upregulated the expression of glial fibrillary acidic protein (GFAP) by Müller cells, increased the number of dying (TUNEL+) photoreceptors, and reduced the number of surviving photoreceptors. Remote ischemic preconditioning mitigated all of these bright light-induced effects. Remote ischemic preconditioning-induced protection was associated with increased retinal expression of BDNF and its low-affinity receptor NGFR. The present study provides evidence, for the first time, that RIP protects photoreceptors against bright light-induced photoreceptor degeneration. This observation is consistent with previous reports of RIP-induced protection of the inner retina and of other vital organs. Brain-derived neurotrophic factor may play a role in mediating the RIP-induced neuroprotection through activation of NGFR.

  16. Vertical ridge augmentation using an equine bone and collagen block infused with recombinant human platelet-derived growth factor-BB: a randomized single-masked histologic study in non-human primates.

    PubMed

    Nevins, Myron; Al Hezaimi, Khalid; Schupbach, Peter; Karimbux, Nadeem; Kim, David M

    2012-07-01

    This study tests the effectiveness of hydroxyapatite and collagen bone blocks of equine origin (eHAC), infused with recombinant human platelet-derived growth factor-BB (rhPDGF-BB), to augment localized posterior mandibular defects in non-human primates (Papio hamadryas). Bilateral critical-sized defects simulating severe atrophy were created at the time of the posterior teeth extraction. Test and control blocks (without growth factor) were randomly grafted into the respective sites in each non-human primate. All sites exhibited vertical ridge augmentation, with physiologic hard- and soft-tissue integration of the blocks when clinical and histologic examinations were done at 4 months after the vertical ridge augmentation procedure. There was a clear, although non-significant, tendency to increased regeneration in the test sites. As in the first two preclinical studies in this series using canines, experimental eHAC blocks infused with rhPDGF-BB proved to be a predictable and technically viable method to predictably regenerate bone and soft tissue in critical-sized defects. This investigation supplies additional evidence that eHAC blocks infused with rhPDGF-BB growth factor is a predictable and technically feasible option for vertical augmentation of severely resorbed ridges.

  17. Conformal Nets II: Conformal Blocks

    NASA Astrophysics Data System (ADS)

    Bartels, Arthur; Douglas, Christopher L.; Henriques, André

    2017-08-01

    Conformal nets provide a mathematical formalism for conformal field theory. Associated to a conformal net with finite index, we give a construction of the `bundle of conformal blocks', a representation of the mapping class groupoid of closed topological surfaces into the category of finite-dimensional projective Hilbert spaces. We also construct infinite-dimensional spaces of conformal blocks for topological surfaces with smooth boundary. We prove that the conformal blocks sati